Record #1 of 144
ID: CN-01294539
AU: Cuzzubbo S
AU: Tissier M
AU: Barlog C
AU: Doridam J
AU: Ursu R
AU: Belin C
AU: Carpentier AF
TI: Neurological adverse events associated with the immune checkpoint inhibitors: review of the literature and characterization of the neurological patterns
SO: Neuro-oncology. Conference: 12th meeting of the european association of neuro-oncology. Germany. Conference start: 20161012. Conference end: 20161016
YR: 2016
VL: 18
PG: iv25-iv26
XR: EMBASE 613652036
PT: Journal: Conference Abstract
KY: adverse drug reaction; brain metastasis; brain vasculitis; clinical trial; controlled clinical trial; controlled study; headache; hearing impairment; human; lymphocytic choriomeningitis; major clinical study; Medline; meningoencephalitis; myasthenia gravis; myelitis; myositis; *neurological complication; phase 2 clinical trial; polyradiculoneuropathy; side effect; toxicity; uveitis; cytotoxic T lymphocyte antigen 4; endogenous compound; immunoglobulin; programmed death 1 receptor; steroid
AB: Introduction: Immune checkpoint inhibitors (anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies) constitute a promising class of cancer treatment, but they are associated with several immune-related adverse events (irAEs). Common grade 3/4 irAEs include dermatitis, enterocolitis, hepatitis and hypophysitis. Much less characterized are the neurological complications (nAEs), which have been reported in less than 1% of patients. To better define the neurological patterns of these nAEs, we reviewed the literature reporting neurological disorders associated with immune checkpoint inhibitors.Materials And Methods: A systematic search of literature, up to February 2016, mentioning nAEs in patients treated with immune checkpoint inhibitors was conducted in PubMed database. Eligible studies included the case reports and the prospective trials (phase II and III). Patients with brain metastases or tumoral meningitis and the cases of typical myositis, uveitis and hearing loss without neurological disorders were excluded.Results: A total of 67 patients having nAEs were described in case reports (32 cases) or in clinical trials (35 cases). In the clinical trials (58 trials, involving 9227 treated patients), the overall incidence of all-grade nAEs was 3.4% and 3.1% for the patients treated respectively with anti-CTLA4 and anti-PD-1. Grade 1/2 headaches represented more than 60% of these nAEs. Overall incidence of high-grade nAEs was 0.5% for the anti-CTLA-4 group and 0.2% for the anti-PD-1 group. When the type of neurological disorder was mentioned, lymphocytic meningitis and myasthenic syndromes were the most frequently reported (44% and 25% respectively). In the case reports, the most common nAEs related to CTLA-4 blockade included Guillain Barre syndromes (n=3) and other radiculoneuropathies (n=5), meningoradiculitis (n=5), myasthenia gravis (n=4) and less frequently lymphocytic meningitis (n=2), meningoencephalitis (n=2) and myelitis (n=2). Anti-PD-1 treatments were mostly associated with central nervous system toxicity: encephalitis (n=2), cerebral vasculitis (n=1) and PRES (n=1). Occurrence of nAEs was associated with tumor response in 29/32 patients. The median time of onset of nAEs was 6 weeks (1-21) and 7 weeks (1-74) with anti-CTLA-4 and anti-PD-1 treatments, respectively. In almost all cases the outcome was favorablewithin 12 weeks after drug interruption and steroids treatment associated or not with intravenous immunoglobulins. Conclusions: Neurological complications reported with immune checkpoint inhibitors are non-specific and pleomorphic, the most common being meningitis, radiculoneuropathy and myasthenic syndromes. In almost all cases, the outcome was favorable after drug interruption and steroid treatment. As suggested for other irAEs, nAEs may be associated with a clinical benefit and could be indicative for tumor-specific immune activation.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/539/CN-01294539/frame.html


Record #2 of 144
ID: CN-01303922
AU: Cuzzubbo S
AU: Tissier M
AU: Roumi A
AU: Javeri F
AU: Barlog C
AU: Doridam J
AU: Ursu R
AU: Belin C
AU: Carpentier AF
TI: Neurological adverse events associated with the immune checkpoint inhibitors: review of the literature and characterization of the clinical patterns
SO: Neuro-oncology. Conference: 21st annual scientific meeting and education day of the society for neuro-oncology. United states. Conference start: 20161117. Conference end: 20161120
YR: 2016
VL: 18
PG: vi143
XR: EMBASE 613469857
PT: Journal: Conference Abstract
KY: adverse drug reaction; brain metastasis; brain vasculitis; controlled clinical trial; controlled study; drug therapy; human; lymphocytic choriomeningitis; Medline; meningoencephalitis; myasthenia gravis; myelitis; *neurological complication; phase 2 clinical trial; polyradiculoneuropathy; side effect; systematic review; toxicity; cytotoxic T lymphocyte antigen 4; endogenous compound; programmed death 1 receptor; steroid
DOI: 10.1093/neuonc/now212.595
AB: INTRODUCTION: Immune checkpoint inhibitors constitute a promising class of cancer treatment, but they are associated with several immunerelated adverse events (irAEs). Common grade 3/4 irAEs include dermatitis, enterocolitis, hepatitis and hypophysitis. Much less characterized are the neurological complications (nAEs). To better define the neurological patterns of these nAEs, we reviewed the literature reporting neurological disorders associated with immune checkpoint inhibitors. MATERIALS AND METHODS: A systematic search of literature up to February 2016 was conducted in PubMed database. Eligible studies included the case reports and the prospective trials (phase II and III). Patients with brain metastases or tumoral meningitis were excluded. RESULTS: A total of 67 patients having nAEs were described. In the clinical trials (58 trials, involving 9227 patients), the overall incidence of all-grade nAEs was 3.4% and 3.1% for the patients treated respectively with anti-CTLA4 and anti-PD-1. Overall incidence of high-grade nAEs was 0.5% for the anti-CTLA-4 group and 0.2% for the anti-PD-1 group. Lymphocytic meningitis and myasthenic syndromes were the most frequently nAEs reported. In the case reports, the most common nAEs related to CTLA-4 blockade included Guillain Barre syndromes and other radiculoneuropathies, meningoradiculitis, myasthenia gravis and less frequently lymphocytic meningitis, meningoencephalitis and myelitis. Anti- PD-1 treatments were mostly associated with central nervous system toxicity: encephalitis, cerebral vasculitis. Occurrence of nAEs was associated with tumor response in 29/32 patients. The median time of onset of nAEs was 6 and 7 weeks with anti-CTLA-4 and anti-PD-1 treatments, respectively. In almost all cases the outcome was favorable after drug interruption and steroids treatment. CONCLUSIONS: Neurological complications reported with immune checkpoint inhibitors are non-specific and pleomorphic, the most common being meningitis, radiculoneuropathy and myasthenic syndromes. In almost all cases, the outcome was favorable after drug interruption and steroid treatment. As suggested for other irAEs, nAEs may be associated with a clinical benefit and could be indicative for tumor-specific immune activation.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/922/CN-01303922/frame.html


Record #3 of 144
ID: CN-01382864
AU: Oppel-Heuchel H
AU: Grimm MO
TI: Therapy monitoring and management of adverse events in PD-1/PD-L1 immune checkpoint inhibition
SO: Der urologe. Ausg. A
YR: 2016
VL: 55
NO: 5
PG: 677-690
PM: PUBMED 27146870
PT: Clinical Trial, Phase III; Journal Article; Randomized Controlled Trial
KY: Antibodies, Monoclonal [adverse effects] [therapeutic use];Antineoplastic Agents [adverse effects] [therapeutic use];B7-H1 Antigen [antagonists & inhibitors];Carcinoma, Renal Cell [drug therapy] [pathology];Disease Progression;Drug Approval;Immunotherapy [adverse effects] [methods];Kidney Neoplasms [drug therapy] [pathology];Programmed Cell Death 1 Receptor [antagonists & inhibitors];Humans[checkword]
DOI: 10.1007/s00120-016-0109-2
AB: Nivolumab was recently approved as the first inhibitor of the programmed death 1 (PD-1) receptor and its ligand (PD-L1) for the treatment of urological cancer, namely metastasized renal cell carcinoma after prior therapy. The use of this new immunotherapy requires special therapy monitoring and management of side effects. An increase of immune cells around the tumor can initially mimic progression (so-called pseudoprogression). Treatment-associated side effects of higher grade according to the common terminology criteria for adverse events (CTCAE grades 3 or 4) are relatively rare; however, new immune-mediated side effects can occur and affect the skin, liver (hepatitis), kidneys (nephritis), gastrointestinal tract (diarrhea and colitis), lungs (pneumonitis) and endocrine organs (hyperthyroidism, hypothyroidism and hypophysitis). Treatment has to be delayed or discontinued depending on the kind and degree of side effects; furthermore, corticosteroids can be administered as immunosuppressants. When recognized in time and with correct management, immune-mediated side effects are basically reversible.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/864/CN-01382864/frame.html


Record #4 of 144
ID: CN-01332273
AU: Morganstein DL
AU: Lai Z
AU: Spain L
AU: Diem S
AU: Levine D
AU: Mace C
AU: Gore M
AU: Larkin J
TI: Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and programmed death receptor protein-1 inhibitors in the treatment of melanoma
SO: Clinical endocrinology
YR: 2017
VL: (no pagination)
XR: EMBASE 614311707
PT: Journal: Article In Press
KY: clinical study; clinical trial; controlled clinical trial; controlled study; drug combination; drug therapy; female; *Graves disease; human; hypothyroidism; *melanoma; phase 3 clinical trial; subclinical hyperthyroidism; thyroid function test; *cytotoxic T lymphocyte antigen 4; *death receptor; endogenous compound; ipilimumab; nivolumab; pembrolizumab; programmed death 1 receptor; *receptor protein
DOI: 10.1111/cen.13297
AB: Context: Checkpoint inhibitors are emerging as important cancer therapies but are associated with a high rate of immune side effects, including endocrinopathy. Objective: To determine the burden of thyroid dysfunction in patients with melanoma treated with immune checkpoint inhibitors and describe the clinical course. Design and patients: Consecutive patients with melanoma treated with either ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab and nivolumab were identified. Baseline thyroid function tests were used to exclude those with pre-existing thyroid abnormalities, and thyroid function tests during treatment used to identify those with thyroid dysfunction. Results: Rates of overt thyroid dysfunction were in keeping with the published phase 3 trials. Hypothyroidism occurred in 13.0% treated with a programmed death receptor-1 (PD-1) inhibitor and 22.2% with a combination of PD-1 inhibitor and ipilimumab. Transient subclinical hyperthyroidism was observed in 13.0% treated with a PD-1 inhibitor, 15.9% following a PD-1 inhibitor, and 22.2% following combination treatment with investigations suggesting a thyroiditic mechanism rather than Graves' disease, and a high frequency of subsequent hypothyroidism. Any thyroid abnormality occurred in 23.0% following ipilimumab, 39.1% following a PD-1 inhibitor and 50% following combination treatment. Abnormal thyroid function was more common in female patients. Conclusion: Thyroid dysfunction occurs commonly in patients with melanoma treated with immune checkpoint inhibitors, with rates, including subclinical dysfunction, occurring in up to 50%. Copyright © 2017 John Wiley & Sons Ltd.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/273/CN-01332273/frame.html


Record #5 of 144
ID: CN-01336503
AU: Morganstein DL
AU: Lai Z
AU: Spain L
AU: Diem S
AU: Levine D
AU: Mace C
AU: Gore M
AU: Larkin J
TI: Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and programmed death receptor protein-1 inhibitors in the treatment of melanoma
SO: Clinical endocrinology
YR: 2017
VL: 86
NO: 4
PG: 614-620
XR: EMBASE 614311707
PT: Journal: Article
KY: adult; aged; article; cancer combination chemotherapy; collimator; corticosteroid therapy; drug uptake; drug use; female; Graves disease/si [Side Effect]; human; hypothyroidism/si [Side Effect]; major clinical study; male; medical record review; *melanoma/dt [Drug Therapy]; melanoma/dt [Drug Therapy]; middle aged; priority journal; subclinical hyperthyroidism/si [Side Effect]; supraventricular tachycardia/dt [Drug Therapy]; *thyroid disease/si [Side Effect]; thyroid disease/si [Side Effect]; thyroid function; thyrotropin blood level; beta adrenergic receptor blocking agent/dt [Drug Therapy]; corticosteroid; cytotoxic T lymphocyte antigen 4/ec [Endogenous Compound]; *ipilimumab/ae [Adverse Drug Reaction]; *ipilimumab/cb [Drug Combination]; *ipilimumab/dt [Drug Therapy]; *nivolumab/ae [Adverse Drug Reaction]; *nivolumab/cb [Drug Combination]; *nivolumab/dt [Drug Therapy]; *pembrolizumab/ae [Adverse Drug Reaction]; *pembrolizumab/dt [Drug Therapy]; pertechnetic acid tc 99m/iv [Intravenous Drug Administration]; pertechnetic acid tc 99m/pk [Pharmacokinetics]; programmed death 1 receptor/ec [Endogenous Compound]; thyroid peroxidase antibody/ec [Endogenous Compound]; thyrotropin/ec [Endogenous Compound]; thyroxine/ec [Endogenous Compound]; clinical study; clinical trial; controlled clinical trial; controlled study; drug combination; drug therapy; *Graves disease; hypothyroidism; *melanoma; phase 3 clinical trial; subclinical hyperthyroidism; thyroid function test; *cytotoxic T lymphocyte antigen 4; *death receptor; endogenous compound; ipilimumab; nivolumab; pembrolizumab; programmed death 1 receptor; *receptor protein
DOI: 10.1111/cen.13297
AB: Context: Checkpoint inhibitors are emerging as important cancer therapies but are associated with a high rate of immune side effects, including endocrinopathy. Objective: To determine the burden of thyroid dysfunction in patients with melanoma treated with immune checkpoint inhibitors and describe the clinical course. Design and patients: Consecutive patients with melanoma treated with either ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab and nivolumab were identified. Baseline thyroid function tests were used to exclude those with pre-existing thyroid abnormalities, and thyroid function tests during treatment used to identify those with thyroid dysfunction. Results: Rates of overt thyroid dysfunction were in keeping with the published phase 3 trials. Hypothyroidism occurred in 13.0% treated with a programmed death receptor-1 (PD-1) inhibitor and 22.2% with a combination of PD-1 inhibitor and ipilimumab. Transient subclinical hyperthyroidism was observed in 13.0% treated with a PD-1 inhibitor, 15.9% following a PD-1 inhibitor, and 22.2% following combination treatment with investigations suggesting a thyroiditic mechanism rather than Graves' disease, and a high frequency of subsequent hypothyroidism. Any thyroid abnormality occurred in 23.0% following ipilimumab, 39.1% following a PD-1 inhibitor and 50% following combination treatment. Abnormal thyroid function was more common in female patients. Conclusion: Thyroid dysfunction occurs commonly in patients with melanoma treated with immune checkpoint inhibitors, with rates, including subclinical dysfunction, occurring in up to 50%. Copyright © 2016 John Wiley & Sons Ltd
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/503/CN-01336503/frame.html


Record #6 of 144
ID: CN-01251875
AU: Wolf D
TI: Checkpoint-inhibition in oncology
SO: Oncology research and treatment. Conference: jahrestagung der deutschen, osterreichischen und schweizerischen gesellschaften fur hamatologie und medizinische onkologie 2016. Germany. Conference start: 20161014. Conference end: 20161018
YR: 2016
VL: 39
PG: 27
XR: EMBASE 613153218
PT: Journal: Conference Abstract
KY: cancer patient; chemotherapy; clinical study; colitis; colorectal cancer; controlled clinical trial; controlled study; disease carrier; drug therapy; female; gene activation; gene frequency; human; hypophysitis; immunocompetent cell; infusion related reaction; long term survival; melanoma; Merkel cell tumor; metastasis; mismatch repair; mutational load; non small cell lung cancer; *oncology; ovary cancer; overall survival; phase 1 clinical trial; phase 2 clinical trial; physician; pneumonia; side effect; smoking; surgery; survival rate; T lymphocyte activation; antibody; blocking agent; CD137 antigen; CD28 antigen; corticosteroid; cytotoxic T lymphocyte antigen 4; endogenous compound; glucocorticoid induced tumor necrosis factor receptor; ligand; programmed death 1 ligand 1; programmed death 1 receptor
DOI: 10.1159/000449050
AB: It was in 2011, when Hanahan and Weinberg renewed their initial "hallmark of cancer" concept by adding the ability of malignant tumors to escape from an efficient immune cell attack (termed cancer immune-evasion). It was already assumed for decades that tumors are able shape the immune system, thereby actively preventing their elimination. Visionaries such as Paul Ehrlich more than a century ago already envisioned that "magic (e.g. immunological) bullets" may overcome tolerance to cancer. Immune cell activation is fine-tuned by a number of receptor/ligand-pairs, such as immune-activating (CD28, GITR or CD137) and immune-inhibitory (PD1, CTLA-4, LAG3, TIM3) proteins. CTLA-4 and PD-1 on T and PD-L1 on cancer cells represent the most prominent checkpoint-molecules, since both targets can be succesfully blocked in a therapeutic setting by antibodies, leading to their approval in various solid metastatic diseases (melanoma, NSCLC and RCC). In addition, various proof-of-concept Phase 1/2 studies documented very encouraging response and survival rates in other tumors, (e.g. mismatch repair deficient colorectal cancer, Merkel cell carcinoma, ovarian cancer). Most strikingly, these compounds induce long-term survival in a subgroup of immune-susceptible patients. Clinically applicable response predictors are not available so far, even though in some tumors a greater overall survival can be seen in PD-L1 positive tumors. Moreover, it appears that "immunological visibility" based on the genetic instability appears to be associated with improved response rates to checkpoint-blocking agents. This explains superior response rates seen in smoking NSCLC patients carrying a higher mutational load leading to T cell activation based on the generation of mutated neo-antigens. The tolerability of checkpoint-antibodies is very good. In addition to infusion-related reactions, physicians particularly have to check for immune-related side-effects (e.g. pneumonitis, colitis, hypophysitis), as they may need a rapid therapeutic intervention with corticosteroids. In summary, immune-oncology (IO) represents a new therapy pillar in the treatment of solid tumors, which complements the classic treatment modalities of surgery, radiation and chemotherapy, as well as targeted drugs. Combination studies with classical therapeutics and different IO-agents fuel the hope that IO therapies will help to improve outcome of more cancer patients in the near future.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/875/CN-01251875/frame.html


Record #7 of 144
ID: CN-01377977
AU: Santa-Maria CA
AU: Jain S
AU: Flaum L
AU: Park J-H
AU: Kato T
AU: Gross L
AU: Uthe R
AU: Tellez C
AU: Stein R
AU: Rademaker A
AU: Gradishar WJ
AU: Nakamura Y
AU: Giles FJ
AU: Cristofanilli M
TI: A phase II study of PD-L1 and CTLA-4 inhibition and immunopharmcogenomics in metastatic breast cancer
SO: Cancer research. Conference: 39th annual CTRC-AACR san antonio breast cancer symposium. United states
YR: 2017
VL: 77
NO: 4 Supplement 1) (no pagination
XR: EMBASE 616062987
PT: Conference Abstract
KY: biopsy; blood; chemotherapy; clinical article; clinical trial; clonal variation; controlled clinical trial; *controlled study; drug combination; drug therapy; *female; *gene inactivation; genetic marker; hormonal therapy; human; human tissue; immune system; male; *metastatic breast cancer; phase 2 clinical trial; *cytotoxic T lymphocyte antigen 4; durvalumab; endogenous compound; *programmed death 1 ligand 1; T lymphocyte receptor; ticilimumab
DOI: 10.1158/1538-7445.SABCS16OT3-01-01
AB: Background A hallmark of cancer is its ability to evade the immune system, however, it can be harnessed to detect and destroy cancer cells through inhibition of immune checkpoints such as CTLA-4 and PD-L1. This strategy has complementary and nonredundant mechanisms resulting in immune activation and antitumor synergy; progression free survival benefit has already been demonstrated in melanoma. A critical barrier in developing immunotherapies, however, is the identification of predictive biomarkers of response to therapy. Immunopharmacogenomic biomarkers, such as mutational burden, neoantigen profiles, and T cell receptor sequencing will elucidate the molecular interface between cancer and immune system, and may predict those most likely to benefit. Methods A single arm Phase II study was designed to determine the efficacy of PD-L1 and CTLA-4 inhibition and effects on immunopharmacogenomic dynamics in patients with metastatic breast cancer. The primary endpoint of this proposal is to investigate the response rate of the PD-L1 inhibitor, durvalumab, and the CTLA-4 inhibitor, tremelimumab, in metastatic breast cancer; secondary endpoints will examine the T cell receptor repertoire clonality, tumor mutational burden and neoantigen profiles. A total of 30 patients will be enrolled and treated with durvalumab 1500mg IV and tremelimumab 75mg IV monthly for 4 doses, then durvalumab 750mg every 2 weeks for 18 doses to complete 1 year of therapy with the option to renew therapy for an additional year; biopsies and blood at baseline and 2 months will be collected to assess immunopharmacogenomic biomarkers. Patients are eligible if they have triple negative or ERpositive breast cancer and have progressed on at least one line of chemotherapy and standard endocrine therapy if applicable. This is the first study to investigate immunopharmacogenomic biomarkers of response to dual checkpoint blockade in patients with metastatic breast cancer.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/977/CN-01377977/frame.html


Record #8 of 144
ID: CN-01363775
AU: SantaMaria CA
AU: Jain S
AU: Flaum L
AU: Park JH
AU: Kato T
AU: Gross L
AU: Uthe R
AU: Tellez C
AU: Stein R
AU: Rademaker A
AU: Gradishar WJ
AU: Nakamura Y
AU: Giles FJ
AU: Cristofanilli M
TI: A phase II study of PDL-1 and CTLA-4 inhibition and immunopharmcogenomics in metastatic breast cancer
SO: Cancer research. Conference: 39th annual CTRC-AACR san antonio breast cancer symposium. United states
YR: 2017
VL: 77
NO: 4 Supplement 1) (no pagination
XR: EMBASE 615274377
PT: Conference Abstract
KY: biopsy; blood; chemotherapy; clinical article; clinical trial; clonal variation; controlled clinical trial; *controlled study; drug therapy; *female; *gene inactivation; genetic marker; hormonal therapy; human; human tissue; immune system; *metastatic breast cancer; phase 2 clinical trial; *cytotoxic T lymphocyte antigen 4; durvalumab; endogenous compound; programmed death 1 ligand 1; T lymphocyte receptor; ticilimumab
DOI: 10.1158/1538-7445.SABCS16-OT3-01-01
AB: Background A hallmark of cancer is its ability to evade the immune system, however, it can be harnessed to detect and destroy cancer cells through inhibition of immune checkpoints such as CTLA-4 and PDL-1. This strategy has complementary and nonredundant mechanisms resulting in immune activation and antitumor synergy; progression free survival benefit has already been demonstrated in melanoma. A critical barrier in developing immunotherapies, however, is the identification of predictive biomarkers of response to therapy. Immunopharmacogenomic biomarkers, such as mutational burden, neoantigen profiles, and T cell receptor sequencing will elucidate the molecular interface between cancer and immune system, and may predict those most likely to benefit. Methods A single arm Phase II study was designed to determine the efficacy of PDL-1 and CTLA-4 inhibition and effects on immunopharmacogenomic dynamics in patients with metastatic breast cancer. The primary endpoint of this proposal is to investigate the response rate of the PDL-1 inhibitor, durvalumab, and the CTLA-4 inhibitor, tremelimumab, in metastatic breast cancer; secondary endpoints will examine the T cell receptor repertoire clonality, tumor mutational burden and neoantigen profiles. A total of 30 patients will be enrolled and treated with durvalumab 1500mg IV and tremelimumab 75mg IV monthly for 4 doses, then durvalumab 750mg every 2 weeks for 18 doses to complete 1 year of therapy with the option to renew therapy for an additional year; biopsies and blood at baseline and 2 months will be collected to assess immunopharmacogenomic biomarkers. Patients are eligible if they have triple negative or ERpositive breast cancer and have progressed on at least one line of chemotherapy and standard endocrine therapy if applicable. This is the first study to investigate immunopharmacogenomic biomarkers of response to dual checkpoint blockade in patients with metastatic breast cancer.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/775/CN-01363775/frame.html


Record #9 of 144
ID: CN-01162987
AU: Taylor M
AU: Antonia S
AU: Bendell J
AU: Calvo E
AU: Jager D
AU: Braud F
AU: Ott PA
AU: Pietanza MC
AU: Horn L
AU: Le DT
AU: Morse MA
AU: Lopez-Martin JA
AU: Ascierto PA
AU: Christensen O
AU: S Simon J
AU: Lin C-S
AU: Eder JP
TI: Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): cA209-032
SO: Journal for immunotherapy of cancer
YR: 2015
VL: 3
NO: no pagination
XR: EMBASE 72150413
PT: Journal: Conference Abstract
KY: *small cell lung cancer; *society; *immunotherapy; *neoplasm; human; patient; arm; safety; diarrhea; melanoma; nausea; fatigue; toxicity; monotherapy; progression free survival; fatality; myasthenia gravis; pneumonia; Japan; maculopapular rash; hyperthyroidism; antineoplastic activity; hypothyroidism; pruritus; rash; decreased appetite; death; chemotherapy; case study; population; follow up; overall survival; *nivolumab; *ipilimumab; triacylglycerol lipase; platinum; biological marker; cytotoxic T lymphocyte antigen 4
AB: Background: Treatment options for SCLC after failing platinum-based (PLT) chemotherapy (CT) are limited. Combined blockade of programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) immune checkpoint pathways has anti-tumor activity with a manageable safety profile. Nivolumab is a fully human IgG4 PD-1 immune checkpoint inhibitor approved for melanoma and squamous NSCLC in the US and for melanoma in the EU and Japan. Interim efficacy and safety of nivolumab +/- ipilimumab, a CTLA-4 checkpoint inhibitor, in pretreated SCLC patients are reported. Methods: Patients with progressive disease (PD) after PLT first-line treatment were eligible, regardless of platinum sensitivity, tumor PD-L1 expression, or number of prior CT regimens. Patients were randomized to nivolumab 3 mg/kg IV Q2W or nivolumab+ipilimumab (1+1 mg/kg or 1+3 mg/kg) IV Q3W for 4 cycles, followed by nivolumab 3 mg/kg Q2W. Primary objective was objective response rate (ORR). Additional objectives included safety, progression-free survival (PFS), overall survival (OS), and biomarker analysis. Results: Of 90 patients enrolled (nivolumab, n=40; nivolumab +ipilimumab, n=50 [nivolumab 1+ipilimumab 1, n=3; nivolumab 1 +ipilimumab 3, n=47]), 53% had >2 prior regimens. Efficacy results for evaluable patients are shown (Table 1). 20% of patients in the nivolumab arm and 42% in the nivolumab+ipilimumab arms remain on treatment. Discontinuations due to treatment-related adverse events (TRAEs) occurred in 8% of nivolumab and 11% of nivolumab+ipilimumab patients. TRAEs (all grades) in >10% of patients included fatigue (18%), diarrhea (13%), nausea (10%), and decreased appetite (10%) with nivolumab; and diarrhea (23%), fatigue (21%), rash (21%), pruritus (19%), hypothyroidism (15%), hyperthyroidism (13%), nausea (13%), maculopapular rash (13%), and increased lipase (11%) with nivolumab 1 +ipilimumab 3. Grade 3-4 TRAEs in >5% of patients occurred only in the nivolumab 1+ipilimumab 3 arm and included diarrhea (9%) and increased lipase (6%). Pneumonitis occurred in 2 patients in the nivolumab arm (grade 1-2) and 1 patient in the nivolumab 1+ipilimumab 3 arm (grade 3-4). One patient in the nivolumab 1+ipilimumab 3 arm had treatmentrelated myasthenia gravis with fatal outcome. Updated efficacy, safety, biomarker analysis, and case studies (responses in a patient with PLTrefractory disease and in a patient after crossover to nivolumab/ ipilimumab) will be presented. Conclusions: In this PD-L1 unselected SCLC population with progression after PLT-CT, nivolumab monotherapy and nivolumab+ipilimumab were generally well tolerated with manageable toxicity. Rare severe toxicities will require close follow-up. Durable responses occurred with nivolumab monotherapy and in combination with ipilimumab.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/987/CN-01162987/frame.html


Record #10 of 144
ID: CN-01399962
AU: Rivero J
AU: Bilusic M
AU: Rauckhorsts M
AU: Cordes L
AU: Karsai F
AU: Strauss J
AU: Dahut WL
AU: Schlom J
AU: Gulley JL
AU: Madan RA
TI: Calcitonin response following sequential use of a yeast-CEA therapeutic cancer vaccine and avelumab, a monoclonal anti-PD-LI inhibitor, in metastatic medullary thyroid cancer
SO: Endocrine reviews. Conference: 99th annual meeting of the endocrine society, ENDO 2017. United states
YR: 2017
VL: 38
NO: 3 Supplement 1) (no pagination
XR: EMBASE 617151209
PT: Conference Abstract
KY: adult; adverse drug reaction; cervical lymph node; clinical article; clinical trial; controlled clinical trial; controlled study; diagnosis; disease duration; drug therapy; drug withdrawal; fine needle aspiration biopsy; gene expression; gene inactivation; human; human tissue; immunocompetent cell; immunotherapy; male; middle aged; national health organization; neck dissection; neck tumor; *nonhuman; phase 1 clinical trial; relapse; side effect; surgery; systemic therapy; *thyroid medullary carcinoma; thyroidectomy; vaccination; *yeast; *avelumab; *calcitonin; *cancer vaccine; carcinoembryonic antigen; endogenous compound; programmed death 1 ligand 1; sunitinib; triacylglycerol lipase
AB: Background: Medullary thyroid cancer (MTC) accounts for approximately 4% of thyroid carcinomas, and secretes calcitonin and carcinoembryonic antigen (CEA). Patients with unresectable, metastatic disease are candidates for approved agents with either vandetanib and cabozantinib, but toxicity limits their use. There are ongoing trials exploring the role of less toxic immunotherapy in patients with MTC. Patient findings: A 61-year-old male presented with an enlarging anterior neck mass, fine needle aspiration was consistent with MTC. He underwent total thyroidectomy with bilateral neck dissection. Subsequently, he had multiple local recurrences and has had a total of five neck surgeries in a period of 12 years. Based on the elevated calcitonin levels and persistent local recurrence, 13 years after diagnosis, he started systemic treatment with sunitinib and calcitonin levels nadired to 199 pg/ml (n<10) down from 461 pg/ml. He continued for 5 years and stopped due to side effects. His calcitonin levels after discontinuing sunitinib rose to 2243 pg/ml. He presented to the National Cancer Institute and enrolled on a clinical trial with yeast-based therapeutic cancer vaccine targeting CEA (NCT01856920). During 6-month protocol mandated surveillance he had calcitonin doubling time of 135 days. During the subsequent 3 month vaccine period his doubling time improved to 530 days. He decided to come off study electively for surgical removal of his largest neck lymph node. After surgery, his calcitonin rose to 9765 pg/ml and the patient was enrolled on a phase 1 trial of avelumab, a PD-L1 inhibitor (NCT01772004). He then had 5 consecutive declines in his calcitonin to 5732 pg/ml while on the immune checkpoint inhibitor, a greater than 40% decline not previously seen in his NCI clinical course. These findings coincided with an immune-related adverse event (asymptomatic rise in grade 3 lipase) which led to protocol-mandated treatment discontinuation. A subsequent analysis of the patient's lymph node resected post vaccination revealed tumor that was PD-L1 positive. Conclusion: Here we present a case with recurrent MTC who was treated initially with sunitinib, and then subsequently enrolled on a clinical trial with yeast-CEA vaccine. After a surgical resection, the tumor sample resected demonstrated positive PD-L1 expression. The patient had a 40% decline in serologic markers on an anti- PD-L1 therapy (avelumab). Emerging data suggest that immune cells mobilized to the tumor via immunotherapy (vaccine) could enhance PD-L1 expression, although the absence of baseline tissue prevents confirmation in this case. This case highlights the potential for immunotherapy or sequential immunotherapy in MTC. A trial will open at the NCI treating patients (both with previous immunotherapy and immunotherapy naive) with an immune checkpoint inhibitor.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/962/CN-01399962/frame.html


Record #11 of 144
ID: CN-01443899
AU: Osorio JC
AU: Ni A
AU: Chaft JE
AU: Pollina R
AU: Kasler MK
AU: Stephens D
AU: Rodriguez C
AU: Cambridge L
AU: Rizvi H
AU: Wolchok JD
AU: Merghoub T
AU: Rudin CM
AU: Fish S
AU: Hellmann MD
TI: Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer
SO: Annals of oncology : official journal of the european society for medical oncology
YR: 2017
VL: 28
NO: 3
PG: 583-589
PM: PUBMED 27998967
PT: Clinical Trial, Phase I; Journal Article; Randomized Controlled Trial
KY: Adolescent;Antibodies, Monoclonal [administration & dosage] [adverse effects];Antibodies, Monoclonal, Humanized [administration & dosage] [adverse effects];Carcinoma, Non-Small-Cell Lung [drug therapy] [genetics] [immunology] [pathology];Disease-Free Survival;Drug-Related Side Effects and Adverse Reactions [pathology];Hyperthyroidism [chemically induced] [genetics] [immunology] [pathology];Neoplasm Staging;Programmed Cell Death 1 Receptor [antagonists & inhibitors] [genetics] [immunology];T-Lymphocytes [drug effects] [immunology] [pathology];Thyroid Gland [drug effects] [immunology] [pathology];Adult[checkword];Aged[checkword];Female[checkword];Humans[checkword];Male[checkword];Middle Aged[checkword]
DOI: 10.1093/annonc/mdw640
AB: Patient and methods: Patients with advanced non-small-cell lung cancer (NSCLC) treated with pembrolizumab at Memorial Sloan Kettering Cancer Center (n = 51) as part of KEYNOTE-001 (NCT01295827) were included. Thyroid function test and anti-thyroid antibodies were assessed prospectively at each study visit, beginning before the first treatment. Frequency of development of thyroid dysfunction, association with anti-thyroid antibodies, clinical course, and relationship with progression-free survival and overall survival to treatment with pembrolizumab was evaluated.Results: Of 51 patients treated, 3 were hypothyroid and 48 were not at baseline. Ten of 48 [21%, 95% confidence interval (CI) 10% to 35%] patients developed thyroid dysfunction requiring thyroid replacement. Anti-thyroid antibodies were present in 8 of 10 patients who developed thyroid dysfunction, compared with 3 of 38 who did not (80% versus 8%, P < 0.0001). Thyroid dysfunction occurred early (median, 42 days) in the pembrolizumab course, and a majority (6 of 10 patients) experienced brief, transient hyperthyroidism preceding the onset of hypothyroidism; no persistent hyperthyroidism occurred. Both hyperthyroidism and hypothyroidism were largely asymptomatic. Overall survival with pembrolizumab was significantly longer in subjects who developed thyroid dysfunction (hazard ratio, 0.29; 95% CI 0.09-0.94; P = 0.04).Conclusions: Thyroid dysfunction during pembrolizumab treatment of NSCLC is common and is characterized by early-onset, frequently preceded by transient hyperthyroidism, closely associated with anti-thyroid antibodies, and may be associated with improved outcomes. The presence of antibody-mediated toxicity in T-cell-directed therapy suggests an under-recognized impact of PD-1 biology in modulating humoral immunity.Background: Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated durable responses and prolonged survival in a variety of malignancies. Treatment is generally well tolerated although immune-related adverse events (irAEs) can occur. Autoimmune thyroid dysfunction is among the most common irAE, but an assessment of the clinical, mechanistic, and immunologic features has not been previously described.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/899/CN-01443899/frame.html


Record #12 of 144
ID: CN-01397513
AU: Leonardi GC
AU: Gainor JF
AU: Azimi RS
AU: Riess J
AU: Rizvi H
AU: Hellmann MD
AU: Awad MM
TI: Use of PD-1 pathway inhibitors among patients with non-small cell lung cancer (NSCLC) and preexisting autoimmune disorders
SO: Journal of clinical oncology. Conference: 2017 annual meeting of the american society of clinical oncology, ASCO. United states
YR: 2017
VL: 35
NO: 15 Supplement 1) (no pagination
XR: EMBASE 617435461
PT: Conference Abstract
KY: adverse drug reaction; cancer patient; clinical article; clinical trial; controlled clinical trial; controlled study; diabetes insipidus; disease duration; disease exacerbation; drug therapy; *female; follow up; human; hypertransaminasemia; hypothyroidism; inflammatory bowel disease; *male; monotherapy; multicenter study; nervous system; *non small cell lung cancer; pneumonia; retrospective study; *rheumatoid arthritis; safety; side effect; symptom; thyroiditis; toxicity; endogenous compound; *programmed death 1 receptor; steroid
AB: Background: Since patients (pts) with NSCLC and autoimmune (AI) disease were largely excluded from immune checkpoint inhibitor clinical trials, we aimed to determine the safety of PD-1 inhibitors in NSCLC pts with a history of AI diseases. Methods: As part of a multi-center, retrospective study, we collected clinicopathologic data from pts with advanced stage IIIB or stage IV NSCLC with a history of AI disease and who received treatment with a PD-1 inhibitor as monotherapy. Qualifying AI disorders included but were not limited to: thyroiditis (excluding hypothyroidism without clear autoimmune etiology), inflammatory bowel disease, as well as rheumatologic, neurologic and dermatologic conditions. Results: We identified 46 pts with NSCLC treated with a PD-1 inhibitor who also had a history of AI disease. At the time of PD-1 inhibitor treatment initiation, 13% of pts had active AI symptoms and 19% were receiving immunomodulatory agents for their AI condition. The median period of follow up after initiation of anti-PD-1 therapy was 17.4 weeks (range 0.6-72.1 weeks). Exacerbation of the underlying AI condition occurred in 8 pts (17%). Two of these pts required steroid treatment (both for rheumatoid arthritis), and three of these pts required temporary interruption of treatment due AI disease flare. Overall, twelve (26%) pts developed at least one immune-related adverse event (irAE) unrelated to the underlying AI condition (8 grade 1-2, 4 grade 3); there were no cases of grade 4-5 irAEs. PD-1 therapy was permanently discontinued in 3 cases due to the development of an irAE (1 for grade 1 pneumonitis, 1 for grade 3 transaminitis, 1 for grade 3 diabetes insipidus). Conclusions: In pts with NSCLC and a history of AI conditions treated with PD-1 blockade, symptomatic flare of underlying AI disease was uncommon. The rate of immune-related toxicities in this population appears similar to published studies in pts without baseline AI conditions. Further analysis of pts with active AI conditions is needed to clarify the safety profile in this population.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/513/CN-01397513/frame.html


Record #13 of 144
ID: CN-01173497
AU: Antonia SJ
AU: Bendell J
AU: Taylor M
AU: Calvo E
AU: Jager D
AU: Braud F
AU: Ott PA
AU: Pietanza MC
AU: Horn L
AU: Le DT
AU: Morse MA
AU: Lopez-Martin JA
AU: A Ascierto P
AU: Christensen O
AU: Grosso JF
AU: Simon J
AU: Lin C
AU: Eder JP
TI: Phase 1/2 study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): cA209-032
SO: Annals of oncology. Conference: 17th national congress of medical oncology rome italy. Conference start: 20151023 conference end: 20151025. Conference publication: (var.pagings)
YR: 2015
VL: 26
NO: no pagination
XR: EMBASE 72205349
PT: Journal: Conference Abstract
KY: *small cell lung cancer; *oncology; safety; human; diarrhea; nausea; fatigue; rash; neoplasm; arm; open study; Japan; population; myasthenia gravis; antineoplastic activity; pneumonia; chemotherapy; endocrine disease; pruritus; patient; decreased appetite; *nivolumab; *ipilimumab; biological marker; cytotoxic T lymphocyte antigen 4; platinum
DOI: 10.1093/annonc/mdv343.05
AB: Background: Patients ( pts) with SCLC respond to initial platinum (PLT) based chemotherapy (CT), but rapidly progress. Combined blockade of PD-1 and CTLA-4 immune checkpoint pathways has anti-tumor activity with a manageable safety profile. Nivolumab (NIVO) is a fully human IgG4 PD-1 immune checkpoint inhibitor approved in the US & Japan. Interim safety and efficacy of NIVO +/- ipilimumab (IPI), a CTLA-4 checkpoint inhibitor, in pretreated SCLC pts are reported. Material and methods: Pts who were PLT sensitive or refractory and had progressive disease were enrolled regardless of tumor PD-L1 status or number of prior CT regimens. This open-label study randomized pts to NIVO 3 mg/kg IV Q2W or NIVO + IPI (1 + 1 mg/kg, 1 + 3 mg/kg, or 3 + 1 mg/kg) IV Q3W for 4 cycles followed by NIVO 3 mg/kg Q2W. Primary objective was overall response rate (ORR). Other objectives were safety, PFS, OS and biomarker analysis. Results: Seventy-five pts were enrolled (NIVO, n = 40; NIVO + IPI, n = 35); 59% had >2 prior regimens. Drug-related adverse events (DrAEs) in >10% were fatigue (18%), diarrhea (13%), nausea (10%), and decreased appetite (10%) with NIVO; and fatigue (29%), diarrhea (17%), pruritus (14%), nausea, endocrine disorders, and rash (11% each) with NIVO + IPI. Gr 3-4 DrAEs in >5% included diarrhea and rash (6% each; NIVO + IPI). Drug-related pneumonitis occurred in 2 pts (1 per arm). One pt experienced a drug-related SAE of myasthenia gravis on study which was fatal. Of 40 evaluable NIVO pts, partial response (PR) was seen in 6 (15%; duration of ongoing responses [DOR] 80-251+ days); stable disease (SD) in 9 (22.5%); and progressive disease (PD) in 25 (62.5%). In 20 evaluable NIVO + IPI pts, 1 had complete response (CR) (5%; DOR 322+ days); 4 had PR (20%; DOR 41-83+ days); 6 had SD (30%), and 9 had PD (45%). In the NIVO + IPI arm, 12 pts had not reached first tumor assessment and 3 were not evaluable. Nine pts (23%) continue treatment with NIVO and 19 (54%) with NIVO + IPI. Conclusions: In this PD-L1 unselected SCLC population with progression post-PLT, NIVO alone or combined with IPI was tolerable. ORR was 15% (NIVO) and 25% (NIVO + IPI) for evaluable pts; durable responses were noted. Updated safety, clinical activity and biomarker analysis will be presented.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/497/CN-01173497/frame.html


Record #14 of 144
ID: CN-01250018
AU: Evans EE
AU: Bussler H
AU: Torno S
AU: Mallow C
AU: Winters LA
AU: Reilly C
AU: Klimatcheva E
AU: Veeraraghavan J
AU: Jonason AS
AU: Scrivens M
AU: Kirk R
AU: Howell A
AU: Balch L
AU: Leonard JE
AU: Paris M
AU: Fisher TL
AU: Smith ES
AU: Zauderer M
TI: Antibody blockade of Semaphorin 4D neutralizes barrier to immune infiltration and facilitates immune-mediated tumor rejection
SO: Cancer immunology research. Conference: CRI-CIMT-EATI-AACR inaugural international cancer immunotherapy conference: translating science into survival. United states. Conference start: 20150916. Conference end: 20150919
YR: 2016
VL: 4
NO: 1 Supplement) (no pagination
XR: EMBASE 613321758
PT: Journal: Conference Abstract
KY: animal model; antineoplastic activity; breast carcinoma; cell infiltration; cell line; chemotherapy; clinical trial; controlled clinical trial; controlled study; drug combination; drug therapy; female; flow cytometry; gene activation; gene disruption; *gene inactivation; human; human tissue; immunocompetent cell; immunohistochemistry; immunological memory; immunotherapy; leukocyte culture; lymphocyte count; macrophage; monotherapy; murine; nonhuman; oncogene; oncology; phase 1 clinical trial; preclinical study; progression free survival; response evaluation criteria in solid tumors; safety; T lymphocyte; transactivation; treatment duration; tumor growth; tumor microenvironment; tumor model; tumor regression; *tumor rejection; *antibody; cytokine; cytotoxic T lymphocyte antigen 4; endogenous compound; epidermal growth factor receptor 2; *semaphorin; semaphorin 3F
DOI: 10.1158/2326-6074.CRICIMTEATIAACR15-A119
AB: Semaphorin 4D (SEMA4D, CD100) and its receptor plexin-B1 are broadly expressed in cancer and expression correlates with invasive disease in several human tumors. SEMA4D normally functions to regulate the motility and differentiation of multiple cell types, including those of the immune, vascular, and nervous systems. In the setting of cancer, we describe a novel immunomodulatory function of SEMA4D in regulation of immune cell infiltration and activity in the tumor microenvironment (TME). Purpose: Characterize immune-related and anti-tumor activity mediated by antibody neutralization of SEMA4D, as a single agent and in combination with other immunomodulatory therapies. Methods: Blockade of SEMA4D with monoclonal murine antibody was evaluated in subcutaneous models, as well as an orthotopic ERBB2+ breast carcinoma syngeneic model. Anti-tumor immune response in preclinical models was characterized by selective in vivo immune cell depletions, as well as immunohistochemistry, flow cytometry, and functional assays. The safety and tolerability of a humanized anti-SEMA4D antibody VX15/2503 was assessed in Phase I clinical trials in oncology. Results: SEMA4D restricts migration of macrophage cell lines in vitro. Strong expression of SEMA4D at the invasive margins of actively growing in vivo tumors modulates the infiltration and spatial distribution of leukocytes in the TME. Antibody neutralization of SEMA4D disrupts this gradient and facilitates recruitment of potent antigen presenting cells and T lymphocytes into the TME, shifting the balance of cytokines toward increased Th1 and reduced immunosuppressive cytokines. This orchestrated change in the tumor architecture was associated with durable tumor rejection and immunologic memory in preclinical models. Immune-mediated tumor rejection may enhance the disruption of ERBB2 transactivation with SEMA4D receptors, which has been reported for ERBB2 and Met oncogenes. Importantly, the immunomodulatory activity of anti-SEMA4D antibody can also be further enhanced by combination with other immunotherapies, including immune checkpoint inhibition and chemotherapy. Strikingly, the combination of anti-SEMA4D antibody with antibody to CTLA-4 acts synergistically to promote complete tumor rejection and survival, with significant 58% increase in tumor regression and maximal increase in survival, as compared to monotherapy. Treatment with anti-SEMA4D antibodies was well tolerated in nonclinical and clinical studies, including completion of a Phase I prospective multiple ascending dose trial in patients with advanced refractory solid tumors. Weekly doses of between 0.3 and 20 mg/kg were administered; no MTD was determined. Patients with the longest duration of treatment, 48-55 weeks, included colorectal, breast, and a papillary thyroid patient, who had a partial response by RECIST. Progression free survival correlated with elevated baseline lymphocyte counts, supporting an immune mediated mechanism of action for VX15/2503. Conclusion: Inhibition of SEMA4D represents a novel mechanism and therapeutic strategy to promote functional immune infiltration into the tumor and inhibit tumor progression. A phase 1b/2a trial of combination therapy with immune checkpoint inhibition is planned.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/018/CN-01250018/frame.html


Record #15 of 144
ID: CN-01398185
AU: Stroud CRG
AU: Cherry CR
AU: Naqash AR
AU: Sharma N
AU: Cherukuri SD
AU: Parent T
AU: Hardin J
AU: Walker PR
TI: Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade
SO: Journal of clinical oncology. Conference: 2017 annual meeting of the american society of clinical oncology, ASCO. United states
YR: 2017
VL: 35
NO: 15 Supplement 1) (no pagination
XR: EMBASE 617538429
PT: Conference Abstract
KY: adverse drug reaction; blood clotting disorder; cancer patient; clinical trial; colitis; controlled clinical trial; controlled study; cost control; cytokine release syndrome; disease course; drug therapy; encephalitis; female; hepatitis; hospital patient; human; hypophysitis; infusion; lung cancer; major clinical study; male; medical record; pancreatitis; pneumonia; randomized controlled trial; safety; side effect; symptom; systemic inflammatory response syndrome; C reactive protein; corticosteroid; endogenous compound; infliximab; nivolumab; *programmed death 1 receptor; *tocilizumab
AB: Background: Immune checkpoint inhibitors are poised to revolutionize the management of a growing number of malignancies. Unfortunately, the management of steroid-refractory immune mediated adverse events (irAEs) is based on a paucity of randomized data and limited to single center experiences. Our initial experience with the IL-6 receptor antagonist tocilizumab showed clinical improvement in a wide variety of irAEs. As a result, we adopted the use of tocilizumab for the management of steroid-refractory irAEs. Methods: The character and clinical course of irAEs were abstracted from the medical record and analyzed. The dose of tocilizumab was 4 mg/kg given IV over 1 hour. C-reactive protein was drawn at first nivolumab infusion and at q 2 weeks (and with irAEs) thereafter. Clinical improvement was defined as either: documentation of resolution of symptoms or hospital d/c within 7 days. Results: Of the initial 87 patients that were treated with nivolumab, 34 required tocilizumab (39.1%). All pts were on corticosteroids. The majority (88.2%) were lung cancer patients. The index grade 3/4 irAE was pneumonitis in 35.3%, cytokine release syndrome/SIRS in 35.3%, cerebritis in 14.7% and one case each of hypophysitis, colitis, pancreatitis, hepatitis and immune mediated coagulopathy. Median time between first nivolumab and initiation of tocilizumab was 76 days (range 1-429). Median CRP at initial tocilizumab dose was 100.5 mg/L (2.0 -350.4). Clinical improvement was noted in 27/34 pts (79.4%). 52.9% of pts required a single dose, while 35.3% required two, 8.8% required three and 1 pt required 4 doses. Twenty seven doses were given in the inpatient setting (49.1%). Median time to discharge was 4 days (range 1- 27). Seventy four percent of pts were discharged home. For the 55 doses of tocilizumab that were delivered there was a cost savings of $147,174.94 (WAC) during the 18 month period versus infliximab 5 mg/kg IV dose. Conclusions: Tocilizumab is a therapeutic option for the management of steroid refractory irAEs secondary to immune checkpoint blockade. However, randomized trials are needed to better elucidate the relative efficacy and safety of these agents.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/185/CN-01398185/frame.html


Record #16 of 144
ID: CN-01295310
AU: Naing A
AU: Papadopoulos KP
AU: Autio KA
AU: Wong DJ
AU: Patel M
AU: Falchook G
AU: Pant S
AU: Ott PA
AU: Whiteside M
AU: Patnaik A
AU: Mumm J
AU: Janku F
AU: Chan I
AU: Bauer T
AU: Colen R
AU: VanVlasselaer P
AU: Brown GL
AU: Tannir NM
AU: Oft M
AU: Infante J
TI: Immune activation by PEGylated human IL-10 (AM0010) and anti-tumor activity in renal cancer alone and in combination with anti-PD-1
SO: Journal for immunotherapy of cancer. Conference: 31st annual meeting and associated programs of the society for immunotherapy of cancer, SITC 2016. United states. Conference start: 20161109. Conference end: 20161113
YR: 2016
VL: 4
NO: no pagination
XR: EMBASE 613519014
PT: Journal: Conference Abstract
KY: anemia; *antineoplastic activity; CD8 T lymphocyte; cell clone; cell proliferation; clinical article; clinical trial; clonal variation; colitis; controlled clinical trial; controlled study; drug therapy; drug withdrawal; endocrine system; fatigue; gene inactivation; human; human tissue; hypertriglyceridemia; immune response; *kidney cancer; lymphocyte count; monotherapy; peripheral blood mononuclear cell; phase 1 clinical trial; phase 3 clinical trial; pneumonia; progression free survival; regulatory T lymphocyte; T lymphocyte activation; thrombocytopenia; endogenous compound; *interleukin 10; interleukin 18; interleukin 4; interleukin 7; nivolumab; pembrolizumab; *programmed death 1 receptor; transforming growth factor beta; tumor necrosis factor
DOI: 10.1186/s40425-016-0173-6
AB: Background IL-10 is regarded as an anti-inflammatory cytokine, but it is at least equally important for the cytotoxicity and proliferation of antigen activated CD8+ T cells. Activation of CD8+ T cells through the T cell receptor elevates IL-10 receptors and PD-1 on the cells. This provides the mechanistic rationale for combining AM0010 and anti-PD-1 for the treatment of cancer patients. A phase I clinical trial investigated the tolerability and anti-tumor activity of AM0010 alone and in combination with anti-PD-1 immune checkpoint inhibitors. Methods Patients with advanced RCC were treated with AM0010 (daily SC) alone or in combination with pembrolizumab (q3wk IV) or nivolumab (q2wk IV). Tumor responses were monitored following irRC. Immune responses were measured by analysis of serum cytokines, and the activation and clonality of T cells in peripheral blood mononuclear cells. Nineteen patients with RCC (15 evaluable), were treated with AMO010 alone (20 mg/kg). Eight patients were treated in combination with pembrolizumab (2 mg/kg) and 15 patients with nivolumab (3 mg/kg). Results AM0010 alone or in combination with anti-PD-1 was tolerated well (observation periods exceeding 16 months). All TrAEs were transient and TrAEs leading to study discontinuation were not observed. There was no colitis, pneumonitis, or endocrine disruptions. G3/4 TrAEs in monotherapy included anemia (9), hypertriglyceridemia (3), thrombocytopenia (2), ALT/AST increase (2) and fatigue (2). AM0010 combination with anti-PD-1 did not increase TrAEs. Objective responses (PR/CR) were observed in 4 of 15 evaluable RCC patients in monotherapy (27 %), in 4 of 8 patients in AM0010/pembrolizumab (50 %). Progression-free survival (PFS) was 3 and 9.4 months, respectively. The AM0010/nivolumab cohort is currently in progress. AM0010 alone and also in combination with anti-PD-1 increased Th1 cytokines (IL-18, IFNg, TNFa), CD8+ T cell associated effector molecules such as FasL and LymphotoxinB as well as cytokines stimulating T cell proliferation (IL-4, IL-7). As a result, the number and proliferation of activated, PD-1+/LAG-3+ CD8+ T cells in the blood of patients were increased on AM0010. In contrast, the proliferation of FoxP3+ Tregs and TGFb was decreased. AM0010 alone or with anti-PD-1 induced oligoclonal expansion of T cell clones in the blood without affecting total lymphocyte counts. In particular, selected T cells clones previously not detected in the blood of patients before treatment were strongly expanded (de novo amplification). Conclusions AM0010 alone or in combination with anti-PD-1 is well-tolerated. The clinical activity and the observed CD8+ T cell activation encourages the continued exploration of AM0010 in phase III studies. (Figure Presented).
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/310/CN-01295310/frame.html


Record #17 of 144
ID: CN-01250560
AU: Evans EE
AU: Fisher TL
AU: Edington C
AU: Bussler H
AU: Torno S
AU: Jonason Jr AS
AU: Veeraraghavan J
AU: Reilly C
AU: Doherty MA
AU: Seils J
AU: Winter LA
AU: Pandina T
AU: Mallow C
AU: Kirk R
AU: Howell A
AU: Giralico S
AU: Scrivens M
AU: Klimatcheva K
AU: Bowers WJ
AU: Paris M
AU: Rasco DW
AU: Ramanathan RK
AU: Patnaik A
AU: Weiss GJ
AU: Mutz D
AU: Blaydorn L
AU: Tolcher AW
AU: Iddison V
AU: Smith ES
AU: Leonard JE
AU: Zauderer M
TI: Phase 1 study of VX15/2503, an immunomodulatory antibody to Semaphorin 4D that reverses tumor growth in preclinical studies
SO: Cancer immunology research. Conference: AACR special conference: tumor immunology and immunotherapy: a new chapter. United states. Conference start: 20141201. Conference end: 20141204
YR: 2015
VL: 3
NO: 10 Supplement) (no pagination
XR: EMBASE 613267042
PT: Journal: Conference Abstract
KY: adult; animal model; breast cancer; cancer patient; chemotherapy; colon cancer; controlled clinical trial; *controlled study; differentiation; disease model; drug combination; drug therapy; fatigue; female; gene inactivation; human; human tissue; human versus animal comparison; inflammatory cell; major clinical study; membrane; metastasis; murine; nausea; nonhuman; pancreas cancer; phase 1 clinical trial; *preclinical study; regulatory T lymphocyte; response evaluation criteria in solid tumors; solid tumor; solubility; treatment duration; *tumor growth; tumor microenvironment; tumor rejection; *antibody; cyclophosphamide; cytokine; cytotoxic T lymphocyte antigen 4; endogenous compound; gamma glutamyltransferase; plexin; programmed death 1 receptor; *semaphorin; semaphorin 3F
DOI: 10.1158/2326-6074.TUMIMM14-A67
AB: Semaphorin 4D (SEMA4D, CD100) normally functions to regulate the motility and differentiation of multiple cell types, including those of the immune, vascular, and nervous systems. In the setting of cancer, SEMA4D promotes tumor progression and metastasis. SEMA4D and its receptor plexin B1 are broadly expressed in murine and human tumors; expression correlates with invasive disease in several human tumors. SEMA4D is highly expressed on T cells and is also released as a biologically active soluble molecule by activated inflammatory cells. Preclinical studies demonstrate a novel immunomodulatory function of SEMA4D, whereby SEMA4D influences the recruitment and distribution of leukocytes in the tumor microenvironment. Antibody blockade of SEMA4D with the murine progenitor of VX15/2503 regulates the balance and activity of inflammatory and tolerance-inducing cells and cytokines to effectively delay tumor growth and promote durable tumor rejection in syngeneic colon and breast cancer models. Combination of anti-SEMA4D antibody with immune checkpoint inhibitor anti-CTLA-4 enhances anti-tumor immune activity and synergistically increases tumor rejection. Combinations with anti-PD-1 or cyclophosphamide, an immunomodulatory chemotherapy reported to differentially affect regulatory T cells, also increases efficacy and frequency of tumor rejection. Inhibition of SEMA4D represents a novel mechanism and therapeutic strategy to promote immune infiltration and distribution in the tumor microenvironment and inhibit tumor progression. The humanized anti-SEMA4D antibody, VX15/2503, has successfully completed a Phase I multiple ascending dose trial in adult patients with advanced refractory solid tumors. Patients were administered weekly IV doses of VX15/2503 until progression. Dose levels were 0.3 to 20 mg/kg. Tumors were assessed by RECIST 1.1 after each 8 dose cycle. The study has concluded (n=42 Pts); sex 40%M/60%F. Mean age (yrs) 64.8; ECOG 0/1/2 are 28.6%/69%/2.4%. No MTD was found. One DLT (grade 3 GGT elevation; 15 mg/kg) was reported in a pancreatic cancer patient with disease progression. The most frequent treatment-related AE's (n=42 pts) included grade 1/2 nausea (14.3%) and fatigue (11.9%) and 15 unrelated SAE's were reported in 12 patients. Thirteen of 42 pts at all dose levels exhibited stable disease for at least 8 weeks. Patients with the longest duration of treatment, 48-55 weeks, included colorectal (9 mg/kg); breast (15 mg/kg); and papillary thyroid (20 mg/kg) this patient had a partial response by RECIST and stable disease for at least 6 months following cessation of treatment at 48 weeks. VX15/2503 serum concentrations of > 0.3 ug/mL produced complete saturation of membrane SEMA4D on circulating T cells. HAHA responses (titer > 100) with possible effects on PK were observed in 4 of 41 patients (10%); in only 1 patient (2%) was an effect of HAHA on PD observed. VX15/2503 was well tolerated at dose levels up to 20 mg/kg, with 459 doses administered to 42 patients. A phase 1b/2a trial of combination therapy with anti-CTLA-4 is planned.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/560/CN-01250560/frame.html


Record #18 of 144
ID: CN-01333797
AU: Femia D
AU: Prinzi N
AU: Pusceddu S
AU: Concas L
AU: Lo Russo G
AU: Claudio V
AU: Milione M
AU: Dinoi G
AU: Raimondi A
AU: Michele P
AU: Filippo DB
AU: Buzzoni R
TI: Complete response to avelumab in Merkel Cell Carcinoma, and potential correlation with toxicity: a case report
SO: Annals of oncology. Conference: 18th national congress of medical oncology. Italy. Conference start: 20161028. Conference end: 20161030
YR: 2016
VL: 27
NO: no pagination
XR: EMBASE 614511125
PT: Journal: Conference Abstract
KY: adult; cancer size; case report; chemotherapy; clinical trial; controlled clinical trial; controlled study; *developmental toxicity; drug therapy; gene expression; gene inactivation; human; laboratory test; male; *Merkel cell tumor; middle aged; pharmacokinetics; phase 2 clinical trial; *remission; response evaluation criteria in solid tumors; safety; skin metastasis; X-ray computed tomography; *avelumab; blocking antibody; cisplatin; endogenous compound; etoposide; levothyroxine; platinum; programmed death 1 ligand 1; programmed death 1 receptor; thyrotropin
DOI: 10.1093/annonc/mdw345.42
AB: Background: Merkel Cell Carcinoma (MCC) is a rare and aggressive primary cutaneous neuroendocrine cancer linked (in the vast majority of cases) to exposure to the Merkel Polyomavirus (MCPyV). This tumor has high recurrence and mortality rates. Chemotherapy with cisplatin and etoposide may be an effective treatment for metastatic MCC, but responses are often transient, and no trials have established platinum-based therapy as a standard of care. The blockade of the programmed death 1 (PD-1) immune inhibitory pathway by avelumab, an anti-PD-L1 checkpoint inhibitor, is being investigated in a number of solid neoplasms. This strategy can also be of interest in MCC because these tumors often express PD-L1. Methods: A 60-year-old man was referred to our center in August 2015 for advanced MCC with nodes and skin metastases (stage IV), after progression following first line platinum-based chemotherapy. A phase II, open-label, multicenter trial to investigate the clinical activity and safety of avelumab (MSB0010718C, an anti PD-L1 monoclonal antibody) in patients with metastatic MCC was open for enrolment at our institution. The patient was eligible for treatment and entered the study in August 2015. Results: The patient received avelumab 10mg/kg IV every 2 weeks. The first CT scan after 6 weeks of treatment showed a 2-fold increase of the size of the lesion, judged as a pseudoprogression. The patient continued avelumab and the following CT scan (12 weeks) showed complete response by RECIST criteria. During treatment, laboratory test showed an increase of TSH (180 ng/mL) and CPK (1890 ng/mL), which responded to therapy with levothyroxine . The patient remains in the avelumab trial, and he maintains complete response 5 months later. Conclusions: PD-L1 blocking antibodies could be promising therapies in patients with metastatic MCC. While the results of the ongoing clinical trial are awaited in 2016, this case report documents, for the first time to our knowledge, a complete response to avelumab in an MCC patient. This case report also suggests the potential correlation between development of toxicities and response to avelumab; further analysis on this issue may be warranted.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/797/CN-01333797/frame.html


Record #19 of 144
ID: CN-01295308
AU: Antonarakis ES
AU: Drake CG
AU: Wu H
AU: Poehlein C
AU: Bono J
TI: Phase II study of pembrolizumab in patients with metastatic castration-resistant prostate cancer previously treated with targeted endocrine therapy and taxane chemotherapy: kEYNOTE-199
SO: Journal for immunotherapy of cancer. Conference: 31st annual meeting and associated programs of the society for immunotherapy of cancer, SITC 2016. United states. Conference start: 20161109. Conference end: 20161113
YR: 2016
VL: 4
NO: no pagination
XR: EMBASE 613519020
PT: Journal: Conference Abstract
KY: adult; adverse drug reaction; bone metastasis; bone scintiscanning; cancer epidemiology; *castration resistant prostate cancer; *chemotherapy; clinical trial; consensus development; controlled clinical trial; controlled study; disease control; drug therapy; exploratory research; gene expression; histology; *hormonal therapy; human; human tissue; imaging; major clinical study; *male; monotherapy; nomenclature; overall survival; phase 2 clinical trial; progression free survival; prostate adenocarcinoma; response evaluation criteria in solid tumors; safety; screening; side effect; testosterone blood level; young adult; abiraterone; androgen; docetaxel; endogenous compound; enzalutamide; *pembrolizumab; programmed death 1 ligand 1
DOI: 10.1186/s40425-016-0172-7
AB: Background Treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) has focused on suppression of testosterone and androgen receptor signaling, palliative radiation therapy, and chemotherapy. As expression of the programmed death-1 (PD-1) receptor and its ligand PD-L1 is present in mCRPC lesions, particularly after initial treatment with antiandrogen and/or chemotherapy, targeting this pathway may be an attractive treatment option. Pembrolizumab, an anti-PD-1 antibody that blocks interaction between PD-1 and its ligands, PD-L1 and PD-L2, produced durable responses in patients with heavily pretreated PD-L1-positive prostate cancer in the KEYNOTE-028 study. KEYNOTE-199 is a nonrandomized, multinational, open-label phase II study to evaluate pembrolizumab monotherapy in patients with mCRPC previously treated with chemotherapy. Methods Eligible patients must be >18 years old with histologically or cytologically confirmed adenocarcinoma of the prostate without small-cell histology, measurable disease per RECIST v1.1 or detectable bone metastases by whole-body bone scintigraphy and no RECIST v1.1 measurable tumors, supplied tumor sample for PD-L1 expression (new or archived), progression of disease within 6 months before screening, and ECOG performance status 0-2. Patients must have been treated with >1 targeted endocrine therapy (abiraterone or enzalutamide) and <2 chemotherapy regimens, 1 of which must have contained docetaxel. Patients also must have ongoing androgen deprivation with serum testosterone <50 ng/dL. Patients will be enrolled into 1 of 3 cohorts based on PD-L1 status and RECIST v1.1 measurability: patients with PD-L1-positive, RECIST v1.1 measurable disease (cohort 1, n=100), patients with PD-L1-negative, RECIST v1.1 measurable disease (cohort 2, n=100), and patients with bone metastases and RECIST v1.1 nonmeasurable disease (cohort 3, n=50). Patients will receive pembrolizumab 200 mg every 3 weeks until documented confirmed disease progression, unacceptable adverse events (AEs), or illness that prevents further treatment. Imaging response will be assessed every 9 weeks for approximately 1 year and every 12 weeks thereafter, per central imaging vendor review using RECIST v1.1 criteria and the Prostate Cancer Clinical Trials Working Group 3 guidelines. AEs will be monitored throughout the study and graded per Common Terminology Criteria for Adverse Events, version 4.0. Primary end points are the objective response rate and duration of response for cohorts 1 and 2 combined and by each cohort. Key secondary end points include safety and tolerability, disease control rate, radiographic progression-free survival, and overall survival for each cohort and all 3 combined. Exploratory translational analyses and expression of other immune checkpoints will also be evaluated.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/308/CN-01295308/frame.html


Record #20 of 144
ID: CN-01362794
AU: Engert A
AU: Santoro A
AU: Shipp M
AU: Zinzani PL
AU: Timmerman J
AU: Ansell S
AU: Armand P
AU: Fanale M
AU: Ratanatharathorn V
AU: Kuruvilla J
AU: Cohen J
AU: Collins G
AU: Savage K
AU: Trneny M
AU: Kato K
AU: Farsaci B
AU: Parker S
AU: Rodig S
AU: Younes A
TI: Checkmate 205: a phase 2 study of nivolumab in patients with classical hodgkin lymphoma following autologous stem cell transplantation and brentuximab vedotin
SO: Haematologica. Conference: 21st congress of the european hematology association. Denmark
YR: 2016
VL: 101
PG: 319
XR: EMBASE 615559163
PT: Conference Abstract
KY: adult; adverse drug reaction; *autologous stem cell transplantation; Canada; cancer susceptibility; *classical Hodgkin lymphoma; clinical trial; comparative effectiveness; controlled clinical trial; *controlled study; drug therapy; Europe; fatigue; fever; follow up; health status; heart arrhythmia; human; hypersensitivity; hypothyroidism; informed consent; infusion; major clinical study; meningitis; multiple organ failure; patient reported outcome; pharmacokinetics; phase 1 clinical trial; phase 2 clinical trial; pneumonia; positron emission tomography; quality of life; rash; response time; safety; side effect; symptom; thyroiditis; treatment failure; tumor growth; tumor regression; visual analog scale; *brentuximab vedotin; endogenous compound; immunoglobulin G4; *nivolumab; programmed death 1 receptor
AB: Background: Classical Hodgkin lymphoma (cHL) is characterized by Hodgkin Reed-Sternberg cells, which contain genetic aberrations at 9p24.1 leading to overexpression of the programmed death receptor-1 (PD-1) ligands PD-L1 and PD-L2. Thus, cHL may be uniquely sensitive to PD-1 blockade. Nivolumab (Nivo) is a fully human IgG4 immune checkpoint inhibitor antibody targeting PD-1 that showed promising results in a phase 1b study (NCT01592370) in patients (pts) with relapsed/refractory cHL (Ansell SM et al. NEJM 2015;372:311-9) who currently have limited treatment options. Aims: This study, Cohort B of the phase 2 Checkmate 205 study (NCT02181738), evaluated the efficacy and safety of nivo in pts with cHL who had received brentuximab vedotin (BV) after failed autologous stem cell transplantation (ASCT). Methods: Nivo was given at 3 mg/kg IV every 2 weeks (wk). Response was assessed using 2007 IWG criteria, by both an independent radiologic review committee (IRRC) and investigators (Inv). The primary endpoint was IRRCassessed objective response rate (ORR). Quality of life was assessed by EQ- 5D VAS (0-100 scale) and EORTC QLQ-C30. Written informed consent was obtained for all pts. Results of the primary ORR analysis after approximately 6 months (mo) minimum follow-up are reported. Results: Among 80 pts enrolled and treated, the main characteristics included median (range) age, 37 years (18-72) and median (range), 4 prior regimens (3-15). 33 pts enrolled from Europe; 47 were from the US or Canada. At data cut-off (October 2015), 51 pts (64%) remained on therapy. Of 29 pts (36%) who discontinued, the most common reason was disease progression (n=13). Only 4 pts discontinued due to an AE. 90% of pts had drug-related AEs, including 25% Grade 3-4 AEs and 1% Grade 5 (multi-organ failure). The most common drug-related AEs were fatigue (25%), infusion reaction (20%), and rash (16%). The most common serious AEs were pyrexia, tumor progression, arrhythmia, infusion reaction, septic meningitis, and pneumonia (<4% each). Most common immune-mediated AEs were hypothyroidism/thyroiditis (14%), rash (10%), and hypersensitivity (6%). All 6 pts who stopped nivo and received subsequent stem cell transplant were alive at data cut-off. After median (range) follow-up of 8.9 mo (1.9-11.7), IRRC ORR (95% CI) was 66% (54.8%, 76.4%); CR and PR rates were 8.8% (3.6%, 17.2%) and 57.5% (45.9%, 68.5%), respectively. Almost all pts had some degree of tumor regression (Figure). All but one responder had tumor reduction of >50% from baseline; the other had response determined by negative FDG-PET scan. In 43 pts who had no response (SD or PD) to BV, nivo treatment resulted in IRRC ORR of 72% (31/43). Median (range) time to response was 2.1 mo (1.6-5.7). Inv ORR (95% CI) was 73% (61.4%, 81.9%); CR and PR rates were 27.5% (18.1%, 38.6%) and 45.0% (33.8%, 56.5%), respectively. At data cut-off, 62% (33/53) of IRRC responders remained in response. IRRC 6-mo PFS was 77%; OS was 99%. Mean EQ-5D VAS score increased over time, from 62 at baseline to 80 at Wk 33, with a clinically meaningful improvement in health state by Wk 9 (>7-point change). EORTC QLQ-C30 findings suggested a trend towards improvement in functional, symptom, and global health scores. Summary/Conclusions: In pts with cHL who progressed following ASCT and BV, nivo is associated with a high response rate, long-lasting responses, and an acceptable safety profile. PFS and OS are encouraging in this heavily pretreated population. Patient reported outcomes suggest improvement in quality of life while on nivo treatment.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/794/CN-01362794/frame.html


Record #21 of 144
ID: CN-01378454
AU: Wood L
AU: Davies M
AU: Rubin K
AU: Madden K
AU: Brennan L
AU: Dahl N
AU: Walker D
AU: Gagnier P
AU: Li X
AU: Kottschade L
TI: Management of endocrinopathies associated with nivolumab and ipilimumab combination therapy in solid tumors
SO: BJU international. Conference: 15th international kidney cancer symposium. United states
YR: 2016
VL: 118
PG: 29
XR: EMBASE 616030205
PT: Conference Abstract
KY: *adrenal insufficiency; adverse drug reaction; clinical article; clinical trial; controlled clinical trial; controlled study; disease course; drug combination; drug therapy; drug withdrawal; fatigue; female; headache; human; hyperthyroidism; hypophysitis; hypothyroidism; kidney metastasis; male; melanoma; nausea; *non small cell lung cancer; nuclear magnetic resonance imaging; phase 1 clinical trial; phase 2 clinical trial; safety; side effect; symptom; toxicity; endogenous compound; glucocorticoid; *ipilimumab; *nivolumab; thyroid hormone; thyrotropin
DOI: 10.1111/bju.13694
AB: Background: Combination therapy with nivolumab and ipilimumab (N + I) is approved for first- line treatment of advanced melanoma (MEL). Recent phase I studies have shown promising efficacy with N + I in patients with non-small cell lung cancer (NSCLC) and metastatic renal cell carcinoma (RCC). With N + I, select adverse events (ie, immune-related AEs) most commonly affect the skin, gastrointestinal tract, endocrine organs, and liver. Unlike other immune-related AEs, endocrinopathies can persist despite discontinuation or completion of therapy. Here, we review endocrine select AEs associated with N + I in solid tumors and provide practical guidance regarding their management. Methods: Safety data were included from phase II (CheckMate 069) and phase III (CheckMate 067) studies for MEL, and phase I studies for NSCLC (CheckMate 012) and RCC (CheckMate 016). Data are reported for nivolumab 1 mg/kg + ipilimumab 3 mg/kg Q3W x 4 (N1I3) for MEL, nivolumab 3 mg/kg Q2W + ipilimumab 1 mg/kg Q6W (N3I1) for NSCLC, and N3I1 or N1I3 for RCC, followed by nivolumab Q2W. Patients were treated until disease progression, unacceptable toxicity, or withdrawal of consent. Results: In patients with MEL who received N + I combination therapy, ~32% experienced any treatment-related endocrine select AEs, of which 5-6% were grade 3-4 (Table). Endocrine select AEs of any grade occurred in 21% of patients with NSCLC, 28% of patients with RCC who received N3I1, and 43% of patients with RCC who received N1I3. The most common treatment-related endocrine select AEs across tumor types were hypothyroidism, hyperthyroidism, and adrenal insufficiency. No treatment-related grade 5 endocrinopathies were observed with N + I in any study. Median time to onset for endocrine select AEs was 6 weeks in MEL. Only 2-3% of patients discontinued due to treatment-related endocrine select AEs. Some patients (typically those with lower grade AEs) can continue nivolumab if the AEs are related to ipilimumab. Persistent or worsening fatigue, headaches, and nausea are common symptoms, and may be associated with hypophysitis. Baseline labs (including thyroid- stimulating hormone) should be performed. MRI with pituitary cut can be used to evaluate potential immunemediated hypophysitis. Patients with thyroid dysfunction need symptomatic management and thyroid hormone replacement, and those with adrenal insufficiency may require long-term glucocorticoid replacement. Conclusions: Endocrine select AEs are manageable with established treatment algorithms. Given the unique nature of endocrine AEs, early identification is critical and a multidisciplinary team approach is required to effectively manage these patients.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/454/CN-01378454/frame.html


Record #22 of 144
ID: CN-01250555
AU: Bajor DL
AU: Mick R
AU: Riese MJ
AU: Lee RP
AU: Xu X
AU: Torigian DA
AU: Stelekati E
AU: Sweeney M
AU: Sullivan BJ
AU: Schuchter LM
AU: Amaravadi R
AU: Wherry EJ
AU: Vonderheide RH
TI: Phase I study of combination immunotherapy with agonistic CD40 monoclonal antibody (mAb) CP-870,893 (aCD40) and anti-CTLA-4 antibody tremelimumab (treme) in patients with metastatic melanoma
SO: Cancer immunology research. Conference: AACR special conference: tumor immunology and immunotherapy: a new chapter. United states. Conference start: 20141201. Conference end: 20141204
YR: 2015
VL: 3
NO: 10 Supplement) (no pagination
XR: EMBASE 613267170
PT: Journal: Conference Abstract
KY: adverse drug reaction; antineoplastic activity; CD8 T lymphocyte; chemotherapy; chill; clinical article; clinical trial; colitis; controlled clinical trial; *controlled study; cytokine release syndrome; disease duration; disease free survival; drug combination; drug therapy; fever; follow up; human; human cell; hypophysitis; *immunotherapy; infusion; maximum tolerated dose; metastasis; *metastatic melanoma; nomenclature; overall survival; peripheral lymphocyte; phase 1 clinical trial; phenotype; progression free survival; remission; response evaluation criteria in solid tumors; side effect; Student t test; symptom; systemic juvenile idiopathic arthritis; toxicity; uveitis; antihistaminic agent; antipyretic agent; biological marker; *CD40 antigen; *cp 870893; cytotoxic T lymphocyte antigen 4; *cytotoxic T lymphocyte antigen 4 antibody; endogenous compound; eomesodermin; programmed death 1 receptor; *ticilimumab
DOI: 10.1158/2326-6074.TUMIMM14-A38
AB: Purpose: Combining therapeutic activation of immune cells and checkpoint inhibition may improve response rates and overall survival in patients with metastatic melanoma. CP-870,893 (aCD40) is an agonistic fully human IgG2 mAb targeting the immune stimulatory molecule CD40. Treme is a fully human IgG2 mAb targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA4), a negative co-stimulatory molecule found on T cells. Methods: Patients with histologically confirmed metastatic melanoma, measurable disease by RECIST 1.0, and no history of autoimmune diseases or previous treatments targeting CD40 or CTLA-4 were enrolled on a single-arm open-label dose escalation phase 1 study. aCD40 and treme were dosed i.v. every 3 weeks and 12 weeks, respectively , for a potential total of 16 doses of aCD40 and 4 doses of treme. Dose escalation followed a 3 + 3 strategy with alternating increases of aCD40 (range 0.1-0.2 mg/kg) and treme (range 6-15 mg/kg) in each cohort. Patient outcomes were scored using the Common Terminology Criteria for Adverse Events v3.0. Flow cytometric analysis of baseline blood samples was compared to samples obtained at least 3 weeks after the last dose of aCD40 and treme. Results were compared by paired t test. Results: Toxicity: Twenty-four patients were enrolled and treated at 4 different dose levels. Two patients were replaced per protocol due to rapid, symptomatic progression of disease; these patients were not evaluated for response but were included in toxicity analysis. Patients had received a median of 1 (range 0-5) prior treatments for metastatic disease prior to enrollment. Dose-limiting toxicities (DLT), considered to be likely due to treatment, were colitis (n=1) and hypophysitis (n=1) at 0.2mg/kg aCD40 and 15mg/kg treme and uveitis (n=1) at 0.2mg/kg aCD40 and 10mg/kg treme. Cytokine release syndrome (CRS), grade 1-2, occurring within 24 hours of CP administration, was the most common treatment-related toxicity occurring in 19 (79.2%) patients and typically involving chills and fever. CRS symptoms were controlled with standard supportive care in the chemotherapy infusion suite and with instructed use of antipyretics and antihistamines at home. All episodes of CRS resolved within 24 hours of aCD40 administration. The estimated maximum tolerated dose was 0.2 mg/kg of aCD40 and 10 mg/kg of treme. Outcomes: Overall objective response rate was 27.3% (best response): two patients (9.1%) had complete responses to treatment and four (18.2%) patients had partial responses. The median follow-up was 22 months with a median progression free survival of 2.5 months (95% CI: 2.0-3.1 months) and a median overall survival (OS) of 26.1 months (95% CI: 13.1-39.1 months). Two patients remain disease free for more than 18 months after study completion without further medical treatment. Correlative studies: Flow cytometric analysis of peripheral blood lymphocytes revealed changes in CD8+ T cell phenotypes. Double positive granzyme B+ and Ki-67+ cells increased from 0.56 +/- 0.17% (mean +/- standard error) for all CD8+ T cells at baseline to 1.01 +/- 0.23% post-treatment (p=0.03). CD8+ T cells expressing both programmed cell death 1 and eomesodermin were also higher after treatment, increasing from 7.7 +/- 1.1% to 10.4 +/-1.8% (p= 0.04) of all CD8+ T cells. Conclusion: Combination therapy with aCD40 and treme was well-tolerated in patients with metastatic melanoma, with rates of CRS and other toxicity similar to previously reported rates for aCD40 or treme treatments alone. Overall objective response rate was 27.3%, with median OS of 26.1 months including two patients still disease-free. This antitumor activity, and biomarker evidence of immune activation, provides a rationale for expanded study.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/555/CN-01250555/frame.html


Record #23 of 144
ID: CN-01394037
AU: Long GV
AU: Atkinson V
AU: Cebon JS
AU: Jameson MB
AU: Fitzharris BM
AU: McNeil CM
AU: Hill AG
AU: Ribas A
AU: Atkins MB
AU: Thompson JA
AU: Hwu W-J
AU: Hodi FS
AU: Menzies AM
AU: Guminski AD
AU: Kefford R
AU: Kong BY
AU: Tamjid B
AU: Srivastava A
AU: Lomax AJ
AU: Islam M
AU: Shu X
AU: Ebbinghaus S
AU: Ibrahim N
AU: Carlino MS
TI: Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial
SO: Lancet oncology
YR: 2017
VL: (no pagination)
XR: EMBASE 617398898
PT: Article In Press
KY: adult; adverse drug reaction; antineoplastic activity; Australia; autoimmune disease; brain metastasis; clinical trial; controlled clinical trial; controlled study; death; diabetes mellitus; drug combination; drug therapy; drug withdrawal; *female; follow up; funding; human; hyperthyroidism; hypothyroidism; major clinical study; *male; *melanoma; monotherapy; multicenter study; New Zealand; oncology; organ; overall survival; patient history of chemotherapy; pharmacokinetics; pneumonia; progression free survival; randomized controlled trial; response evaluation criteria in solid tumors; safety; side effect; toxicity; young adult; immunosuppressive agent; *ipilimumab; *pembrolizumab; steroid
DOI: 10.1016/S1470-2045%2817%2930428-X
AB: Background: Reduced-dose nivolumab in combination with standard-dose ipilimumab improves objective response and progression-free survival compared with standard-dose ipilimumab alone, but increases toxicity. We assessed the safety and anti-tumour activity of standard-dose pembrolizumab in combination with reduced-dose ipilimumab. Methods: In this open-label, phase 1b trial, we recruited patients from 12 medical centres in Australia, New Zealand, and the USA. Eligible patients were aged at least 18 years, had advanced melanoma, had an Eastern Coooperative Oncology Group performance status of 0 or 1, had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, had adequate organ function, had resolution of toxic effects of the most recent previous chemotherapy to grade 1 or less, had no active autoimmune disease requiring systemic steroids or immunosuppressive agents, had no active non-infectious pneumonitis, had no uncontrolled thyroid dysfunction or diabetes, had no active brain metastases, and had not received previous immune checkpoint inhibitor therapy. Patients received intravenous pembrolizumab 2 mg/kg plus intravenous ipilimumab 1 mg/kg every 3 weeks for four doses, followed by intravenous pembrolizumab 2 mg/kg every 3 weeks for up to 2 years or disease progression, intolerable toxicity, withdrawal of consent, or investigator decision. The primary endpoint was safety and tolerability. The proportion of patients achieving an objective response assessed per RECIST version 1.1 by independent central review and overall survival were secondary endpoints. We also assessed progression-free survival. The primary endpoint was assessed in all patients who received at least one dose of combination therapy. Activity was assessed in all enrolled patients. This trial is registered with ClinicalTrials.gov, number NCT02089685. Enrolment into this cohort is closed, but patients are still being monitored for safety and anti-tumour activity. Findings: Between Jan 13, 2015, and Sept 17, 2015, we enrolled and treated 153 patients. As of the Oct 17, 2016, cutoff date, median follow-up was 17.0 months (IQR 14.8-18.8). 110 (72%) of 153 patients received all four pembrolizumab plus ipilimumab doses; 64 (42%) remained on pembrolizumab monotherapy. 110 grade 3-4 treatment-related adverse events occurred in 69 (45%) patients. No treatment-related deaths occurred. Treatment-related adverse events led to discontinuation of pembrolizumab and ipilimumab in 22 (14%) patients, including 17 (11%) who discontinued both treatments for the same event and five (3%) who discontinued ipilimumab for one event and later discontinued pembrolizumab for another. 12 (8%) patients discontinued ipilimumab only and 14 (9%) discontinued pembrolizumab only because of treatment-related adverse events. 158 immune-mediated adverse events of any grade occurred in 92 (60%) patients, and 50 immune-mediated adverse events of grade 3-4 occurred in 42 (27%) patients; the most common immune-mediated adverse events were hypothyroidism (25 [16%]) and hyperthyroidism (17 [11%]). 93 (61% [95% CI 53-69]) patients achieved an objective response. Estimated 1 year progression-free survival was 69% (95% CI 60-75), and estimated 1 year overall survival was 89% (95% CI 83-93). Interpretation: Standard-dose pembrolizumab given in combination with four doses of reduced-dose ipilimumab followed by standard-dose pembrolizumab has a manageable toxicity profile and provides robust anti-tumour activity in patients with advanced melanoma. These data suggest that standard-dose pembrolizumab plus reduced-dose ipilimumab might be a tolerable, efficacious treatment option for patients with advanced melanoma. A randomised phase 2 trial of alternative dosing strategies of this combination is underway. Funding: Merck & Co, Inc. Copyright © 2017 Elsevier Ltd.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/037/CN-01394037/frame.html


Record #24 of 144
ID: CN-01335151
AU: Falchi L
AU: Sawas A
AU: Deng C
AU: Amengual JE
AU: Lichtenstein E
AU: Khan K
AU: Schwartz LH
AU: O'Connor OA
TI: PD-1 blockade after epigenetic therapy in patients with relapsed or refractory hodgkin lymphoma: higher-than-expected rate of complete responses
SO: Blood. Conference: 58th annual meeting of the american society of hematology, ASH 2016. United states. Conference start: 20161203. Conference end: 20161206
YR: 2016
VL: 128
NO: 22) (no pagination
XR: EMBASE 614247475
PT: Journal: Conference Abstract
KY: acute kidney failure; acute myeloid leukemia; adult; autologous stem cell transplantation; cellular immunity; clinical article; clinical trial; controlled clinical trial; controlled study; diarrhea; DNA transcription; drug therapy; drug toxicity; *epigenetics; exposure; fatigue; follow up; gene expression; *Hodgkin disease; human; human cell; infusion; myelodysplastic syndrome; ovarian cancer cell line; phase 1 clinical trial; positron emission tomography; progression free survival; *remission; respiratory failure; thrombocytopenia; transcription initiation; tumor cell; tumor volume; writing; azacitidine; brentuximab vedotin; endogenous compound; nivolumab; pembrolizumab; *programmed death 1 receptor; thyrotropin
AB: Background: Patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) after brentuximab vedotin (Bv) and autologous stem cell transplantation (ASCT) represent an unmet medical need. Allogeneic SCT can be curative, but is burdened with significant morbidity and mortality. Nivolumab and pembrolizumab are anti-programmed death (PD)-1 monoclonal antibodies and are referred to as immune checkpoint inhibitors (ICI). These agents have shown remarkable activity in patients with R/R cHL, but rarely induce complete response (CR). Studies on ovarian cancer cell lines have shown that exposure of tumor cells to the hypomethylating agent (HMA) 5-azacitidine, may induce transcription of latent endogenous retroviral genes, which then trigger a T-cell-mediated immune response. Therefore, HMA can act as "immunologic primers" and enhance the efficacy of ICI. We reviewed our experience with ICI in patients with R/R cHL, and compared responses between those who had been previously exposed to 5-azacitidine to those who had not. Methods: Twelve patients with R/R cHL received pembrolizumab at the dose of 2 mg/kg every 3 weeks (N = 9), or nivolumab at the dose of 3 mg/kg every 2 weeks (N = 3). Response was assessed by positron emission tomography/computerized tomography. For patients who were transplant candidate, ICI were used as a bridge to the procedure. Results: The patient median age was 35 years [range 25-79]. The median number of prior treatments was 11 [range 3-16] and 75% of patients had had > 7 lines of therapy. All patients had received ASCT and Bv. Six had been exposed to 5-azacitidine for a median of 2.5 months [range 2-16] as part of a phase 1 study (NCT01998035). Four of them had received it immediately prior to ICI, the other two within 14 months of starting ICI. A total of 141 patientcourses were completed, with a median of 7 courses per patient [range 1-39]. There were 6 grade > 3 adverse events (AE): infusion reaction (N = 1), thrombocytopenia (N = 1), grade-5 respiratory failure (N = 1), myelodysplastic syndrome, (N = 2, one of which pre-existent, both evolved into fatal acute myeloid leukemia (AML)), and acute kidney injury (N = 1, pre-existent). Grade 1-2 AE included infusion reaction (5), elevated thyroid stimulating hormone levels (3), diarrhea (2), fatigue (1). Ten patients are evaluable for response: 7 (70%) achieved CR, one partial response, one a reduction of tumor burden and one stable disease. Five of the 6 patients who received 5-azacitidine prior to ICI achieved CR, while only 2 of 4 who did not receive prior 5-azacitidine achieved CR. One patient's evaluation is pending at this time. At a median followup of 14.2 months [range 0.5-17.7], 9 patients are alive and 7 are still receiving treatment. Two patients with radiographic progression continue to be treated given sustained clinical benefit. One patient transitioned to allogeneic SCT while in complete remission and one discontinued due to symptomatic progression. The median progression-free survival has not been reached as of this writing (7.9+ months). Conclusions: We report the largest cohort of patients treated with ICI after being exposed to HMA. In these patients with very heavily pretreated cHL we observed a higher-than-expected CRR. Most serious AE were not related to ICI therapy. The finding that most CR clustered in patients previously exposed to 5-azacitidine may reflect synergism between HMA and ICI and support the notion of HMA-mediated "immunologic priming". This hypothesis is being tested in prospective clinical trials at our institution.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/151/CN-01335151/frame.html


Record #25 of 144
ID: CN-01077270
AU: Albarel F
AU: Gaudy C
AU: Castinetti F
AU: Carré T
AU: Morange I
AU: Conte-Devolx B
AU: Grob JJ
AU: Brue T
TI: Long-term follow-up of ipilimumab-induced hypophysitis, a common adverse event of the anti-CTLA-4 antibody in melanoma
SO: European journal of endocrinology
YR: 2015
VL: 172
NO: 2
PG: 195-204
PM: PUBMED 25416723
XR: EMBASE 2015737095
PT: Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't
KY: Antibodies, Monoclonal [adverse effects];CTLA-4 Antigen [blood];Double-Blind Method;Follow-Up Studies;Ipilimumab;Melanoma [blood] [drug therapy];Pituitary Diseases [blood] [chemically induced] [diagnosis];Skin Neoplasms [blood] [drug therapy];Time Factors;Adult[checkword];Aged[checkword];Female[checkword];Humans[checkword];Male[checkword];Middle Aged[checkword];adult; *adverse outcome; article; asthenia; clinical evaluation; clinical feature; controlled study; corticotroph deficiency; corticotroph deficiency/dt [Drug Therapy]; diarrhea/si [Side Effect]; disease severity; drug withdrawal; enterocolitis/si [Side Effect]; female; follow up; gonadotroph deficiency; headache; hepatitis/si [Side Effect]; hormone deficiency/dt [Drug Therapy]; human; hyperprolactinemia; *hypophysitis/si [Side Effect]; image analysis; kidney failure/si [Side Effect]; libido disorder; major clinical study; male; *melanoma/dt [Drug Therapy]; outcome assessment; rash/si [Side Effect]; symptom; thyrotroph deficiency; weakness; glucocorticoid/dt [Drug Therapy]; *ipilimumab/ae [Adverse Drug Reaction]; *ipilimumab/cm [Drug Comparison]; *ipilimumab/dt [Drug Therapy]; placebo
DOI: 10.1530/EJE-14-0845
AB: DESIGN AND PATIENTS: Fifteen patients, treated for malignant melanoma and who presented ipilimumab-induced hypophysitis, were observed between June 2006 and August 2012 in Timone Hospital, Marseille.METHODS: Symptoms, pituitary function, and pituitary imaging at diagnosis of hypophysitis and during the follow-up were recorded.RESULTS: Of 131 patients treated with ipilimumab or a placebo, 15 patients (10 mg/kg in 11/15) presented with hypophysitis (≥11.5%) at 9.5±5.9 weeks (mean±s.d.) after treatment start, occurring in 66% after the third infusion. The main initial symptoms were headache (n=13) and asthenia (n=11). All patients but one had at least one hormonal defect: thyrotroph (n=13), gonadotroph (n=12), or corticotroph (n=11) deficiencies. None had diabetes insipidus. Pituitary imaging showed a moderately enlarged gland in 12 patients. Clinical symptoms improved rapidly on high-dose glucocorticoids (n=11) or physiological replacement doses (n=4). At the end of follow-up (median 33.6 months, range 7-53.5), corticotroph deficiency remained in 13 patients, 11 recovered thyrotroph and ten gonadotroph functions. Pituitary imaging remained abnormal in 11 patients.CONCLUSION: Ipilimumab-induced hypophysitis is a common side-effect with frequent hormonal deficiencies at diagnosis. Usually, hormonal deficiencies improved, except for corticotroph function. Patients receiving these immunomodulatory therapies should be closely monitored especially by systematic baseline hormone measurements after the third infusion and remain at a risk of adrenal insufficiency in the long-term.OBJECTIVE: Few data are published on the long-term follow-up of ipilimumab-induced hypophysitis, a cytotoxic T-lymphocyte antigen 4 antibody. We characterized hypophysitis in terms of clinical signs, endocrinological profile, and imaging at diagnosis and during a long-term follow-up.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/270/CN-01077270/frame.html


Record #26 of 144
ID: CN-01295361
AU: Haymaker C
AU: Uemura M
AU: Murthy R
AU: James M
AU: Wang D
AU: Brevard J
AU: Monaghan C
AU: Swann S
AU: Geib J
AU: Cornfeld M
AU: Chunduru S
AU: Agrawal S
AU: Yee C
AU: Wargo J
AU: Patel SP
AU: Amaria R
AU: Tawbi H
AU: Glitza I
AU: Woodman S
AU: Hwu W-J
AU: Davies MA
AU: Hwu P
AU: Overwijk WW
AU: Bernatchez C
AU: Diab A
TI: Reactivating the anti-tumor immune response by targeting innate and adaptive immunity in a phase I/II study of intratumoral IMO-2125 in combination with systemic ipilimumab in patients with anti-PD-1 refractory metastatic melanoma
SO: Journal for immunotherapy of cancer. Conference: 31st annual meeting and associated programs of the society for immunotherapy of cancer, SITC 2016. United states. Conference start: 20161109. Conference end: 20161113
YR: 2016
VL: 4
NO: no pagination
XR: EMBASE 613518679
PT: Journal: Conference Abstract
KY: *adaptive immunity; adult; adverse drug reaction; antineoplastic activity; CD8 T lymphocyte; clinical trial; controlled clinical trial; *controlled study; drug combination; fever; gene expression; human; human tissue; hypophysitis; *innate immunity; intratumoral drug administration; major clinical study; maturation; *metastatic melanoma; myeloid dendritic cell; pharmacokinetics; phase 1 clinical trial; phase 2 clinical trial; probability; safety; side effect; T lymphocyte activation; toxicity; tumor biopsy; *tumor resistance; upregulation; B Raf kinase; biological marker; CD4 antigen; endogenous compound; gamma interferon; HLA DR antigen; *ipilimumab; Ki 67 antigen; *programmed death 1 receptor
DOI: 10.1186/s40425-016-0172-7
AB: Background While checkpoint inhibitor (CPI) therapy has transformed metastatic melanoma (MM) treatment, many patients remain refractory. We reasoned that combining CPI with an agent that activates antigen presenting cells and improves T cell priming may result in improved response. Our approach is to modulate the tumor microenvironment through intratumoral (i.t.) injection of the TLR9 agonist, IMO-2125, in combination with ipilimumab (ipi). We hypothesize that this will result in dendritic cell (DC) activation and induction of tumor-specific CD8<sup>+</sup>T cells which will synergize with ipilimumab to overcome immune-escape. Based on this rationale we initiated a phase I/II clinical trial. Methods Adults with refractory MM despite up to 2 lines of CPI including PD-1 blockade therapy (with or without a BRAF inhibitor) are eligible. IMO-2125, in doses escalating from 4mg to 32mg, is given i.t. weeks 1, 2, 3, 5, 8, and 11 along with ipilimumab i.v 3 mg/kg weeks 2, 5, 8, and 11. Dose-limiting toxicity (DLT) i evaluated using a modified Toxicity Probability Interval design Primary endpoints are safety, tumor response, and PK. Blood and injected and distal tumor biopsies are obtained pre- and on-treatment. Immune analyses include DC subsets and their ac tivation status as well as T cell activation, function and prolifer ation. T cell repertoire diversity will be evaluated by high throughput CDR3 sequencing. Results As of August 2, 2016, 11 pts have been enrolled. DLT has no been observed. Grade 3 hypophysitis (2 subjects) is the onl immune-related AE observed to date. No other drug-related grade 3-5 AEs were documented and only 1 subject experi enced a grade 2 fever. Five patients are evaluable for response - 2 PR, 2SD, 1PD per investigator assessment. Fresh tumor biop sies show maturation (upregulation of HLA-DR) of the myeloid DC1 subset (CD1c<sup>+</sup>CD303<sup>-</sup>) in the IMO-2125 injected tumor le sion 24 hrs post-treatment compared to pre-treatment biopsy On-treatment biopsy results are consistent with a higher rate o proliferative (Ki67) effector CD4+ and CD8+ T cells in re sponders. Cytokine analysis shows a 2-3 fold increase in circu lating IFNgamma levels compared to pretreatment in responders. Conclusions Though preliminary, these results demonstrate that the combination of ipi and IMO-2125 is well tolerated with encouraging preliminar activity in a PD-1 refractory population. Dose escalation is ongoing and a phase II expansion will include IMO-2125 in combination with both ipi and anti-PD-1. Updated safety, antitumor activity, and biomarker data will be presented.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/361/CN-01295361/frame.html


Record #27 of 144
ID: CN-01365002
AU: El-Khoueiry AB
AU: Sangro B
AU: Yau T
AU: Crocenzi TS
AU: Kudo M
AU: Hsu C
AU: Kim T-Y
AU: Choo S-P
AU: Trojan J
AU: Welling TH
AU: Meyer T
AU: Kang Y-K
AU: Yeo W
AU: Chopra A
AU: Anderson J
AU: dela Cruz C
AU: Lang L
AU: Neely J
AU: Tang H
AU: Dastani HB
AU: Melero I
TI: Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial
SO: Lancet
YR: 2017
VL: (no pagination)
XR: EMBASE 615612852
PT: Article In Press
KY: adrenal insufficiency; adult; adverse drug reaction; antiviral therapy; Canada; cancer epidemiology; Child Pugh score; chronic hepatitis B; clinical trial; controlled clinical trial; controlled study; disease course; drug therapy; follow up; funding; Germany; hepatitis C; Hong Kong; human; human versus animal comparison; Italy; Japan; *liver cell carcinoma; major clinical study; maximum tolerated dose; nonhuman; oncology; pemphigoid; pharmacokinetics; phase 1 clinical trial; phase 2 clinical trial; response evaluation criteria in solid tumors; safety; screening; side effect; Singapore; South Korea; Spain; T lymphocyte activation; Taiwan; virus load; endogenous compound; *nivolumab; programmed death 1 receptor; sorafenib
DOI: 10.1016/S0140-6736%2817%2931046-2
AB: Background: For patients with advanced hepatocellular carcinoma, sorafenib is the only approved drug worldwide, and outcomes remain poor. We aimed to assess the safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis. Methods: We did a phase 1/2, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab in adults (>18 years) with histologically confirmed advanced hepatocellular carcinoma with or without hepatitis C or B (HCV or HBV) infection. Previous sorafenib treatment was allowed. A dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39 sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan). At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group performance status of 1 or less. Patients with HBV infection had to be receiving effective antiviral therapy (viral load <100 IU/mL); antiviral therapy was not required for patients with HCV infection. We excluded patients previously treated with an agent targeting T-cell costimulation or checkpoint pathways. Patients received intravenous nivolumab 0.1-10 mg/kg every 2 weeks in the dose-escalation phase (3+3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase to patients in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected. Primary endpoints were safety and tolerability for the escalation phase and objective response rate (Response Evaluation Criteria In Solid Tumors version 1.1) for the expansion phase. This study is registered with ClinicalTrials.gov, number NCT01658878. Findings: Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15-26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6-28) in the dose-escalation phase. Interpretation: Nivolumab had a manageable safety profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma. Funding: Bristol-Myers Squibb. Copyright © 2017 Elsevier Ltd.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/002/CN-01365002/frame.html


Record #28 of 144
ID: CN-01397871
AU: Mayadev J
AU: Brady WE
AU: Lin YG
AU: Silva DM
AU: Lankes HA
AU: Fracasso PM
AU: Ghamande SA
AU: Moore KN
AU: Pham HQ
AU: Wilkinson KJ
AU: Kennedy VA
AU: Aghajanian C
AU: Koh W-J
AU: Monk BJ
AU: Schilder RJ
TI: A phase I study of sequential ipilimumab in the definitive treatment of node positive cervical cancer: GOG 9929
SO: Journal of clinical oncology. Conference: 2017 annual meeting of the american society of clinical oncology, ASCO. United states
YR: 2017
VL: 35
NO: 15 Supplement 1) (no pagination
XR: EMBASE 617434693
PT: Conference Abstract
KY: acute toxicity; cell level; chemoradiotherapy; clinical article; clinical trial; controlled clinical trial; *controlled study; disease free survival; distress syndrome; drug therapy; drug toxicity; endocrine disease; female; follow up; gene expression regulation; human; immunomodulation; maximum tolerated dose; paraaortic lymph node; pelvis lymph node; pharmacokinetics; phase 1 clinical trial; prognosis; radiation; radioimmunotherapy; radiotherapy; rash; safety; T lymphocyte; *uterine cervix cancer; adjuvant; CD4 antigen; CD8 antigen; cisplatin; cytotoxic T lymphocyte antigen 4; endogenous compound; inducible T cell costimulator; *ipilimumab; programmed death 1 receptor; triacylglycerol lipase
AB: Background: The outcome of lymph node positive (LN) cervical cancer (CC) with chemoradiation (CRT) is dismal, especially with involved para-aortic nodes (PAN). The anti-CTLA-4 immune checkpoint inhibitor ipilimumab (ipi) holds promise. We report the safety, tolerability, and efficacy in this GOG phase I study examining sequential ipi after CRT for CC. Methods: Patients (pts) with LN CC were treated with 6 weekly doses of cisplatin (40 mg/m<sup>2</sup>) and extended field radiation (RT). 2-6 weeks after RT, if there was no progression of disease, sequential ipi was given at the following dose levels: dose level 1: 3mg/kg, level 2: 10mg/kg, and an expansion cohort of 10mg/kg. The primary endpoints (endpts) were the maximum tolerated dose (MTD), and dose-limiting toxicities (DLT) of adjuvant ipi. Secondary endpt included the 1-yr disease free survival (DFS). Translational endpts included the effect of CRT on enumeration and subsets of T-cells, and CTLA4, PD-1 and ICOS expression. Results: 34 pts were enrolled, and 19 pts are evaluable for the endpts: 14 pts went off study to reasons unrelated to the study drug, 1 pt continues in her DLT evaluable period. Of the evaluable pts, all had pelvic LN, with 25% PAN. All pts completed CRT, 90% had 4 cycles of ipi, and the other 10% had 2 cycles of ipi. The ipi MTD was 10 mg/kg. There were 3 pts (16%) with acute grade 3 toxicity (lipase, ANC, rash) which self-resolved. Most of the acute toxicities were grade 1-2 GI distress, rash, endocrinopathies. There were no minor or major RT quality deviations. With a median follow up of 12 months, there were no major late toxicities reported, with a 1-year DFS of 74%. There was no difference in CD4 - and CD8 - T cell levels nor CTLA-4 expression with sequential ipi. CRT itself increased ICOS and PD-1 expression. Conclusions: This study is the first to describe the safety of immunotherapy sequencing with definitive CRT in CC. Our data suggests that immunotherapy is tolerable and shows possible activity in this population with a historical dismal prognosis with standard therapy. CRT increased ICOS and PD-1 expression which was sustained with ipi, illustrative of immune modulation targets for future clinical trials and radioimmunotherapy combinations.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/871/CN-01397871/frame.html


Record #29 of 144
ID: CN-01399125
AU: Garcia-Manero G
AU: Daver N
AU: Montalban-Bravo G
AU: Jabbour E
AU: Nardo C
AU: Kornblau S
AU: Bose P
AU: Alvarado Y
AU: Ohanian M
AU: Borthakur G
AU: Cortes J
AU: Naqvi K
AU: Pemmaraju N
AU: Huang X
AU: Nogueras-Gonzalez G
AU: Bueso-Ramos C
AU: Gasior Y
AU: Bayer V
AU: Pierce S
AU: Yang H
AU: Colla S
AU: Kantarjian H
TI: An update of a phase II study of nivolumab (Nivo) or ipilimumab (IPI) with azacitidine in PTS with previously treated or untreated myelodysplastic syndromes (MDS)
SO: Haematologica. Conference: 22th congress of the european hematology association. Spain
YR: 2017
VL: 102
PG: 183
XR: EMBASE 617380072
PT: Conference Abstract
KY: adrenal insufficiency; adult; aged; biological activity; brain hemorrhage; clinical trial; colitis; controlled clinical trial; controlled study; differentiation; drug combination; drug therapy; *female; gene expression; human; major clinical study; *male; monotherapy; mortality; *myelodysplastic syndrome; nephritis; pharmacokinetics; phase 2 clinical trial; pneumonia; rash; safety; stem cell; study design; thyroiditis; toxicity; *azacitidine; endogenous compound; *ipilimumab; *nivolumab; programmed death 1 ligand 1; programmed death 1 receptor
AB: Background: Outcomes of pts with MDS after hypomethylating agent (HMA) failure remain poor. Upregulation of PD-1, PD-L1 and CTLA-4 in MDS CD34<sup>+</sup> cells after exposure and loss of response to HMA have been reported. Nivo and Ipi are monoclonal antibodies targeting PD-1 and CTLA-4, respectively, with clinical activity in solid tumors. Aims: To evaluate the potential activity of immune checkpoint antibodies in patients with previously treated or untreated MDS. Methods: We designed a phase II study of Nivo or Ipi in monotherapy or combination for pts with MDS. Pts with prior therapy with HMA were to be treated in one of 3 consecutive cohorts: cohort #1: Nivo 3mg/kg iv days 1 and 15 of a 28 day cycle; cohort #2: Ipi 3mg/kg iv on day 1 of a 21 day cycle; cohort #3: Nivo 3mg/kg iv on days 1 and 15 + Ipi 3mg/kg iv on day 1 of a 28 day cycle. The study design allowed for AZA add-back after 6 cycles of therapy if there was no response or progression. Pts with previously untreated MDS were to be treated in one of 3 consecutive cohorts combining AZA 75mg/m<sup>2</sup> iv daily days 1-5 of a 28 day cycle with: cohort #4: Nivo 3mg/kg iv Days 6 and 20; cohort #5: Ipi 3mg/kg iv on day 6; and cohort #6: Nivo 3mg/kg iv on days 6 and 20 + Ipi 3mg/kg iv on day 6. The maximum size per cohort is 20 pts. The primary endpoint is to determine the safety of Nivo or Ipi as single agents or in combination with AZA. Secondary objectives included overall response rate (ORR) and assessment of biological activity. Responses were evaluated following the revised 2006 IWG criteria. The study included stopping rules for response and toxicity. Results: A total of 63 pts have been enrolled, 54 (86%) are evaluable for response and toxicity including 21 treated with frontline AZA+Nivo, and 15 and 18 with Nivo or Ipi after HMA failure, respectively Median age is 69 years (range 39-85). The median number of treatment cycles was 3 (range 1-11). A total of 3 (27%) pts in the AZA+Nivo cohort, 6 (40%) in the Nivo cohort, and 3 (33%) in the Ipi cohort having related grade >=3 non-hematologic AEs. Therefore, the stopping rule for toxicity was not met in any of the cohorts. Delays of therapy due to AEs were required in 9 pts due to: rash (N=1), adrenal insufficiency (N=1), colitis (N=1), thyroiditis (N=2), pneumonitis (N=3), and nephritis (N=1). Early 8-week mortality occurred in 1 patient due to a non-related intracranial hemorrhage. The ORR was 80% (13/21) in the AZA+Nivo cohort including 6 CR. The ORR was 0% and 30% (5/18) in the Nivo and Ipi arms, respectively. Therefore, the stopping rule for response was met on the Nivo arm, and enrollment after patient 15 was stopped. Immunophenotypic analysis of stem cell and progenitor compartments was performed in 27 pts, including PD-1 and PD-L1 expression analysis in 16 pts. Increased PD-1 and PD-L1 expression on progenitor and stem cell compartments was observed in 3 and 4 pts, respectively. Treatment with PD-1 inhibitors could not overcome the aberrant differentiation patterns. No differences in response were observed based on PD-1 bone marrow expression. Summary/Conclusions: Preliminary results indicate that PD-1 blockade with Nivo in combination with AZA in untreated higher-risk MDS pts is associated with a tolerable safety profile and clinical activity. Single-agent Ipi is capable of inducing responses in previously treated MDS pts. Single-agent Nivo did not show clinical activity.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/125/CN-01399125/frame.html


Record #30 of 144
ID: CN-01397684
AU: Spira AI
AU: Middleton MR
AU: Naing A
AU: Autio KA
AU: Nemunaitis JJ
AU: Bendell JC
AU: Gordon M
AU: Humphrey RW
AU: Wong C
AU: Rizvi NA
TI: PROCLAIM-001: a first-in-human trial to assess tolerability of the proteaseactivatable anti-PD-L1 Probody CX-072 in solid tumors and lymphomas
SO: Journal of clinical oncology. Conference: 2017 annual meeting of the american society of clinical oncology, ASCO. United states
YR: 2017
VL: 35
NO: 15 Supplement 1) (no pagination
XR: EMBASE 617435105
PT: Conference Abstract
KY: adverse drug reaction; antineoplastic activity; autoimmune disease; blood; cancer susceptibility; clinical trial; controlled clinical trial; controlled study; disease course; drug combination; drug therapy; exploratory research; human; infection; *lymphoma; male; *melanoma; monotherapy; phase 1 clinical trial; phase 2 clinical trial; preclinical study; side effect; toxicity; tumor resistance; B Raf kinase; endogenous compound; ipilimumab; mitogen activated protein kinase kinase inhibitor; *programmed death 1 ligand 1; proteinase; vemurafenib
AB: Background: CX-072 is a novel Probody? therapeutic (PbTx) targeting PD-L1. PbTx's are fully recombinant antibody prodrugs designed to be converted to active antibodies by tumor-associated proteases that are highly expressed malignant tissue; the PbTx remains largely inactive in normal tissues. In pre-clinical tumor models, a PD-L1-directed PbTx provided comparable anti-tumor efficacy to its parental anti-PD-L1 antibody, but displayed reduced auto-immunity in a model of Type 1 diabetes. Based on these preclinical data, CX-072 has the potential to enable combination therapies that are otherwise poorly tolerated. This Phase 1/2 study (PROCLAIM-001 (PRObody CLinical Assessment In Man) assesses the tolerability and antitumor activity of CX-072 in humans with an emphasis on immune-related adverse events, particularly in combinations. CX-072 will be administered as monotherapy (Part A), in combination with 2 schedules of ipilimumab (Parts B1 and B2) and in combination with vemurafenib (Part C). The expansion cohort (Part D) will include CX-072 monotherapy in PD-L1 responsive tumor types. Methods: Key eligibility criteria are as follows: Parts A and B1: checkpoint inhibitor-naive patients with advanced, refractory solid tumor or lymphoma (unmeasurable disease allowed) for whom approved PD agents are not available. Part B2: advanced, refractory solid tumors or lymphomas with measurable disease who have progressed on a previous treatment with a PD-(L)1 inhibitor, but did not discontinue due to toxicity. Part C: checkpoint inhibitor, BRAF-inhibitor and MEK-inhibitor-naive metastatic V600E BRAFmutated melanoma. Patients without an active autoimmune disease, ongoing infection, and ECOG PS 0-1 may be eligible to participate in the study. Dose escalation follows the 3+3 design in all arms. Ipilimumab (Parts B1 and B2) is dosed at the approved 3 mg/kg every 3 weeks x 4. The dose of vemurafenib (Part C) is 960 mg/kg twice daily. Exploratory biomarkers are used to characterize tumor protease activity, inflammatory changes within the tumor, and CX-072 activation in tumor versus peripheral blood.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/684/CN-01397684/frame.html


Record #31 of 144
ID: CN-01413008
AU: Long GV
AU: Atkinson V
AU: Cebon JS
AU: Jameson MB
AU: Fitzharris BM
AU: McNeil CM
AU: Hill AG
AU: Ribas A
AU: Atkins MB
AU: Thompson JA
AU: Hwu WJ
AU: Hodi FS
AU: Menzies AM
AU: Guminski AD
AU: Kefford R
AU: Kong BY
AU: Tamjid B
AU: Srivastava A
AU: Lomax AJ
AU: Islam M
AU: Shu X
AU: Ebbinghaus S
AU: Ibrahim N
AU: Carlino MS
TI: Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial
SO: The lancet. Oncology
YR: 2017
VL: 18
NO: 9
PG: 1202-1210
PM: PUBMED 28729151
PT: Clinical Trial, Phase I; Journal Article; Multicenter Study; Randomized Controlled Trial
KY: Antibodies, Monoclonal [therapeutic use];Antibodies, Monoclonal, Humanized [therapeutic use];Antineoplastic Agents [therapeutic use];Australia;Disease-Free Survival;Dose-Response Relationship, Drug;Drug Therapy, Combination;Ipilimumab;Melanoma [drug therapy] [mortality] [secondary];New Zealand;Treatment Outcome;United States;Aged[checkword];Female[checkword];Humans[checkword];Male[checkword];Middle Aged[checkword]
DOI: 10.1016/S1470-2045(17)30428-X
AB: METHODS: In this open-label, phase 1b trial, we recruited patients from 12 medical centres in Australia, New Zealand, and the USA. Eligible patients were aged at least 18 years, had advanced melanoma, had an Eastern Coooperative Oncology Group performance status of 0 or 1, had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, had adequate organ function, had resolution of toxic effects of the most recent previous chemotherapy to grade 1 or less, had no active autoimmune disease requiring systemic steroids or immunosuppressive agents, had no active non-infectious pneumonitis, had no uncontrolled thyroid dysfunction or diabetes, had no active brain metastases, and had not received previous immune checkpoint inhibitor therapy. Patients received intravenous pembrolizumab 2 mg/kg plus intravenous ipilimumab 1 mg/kg every 3 weeks for four doses, followed by intravenous pembrolizumab 2 mg/kg every 3 weeks for up to 2 years or disease progression, intolerable toxicity, withdrawal of consent, or investigator decision. The primary endpoint was safety and tolerability. The proportion of patients achieving an objective response assessed per RECIST version 1.1 by independent central review and overall survival were secondary endpoints. We also assessed progression-free survival. The primary endpoint was assessed in all patients who received at least one dose of combination therapy. Activity was assessed in all enrolled patients. This trial is registered with ClinicalTrials.gov, number NCT02089685. Enrolment into this cohort is closed, but patients are still being monitored for safety and anti-tumour activity.FINDINGS: Between Jan 13, 2015, and Sept 17, 2015, we enrolled and treated 153 patients. As of the Oct 17, 2016, cutoff date, median follow-up was 17·0 months (IQR 14·8-18·8). 110 (72%) of 153 patients received all four pembrolizumab plus ipilimumab doses; 64 (42%) remained on pembrolizumab monotherapy. 110 grade 3-4 treatment-related adverse events occurred in 69 (45%) patients. No treatment-related deaths occurred. Treatment-related adverse events led to discontinuation of pembrolizumab and ipilimumab in 22 (14%) patients, including 17 (11%) who discontinued both treatments for the same event and five (3%) who discontinued ipilimumab for one event and later discontinued pembrolizumab for another. 12 (8%) patients discontinued ipilimumab only and 14 (9%) discontinued pembrolizumab only because of treatment-related adverse events. 158 immune-mediated adverse events of any grade occurred in 92 (60%) patients, and 50 immune-mediated adverse events of grade 3-4 occurred in 42 (27%) patients; the most common immune-mediated adverse events were hypothyroidism (25 [16%]) and hyperthyroidism (17 [11%]). 93 (61% [95% CI 53-69]) patients achieved an objective response. Estimated 1 year progression-free survival was 69% (95% CI 60-75), and estimated 1 year overall survival was 89% (95% CI 83-93).INTERPRETATION: Standard-dose pembrolizumab given in combination with four doses of reduced-dose ipilimumab followed by standard-dose pembrolizumab has a manageable toxicity profile and provides robust anti-tumour activity in patients with advanced melanoma. These data suggest that standard-dose pembrolizumab plus reduced-dose ipilimumab might be a tolerable, efficacious treatment option for patients with advanced melanoma. A randomised phase 2 trial of alternative dosing strategies of this combination is underway.FUNDING: Merck & Co, Inc.BACKGROUND: Reduced-dose nivolumab in combination with standard-dose ipilimumab improves objective response and progression-free survival compared with standard-dose ipilimumab alone, but increases toxicity. We assessed the safety and anti-tumour activity of standard-dose pembrolizumab in combination with reduced-dose ipilimumab.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/008/CN-01413008/frame.html


Record #32 of 144
ID: CN-01416751
AU: Gay CL
AU: Bosch RJ
AU: Ritz J
AU: Hataye JM
AU: Aga E
AU: Tressler RL
AU: Mason SW
AU: Hwang CK
AU: Grasela DM
AU: Ray N
AU: Cyktor JC
AU: Coffin JM
AU: Acosta EP
AU: Koup RA
AU: Mellors JW
AU: Eron JJ
TI: Clinical Trial of the Anti-PD-L1 Antibody BMS-936559 in HIV-1 Infected Participants on Suppressive Antiretroviral Therapy
SO: Journal of infectious diseases
YR: 2017
VL: 215
NO: 11
PG: 1725-1733
PM: PUBMED 618374600
XR: EMBASE 618374600
PT: Article
KY: adult; *antagonists and inhibitors; CD8 T lymphocyte; clinical trial; controlled study; HIV Infections/dt [Drug Therapy]; human; Human immunodeficiency virus 1; immunology; male; middle aged; phase 1 clinical trial; randomized controlled trial; virology; antiretrovirus agent/dt [Drug Therapy]; CD274 protein, human; monoclonal antibody/dt [Drug Therapy]; programmed death 1 ligand 1
DOI: 10.1093/infdis/jix191
AB: Background: Reversing immune exhaustion with an anti-PD-L1 antibody may improve human immunodeficiency virus type 1 (HIV-1)-specific immunity and increase clearance of HIV-1-expressing cells. Methods: We conducted a phase I, randomized, double-blind, placebo-controlled, dose-escalating study of BMS-936559, including HIV-1-infected adults aged >18 to <70 years on suppressive antiretroviral therapy with CD4+ counts >350 cells/muL and detectable plasma HIV-1 RNA by single-copy assay. Data on single infusions of BMS-936559 (0.3 mg/kg) versus placebo are described. The primary outcomes were safety defined as any grade 3 or greater or immune-related adverse event (AE) and the change in HIV-1 Gag-specific CD8+ T cell responses from baseline to day 28 after infusion. Results: Eight men enrolled: 6 received 0.3 mg/kg of BMS-936559, and 2 received placebo infusions. There were no BMS-936559-related grade 3 or greater AEs. In 1 participant, asymptomatic hypophysitis (a protocol-defined immune-related AE) was identified 266 days after BMS-936559 infusion; it resolved over time. The mean percentage of HIV-1 Gag-specific CD8+ T cells expressing interferon gamma increased from baseline (0.09%) through day 28 (0.20%; P = .14), driven by substantial increases in 2 participants who received BMS-936559. Conclusions: In this first evaluation of an immunologic checkpoint inhibitor in healthy HIV-1-infected persons, single low-dose BMS-936559 infusions appeared to enhance HIV-1-specific immunity in a subset of participants. Clinical Trials Registration: NCT02028403.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/751/CN-01416751/frame.html


Record #33 of 144
ID: CN-00962922
AU: Le DT
AU: Lutz E
AU: Uram JN
AU: Sugar EA
AU: Onners B
AU: Solt S
AU: Zheng L
AU: Diaz LA
AU: Donehower RC
AU: Jaffee EM
AU: Laheru DA
TI: Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer
SO: Journal of immunotherapy (hagerstown, md. : 1997)
YR: 2013
VL: 36
NO: 7
PG: 382-389
PM: PUBMED 23924790
PT: Clinical Trial, Phase I; Journal Article; Randomized Controlled Trial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
KY: Antibodies, Monoclonal [administration & dosage];Antineoplastic Agents [administration & dosage];CTLA-4 Antigen [immunology];Cancer Vaccines [administration & dosage];Carcinoma, Pancreatic Ductal [diagnostic imaging] [immunology] [therapy];Combined Modality Therapy;GPI-Linked Proteins [immunology];Granulocyte-Macrophage Colony-Stimulating Factor [genetics];Ipilimumab;Pancreatic Neoplasms [diagnostic imaging] [immunology] [therapy];Radiography;T-Lymphocytes [immunology];Transfection;Adult[checkword];Aged[checkword];Female[checkword];Humans[checkword];Male[checkword];Middle Aged[checkword]
DOI: 10.1097/CJI.0b013e31829fb7a2
AB: Preclinical reports support the concept of synergy between cancer vaccines and immune checkpoint blockade in nonimmunogenic tumors. In particular, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibodies have been successfully combined with GM-CSF cell-based vaccines (GVAX). Ipilimumab (anti-CTLA-4) has been tested as a single agent in patients with pancreatic ductal adenocarcinoma (PDA) resulting in a delayed response at a dose of 3 mg/kg. Our study evaluated ipilimumab 10 mg/kg (arm 1) and ipilimumab 10 mg/kg + GVAX (arm 2). A total of 30 patients with previously treated advanced PDA were randomized (1:1). Induction doses were administered every 3 weeks for a total of 4 doses followed by maintenance dosing every 12 weeks. Two patients in arm 1 showed evidence of stable disease (7 and 22 wk) but none demonstrated CA19-9 biochemical responses. In contrast, 3 patients in arm 2 had evidence of prolonged disease stabilization (31, 71, and 81 wk) and 7 patients experienced CA19-9 declines. In 2 of these patients, disease stabilization occurred after an initial period of progression. The median overall survival (OS) (3.6 vs. 5.7 mo, hazards ratio: 0.51, P = 0.072) and 1 year OS (7 vs. 27%) favored arm 2. Similar to prior ipilimumab studies, 20% of patients in each arm had grade 3/4 immune-related adverse events. Among patients with OS > 4.3 months, there was an increase in the peak mesothelin-specific T cells (P = 0.014) and enhancement of the T-cell repertoire (P = 0.031). In conclusion, checkpoint blockade in combination with GVAX has the potential for clinical benefit and should be evaluated in a larger study.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/922/CN-00962922/frame.html


Record #34 of 144
ID: CN-01397600
AU: Khushalani NI
AU: Markowitz J
AU: Eroglu Z
AU: Giuroiu I
AU: Ladanova V
AU: Reiersen P
AU: Rich J
AU: Thapa R
AU: Schell MJ
AU: Sotomayor EM
AU: Weber JR
TI: A phase I trial of panobinostat with ipilimumab in advanced melanoma
SO: Journal of clinical oncology. Conference: 2017 annual meeting of the american society of clinical oncology, ASCO. United states
YR: 2017
VL: 35
NO: 15 Supplement 1) (no pagination
XR: EMBASE 617435275
PT: Conference Abstract
KY: acetylation; adverse drug reaction; aged; anemia; clinical article; clinical trial; colitis; controlled clinical trial; *controlled study; dehydration; diarrhea; dizziness; drug combination; drug therapy; fatigue; female; human; hydronephrosis; hypophysitis; hypotension; immunomodulation; male; maximum permissible dose; *melanoma; nausea; overall survival; phase 1 clinical trial; prevention; progression free survival; promoter region; rash; side effect; T lymphocyte; thrombocytopenia; toxicity; tumor biopsy; biological marker; endogenous compound; eomesodermin; glucose; histone deacetylase; *ipilimumab; *panobinostat; sodium; triacylglycerol lipase
AB: Background: Immune checkpoint blockade is standard therapy for advanced melanoma (MEL), yet not all patients (pts) benefit. Panobinostat (PAN), a pan inhibitor of class I, II, and IV histone deacetylases (HDAC) is immunomodulatory, decreases tumor associated inhibitory cytokines and inhibition of e ector T-cells. This dose finding study aimed to determine the safety and efficacy of escalating doses of PAN combined with ipilimumab (IPI) in advanced MEL. Methods: Eligible pts with unresectable stage 3/4 MEL, up to 3 prior lines of therapy, and adequate laboratory values were treated with oral PAN 5mg thrice weekly (TIW) plus IPI at 3mg/kg IV every 3 weeks X 4 doses, followed by maintenance PAN until progression or intolerance. Using a modified Ji design, PAN dose escalation by 5mg was planned in 3-12 pt cohorts up to a maximum dose of 20mg TIW, without intra-pt dose escalation. Dose limiting toxicity (DLT) was assessed up to day 84 from start of therapy. Results: Seventeen pts (M/F: 13/4), median age 66 yrs (48, 80) were treated with a median of 4 cycles of IPI (1,4). Of 6 pts treated at PAN 5mg TIW, there was one DLT (G3 hydronephrosis). Eleven pts received PAN 10mg TIW; of 9 evaluable for DLT, there were 3 DLTs (G3 rash, G3 diarrhea, G4 thrombocytopenia) preventing further dose escalation. Other G3 toxicities included anemia, hypophysitis, diarrhea, fatigue (all n = 2); rash, colitis, nausea, dehydration, dizziness, hypotension, lipase, sodium, & glucose (all n = 1). Three pts had previous anti- PD1 therapy. The response rate was 12% (2 PRs) with 35% stable disease. One pt remains on PAN > 24m since start of therapy. Median progression free- and overall survival was 2.23m (95% CI,1.57, 5.8) and 20.97m (95% CI, 8.97, NR) respectively. Biomarker analysis from peripheral blood and limited tumor biopsies pre-and on treatment examining immunoregulatory markers, including EOMES promoter acetylation in T-cells from PAN are ongoing. Conclusions: At tolerated doses, PAN does not appear to increase response to standard IPI in advanced MEL. Biomarker analyses will inform if immunomodulation by PAM improves efficacy of IPI. Combinations with selective HDAC inhibitors may be more appropriate for future study.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/600/CN-01397600/frame.html


Record #35 of 144
ID: CN-01410511
AU: Gay CL
AU: Bosch RJ
AU: Ritz J
AU: Hataye JM
AU: Aga E
AU: Tressler RL
AU: Mason SW
AU: Hwang CK
AU: Grasela DM
AU: Ray N
AU: Cyktor JC
AU: Coffin JM
AU: Acosta EP
AU: Koup RA
AU: Mellors JW
AU: Eron JJ
TI: Clinical Trial of the Anti-PD-L1 Antibody BMS-936559 in HIV-1 Infected Participants on Suppressive Antiretroviral Therapy
SO: Journal of infectious diseases
YR: 2017
VL: 215
NO: 11
PG: 1725-1733
PM: PUBMED 28431010
PT: Clinical Trial, Phase I; Journal Article; Randomized Controlled Trial
KY: Anti-Retroviral Agents [therapeutic use];Antibodies, Monoclonal [therapeutic use];B7-H1 Antigen [antagonists & inhibitors];CD8-Positive T-Lymphocytes;HIV Infections [drug therapy] [immunology] [virology];HIV-1;Adult[checkword];Humans[checkword];Male[checkword];Middle Aged[checkword]
DOI: 10.1093/infdis/jix191
AB: Methods: We conducted a phase I, randomized, double-blind, placebo-controlled, dose-escalating study of BMS-936559, including HIV-1-infected adults aged >18 to <70 years on suppressive antiretroviral therapy with CD4+ counts >350 cells/μL and detectable plasma HIV-1 RNA by single-copy assay. Data on single infusions of BMS-936559 (0.3 mg/kg) versus placebo are described. The primary outcomes were safety defined as any grade 3 or greater or immune-related adverse event (AE) and the change in HIV-1 Gag-specific CD8+ T cell responses from baseline to day 28 after infusion.Results: Eight men enrolled: 6 received 0.3 mg/kg of BMS-936559, and 2 received placebo infusions. There were no BMS-936559-related grade 3 or greater AEs. In 1 participant, asymptomatic hypophysitis (a protocol-defined immune-related AE) was identified 266 days after BMS-936559 infusion; it resolved over time. The mean percentage of HIV-1 Gag-specific CD8+ T cells expressing interferon γ increased from baseline (0.09%) through day 28 (0.20%; P = .14), driven by substantial increases in 2 participants who received BMS-936559.Conclusions: In this first evaluation of an immunologic checkpoint inhibitor in healthy HIV-1-infected persons, single low-dose BMS-936559 infusions appeared to enhance HIV-1-specific immunity in a subset of participants.Clinical Trials Registration: NCT02028403.Background: Reversing immune exhaustion with an anti-PD-L1 antibody may improve human immunodeficiency virus type 1 (HIV-1)-specific immunity and increase clearance of HIV-1-expressing cells.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/511/CN-01410511/frame.html


Record #36 of 144
ID: CN-01399289
AU: Kadia T
AU: Kantarjian H
AU: Jabbour E
AU: Ravandi F
AU: Daver N
AU: Cardenas P
AU: Brandt M
AU: Konopleva M
AU: Cortes J
TI: Nivolumab maintenance therapy for patients with high-risk acute myeloid leukemia in remission
SO: Haematologica. Conference: 22th congress of the european hematology association. Spain
YR: 2017
VL: 102
PG: 54
XR: EMBASE 617379016
PT: Conference Abstract
KY: *acute myeloid leukemia; adult; aged; bone marrow; *cancer susceptibility; clinical article; clinical trial; controlled clinical trial; controlled study; cytotoxic T lymphocyte; disease assessment; disease control; drug therapy; *female; flow cytometry; follow up; graft versus leukemia effect; human; hypertransaminasemia; hypothyroidism; immunocompetent cell; immunosurveillance; karyotype; leukemia relapse; *leukemia remission; *maintenance therapy; *male; minimal residual disease; mutation; organ; pharmacokinetics; phase 2 clinical trial; pneumonia; recurrence free survival; safety; stem cell; thyroiditis; cytotoxic agent; DNA methyltransferase 3A; endogenous compound; Janus kinase 2; *nivolumab; protein p53; steroid; thyroid hormone
AB: Background: Dose intensification and newer drug combinations during induction have led to high rates of complete remission (CR) in pts with newly diagnosed AML. However, disease relapse remains a major source of failure. With the exception of allogeneic (allo) stem cell transplant (SCT), there are few options for post-consolidation maintenance of remission in high-risk pts. Prior attempts to develop maintenance therapy using cytotoxic drugs in AML have been unsuccessful. Immune mediated disease control by engaging tumor-specific cytotoxic T-cells may be important in suppressing leukemia relapse, as is seen with graft vs leukemia effect following allo SCT. Immune checkpoint inhibitors may be effective in restoring host immune surveillance in the setting of post-remission maintenance. Aims:We designed a pilot phase II clinical trial studying the efficacy and safety of nivolumab (nivo) as maintenance therapy in AML pts with high-risk disease in remission, who were not being considered for SCT. Methods: AML pts >=18 years with a high-risk feature in 1st CR (CR1) or any patient in 2nd CR (CR2) who had received induction and at least 1 consolidation cycle were eligible for enrollment. Pts should be within 12 months of achieving CR, have PS <=2, and adequate organ function. Pts were treated with nivo 3mg/kg IV every 2 weeks for 6 months. 1 cycle was 4 weeks. After 6 months, nivo could be given every 4 weeks until 12 months on study, and then every 3 months until relapse. All pts had baseline cytogenetic and molecular testing, and minimal residual disease (MRD) assessment by flow cytometry. Peripheral blood and bone marrow samples were collected at baseline and during treatment for immune correlative studies to explore immune cell repertoire and biomarkers for response. Results: Eight pts have been treated, with a median age of 60 years (range, 49-71). 7 pts were in CR and 1 in CRi at the time of enrollment; 5 pts (63%) were in CR1, 2 pts (25%) were in CR2, and 1 pt (13%) in CR4 was inadvertently enrolled and treated on the trial. Baseline characteristics are outlined in Table 1. AML-related mutations detected at start of therapy include: IDH2 (n=2), NPM1 (2), TET2 (2), and 1 each of TP53, JAK2, ASXL1, and DNMT3a. High risk features at the time of enrollment were as follows: 2 (25%) persistent MRD, 2 (25%) adverse karyotype, 1 (13%) adverse mutational profile, and 3 pts (38%) in CR2 or beyond. Pts have received a median of 4 (1-13) cycles of therapy. With a median followup of 6+months (1-14), the 6-and 12-month estimated RFS were 88%and 73%, respectively. The 6-and 12-month estimated OS were 100%(Figure 1). The one patient who died was discovered after enrollment to actually be in CR4. This patient relapsed approximately 8 months after achieving CR4. The regimen was well tolerated overall, with 4 pts having possible immune-related events. 1 patient had grade 3 thyroiditis leading to hypothyroidism, treated successfully with steroids and thyroid hormone supplementation, who continues on treatment. 1 patient had grade 4 transaminase elevation which responded to dose interruption and who continues on treatment. 2 pts had grade 3 possible pneumonitis treated successfully with steroids and dose interruption-both of whom continue on treatment (Table 1). Summary/Conclusions: Nivo appears to be a feasible maintenance strategy in high-risk AML pts who are not candidates for SCT. The study continues to surpass the pre-specified expected rate of 6-month relapse-free survival of high-risk pts based on a historical cohort. Correlative studies profiling the immune repertoire of pts before and during treatment are being finalized and will be summarized.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/289/CN-01399289/frame.html


Record #37 of 144
ID: CN-01295321
AU: Yu EY
AU: Wu H
AU: Schloss C
TI: KEYNOTE-365: multicohort, phase Ib/II study of pembrolizumab combination therapy in patients with metastatic castration-resistant prostate cancer (mCRPC)
SO: Journal for immunotherapy of cancer. Conference: 31st annual meeting and associated programs of the society for immunotherapy of cancer, SITC 2016. United states. Conference start: 20161109. Conference end: 20161113
YR: 2016
VL: 4
NO: no pagination
XR: EMBASE 613518895
PT: Journal: Conference Abstract
KY: adverse drug reaction; cancer growth; *castration resistant prostate cancer; chemotherapy; clinical trial; consensus development; controlled clinical trial; controlled study; drug combination; drug therapy; histology; human; human tissue; imaging; major clinical study; *male; overall survival; pharmacokinetics; phase 1 clinical trial; phase 2 clinical trial; progression free survival; prostate adenocarcinoma; response evaluation criteria in solid tumors; safety; screening; side effect; testosterone blood level; abiraterone acetate; androgen; docetaxel; endogenous compound; enzalutamide; ligand; olaparib; *pembrolizumab; programmed death 1 receptor; prostate specific antigen
DOI: 10.1186/s40425-016-0172-7
AB: Background Approved treatments for mCRPC include second-generation endocrine therapies (abiraterone and enzalutamide) and taxanes (docetaxel and cabazitaxel). These agents may increase programmed death ligand 1 (PD-L1) expression and/or facilitate release of neoantigens. Additionally, the PARP inhibitor, olaparib, has activity in patients with mCRPC who have DNA-repair defects. Pembrolizumab is an anti-programmed death 1 (PD-1) antibody that blocks the interaction between the immune checkpoint receptor PD-1 and its ligands. KEYNOTE-365 (ClinicalTrials.-gov, NCT02861573) is an international, nonrandomized, multicohort, open-label phase Ib/II study evaluating the safety and response rate of pembrolizumab in combination with olaparib (cohort A), docetaxel + prednisone (cohort B), or enzalutamide (cohort C) in patients with mCRPC. Methods Key eligibility criteria include: histologically or cytologically confirmed adenocarcinoma of the prostate without small-cell histology, documented prostate cancer progression within 6 months preceding screening, and ongoing androgen deprivation with serum testosterone < 50 ng/dL. Cohort A will include patients previously treated with docetaxel (prior treatment with 1 other chemotherapy is allowed, as well as <2 second-generation hormonal manipulations); cohort B will include patients previously treated with either abiraterone acetate or enzalutamide (but not both) before chemotherapy; and cohort C will include patients previously treated with abiraterone acetate before chemotherapy. Patients will receive pembrolizumab 200 mg once every 3 weeks (Q3W) (all cohorts) and either olaparib 400 mg twice daily (cohort A), docetaxel 75 mg/m<sup>2</sup> Q3W + prednisone 5 mg twice daily (cohort B), or enzalutamide 160 mg every day (cohort C). Treatments will continue until disease progression or unacceptable adverse events (AEs). There will be a maximum of 35 cycles of pembrolizumab (all cohorts) and 10 cycles of docetaxel + prednisone (cohort B). Patients who must discontinue a combination component may continue with the other drug until progression/unacceptable AEs. Response will be assessed by evaluating prostate-specific antigen (PSA) levels Q3W, and with radiologic imaging every 9 weeks for the first year and every 12 weeks thereafter. Primary endpoints are safety/tolerability and PSA response rate (decline of >50% from baseline measured twice at least 3 weeks apart). Secondary end points include time to PSA progression, radiographic progression-free survival based on investigator-assessed RECIST v1.1 per the Prostate Cancer Working Group 3 guidelines, and overall survival. Approximately 70 patients will be enrolled in each cohort.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/321/CN-01295321/frame.html


Record #38 of 144
ID: CN-01294372
AU: Subudhi SK
AU: Aparicio A
AU: Gao J
AU: Zurita-Saavedra A
AU: Araujo JC
AU: Logothetis CJ
AU: Brinda KR
AU: Allison JP
AU: Vence L
AU: Emerson RO
AU: Yusko E
AU: Vignali M
AU: Robins HS
AU: Sun J
AU: Sharma P
TI: Exploratory biomarkers that predict for clinical outcomes in a Phase II trial with ipilimumab plus finite androgen deprivation therapy for metastatic non-castrate prostate cancer
SO: Cancer research. Conference: 107th annual meeting of the american association for cancer research, AACR 2016. United states. Conference start: 20160416. Conference end: 20160420
YR: 2016
VL: 76
NO: 14 Supplement) (no pagination
XR: EMBASE 613609405
PT: Journal: Conference Abstract
KY: adverse drug reaction; *androgen deprivation therapy; blood; clinical article; *clinical outcome; clinical trial; colitis; controlled clinical trial; *controlled study; diarrhea; disease course; documentation; drug combination; drug therapy; *exploratory research; flow cytometry; human; hypertransaminasemia; hypophysitis; male; metastasis; monitoring; next generation sequencing; pharmacokinetics; phase 2 clinical trial; *prostate carcinoma; safety; side effect; toxicity; endogenous compound; *ipilimumab; T lymphocyte receptor
DOI: 10.1158/1538-7445.AM2016-1402
AB: Background: Androgen deprivation therapy (ADT) is a standard treatment that, although not curative, often induces dramatic responses in patients with advanced prostate cancer by inducing tumor cell death, which may provoke antigen release to initiate T cell responses. Ipilimumab blocks the inhibitory immune checkpoint, CTLA-4, which enhances T cell responses and induces both clinical benefit and unique toxicities in a subset of patients with advanced cancer. We designed a clinical study combining ipilimumab with finite ADT in men with metastatic prostate cancer to estimate therapeutic efficacy, determine safety, and identify predictive biomarkers for clinical outcomes. Methods: We screened 30 patients and enrolled 27 patients between July, 2011 and June, 2013 for an open-labelled, single-center, Phase II study of ipilimumab plus finite ADT as first-line therapy for metastatic non-castrate prostate cancer. Eligible patients had histological confirmation of prostate carcinoma and radiographic documentation of metastatic disease. ADT was given for a finite duration of eight months with concurrent ipilimumab (10 mg/kg) for up to four doses, each given four-weeks apart. The primary endpoint was the proportion of patients with undetectable PSA (<0.2 ng/mL) at seven months post-treatment initiation with ADT. In addition, we performed comprehensive immune monitoring of the peripheral blood using multi-parametric flow cytometry and next-generation sequencing of T cell receptors. Findings: All 27 of the enrolled patients were evaluable for safety and toxicity, and 24 of these patients were evaluable for therapeutic effectiveness. Ten of the 24 (42%) patients achieved the primary endpoint of undetectable PSA levels at seven months post-treatment initiation. The median time to PSA progression was 10.0 (IQR 5.9-13.3) months from treatment initiation, and one (4%) of the 24 patients continues to have a PSA response that is ongoing for 40.7 months. The trial was closed as prespecified due to grade 3 toxicities that occurred in 12 (44%) of 27 patients. The most common grade 3 adverse events were transaminitis, colitis/diarrhea, and hypophysitis. Immunological biomarkers were identified that potentially predict for clinical benefit and grade 3 toxicities in this small study. No grade 4 or 5 toxicities were observed. Interpretation: Although the combination of 10 mg/kg ipilimumab plus finite ADT led to toxicities that met a prespecified endpoint for closure of the trial, our current knowledge and experience about combination therapies and dose of ipilimumab leads us to postulate that additional clinical trials evaluating ipilimumab at 3 mg/kg plus ADT is warranted. In addition, we identified candidate immunological biomarkers that need to be further tested as predictive markers of clinical benefit and grade 3 toxicities.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/372/CN-01294372/frame.html


Record #39 of 144
ID: CN-01451704
AU: Boyer M
AU: Spigel D
AU: Mainwaring P
AU: Lena H
AU: Mccleod M
AU: Losonczy G
AU: Sanborn R
AU: Natale R
AU: Tang M
AU: Lai J
AU: Kallinteris N
AU: Shan J
AU: Gerber D
TI: Improved outcome for immune checkpoint inhibitors (ICI) in patients previously treated with bavituximab in the sunrise trial
SO: Journal of thoracic oncology. Conference: 18th world conference on lung cancer of the international association for the study of lung cancer, IASLC 2017. Japan
YR: 2017
VL: 12
NO: 11 Supplement 2
PG: S1840-S1841
XR: EMBASE 620147793
PT: Conference Abstract
KY: adult; cancer staging; cancer survival; cold stress; colitis; controlled study; drug combination; drug therapy; female; hazard ratio; human; hypothyroidism; immune related gene; major clinical study; male; *non small cell lung cancer; overall survival; phase 3 clinical trial; pneumonia; randomization; randomized controlled trial; toxicity; *bavituximab; docetaxel; endogenous compound; placebo; programmed death 1 ligand 1; programmed death 1 receptor
AB: Background: Bavituximab targets exposed phosphatidylserine (PS) in the tumor microenvironment, resulting in repolarization of myeloid suppressor cells/M2 macrophages to M1, production of pro-inflammatory cytokines such as IFNgamma and IL-12, dendritic cell maturation, and tumor specific cytotoxic T-cell activation. SUNRISE was a Phase III trial of docetaxel with bavituximab (D+B) or placebo (D+P) in patients with treated Stage IIIb/IV non-squamous NSCLC. Recent correlative analyses from SUNRISE suggest bavituximab is more active in PD-L1 negative, immune cold tumors and thus may complement PD-1/PD-L1 ICI. Method: This subgroup analysis included all patients who received subsequent ICI after discontinuing SUNRISE study drug. We calculated overall survival (OS) both from randomization and start of subsequent ICI. Result: Ninety-three of 597 randomized patients (16%) received ICI as next line of therapy after SUNRISE assigned treatment. Baseline characteristics were balanced between the treatment groups and consistent with the ITT population. From randomization, mOS was not reached (95% confidence interval [CI], 15.2-NA) in D+B (N=46) and 12.6 months (95% CI, 10.4-17.8) in D+P (N=47) (hazard ratio [HR], 0.46; P=0.006) (Figure). From start of ICI, mOS was not reached (95% CI, 10.2-NA) in D+B and 6.2 months (95% CI, 3.9-8.7) in D+P (HR, 0.42; P=0.002). The mPFS was 6.0 months (95% CI, 3.5-6.5) in D+B and 4.4 months (95% CI, 2.6-6.3) in D+P (HR, 1.00; P=0.991). ORR was 20% vs. 13% (Odds ratio 0.6; P=0.41) for D+B and D+P, respectively. The safety profile was similar between groups and no immune related (IR) toxicities (colitis, pneumonitis, hypothyroidism) were reported. Conclusion: Within the limits of a subgroup analysis, a significant improvement in OS was observed for patients previously treated with D+B. Furthermore, bavituximab has not been associated with IR toxicities and might serve as a useful drug in combination with ICI for the treatment of immune cold tumors. (Figure Presented).
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/704/CN-01451704/frame.html


Record #40 of 144
ID: CN-01329066
AU: Morris VK
AU: Salem ME
AU: Nimeiri H
AU: Iqbal S
AU: Singh P
AU: Ciombor K
AU: Polite B
AU: Deming D
AU: Chan E
AU: Wade JL
AU: Xiao L
AU: Bekaii-Saab T
AU: Vence L
AU: Blando J
AU: Mahvash A
AU: Foo WC
AU: Ohaji C
AU: Pasia M
AU: Bland G
AU: Ohinata A
AU: Rogers J
AU: Mehdizadeh A
AU: Banks K
AU: Lanman R
AU: Wolff RA
AU: Streicher H
AU: Allison J
AU: Sharma P
AU: Eng C
TI: Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study
SO: Lancet oncology
YR: 2017
VL: (no pagination)
XR: EMBASE 614502725
PT: Journal: Article In Press
KY: adverse drug reaction; anemia; *anus cancer; cancer therapy; clinical article; clinical trial; controlled clinical trial; *controlled study; drug therapy; fatigue; funding; human; hypothyroidism; immunotherapy; monotherapy; multicenter study; national health organization; nonhuman; phase 2 clinical trial; rare disease; rash; remission; response evaluation criteria in solid tumors; side effect; Texas; tumor resistance; university; Wart virus; endogenous compound; *nivolumab
DOI: 10.1016/S1470-2045%2817%2930104-3
AB: Background: Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy associated with infection by human papillomavirus (HPV). No consensus treatment approach exists for the treatment of metastatic disease. Because intratumoral HPV oncoproteins upregulate immune checkpoint proteins such as PD-1 to evade immune-mediated cytotoxicity, we did a trial of the anti-PD-1 antibody nivolumab for patients with metastatic SCCA. Methods: We did this single-arm, multicentre, phase 2 trial at ten academic centres in the USA. We enrolled patients with treatment-refractory metastatic SCCA, who were given nivolumab every 2 weeks (3 mg/kg). The primary endpoint was response according to Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. At the time of data cutoff, the study was ongoing, with patients continuing to receive treatment. The study is registered with ClinicalTrials.gov, number NCT02314169. Results: We screened 39 patients, of whom 37 were enrolled and received at least one dose of nivolumab. Among the 37 patients, nine (24% [95% CI 15-33]) had responses. There were two complete responses and seven partial responses. Grade 3 adverse events were anaemia (n=2), fatigue (n=1), rash (n=1), and hypothyroidism (n=1). No serious adverse events were reported. Interpretation: To our knowledge, this is the first completed phase 2 trial of immunotherapy for SCCA. Nivolumab is well tolerated and effective as a monotherapy for patients with metastatic SCCA. Immune checkpoint blockade appears to be a promising approach for patients with this orphan disease. Funding: National Cancer Institute/Cancer Therapy Evaluation Program, the HPV and Anal Cancer Foundation, the E B Anal Cancer Fund, The University of Texas MD Anderson Moon Shots Program, and an anonymous philanthropic donor. Copyright © 2017 Elsevier Ltd.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/066/CN-01329066/frame.html


Record #41 of 144
ID: CN-01115787
AU: Lutz ER
AU: Wu AA
AU: Bigelow E
AU: Sharma R
AU: Mo G
AU: Soares K
AU: Solt S
AU: Dorman A
AU: Wamwea A
AU: Yager A
AU: Laheru D
AU: Wolfgang CL
AU: Wang J
AU: Hruban RH
AU: Anders RA
AU: Jaffee EM
AU: Zheng L
TI: Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation
SO: Cancer immunology research
YR: 2014
VL: 2
NO: 7
PG: 616-631
PM: PUBMED 24942756
PT: Journal Article; Randomized Controlled Trial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
KY: Adenocarcinoma [genetics] [immunology] [therapy];Antineoplastic Agents, Alkylating [administration & dosage] [therapeutic use];Cancer Vaccines [therapeutic use];Cell Aggregation [immunology];Chemotherapy, Adjuvant;Cyclophosphamide [administration & dosage] [therapeutic use];Drug Administration Schedule;Gene Expression Profiling [methods];Gene Expression Regulation, Neoplastic [immunology];Interferon-gamma [biosynthesis];Lymphocyte Activation [immunology];Lymphocytes, Tumor-Infiltrating [drug effects] [immunology];Pancreatic Neoplasms [genetics] [immunology] [therapy];T-Lymphocytes, Regulatory [immunology];Up-Regulation [immunology];Humans[checkword]
DOI: 10.1158/2326-6066.CIR-14-0027
AB: Pancreatic ductal adenocarcinoma (PDAC) is considered a "nonimmunogenic" neoplasm. Single-agent immunotherapies have failed to demonstrate significant clinical activity in PDAC and other "nonimmunogenic" tumors, in part due to a complex tumor microenvironment (TME) that provides a formidable barrier to immune infiltration and function. We designed a neoadjuvant and adjuvant clinical trial comparing an irradiated, granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting, allogeneic PDAC vaccine (GVAX) given as a single agent or in combination with low-dose cyclophosphamide to deplete regulatory T cells (Treg) as a means to study how the TME is altered by immunotherapy. Examination of resected PDACs revealed the formation of vaccine-induced intratumoral tertiary lymphoid aggregates in 33 of 39 patients 2 weeks after vaccine treatment. Immunohistochemical analysis showed these aggregates to be regulatory structures of adaptive immunity. Microarray analysis of microdissected aggregates identified gene-expression signatures in five signaling pathways involved in regulating immune-cell activation and trafficking that were associated with improved postvaccination responses. A suppressed Treg pathway and an enhanced Th17 pathway within these aggregates were associated with improved survival, enhanced postvaccination mesothelin-specific T-cell responses, and increased intratumoral Teff:Treg ratios. This study provides the first example of immune-based therapy converting a "nonimmunogenic" neoplasm into an "immunogenic" neoplasm by inducing infiltration of T cells and development of tertiary lymphoid structures in the TME. Post-GVAX T-cell infiltration and aggregate formation resulted in the upregulation of immunosuppressive regulatory mechanisms, including the PD-1-PD-L1 pathway, suggesting that patients with vaccine-primed PDAC may be better candidates than vaccine-naïve patients for immune checkpoint and other immunomodulatory therapies.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/787/CN-01115787/frame.html


Record #42 of 144
ID: CN-01303117
AU: Moskowitz CH
AU: Zinzani PL
AU: Fanale MA
AU: Armand P
AU: Johnson NA
AU: Radford JA
AU: Ribrag V
AU: Molin D
AU: Vassilakopoulos TP
AU: Tomita A
AU: Tresckow B
AU: Shipp MA
AU: Gustafson E
AU: Zhang Y
AU: Ricart AD
AU: Balakumaran A
AU: Chen RW
TI: Pembrolizumab in relapsed/refractory classical hodgkin lymphoma: primary end point analysis of the phase 2 keynote-087 study
SO: Blood. Conference: 58th annual meeting of the american society of hematology, ASH 2016. United states. Conference start: 20161203. Conference end: 20161206
YR: 2016
VL: 128
NO: 22) (no pagination
XR: EMBASE 614224942
PT: Journal: Conference Abstract
KY: antineoplastic activity; autologous stem cell transplantation; chemotherapy; *classical Hodgkin lymphoma; comparative effectiveness; controlled clinical trial; controlled study; death; diarrhea; drug resistance; drug therapy; drug toxicity; fatigue; fever; flow cytometry; gene expression; genetic marker; headache; human; human tissue; hypothyroidism; informed consent; memory T lymphocyte; meta analysis; natural killer cell; nausea; neutropenia; organ culture; overall survival; pharmacokinetics; phase 1 clinical trial; phase 2 clinical trial; progression free survival; rash; regulatory T lymphocyte; relapse; remission; safety; single blind procedure; T lymphocyte subpopulation; thrombocytopenia; treatment failure; tumor volume; biological marker; brentuximab vedotin; endogenous compound; paraffin; *pembrolizumab; programmed death 1 ligand 1; programmed death 1 receptor
AB: Background: Classical Hodgkin lymphoma (cHL) is characterized by chromosome 9p24.1 alterations (including amplification), leading to overexpression of the PD-L1 and PD-L2 immune checkpoint ligands. This genetically determined dependence on the PD-1 pathway makes cHL an attractive target for PD-1 blockade with the anti-PD-1 monoclonal antibody, pembrolizumab. In the phase 1b KEYNOTE-013 study, pembrolizumab demonstrated high antitumor activity (objective response rate [ORR] of 65%) in heavily pretreated patients with cHL. KEYNOTE-087 is a phase 2 study designed to further evaluate the efficacy and safety of pembrolizumab in different subgroups of patients with relapsed/refractory (R/R) cHL. Methods: KEYNOTE-087 (ClinicalTrials.gov, NCT02453594) is a multicenter, single-arm, multicohort phase 2 study of pembrolizumab in 3 cohorts of patients with R/R cHL: R/R cHL after autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV) therapy (cohort 1); ineligibility for ASCT due to chemoresistance (no response to salvage chemotherapy) and BV therapy failure (cohort 2); and R/R cHL after ASCT but not treated with BV after ASCT (cohort 3). Patients received pembrolizumab at a fixed dose of 200 mg intravenously every 3 weeks. Response was assessed every 12 weeks according to the 2007 Revised Response Criteria for Malignant Lymphomas. The primary end point was ORR per blinded independent central review (BICR); secondary end points included ORR per investigator review (IR), complete remission rate (CRR), progression-free survival, and overall survival. All patients who received at least 1 dose of pembrolizumab were included in the analyses. Informed consent was obtained for all patients. Biomarkers included PD-L1/PD-L2 expression in formalinfixed, paraffin-embedded tissue; flow cytometry-based evaluation of absolute and relative numbers of circulating NK cells and T-cell subsets (naive and memory T cells, activated T cells, and regulatory T cells); and gene expression using the NanoString and Illumina RNAseq platforms. The data cutoff date for these analyses was June 27, 2016. Results: Among 210 treated patients in cohorts 1 (n = 69), 2 (n = 81), and 3 (n = 60), all patients had refractory disease or relapsed HL. Of these, 98.6%, 96.3%, and 60.0% had received >3 prior lines of therapy, and by design 100% of patients in cohorts 1 and 2 had progressive disease after BV. 41.7% of patients received BV before ASCT in cohort 3. Per IR, ORR (95% CI) was 66.7% (54.3%-77.6%) in cohort 1 (46/69 patients), 65.4% (54.0%-75.7%) in cohort 2 (53/81 patients), and 68.3% (55.0%-79.7%) in cohort 3 (41/60 patients). The CRR was 29.0% in cohort 1, 24.7% in cohort 2, and 21.7% in cohort 3. Per BICR, the ORRs (95% CI) for each cohort were 72.5% (60.4%-82.5%), 65.4% (54.0%-75.7%), and 66.7% (53.3%-78.3%), respectively, and the CRRs were 21.7%, 22.2%, and 21.7%, respectively. A pooled analysis with hierarchical mutually exclusive categories of refractory disease (RD, n = 170) or relapse after >3 prior lines of therapy (Re >3, n = 40) was conducted across cohorts. Per BICR, ORR was 70.0% (62.5%-76.8%) in RD and 60.0% (43.3%-75.1%) in Re >3. Among patients with postbaseline assessment across all cohorts, 93.7% (192/205) experienced a decrease from baseline in tumor size (Figure). With a median of 9 treatment cycles, the most common treatment-related AEs (TRAEs) were pyrexia (11.0%), hypothyroidism (10.5%), diarrhea (6.7%), fatigue (6.7%), headache (6.2%), rash (6.2%), and nausea (5.7%). The most common grade 3/4 TRAEs were neutropenia (1.4%), thrombocytopenia (1.0%), and diarrhea (1.0%). Two patients died; neither death was considered to be treatment-related. At the time of analysis, 115 patients (80% of responders) had an ongoing response. Two hundred patients had evaluable pretreatment tumor tissue (archival or obtained for study) for biomarker analyses. Conclusions: PD-1 blockade with pembrolizumab had substantial clinical activity in subsets of heavily pretreated patients with cHL. Of note, pembrolizumab induced a high ORR in chemoresistant cHL. Additional results, including duration of response per BICR and biomarker analysis, will be presented at the meeting.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/117/CN-01303117/frame.html


Record #43 of 144
ID: CN-01367118
AU: Ascierto PA
AU: Vecchio M
AU: Robert C
AU: Mackiewicz A
AU: Chiarion-Sileni V
AU: Arance A
AU: Lebbe C
AU: Bastholt L
AU: Hamid O
AU: Rutkowski P
AU: McNeil C
AU: Garbe C
AU: Loquai C
AU: Dreno B
AU: Thomas L
AU: Grob J-J
AU: Liszkay G
AU: Nyakas M
AU: Gutzmer R
AU: Pikiel J
AU: Grange F
AU: Hoeller C
AU: Ferraresi V
AU: Smylie M
AU: Schadendorf D
AU: Mortier L
AU: Svane IM
AU: Hennicken D
AU: Qureshi A
AU: Maio M
TI: Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial
SO: Lancet oncology
YR: 2017
VL: (no pagination)
XR: EMBASE 615174500
PT: Article In Press
KY: adverse drug reaction; cancer size; clinical trial; colitis; controlled clinical trial; controlled study; diarrhea; double blind procedure; drug therapy; follow up; funding; hazard ratio; human; hypophysitis; interactive voice response system; intravenous drug administration; landscape; major clinical study; metastasis; *metastatic melanoma; multicenter study; oncology; overall survival; phase 2 clinical trial; phase 3 clinical trial; randomized controlled trial; safety; side effect; staff; tumor resistance; *visually impaired person; alanine aminotransferase; B Raf kinase; endogenous compound; *ipilimumab
DOI: 10.1016/S1470-2045%2817%2930231-0
AB: Background: A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3-4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit-risk profile of ipilimumab 10 mg/kg versus 3 mg/kg. Methods: This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov, number NCT01515189. Findings: Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to ipilimumab 10 mg/kg (365 patients; 364 treated) or ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14.5 months (IQR 4.6-42.3) for the ipilimumab 10 mg/kg group and 11.2 months (4.9-29.4) for the ipilimumab 3 mg/kg group. Median overall survival was 15.7 months (95% CI 11.6-17.8) for ipilimumab 10 mg/kg compared with 11.5 months (9.9-13.3) for ipilimumab 3 mg/kg (hazard ratio 0.84, 95% CI 0.70-0.99; p=0.04). The most common grade 3-4 treatment-related adverse events were diarrhoea (37 [10%] of 364 patients in the 10 mg/kg group vs 21 [6%] of 362 patients in the 3 mg/kg group), colitis (19 [5%] vs nine [2%]), increased alanine aminotransferase (12 [3%] vs two [1%]), and hypophysitis (ten [3%] vs seven [2%]). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two (<1%) patients died from treatment-related adverse events. Interpretation: In patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of ipilimumab in refractory patients with unmet medical needs could warrant further assessment. Funding: Bristol-Myers Squibb. Copyright © 2017 Elsevier Ltd.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/118/CN-01367118/frame.html


Record #44 of 144
ID: CN-01293869
AU: Hanseree P
AU: Poehls JL
TI: Ipilimumab-induced hypophysitis-recurrence of symptoms during the course of steroid treatment
SO: Endocrine reviews. Conference: 97th annual meeting and expo of the endocrine society, ENDO 2015. United states. Conference start: 20150305. Conference end: 20150308
YR: 2015
VL: 36
NO: no pagination
XR: EMBASE 613816511
PT: Journal: Conference Abstract
KY: adult; adverse drug reaction; case report; controlled clinical trial; controlled study; diagnosis; *disease duration; dizziness; drug megadose; drug therapy; fatigue; female; free liothyronine index; free thyroxine index; headache; human; *hypophysitis; infusion; inguinal lymph node; low drug dose; lymph node biopsy; metastatic melanoma; middle aged; nausea and vomiting; nuclear magnetic resonance imaging; optic chiasm; physician; pituitary stalk; polydipsia; polyuria; randomized controlled trial; *relapse; side effect; *symptom; visual field; weight gain; corticotropin; electrolyte; endogenous compound; *hydrocortisone; *ipilimumab; levothyroxine; methylprednisolone; prednisone; thyrotropin
AB: Background: Ipilimumab is a monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 that was approved by FDA as monotherapy for metastatic melanoma in March 2011. There have been reports of immune-related adverse events affecting different organs. The most common endocrinopathy is hypophysitis with the incidence of 1.8-17%(1). Clinical case: 53 year old female with history of resected metastatic melanoma (N2b) of unknown primary site diagnosed by right inguinal lymph node biopsy. She entered a clinical trial and was randomized to ipilimumab therapy. After completing her fourth course of ipilimumab, she presented with headache that had progressively worsened over 2 weeks. She also noted fatigue, dizziness, and weight gain. She denied nausea, vomiting, visual symptoms, polydipsia or polyuria. Labs showed low TSH 0.23 uIU/mL(0.36-4.20 uIU/mL), low free T4 0.44 ng/dL(0.70-1.45 ng/dL), low free T3 2.0 pg/mL(2.2-4.0 pg/mL), low 8AM cortisol 3.3 mcg/dL(4.3-22.4 mcg/dL) with inappropriately normal ACTH 22 pg/mL(7-45 pg/mL). Electrolytes were normal. MRI of the brain demonstrated diffuse enlargement of the pituitary gland measuring 1.2 cm with mass effect on the optic chiasm and thickening of the pituitary infundibulum, suggestive of hypophysitis. Visual field exam was normal. Patient received high dose methylprednisolone infusions, about 2mg/kg on day 1, and about 1mg/kg on day 2 and 3. Levothyroxine 50 mcg daily was also started. Headache resolved 2 days after starting treatment and patient was discharged home with tapering course of prednisone. Headache recurred during the 4th week as she was tapered to replacement dose of hydrocortisone. Repeat MRI at that time showed pituitary gland had decreased to 1 cm with minimal residual inflammation. Hydrocortisone was changed back to prednisone 20 mg daily for 3 days and headache improved. Repeat TSH and free T4 were normal. When prednisone taper tried again, the patient had recurrent headache. Repeat MRI 8 weeks after initial presentation showed decrease in the size of pituitary now measuring 6 mm. Patient was continued on prednisone 20 mg daily with plans to taper in 1-2 weeks if/when headache resolves. Clinical Lessons: The recommended treatment for immune-related adverse events secondary to ipilimumab, including hypophysitis, is high-dose glucocorticoids tapered down gradually over 1 month to replacement doses. Ipilimumab should be held as well. Most patients respond well to this treatment with resolution of symptoms within a few days. This report is to remind physicians to monitor for recurrence of symptoms while tapering steroids as some patients may require a longer tapering course.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/869/CN-01293869/frame.html


Record #45 of 144
ID: CN-01303096
AU: Jain N
AU: Basu S
AU: Thompson PA
AU: Ohanian M
AU: Ferrajoli A
AU: Pemmaraju N
AU: Cortes JE
AU: Estrov Z
AU: Burger JA
AU: Neelapu SS
AU: Lopez W
AU: Thakral B
AU: Bueso-Ramos CE
AU: Blando J
AU: O'Brien SM
AU: Kantarjian HM
AU: Allison J
AU: Keating M
AU: Sharma P
AU: Wierda WG
TI: Nivolumab combined with ibrutinib for CLL and richter transformation: a phase II trial
SO: Blood. Conference: 58th annual meeting of the american society of hematology, ASH 2016. United states. Conference start: 20161203. Conference end: 20161206
YR: 2016
VL: 128
NO: 22) (no pagination
XR: EMBASE 614225004
PT: Journal: Conference Abstract
KY: adult; adverse drug reaction; aged; autoimmune disease; bone marrow; cancer center; clinical article; clinical trial; controlled clinical trial; controlled study; drug combination; drug therapy; female; flow cytometry; follow up; genetic marker; human; immune response; immunohistochemistry; immunotherapy; karyotype; lymphocytic infiltration; male; middle aged; model; molecular recognition; monitoring; monotherapy; organ; phase 2 clinical trial; polymerase chain reaction; preclinical study; remission; side effect; T lymphocyte subpopulation; thyroiditis; tumor flare; young adult; B7 antigen; bilirubin; CD134 antigen; CD86 antigen; creatinine; cytotoxic T lymphocyte antigen 4; endogenous compound; glucocorticoid induced tumor necrosis factor receptor; hepatitis A virus cellular receptor 2; *ibrutinib; inducible T cell costimulator; ligand; *nivolumab; OX40 ligand; programmed death 1 ligand 1; programmed death 1 ligand 2
AB: Background: Treatment outcomes for patients with CLL have improved with the use of targeted agents, such as ibrutinib, yet complete remissions (CR) are rare, and the outcomes of patients with relapsed CLL still remain suboptimal. T cells from patients with CLL express higher levels of checkpoint inhibitory molecules, such as PD-1, compared to normal T cells (Ramsay et al. Blood 2012). Furthermore, CLL cells express ligands for these molecules, including PD-L1 and PD-L2. We hypothesized that blocking this interaction should enable T cell recognition and reactivity against CLL cells. Ibrutinib, via effect on ITK, is known to modulate immune responses, and has been shown to be synergistic with checkpoint blockade in preclinical models (Sagiv-Barfi et al. PNAS. 2015). Therefore, we designed a clinical trial of combined checkpoint inhibitor mAb with ibrutinib for patients with relapsed or refractory (R/R) CLL or Richter transformation (RT). Methods: We designed an investigator-initiated phase II clinical trial combining nivolumab (anti-PD1 monoclonal antibody) with ibrutinib in patients with relapsed/refractory CLL or RT (NCT02420912). The study included two cohorts: Cohort 1 (relapsed/refractory CLL or RT) and cohort 2 (patients with CLL who achieved partial remission after at least 9 months on ibrutinib). In cohort 1, patients received a lead-in window of nivolumab monotherapy for course 1; ibrutinib was added starting with course 2. In cohort 2, patients were already receiving ibrutinib when they entered the study, and continued ibrutinib; nivolumab is added from course 1. Ibrutinib dose was 420 mg once daily. Nivolumab was given 3 mg/kg IV every 2 weeks. Eligibility criteria included age >18 years, adequate organ function (total bilirubin <1.5 x ULN, ALT and AST <3 x ULN, creatinine <1.5 x ULN). Prior allogeneic SCT was allowed. Patients with autoimmune diseases were excluded. The primary objective of the trial was CR/CRi rate in cohort 1, and the rate of conversion from PR to CR/CRi in cohort 2. Peripheral blood and bone marrow samples were collected at baseline and serially on treatment to assess for T cell subsets and immune marker expression (Receptors: PD1, CTLA4, LAG3, TIM3, GITR, OX40, 41BB, ICOS; Ligands: PDL1, PDL2, OX40L, Gal-9, 41BBL, B7-1, B7-2). Immune monitoring studies were conducted by the Immunotherapy Platform at M. D. Anderson Cancer Center. Results: 13 patients have been consented; 12 initiated treatment. We report data on these 12 patients. The median age is 63 years (range, 42-78), 8 were men and 4 women. 9 patients are in cohort 1; 3 patients are in cohort 2. Five patients with relapsed/refractory CLL were treated on cohort 1. Median number of prior therapies were 1 (range 1-3). Prognostic markers included [(del 13q (n=3), del17p (n=1), FISH negative (n=1)]. Three patients achieved PR; one patient had no response and came off study after course 5; one patient was too early for response assessment. Four patients with previously untreated RT (including one with accelerated CLL) were treated in cohort 1. Median number of prior therapies for CLL were 2 (range 1-3). Two patients had a response and are currently in month 5 and 7 of treatment. Figure 1 shows PET response in a 62 year old with del17p, unmutated IGHV, complex karyotype CLL who developed RT with a large oropharyngeal mass. She had complete resolution of this mass at 3 months. One patient progressed after transient response. One patient is too early for response assessment. Three patients were enrolled in cohort 2 [(del 17p (n=2), del13q (n=1); unmutated IGHV (n=2); no PCR amplification (n=1)]. Patients were on ibrutinib from 13-32 months prior to study enrollment. All three patients noted decrease in the lymphocytic infiltrate in the marrow. No patient has achieved CR/CRi. All 3 patients are continuing on study with a follow-up from 5-9 months. One patient in cohort 2 developed thyroiditis. No other immune-related adverse events were noted. One patient had tumor flare. Correlative studies, including flow-cytometry and IHC for PD1 and PDL1 in serial blood and marrow samples are ongoing. Conclusions: The combination of nivolumab and ibrutinib has activity in patients with relapsed, refractory CLL and RT. The trial continues to enroll patients, and updated results will be presented at the ASH meeting. (Figure Presented).
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/096/CN-01303096/frame.html


Record #46 of 144
ID: CN-01360771
AU: Coskun NSS
AU: Simsir IY
AU: Goksel T
TI: A case with a primary adrenal insufficiency secondary to nivolumab
SO: European respiratory journal. Conference: european respiratory society annual congress 2016. United kingdom
YR: 2016
VL: 48
NO: no pagination
XR: EMBASE 614779908
PT: Conference Abstract
KY: abdomen; *Addison disease; adenocarcinoma; adrenal hemorrhage; adrenal insufficiency; adrenal metastasis; adult; adverse drug reaction; arterial pressure; blood gas; carbon dioxide tension; case report; chemotherapy; consciousness; controlled clinical trial; controlled study; diagnosis; driver; dyspnea; emergency ward; gene mutation; glucose blood level; hormone determination; human; hyperkalemia; hyperpigmentation; immunotherapy; infection; lung cancer; male; metabolic alkalosis; middle aged; mucosal dryness; nausea and vomiting; pathology; randomized controlled trial; side effect; thinking; ultrasound; creatinine; endogenous compound; epidermal growth factor receptor; hormone; hydrocortisone; new drug; *nivolumab; potassium; programmed death 1 receptor; reactive oxygen metabolite; sodium; urea
DOI: 10.1183/13993003.congress-2016.PA4853
AB: Abstract Immunological therapy in treatment of lung cancer has been introduced effectively. Nivolumab that is anti PD-1 monoclonal antibody has some immunological side effects. 50 years old male was diagnosed stage IV adenocarcinoma with bilaterally adrenal metastasis. The driver mutations (EGFR, ALK, ROS-1) were not detected. He had been treated with 3 lines chemotherapies. He had not responded any chemotherapy. We started nivolumab in the patient. After 10 days from the first therapy, he admitted to Emergency Unit of our hospital with dyspnea, nausea, vomiting, and changes of consciousness. Arterial blood pressure (80/50 mmHg) and randomized blood sugar (60 mg/dl) was low. He had dry mucosa and hyperpigmentation on his skin. We found Urea:93 mg/dl (>50), Creatinin:2.11 mg/dl (>1.5), Sodium:124 mEq/L (<135), Potassium:6.7 mEq/L (>5) in his blood and pH:7.23, pCO2:34.8, HCO3:14.2 (<22) in arterial blood gases. We thought metabolic alkalosis secondary to hyperkalemia and adrenal insufficiency. Adrenocorticothrophic hormone (ACTH) level was 1234 (>50), cortizol level (at 08:00 AM) 0.96 mcg/dl (<10). In Cranial MR, there was no any acute pathology. In abdomen ultrasound, there was no any finding of adrenal bleeding or infection. The diagnosis of primary adrenal insufficiency was thought to be related with immunological side effect of nivolumab. The patient has been treated with intravenous steroid replacement. After the treatment, levels of sodium, potassium, ACTH, blood sugar and blood pressure has been normalized. We have presented a case with primary adrenal insufficiency secondary to nivolumab, as a very rare immunological side effect of this new drug.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/771/CN-01360771/frame.html


Record #47 of 144
ID: CN-01303127
AU: Garcia-Manero G
AU: Tallman MS
AU: Martinelli G
AU: Ribrag V
AU: Yang H
AU: Balakumaran A
AU: Chlosta S
AU: Zhang Y
AU: Smith BD
TI: Pembrolizumab, a PD-1 inhibitor, in patients with myelodysplastic syndrome (MDS) after failure of hypomethylating agent treatment
SO: Blood. Conference: 58th annual meeting of the american society of hematology, ASH 2016. United states. Conference start: 20161203. Conference end: 20161206
YR: 2016
VL: 128
NO: 22) (no pagination
XR: EMBASE 614224903
PT: Journal: Conference Abstract
KY: adult; adverse drug reaction; aged; arthralgia; classification; clinical article; comparative effectiveness; controlled clinical trial; controlled study; cytopenia; death; drug therapy; fatigue; female; follow up; gastroenteritis; gene expression profiling; gene inactivation; hematologic malignancy; human; hypothyroidism; International Prostate Symptom Score; intravenous drug administration; male; musculoskeletal stiffness; myelodysplastic syndrome; overall survival; peripheral edema; pharmacokinetics; phase 1 clinical trial; *refractory anemia with excess blasts; remission; safety; side effect; solid tumor; toxicity; *treatment failure; tumor lysis syndrome; young adult; azacitidine; biological marker; decitabine; endogenous compound; ligand; *pembrolizumab; *programmed death 1 receptor
AB: Background: Upregulation of the immune checkpoint receptor PD-1 and its ligands, PD-L1 and PD-L2, has been demonstrated in peripheral blood mononuclear cells from patients with MDS (Yang H et al. Leukemia2014;28:1280-1288). This upregulation is enhanced by epigenetic modifiers, such as 5-azacitidine, and has been associated with poor survival. The PD-1 pathway thus represents an attractive target in patients with MDS that has failed first-line treatment with a hypomethylating agent. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands and can restore antitumor immune activity in solid tumors and hematologic malignancies. KEYNOTE-013 (NCT01953692) is a multicenter, multicohort phase 1b study of pembrolizumab in patients with hematologic malignancies. Results from the MDS cohort of KEYNOTE-013 are presented. Methods: Key eligibility criteria for this cohort included age >18 years, primary or secondary MDS with IPSS score of intermediate 1, intermediate 2, or high; and failure (defined as worsening of cytopenias, increase in percentage of bone marrow blasts, or progression to more advanced MDS FAB subtype than at pretreatment) to respond to at least 4 cycles of prior treatment with a hypomethylating agent (azacitidine or decitabine). Pembrolizumab was administered intravenously at a dose of 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Response was assessed by investigator every 6 weeks using IWG 2006 criteria (Cheson BD et al. Blood2006;108:419-425). The primary end points were safety and objective response rate; secondary objectives included overall survival, bone marrow response, and hematologic improvement. Bone marrow samples were collected at predefined time points during the study for analysis of gene expression profiles with the NanoString platform. Results: Among the 28 patients enrolled in the MDS cohort, median age was 73 years (range, 38-84 years), 64% were male, and IPSS scores were intermediate 1 in 10 patients (36%), intermediate 2 in 9 patients (32%), and high in 7 patients (25%). 54% of patients had a FAB classification of refractory anemia with excess blasts. At the time of data cutoff on May 27, 2016, the median follow-up duration was 5.6 months (range, 1-29 months). 10 patients (36%) experienced treatment-related adverse events (AEs); the most frequent were hypothyroidism in 4 patients (14%) and fatigue in 3 patients (11%). Grade 3/4 treatment-related AEs occurred in 2 patients (7%), including grade 3 gastroenteritis and grade 4 tumor lysis syndrome in 1 patient each. 2 patients discontinued because of treatment-related AEs, including grade 4 tumor lysis syndrome in 1 patient, and grade 2 arthralgia, grade 1 musculoskeletal stiffness, and grade 1 peripheral edema in 1 patient. There were no treatment-related deaths. Of the 27 patients evaluated for efficacy, there were no complete remissions (CRs), and 1 patient achieved a partial remission, for an overall response rate of 4% (90% CI, 0.2%-16%). Among the remaining patients, best overall response was marrow CR in 3 patients (11%), stable disease in 14 patients (52%), and progressive disease in 9 patients (33%). Hematologic improvement was seen in 3 patients (11%). The overall survival rate at 24 weeks was 49% across the cohort, including 89% in patients with intermediate 1 IPSS score, 22% in patients with intermediate 2 IPSS score, and 29% in patients with high IPSS score. For patients with intermediate 1 score, the 1-year overall survival rate was 89%; the 2-year overall survival rate was 57%. Biomarker data will be presented. Conclusion: PD-1 blockade with pembrolizumab was associated with a manageable safety profile and potential clinical activity in patients with MDS after failure of first-line treatment with a hypomethylating agent. Future studies in combination with azacitidine are planned.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/127/CN-01303127/frame.html


Record #48 of 144
ID: CN-01401100
AU: Ascierto PA
AU: Vecchio M
AU: Robert C
AU: Mackiewicz A
AU: Chiarion-Sileni V
AU: Arance A
AU: Lebbé C
AU: Bastholt L
AU: Hamid O
AU: Rutkowski P
AU: McNeil C
AU: Garbe C
AU: Loquai C
AU: Dreno B
AU: Thomas L
AU: Grob JJ
AU: Liszkay G
AU: Nyakas M
AU: Gutzmer R
AU: Pikiel J
AU: Grange F
AU: Hoeller C
AU: Ferraresi V
AU: Smylie M
AU: Schadendorf D
AU: Mortier L
AU: Svane IM
AU: Hennicken D
AU: Qureshi A
AU: Maio M
TI: Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial
SO: The lancet. Oncology
YR: 2017
VL: 18
NO: 5
PG: 611-622
PM: PUBMED 28359784
PT: Clinical Trial, Phase III; Comparative Study; Journal Article; Multicenter Study; Randomized Controlled Trial
KY: Alanine Transaminase [blood];Antibodies, Monoclonal [administration & dosage] [adverse effects];Antineoplastic Agents [administration & dosage] [adverse effects];Colitis [chemically induced];Diarrhea [chemically induced];Double-Blind Method;Follow-Up Studies;Hypophysitis [chemically induced];Intention to Treat Analysis;Ipilimumab;Melanoma [drug therapy] [secondary];Survival Rate;Treatment Outcome;Aged[checkword];Female[checkword];Humans[checkword];Male[checkword];Middle Aged[checkword]
DOI: 10.1016/S1470-2045(17)30231-0
AB: METHODS: This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov, number NCT01515189.FINDINGS: Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to ipilimumab 10 mg/kg (365 patients; 364 treated) or ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14·5 months (IQR 4·6-42·3) for the ipilimumab 10 mg/kg group and 11·2 months (4·9-29·4) for the ipilimumab 3 mg/kg group. Median overall survival was 15·7 months (95% CI 11·6-17·8) for ipilimumab 10 mg/kg compared with 11·5 months (9·9-13·3) for ipilimumab 3 mg/kg (hazard ratio 0·84, 95% CI 0·70-0·99; p=0·04). The most common grade 3-4 treatment-related adverse events were diarrhoea (37 [10%] of 364 patients in the 10 mg/kg group vs 21 [6%] of 362 patients in the 3 mg/kg group), colitis (19 [5%] vs nine [2%]), increased alanine aminotransferase (12 [3%] vs two [1%]), and hypophysitis (ten [3%] vs seven [2%]). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two (<1%) patients died from treatment-related adverse events.INTERPRETATION: In patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of ipilimumab in refractory patients with unmet medical needs could warrant further assessment.FUNDING: Bristol-Myers Squibb.BACKGROUND: A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3-4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit-risk profile of ipilimumab 10 mg/kg versus 3 mg/kg.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/100/CN-01401100/frame.html


Record #49 of 144
ID: CN-01293871
AU: Denman D
AU: Mongelluzzo GJ
AU: Lock JH
AU: Panikkar R
AU: Zeng Y
AU: Gingrich P
AU: Hu Y
TI: The growing concern for autoimmune hypophysitis due to ipilimumab
SO: Endocrine reviews. Conference: 97th annual meeting and expo of the endocrine society, ENDO 2015. United states. Conference start: 20150305. Conference end: 20150308
YR: 2015
VL: 36
NO: no pagination
XR: EMBASE 613816491
PT: Journal: Conference Abstract
KY: adult; adverse drug reaction; androgen therapy; *autoimmune hypophysitis; cancer susceptibility; case report; clinical trial; congenital malformation; controlled clinical trial; controlled study; drug megadose; drug therapy; endocrinologist; fatigue; female; follow up; free thyroxine index; headache; human; hypophysis function; hypopituitarism; immunostimulation; male; metastatic melanoma; middle aged; nuclear magnetic resonance imaging; oncologist; randomized controlled trial; remission; side effect; skin; symptom; adjuvant; alpha2a interferon; corticotropin; endogenous compound; hydrocortisone; *ipilimumab; levothyroxine; prednisone; testosterone; thyrotropin
AB: Background: Ipilimumab (IP), a human antibody against cytotoxic T-lymphocyte antigen 4 (anti-CTLA4), is FDA approved for the treatment of unresectable or metastatic malignant melanoma. Here we report two cases of patients treated with IP who developed hypopituitarism from autoimmune hypophysitis (AIH). Case reports: Case 1 is a 52 year old male with stage IIIb malignant melanoma of perianal skin who was enrolled in a "phase III randomized study of adjuvant IP therapy versus high-dose Interferon alpha-2b for resected high-risk melanoma". After receiving four doses of IP (10 mg/kg), the patient presented with a severe headache and extreme fatigue. Lab work revealed total testosterone 32.71 (193 - 740 ng/dL), TSH 0.17 (0.27 - 4.2 uIU/mL), free T4 0.40 (0.7 - 1.7 ng/dL), and cortisol 3.1 (6.2-19.4 ug/dL). MRI showed a diffusely enlarged pituitary gland and infundibulum with homogenous enhancement. Hypopituitarism due to AIH induced by IP was suspected. IP was stopped and he was treated with prednisone 60 mg for five days followed by hydrocortisone, levothyroxine, and androgen replacement. His symptoms were resolved rapidly. At two months follow up, an MRI showed complete resolution of enlarged pituitary; lab results did not show signs of pituitary function recovery. Case 2 is a 56 year old female with stage IIIc metastatic melanoma of her left back who was enrolled in the same trial to receive IP (3 mg/kg). After three doses of IP, she developed headache and mild fatigue. Labs showed TSH 0.15 (0.27 - 4.2 uIU/mL), free T4 0.54 (0.7 - 1.7 ng/dL), cortisol 0.7 (6.2-19.4 ug/dL), and ACTH 5.9 (0-16 pg/ml). MRI showed a diffusely enlarged pituitary gland consistent with hypophysitis. IP was stopped and she was treated with prednisone 60 mg for five days, followed by levothyroxine and hydrocortisone replacement. Her symptoms improved shortly after. At one month follow up, an MRI showed improvement of pituitary size, but lab results did not show signs of pituitary function recovery. Discussion: Both patients developed hypopituitarism due to presumed AIH secondary to IP therapy. AIH is a rare endocrine disease, which has been reported in about 4% of patients involved in IP trials. Most patients developed AIH after receiving the third dose of treatment, which is similar to the cases reported here. Both cases presented with headache and fatigue. Treatments have corrected their clinical symptoms and radiographic abnormalities. However we haven't seen the recovery of endogenous pituitary function several months after the events. The mechanism of AIH induced by IP likely is related to its immunostimulation effect. Whether large dose of steroids have helped their recovery process or not is unknown. Conclusion: AIH is a rare but significant complication from IP treatment. Endocrinologists and Oncologists need to be aware of this, as it can cause hypopituitarism, which could be life threatening if unrecognized.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/871/CN-01293871/frame.html


Record #50 of 144
ID: CN-01247208
AU: Hodi FS
AU: Chesney J
AU: Pavlick AC
AU: Robert C
AU: Grossmann KF
AU: McDermott DF
AU: Linette GP
AU: Meyer N
AU: Giguere JK
AU: Agarwala SS
AU: Shaheen M
AU: Ernstoff MS
AU: Minor DR
AU: Salama AK
AU: Taylor MH
AU: Ott PA
AU: Horak C
AU: Gagnier P
AU: Jiang J
AU: Wolchok JD
AU: Postow MA
TI: Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial
SO: Lancet oncology
YR: 2016
VL: (no pagination)
XR: EMBASE 613251510
PT: Journal: Article In Press
KY: adult; adverse drug reaction; cancer center; cancer epidemiology; clinical trial; colitis; controlled clinical trial; controlled study; death; diarrhea; drug combination; drug therapy; follow up; France; funding; gene mutation; hazard ratio; human; hypophysitis; immunotherapy; interactive voice response system; intravenous drug administration; major clinical study; *melanoma; multicenter study; *overall survival; phase 2 clinical trial; progression free survival; randomization; randomized controlled trial; safety; side effect; staff; stratification; toxicity; visually impaired person; wild type; young adult; alanine aminotransferase; B Raf kinase; cytotoxic T lymphocyte antigen 4 antibody; endogenous compound; *ipilimumab; *nivolumab; placebo; programmed death 1 receptor
DOI: 10.1016/S1470-2045%2816%2930366-7
AB: Background: Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma. Methods: In this multicentre, double-blind, randomised, controlled, phase 2 trial (CheckMate 069) we recruited patients from 19 specialist cancer centres in two countries (France and the USA). Eligible patients were aged 18 years or older with previously untreated, unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo, every 3 weeks for four doses. Subsequently, patients assigned to nivolumab plus ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, whereas patients allocated to ipilimumab alone received placebo every 2 weeks during this phase. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by BRAF mutation status. The study funder, patients, investigators, and study site staff were masked to treatment assignment. The primary endpoint, which has been reported previously, was the proportion of patients with BRAF <sup>V600</sup> wild-type melanoma achieving an investigator-assessed objective response. Overall survival was an exploratory endpoint and is reported in this Article. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all treated patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01927419, and is ongoing but no longer enrolling patients. Findings: Between Sept 16, 2013, and Feb 6, 2014, we screened 179 patients and enrolled 142, randomly assigning 95 patients to nivolumab plus ipilimumab and 47 to ipilimumab alone. In each treatment group, one patient no longer met the study criteria following randomisation and thus did not receive study drug. At a median follow-up of 24.5 months (IQR 9.1-25.7), 2-year overall survival was 63.8% (95% CI 53.3-72.6) for those assigned to nivolumab plus ipilimumab and 53.6% (95% CI 38.1-66.8) for those assigned to ipilimumab alone; median overall survival had not been reached in either group (hazard ratio 0.74, 95% CI 0.43-1.26; p=0.26). Treatment-related grade 3-4 adverse events were reported in 51 (54%) of 94 patients who received nivolumab plus ipilimumab compared with nine (20%) of 46 patients who received ipilimumab alone. The most common treatment-related grade 3-4 adverse events were colitis (12 [13%] of 94 patients) and increased alanine aminotransferase (ten [11%]) in the combination group and diarrhoea (five [11%] of 46 patients) and hypophysitis (two [4%]) in the ipilimumab alone group. Serious grade 3-4 treatment-related adverse events were reported in 34 (36%) of 94 patients who received nivolumab plus ipilimumab (including colitis in ten [11%] of 94 patients, and diarrhoea in five [5%]) compared with four (9%) of 46 patients who received ipilimumab alone (including diarrhoea in two [4%] of 46 patients, colitis in one [2%], and hypophysitis in one [2%]). No new types of treatment-related adverse events or treatment-related deaths occurred in this updated analysis. Interpretation: Although follow-up of the patients in this study is ongoing, the results of this analysis suggest that the combination of first-line nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone in patients with advanced melanoma. The results suggest encouraging survival outcomes with immunotherapy in this population of patients. Funding: Bristol-Myers Squibb. Copyright © 2016 Elsevier Ltd.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/208/CN-01247208/frame.html


Record #51 of 144
ID: CN-01397484
AU: Leung ACF
AU: Kummar S
AU: Agarwala SS
AU: Nemunaitis JJ
AU: Gonzalez R
AU: Drabick JJ
AU: Schmidt EV
AU: Chartash E
AU: Xing B
AU: Currie G
AU: Janssen R
AU: Ribas A
TI: Phase 1b/2, open label, multicenter, study of intratumoral SD-101 in combination with pembrolizumab in anti-PD1 naive & experienced metastatic melanoma patients
SO: Journal of clinical oncology. Conference: 2017 annual meeting of the american society of clinical oncology, ASCO. United states
YR: 2017
VL: 35
NO: 15 Supplement 1) (no pagination
XR: EMBASE 617435503
PT: Conference Abstract
KY: adult; chill; clinical article; clinical trial; controlled clinical trial; controlled study; death; drug therapy; drug withdrawal; fatigue; follow up; headache; human; hypophysitis; injection site pain; male; *metastatic melanoma; middle aged; monotherapy; multicenter study; myalgia; phase 1 clinical trial; pneumonia; response evaluation criteria in solid tumors; safety; toxicity; endogenous compound; *pembrolizumab; programmed death 1 receptor
AB: Background: SD-101 is a synthetic CpG-ODN agonist of TLR 9 that stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells to activate T cell anti-tumor responses. Pembro is a PD-1 inhibitor approved for the treatment of metastatic melanoma. This study, MEL-01 (NCT02521870), assesses the safety and preliminary efficacy of SD-101 in combination with pembro in stage IIIC-IV melanoma. Methods: A modified 3+3 design was used for SD-101 dose escalation of 1, 2, 4, and 8 mg injected in a single tumor lesion Q1W x 4 then Q3W x 7 in combination with pembro (200 mg IV Q3W). Tumor responses were assessed per investigator using RECIST v1.1. Results: In phase Ib, 22 pts were enrolled: median age 64 y/o, male 68%, white 82%, Stage IV/IIIc 86%/14%, LDH > 1 ULN 27%, >= 3 prior lines therapy 36%, anti-PD-1 naive (n = 9) and experienced (n = 13). There has been no dose limiting toxicity (DLT) to date. The most common (>=20%) treatment-related AEs (TRAEs) were transient low-grade fatigue, myalgia, headache, chills and injection site reactions. Grade >= 3 TRAEs were observed in 59.1% pts (most common: myalgia 13.6% and injection site pain 13.6%). Immune-related AEs occurred in 2 pts. One had a G2 pneumonitis on Day 23 resulting in drug withdrawal and the other G3 hypophysitis (85 days after last treatment). No deaths occurred. Responses were observed at all doses in PD-1 inhibitor naive pts, both at the injected and non-injected lesions. A response was seen at the 8 mg dose in PD-1 inhibitor experienced pts. With median f/u of 97 days (max 382), the ORR was 66.7% in the PD-1 inhibitor naive patients with best overall response of CR 22.2% (n = 2), PR 44.4% (n = 4), SD 11.1% (n = 1), PD 11.1% (n = 1), and NE 11.1% (n = 1). In the PD-1 inhibitor experienced pts: PR 7.7% (n = 1) and SD 38.5% (n = 5). Conclusions: The combination of SD-101 and pembro was well tolerated and demonstrates no worsening of the expected toxicities of each of the individual monotherapies. These interim data support enhanced activity of adding SD-101 to pembro in anti-PD-1 naive metastatic melanoma as well as potential activity in anti-PD-1 experienced pts. Additional follow up data through May 15, 2017 will be presented.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/484/CN-01397484/frame.html


Record #52 of 144
ID: CN-01295336
AU: Desai J
AU: Markman B
AU: Sandhu S
AU: Gan H
AU: Friedlander ML
AU: Tran B
AU: Meniawy T
AU: Lundy J
AU: Colyer D
AU: Ameratunga M
AU: Norris C
AU: Yang J
AU: Li K
AU: Wang L
AU: Luo L
AU: Qin Z
AU: Mu S
AU: Tan X
AU: Song J
AU: Millward M
TI: Updated safety, efficacy, and pharmacokinetics (PK) results from the phase I study of BGB-A317, an anti-programmed death-1 (PD-1) mAb in patients with advanced solid tumors
SO: Journal for immunotherapy of cancer. Conference: 31st annual meeting and associated programs of the society for immunotherapy of cancer, SITC 2016. United states. Conference start: 20161109. Conference end: 20161113
YR: 2016
VL: 4
NO: no pagination
XR: EMBASE 613518808
PT: Journal: Conference Abstract
KY: abdominal pain; adverse drug reaction; antineoplastic activity; backache; body weight; clearance; clinical trial; colitis; constipation; controlled clinical trial; *controlled study; diabetic ketoacidosis; diarrhea; disease course; dyspnea; elimination half-life; fatigue; human; human tissue; hyperglycemia; hypotension; hypoxia; major clinical study; maximum tolerated dose; nausea; pharmacokinetics; phase 1 clinical trial; phase 2 clinical trial; pneumonia; population model; *safety; side effect; *solid tumor; endogenous compound; *programmed death 1 receptor
DOI: 10.1186/s40425-016-0172-7
AB: Background BGB-A317 is a humanized IgG4 anti-PD-1 mAb with high specificity and affinity (K<inf>D</inf>=0.15 nM) for PD-1. It blocks PD-L1 and PD-L2 binding and inhibits PD-1-mediated negative signaling in T cell lines and tumor growth in a number of allogeneic xenograft models. Methods A phase I, multicenter study was conducted to evaluate the safety, tolerability, PK and antitumor activity of BGB-A317 in patients with advanced solid tumors. A 3+3 dose escalation design was undertaken. Patients received escalating doses of BGB-A317 intravenously at 0.5, 2, 5 and 10 mg/kg once every two weeks (Q2W). Additional patients were treated at 2 and 5 mg/kg once every three weeks (Q3W). Results As of 27 July 2016, 103 patients were treated across 4 dose-escalating cohorts of BGB-A317 Q2W (0.5 mg/kg, n=3; 2 mg/kg, n=6; 5 mg/kg, n=6 and 10 mg/kg, n=7) and 4 dose-expansion cohorts (2 mg/kg, Q2W, n=20; 2 mg/kg, Q3W, n=21; 5 mg/kg Q2W, n=20 and 5 mg/kg, Q3W, n=20). One DLT (1/6) of grade 3 colitis was observed in the 5 mg/kg Q2W dose-escalating cohort. Maximum tolerated dose was not reached. Recommended phase II dose is 5 mg/kg Q3W. The most common treatment-emergent adverse events (AEs) were grade (G) 1-2 fatigue (42%), nausea (30%), diarrhea (25%), abdominal pain (22%) and constipation (21%). Treatment-related G3 AEs included fatigue (n=2), hypotension (n=2), back pain (n=1), colitis (n=1), diabetes mellitus (n=1), diabetic ketoacidosis (n=1), dyspnea (n=1), elevated ALT (n=1), hyperglycaemia (n=1), hypoxia (n=1) and pneumonitis (n=1). Population PK analysis was conducted using 411 observed BGB-A317 serum concentrations from 31 patients who received doses of 0.5, 2, 5 and 10 mg/kg Q2W and 13 patients who received doses of 2 and 5 mg/kg Q3W. BGB-A317 PK is linear and the terminal elimination half-life is 16 days. Patients' body weight is not a significant covariate on the clearance of A317. Among 99 evaluable patients, preliminary evidence of anti-tumor activities included 16 patients have partial responses (5 to be confirmed) and 20 patients exhibit stable disease. 13 responding patients remain on treatment, ranging from 18 to 38 weeks. Conclusions BGB-A317 demonstrates a favorable safety profile with AEs in keeping with the class effect. Early promising anti-tumor activity has been observed. BGB-A317 PK is linear and systemic clearance is not affected by body weight, which supports fixed dosing. The expanded phase IB study in selected cancer types is ongoing. (Figure Presented).
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/336/CN-01295336/frame.html


Record #53 of 144
ID: CN-01289860
AU: Hodi FS
AU: Chesney J
AU: Pavlick AC
AU: Robert C
AU: Grossmann KF
AU: McDermott DF
AU: Linette GP
AU: Meyer N
AU: Giguere JK
AU: Agarwala SS
AU: Shaheen M
AU: Ernstoff MS
AU: Minor DR
AU: Salama AK
AU: Taylor MH
AU: Ott PA
AU: Horak C
AU: Gagnier P
AU: Jiang J
AU: Wolchok JD
AU: Postow MA
TI: Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial
SO: The lancet. Oncology
YR: 2016
VL: 17
NO: 11
PG: 1558-1568
PM: PUBMED 27622997
XR: EMBASE 613251510
PT: Clinical Trial, Phase II; Journal Article; Multicenter Study; Randomized Controlled Trial
KY: Antibodies, Monoclonal [administration & dosage] [adverse effects] [therapeutic use];Antineoplastic Combined Chemotherapy Protocols [therapeutic use];Double-Blind Method;Ipilimumab;Melanoma [drug therapy] [genetics] [mortality];Mutation;Proto-Oncogene Proteins B-raf [genetics];Humans[checkword];abdominal pain/si [Side Effect]; adrenal insufficiency/si [Side Effect]; adult; *advanced cancer/dt [Drug Therapy]; advanced cancer/dt [Drug Therapy]; alanine aminotransferase blood level; amylase blood level; aphthous stomatitis/si [Side Effect]; article; ascites/si [Side Effect]; aspartate aminotransferase blood level; atrial fibrillation/si [Side Effect]; autoimmune disease/si [Side Effect]; braf gene; cancer registry; *cancer survival; chill/si [Side Effect]; colitis/si [Side Effect]; constipation/si [Side Effect]; controlled study; coughing/si [Side Effect]; decreased appetite/si [Side Effect]; dehydration/si [Side Effect]; diabetic ketoacidosis/si [Side Effect]; diarrhea/si [Side Effect]; disease severity; dizziness/si [Side Effect]; double blind procedure; drug efficacy; drug safety; dyspnea/si [Side Effect]; enterocolitis/si [Side Effect]; eye pain/si [Side Effect]; fatigue/si [Side Effect]; febrile neutropenia/si [Side Effect]; fever/si [Side Effect]; France; gene mutation; Guillain Barre syndrome/si [Side Effect]; headache/si [Side Effect]; heart infarction/si [Side Effect]; heart ventricle arrhythmia/si [Side Effect]; heart ventricle tachycardia/si [Side Effect]; hepatitis/si [Side Effect]; human; hypoalbuminemia/si [Side Effect]; hyponatremia/si [Side Effect]; hypophysitis/si [Side Effect]; hypothermia/si [Side Effect]; hypothyroidism/si [Side Effect]; institutional review; leukocytosis/si [Side Effect]; maculopapular rash/si [Side Effect]; major clinical study; malabsorption/si [Side Effect]; *melanoma/dt [Drug Therapy]; melanoma/dt [Drug Therapy]; multicenter study; mutational analysis; myalgia/si [Side Effect]; nausea/si [Side Effect]; neutropenia/si [Side Effect]; oncogene; *overall survival; pain/si [Side Effect]; pancreatitis/si [Side Effect]; paresthesia/si [Side Effect]; phase 2 clinical trial; pneumonia/si [Side Effect]; priority journal; pruritus/si [Side Effect]; randomized controlled trial; rash/si [Side Effect]; respiratory failure/si [Side Effect]; side effect/si [Side Effect]; triacylglycerol lipase blood level; United States; vomiting/si [Side Effect]; alanine aminotransferase/ec [Endogenous Compound]; amylase/ec [Endogenous Compound]; aspartate aminotransferase/ec [Endogenous Compound]; *ipilimumab/ae [Adverse Drug Reaction]; *ipilimumab/ct [Clinical Trial]; *ipilimumab/cb [Drug Combination]; *ipilimumab/cm [Drug Comparison]; *ipilimumab/cm [Drug Comparison]; *ipilimumab/dt [Drug Therapy]; *ipilimumab/iv [Intravenous Drug Administration]; *nivolumab/ae [Adverse Drug Reaction]; *nivolumab/ct [Clinical Trial]; *nivolumab/cb [Drug Combination]; *nivolumab/cm [Drug Comparison]; *nivolumab/cm [Drug Comparison]; *nivolumab/dt [Drug Therapy]; *nivolumab/iv [Intravenous Drug Administration]; placebo; triacylglycerol lipase/ec [Endogenous Compound]; adverse drug reaction; cancer center; cancer epidemiology; clinical trial; colitis; controlled clinical trial; death; diarrhea; drug combination; drug therapy; follow up; funding; hazard ratio; hypophysitis; immunotherapy; interactive voice response system; intravenous drug administration; *melanoma; progression free survival; randomization; safety; side effect; staff; stratification; toxicity; visually impaired person; wild type; young adult; alanine aminotransferase; B Raf kinase; cytotoxic T lymphocyte antigen 4 antibody; endogenous compound; *ipilimumab; *nivolumab; programmed death 1 receptor
DOI: 10.1016/S1470-2045(16)30366-7
AB: METHODS: In this multicentre, double-blind, randomised, controlled, phase 2 trial (CheckMate 069) we recruited patients from 19 specialist cancer centres in two countries (France and the USA). Eligible patients were aged 18 years or older with previously untreated, unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo, every 3 weeks for four doses. Subsequently, patients assigned to nivolumab plus ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, whereas patients allocated to ipilimumab alone received placebo every 2 weeks during this phase. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by BRAF mutation status. The study funder, patients, investigators, and study site staff were masked to treatment assignment. The primary endpoint, which has been reported previously, was the proportion of patients with BRAFFINDINGS: Between Sept 16, 2013, and Feb 6, 2014, we screened 179 patients and enrolled 142, randomly assigning 95 patients to nivolumab plus ipilimumab and 47 to ipilimumab alone. In each treatment group, one patient no longer met the study criteria following randomisation and thus did not receive study drug. At a median follow-up of 24·5 months (IQR 9·1-25·7), 2-year overall survival was 63·8% (95% CI 53·3-72·6) for those assigned to nivolumab plus ipilimumab and 53·6% (95% CI 38·1-66·8) for those assigned to ipilimumab alone; median overall survival had not been reached in either group (hazard ratio 0·74, 95% CI 0·43-1·26; p=0·26). Treatment-related grade 3-4 adverse events were reported in 51 (54%) of 94 patients who received nivolumab plus ipilimumab compared with nine (20%) of 46 patients who received ipilimumab alone. The most common treatment-related grade 3-4 adverse events were colitis (12 [13%] of 94 patients) and increased alanine aminotransferase (ten [11%]) in the combination group and diarrhoea (five [11%] of 46 patients) and hypophysitis (two [4%]) in the ipilimumab alone group. Serious grade 3-4 treatment-related adverse events were reported in 34 (36%) of 94 patients who received nivolumab plus ipilimumab (including colitis in ten [11%] of 94 patients, and diarrhoea in five [5%]) compared with four (9%) of 46 patients who received ipilimumab alone (including diarrhoea in two [4%] of 46 patients, colitis in one [2%], and hypophysitis in one [2%]). No new types of treatment-related adverse events or treatment-related deaths occurred in this updated analysis.INTERPRETATION: Although follow-up of the patients in this study is ongoing, the results of this analysis suggest that the combination of first-line nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone in patients with advanced melanoma. The results suggest encouraging survival outcomes with immunotherapy in this population of patients.FUNDING: Bristol-Myers Squibb.BACKGROUND: Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/860/CN-01289860/frame.html


Record #54 of 144
ID: CN-01028203
AU: Carra T
AU: Caroline G-M
AU: Albarel F
AU: Monestier S
AU: Mallet S
AU: Brue T
AU: Richard M-A
AU: Grob JJ
TI: Ipilimumab-induced hypophysitis in melanoma patients
SO: Journal of clinical oncology
YR: 2012
VL: 30
NO: 15 SUPPL. 1
XR: EMBASE 71004918
PT: Journal: Conference Abstract
KY: *hypophysitis; *melanoma; *patient; *human; *society; *oncology; supplementation; diagnosis; libido disorder; cytotoxic T lymphocyte; headache; clinical trial (topic); nuclear magnetic resonance imaging; metastatic melanoma; asthenia; immune system; adrenal gland; swelling; hypophysis; adjuvant therapy; *ipilimumab; human monoclonal antibody; placebo; adjuvant; corticosteroid
AB: Background: Ipilimumab (Ipi) is a human monoclonal antibody directed against cytotoxic T-lymphocyte antigene-4 (CTLA-4) recently approved for the treatment of metastatic melanoma (MM) and currently under investigation in the adjuvant setting. Methods: Retrospective analysis of patients treated with ipi between June 2006 and September 2011 in our department in Marseille. As some patients are still blinded in trials, the exact number of patient under ipi is unknown. We present a minimal percentage (>%) assuming that the 120 patients received ipi. Results: A total of 120 patients were treated: 76 stages IV MM, from which 16 in the BMS clinical trials (CA184-022, -024, and-025 and MDX 010-20) and 44 stages III MM (in the BMS CA184-029 trial). Stage IV MM were administered 0.3, 3 or 10mg/kg IV dosage, while stages III MM were randomly assigned to receive 10 mg/ kg or placebo (1:1 ratio). Hypophysitis was diagnosed in 12 patients (>10%): 2/76 patients with stage IV MM (>2. 6 %) and 10/44 patients with stage III MM (>22.7). Diagnosis was performed at the 1<sup>st</sup>, 3<sup>rd</sup> and 4th administration in respectively 2 (1.6%), 6 (50%) and 4 patients (33.3%). Clinical symptoms included headaches (n=11; 91.6%), asthenia (n=7; 58.3%) and decreased libido (n=2; 1.6%). Adrenal, thyroidal and gonadal axis were affected in respectively 6 (50%), 9 (75%) and 7 patients (58.3%). MRI changes were observed in 7 patients (58.3%): pituitary swelling in 5 patients (41.6%) and heterogeneous enhancement in 4 patients (33.3%) including 2 patients with normal biology. Corticosteroids supplementation was required in 11 patients and thyroidian supplementation in 4 patients. Clinical symptoms regressed within one week in 8 patients (66.6%). Conclusions: Ipi-induced hypophysitis is detectable only if clinicians are aware of these unspecific signs. Only MRI can make diagnosis in some patients without clinical and/or biological signs. Our data suggest that it develops especially for 10mg/kg dosage, after the third administration, and that the rate could be higher in patients with a normal immune system (adjuvant treatment), than in metastatic ones. Hormonal supplementation usually controls the disease.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/203/CN-01028203/frame.html


Record #55 of 144
ID: CN-01303137
AU: Garcia-Manero G
AU: Daver NG
AU: Montalban-Bravo G
AU: Jabbour EJ
AU: DiNardo CD
AU: Kornblau SM
AU: Bose P
AU: Alvarado Y
AU: Ohanian M
AU: Borthakur G
AU: Cortes JE
AU: Naqvi K
AU: Pemmaraju N
AU: Huang X
AU: Nogueras-Gonzalez GM
AU: Bueso-Ramos CE
AU: Gasior Y
AU: Bayer VR
AU: Pierce S
AU: Yang H
AU: Colla S
AU: Kantarjian HM
TI: A phase II study evaluating the combination of nivolumab (Nivo) or Ipilimumab (Ipi) with azacitidine in pts with previously treated or untreated myelodysplastic syndromes (MDS)
SO: Blood. Conference: 58th annual meeting of the american society of hematology, ASH 2016. United states. Conference start: 20161203. Conference end: 20161206
YR: 2016
VL: 128
NO: 22) (no pagination
XR: EMBASE 614224878
PT: Journal: Conference Abstract
KY: acute leukemia; adrenal insufficiency; adverse drug reaction; biological activity; brain hemorrhage; clinical article; clinical trial; colitis; controlled clinical trial; controlled study; death; differentiation; disease course; drug combination; drug therapy; follow up; gene expression; human; monotherapy; mortality; *myelodysplastic syndrome; nephritis; pharmacokinetics; phase 2 clinical trial; pneumonia; rash; safety; side effect; solid tumor; stem cell; study design; thyroiditis; toxicity; *azacitidine; cytotoxic T lymphocyte antigen 4; endogenous compound; *ipilimumab; *nivolumab; programmed death 1 ligand 1; programmed death 1 receptor
AB: INTRODUCTION: Outcomes of pts with MDS after hypomethylating agent (HMA) failure remain poor. Improving the response and survival of pts with higher-risk MDS and developing treatments for pts after HMA failure is needed. Upregulation of PD-1, PD-L1 and CTLA-4 in MDS CD34+ cells after exposure and loss of response to HMA have been reported (Yang, Leukemia 2014). Nivo and Ipi are monoclonal antibodies targeting PD-1 and CTLA-4, respectively, with clinical activity in solid tumors. We hypothesized that use of these drugs after HMA failure or in combination with azacitidine (AZA) in the frontline setting may improve treatment outcomes of pts with MDS. METHODS: We designed a phase II study of Nivo or Ipi in monotherapy or combination for pts with MDS. Pts with prior therapy with HMA were to be treated in one of 3 consecutive cohorts: cohort #1: Nivo 3mg/kg iv days 1 and 15 of a 28 day cycle; cohort #2: Ipi 3mg/kg iv on day 1 of a 21 day cycle; cohort #3: Nivo 3 mg/kg iv on days 1 and 15 + Ipi 3 mg/kg iv on day 1 of a 28 day cycle. The study design allowed for AZA add-back after 6 cycles of therapy if there was no response or progression. Pts with previously untreated MDS were to be treated in one of 3 consecutive cohorts combining AZA 75mg/m<sup>2</sup> iv daily days 1-5 of a 28 day cycle in each cohort with: cohort #4: Nivo 3mg/kg iv Days 6 and 20; cohort #5: Ipi 3mg/kg iv on day 6; and cohort #6: Nivo 3 mg/kg iv on days 6 and 20 + Ipi 3 mg/kg iv on day 6. The maximum size per cohort is 20 pts. The primary endpoint is to determine the safety of Nivo or Ipi as single agents or in combination with AZA. Secondary objectives included overall response rate (ORR) and assessment of biological activity. Responses were evaluated following the revised 2006 International Working Group (IWG) criteria. The study included stopping rules for response and toxicity. Adverse events (AEs) were assessed and graded according to the CTCAE v4 criteria. RESULTS: A total of 39 pts were registered between September 2015 and July 2016, with 2 enrollment failures, 13 (35%) treated with frontline AZA+Nivo, and 15 (41%) and 9 (24%) with Nivo or Ipi after HMA failure, respectively. Thirty-five pts (95%) are evaluable for toxicity and 33 (89%) for response at the time of analysis. Patient characteristics are shown in Table 1. The median number of treatment cycles was 4 (range 2-11) in pts treated with AZA+Nivo, 3 (1-8) in the Nivo cohort, and 3 (2-4) in the Ipi cohort. A total of 25 (71%) pts experienced at least one AE during therapy (Table 2), with 3 (27%) pts in the AZA+Nivo cohort, 6 (40%) in the Nivo cohort, and 3 (33%) in the Ipi cohort having related grade >3 non-hematologic AEs. Therefore, the stopping rule for toxicity was not met in any of the cohorts. Delays of therapy due to AEs were required in 9 pts due to: rash (N=1), adrenal insufficiency (N=1), colitis (N=1), thyroiditis (N=2), pneumonitis (N=3), and nephritis (N=1). Early 8-week mortality occurred in 1 patient due to a non-related intracranial hemorrhage. The ORR was 69% (6/11) in the AZA+Nivo cohort including 2 CR, 5 mCR+HI, and 2 HI. The ORR was 0% and 22% (2/9) in the Nivo and Ipi arms, respectively (p=0.156). Therefore, the stopping rule for response was met on the Nivo arm, and enrollment after patient 15 was stopped. A total of 4 and 1 pts required addition of AZA due to lack of response on the Nivo and Ipi arms, respectively. At the present time of follow up, 18 (49%) pts remain on study, with 3 having been taken off study due to death (all in the Nivo arm), 3 due to no response (AZA+Nivo: 1; Nivo: 2), 6 due to progression to acute leukemia (AZA+Nivo: 1; Nivo: 4; Ipi: 1), 1 due to transplant, and 1 due to side effects from therapy in the Ipi arm. Immunophenotypic analysis of stem cell and progenitor compartments (Figure 1A) was performed in 27 pts, including PD-1 and PD-L1 expression analysis in 16 pts. Increased PD-1 and PD-L1 expression on progenitor and stem cell compartments was observed in 3 and 4 pts, respectively (Figure 1B). Treatment with PD-1 inhibitors could not overcome the aberrant differentiation patterns. No differences in response were observed based on PD-1 bone marrow expression. CONCLUSION: Preliminary results indicate that PD-1 blockade with Nivo in combination with AZA in untreated higher-risk MDS pts is associated with a tolerable safety profile and clinical activity. Single- agent Ipi is capable of inducing responses in previously treated MDS pts. Single-agent Nivo did not show clinical activity. Further follow-up is needed to update efficacy and safety data. (Figure Presented).
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/137/CN-01303137/frame.html


Record #56 of 144
ID: CN-01303094
AU: Badros AZ
AU: Hyjek E
AU: Ma N
AU: Lesokhin AM
AU: Rapoport AP
AU: Kocoglu MH
AU: Lederer E
AU: Philip S
AU: Lesho P
AU: Johnson A
AU: Dell C
AU: Goloubeva O
AU: Singh Z
TI: Pembrolizumab in combination with pomalidomide and dexamethasone for relapsed/refractory multiple myeloma (RRMM)
SO: Blood. Conference: 58th annual meeting of the american society of hematology, ASH 2016. United states. Conference start: 20161203. Conference end: 20161206
YR: 2016
VL: 128
NO: 22) (no pagination
XR: EMBASE 614225011
PT: Journal: Conference Abstract
KY: adrenal insufficiency; adult; aged; anemia; blood toxicity; chromosome aberration; clinical article; clinical trial; constipation; controlled clinical trial; controlled study; diagnosis; disease course; dizziness; drug combination; drug therapy; dyspnea; edema; fatigue; follow up; gene expression; genetic susceptibility; heart palpitation; human; hyperglycemia; hypertransaminasemia; hypothyroidism; infusion related reaction; interstitial pneumonia; lymphocytopenia; male; *multiple myeloma; neutropenia; pharmacokinetics; phase 2 clinical trial; plasmacytoma; rash; safety; sepsis; side effect; soft tissue; T lymphocyte; thrombocytopenia; upper respiratory tract infection; vitiligo; blocking antibody; carfilzomib; CD3 antigen; creatinine; *dexamethasone; endogenous compound; lenalidomide; *pembrolizumab; *pomalidomide; programmed death 1 ligand 1; programmed death 1 receptor; vaccine
AB: BACKGROUND: Immunotherapy in MM is emerging as an effective modality in therapy of MM with the approval of several monoclonal antibodies and encouraging results for vaccines and T cell therapy. Programmed death 1 (PD-1) receptor and its ligand (PD-L1) is one mechanism of immune evasion by MM to suppress T cell function. In this trial, we hypothesized that pembrolizumab, a PD-1-blocking antibody, would enhance immune modulatory properties of pomalidomide in RRMM pts. METHODS: In this single center, phase II study, 48 patients with RRMM received 28-day cycles of pembrolizumab (at a dose of 200 mg IV) every 2 weeks (in a run in phase, first 6 patients received 200 mg IV every 4 weeks) plus pomalidomide (4 mg daily x 21 days) and dexamethasone 40 mg weekly. Study objectives were measurements of safety & efficacy and correlation of the CD3/PD-1 on T cells and PD-L1 on plasma cells with response. RESULTS: The median age was 64 years (range: 35-82); 38% were black and 65% were men, Patients had a median of 3 lines of prior therapy (range: 2-6); All patients had received both IMids and Proteosome inhibitors; 70% had prior auto-SCT. 80% were double refractory to both IMids (lenalidomide) and Proteosome inhibitors [bortezomib (n=18) or carfilzomib (n=20)] and an additional 20% were refractory to lenalidomide. The median time from MM diagnosis to study entry was 4 years (range: 1-25). Most common cytogenetic abnormalities were 1q+ (60%), hyperdiploidy (15%) and high-risk FISH [del 17p, t(4:14) and/or t(14:16)] in 38%. Six patients had soft tissue extramedullary plasmacytomas. There were no infusion-related reactions. Hematologic toxicities (> grade 3) were anemia (21%), neutropenia (40%), lymphopenia (15%) and thrombocytopenia (8%). Non-hematologic events Grade >3 were fatigue (15%), hyperglycemia (25%), upper respiratory tract infections (21%), rash (10%); and most frequent grade >2 were dyspnea (54%), dizziness (44%), increased creatinine 38%, edema (35%), rash (30%), constipation 30%) and arrhythmias (19%). Events of clinical significance, autoimmune mediated, included interstitial pneumonitis (13%), hypothyroidism (10%), transaminitis(6%), adrenal insufficiency (4%) and vitiligo (2%). Nine pts had pomalidomide dose reductions due to rash, neutropenia, palpitations and fatigue; one pt reduced pembrolizumab for pneumonitis. At a median follow up of 10 months (range: 2-18): 25 pts continue on the study and 23 pts discontinued therapy due to disease progression (n= 15), side effects (n=7) and protocol violation (n=1). Five pts died while on study due to progressive disease (n=3), sepsis (n=1, sAE), and one from a cardiac event. Three additional pts died off therapy. On intent to treat analysis; the overall response rate (ORR) with > Partial response were observed in of 27 of 48 pts (56%) including: sCR (n=4, 8%), nCR (n=3, 6%), VGPR (n=6, 13%), PR (n=14, 29%). Additionally, 7 pts (15%) had minimal response, 9 (19%) had stable disease, 2 progressed and 3 were not evaluable for response. Of 38 double refractory pts ORR was 55% including, sCR (n=2, 5%), nCR (n=2, 5%), VGPR (n=4, 10%) and PR (n=13, 27%). Of 18 high-risk pts ORR was 33% including VGPR (n=2, 11%) and PR (n=4, 22%). Median duration of response for responding pts was 8.8 months and for pts > VGPR, DOR was 10.7 months. Correlation of PD-1 and PD-L1 expression and response will be presented. CONCLUSION: Pembrolizumab, pomalidomide and dexamethasone shows promising durable therapeutic activity and an acceptable safety profile in RRMM pts.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/094/CN-01303094/frame.html


Record #57 of 144
ID: CN-01419788
AU: Barone A
AU: Hazarika M
AU: Theoret MR
AU: Mishra-Kalyani P
AU: Chen H
AU: He K
AU: Sridhara R
AU: Subramaniam S
AU: Pfuma E
AU: Wang Y
AU: Li H
AU: Zhao H
AU: Zirkelbach JF
AU: Keegan P
AU: Pazdur R
TI: FDA approval summary: pembrolizumab for the treatment of patients with unresectable or metastatic melanoma
SO: Clinical cancer research
YR: 2017
VL: 23
NO: 19
PG: 5661-5665
XR: EMBASE 618870796
PT: Article
KY: adult; adverse event; cancer survival; chemotherapy; controlled study; drug therapy; female; hazard ratio; human; hyperthyroidism; hypothyroidism; major clinical study; male; *metastatic melanoma; overall survival; pneumonia; progression free survival; randomized controlled trial; response evaluation criteria in solid tumors; ipilimumab; *pembrolizumab
DOI: 10.1158/1078-0432.CCR-16-0664
AB: On December 18, 2015, the FDA granted regular approval to pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) for treatment of patients with unresectable or metastatic melanoma based on results of two randomized, open-label, active-controlled clinical trials. In trial PN006, 834 patients with ipilimumab-nave metastatic melanoma were randomized (1:1:1) to pembrolizumab 10 mg/kg i.v. every 2 or 3 weeks until disease progression or ipilimumab 3 mg/kg every 3 weeks for up to four doses. In trial PN002, 540 patients with ipilimumab-refractory metastatic melanoma were randomized (1:1:1) to pembrolizumab 2 or 10 mg/kg i.v. every 3 weeks or to investigator's choice of chemotherapy. In trial PN006, patients randomized to pembrolizumab demonstrated a statistically significant improvement in overall survival compared with ipilimumab [every-2-week arm: hazard ratio (HR) 1/4 0.63; 95% confidence interval (CI), 0.47-0.83; P < 0.001; every-3-week arm: HR 1/4 0.69; 95% CI, 0.52-0.90; P 1/4 0.004]. In both trials, patients receiving pembrolizumab demonstrated statistically significant improvements in progression-free survival. The most common (2%) immune-mediated adverse reactions in a pooled safety analysis were hypothyroidism, pneumonitis, and hyperthyroidism. Key considerations for approval were determination of pembrolizumab dose and interpretation of t b d d i t i RECIST i l t ed RECIST. Copyright © 2017 American Association for Cancer Research.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/788/CN-01419788/frame.html


Record #58 of 144
ID: CN-01399204
AU: Daver N
AU: Basu S
AU: Garcia-Manero G
AU: Cortes J
AU: Ravandi F
AU: Jabbour E
AU: Pemmaraju N
AU: Hendrickson S
AU: Gordon T
AU: Brandt M
AU: Pierce S
AU: Matthews J
AU: Kornblau S
AU: Flores W
AU: Konopleva M
AU: Kantarjian H
AU: Sharma P
TI: Phase IB/II study of nivolumab in combination with azacytidine (AZA) in patients (PTS) with relapsed acute myeloid leukemia (AML)
SO: Haematologica. Conference: 22th congress of the european hematology association. Spain
YR: 2017
VL: 102
PG: 176-177
XR: EMBASE 617379517
PT: Conference Abstract
KY: adult; adverse drug reaction; aged; aspiration; bone marrow cell; cancer susceptibility; CD8 T lymphocyte; clinical trial; colitis; controlled clinical trial; controlled study; cytogenetics; disease duration; drug combination; drug resistance; drug therapy; effector cell; epiglottitis; *female; flow cytometry; gene activation; gene inactivation; human; human cell; hypophysitis; immunotherapy; major clinical study; *male; mortality; nephritis; next generation sequencing; organ; phase 1 clinical trial; phase 2 clinical trial; pneumonia; rash; regulatory T lymphocyte; remission; *secondary acute myeloid leukemia; side effect; toxicity; treatment failure; tumor resistance; upregulation; *azacitidine; CCAAT enhancer binding protein alpha; CD3 antigen; CD4 antigen; CD8 antigen; cytotoxic T lymphocyte antigen 4; DNA methyltransferase 3A; endogenous compound; inducible T cell costimulator; *nivolumab; protein p53; steroid
AB: Background: Blocking PD-1/PD-L1 pathways enhances anti-leukemia responses in murine AML (Zhang et al, Blood 2009). PD-1 positive CD8 T-cells are increased in bone marrow (BM) of pts with AML (Daver et al, AACR 2016). AZA up-regulates PD-1 and interferon-gamma signaling in AML and the upregulation of PD-1 has been associated with emergence of resistance to AZA (Yang et al., Leukemia 2013). Aims: To assess the best response to Aza+Nivo at the end of 3 courses of combination therapy. Methods: Pts were eligible if they had AML and failed prior therapy, had adequate performance status (ECOG <=2), and organ function. The first six pts received AZA 75mg/m<sup>2</sup> Days 1-7 with nivolumab 3mg/kg on Day 1 and 14. Courses were repeated every 4-5 weeks indefinitely. Only one of six pts had a dose limiting toxicity (grade 3 pneumonitis) and this dose was RP2D. 60 additional pts have been treated at the RP2D. Results: 66 pts with a median age of 71 years (range, 44-90), secondary AML (39%), poor risk cytogenetics (35%), median number of prior regimens 2 (range, 1-7) have been enrolled. All 66 pts had baseline next generation sequencing: TP53 (n=14), DNMT3A (n=12), ASXL1 (n=10), TET2 (N=9), and RAS (n=9), IDH2 (n=9), IDH1 (n=6), CEBPA (n=7). 63 pts are evaluable for response: 14 (22%) achieved complete remission (CR)/complete remission with insufficient recovery of counts (CRi) (3 CR, 11 CRi), 7 (11%) had hematologic improvement (HI), 13 (21%) had >=50% BM blast reduction, 5 pts (8%) had stable disease >6 months, and 24 (38%) had progression. 3 pts are too early for response assessment (<3 courses). The median number of courses to CR/CRi/HI was 2 (range, 1-4+). The med OS among the CR/CRi patients was 15.3 months (range, 2.29- 17.25+), HI pts was 9.7 months (range, 4.67-17.45+), and NR was 5.0 months (range, 0.29-16.16). The 4- and 8-week mortality were 5% and 11%, respectively. The median OS for the 63 evaluable pts on Aza+Nivo compares favorably to historical median OS with AZA-based salvage protocols in similar pts treated at MDACC (P=0.10) (Fig 1A and Fig 1B). Grade 3/4 and Grade 2 immune toxicities were observed in 8 (12%) and 7 (11%) pts, respectively. The most common Grade 3/4 AEs on treatment included pneumonitis, colitis, nephritis, skin rash, and hypophysitis. One pt died from grade 4 pneumonitis/epiglottitis. In the remaining 14 cases the toxicities responded rapidly to steroids and 13 of these pts were successfully rechallenged with nivolumab. Time to onset of toxicities ranged from 4 days to 3.5 months. Multicolor flow-cytometry studies and Mass-cytometry (CyTOF) studies are conducted by the Immunotherapy Platform on baseline and on-treatment BM aspirate (end of cycle 1, 2, 4, 8). Baseline and end of cycle (EOC) 1 and 2 BM was evaluated in 6 responders and 19 non-responders. Pts who achieved a response had a baseline higher live total CD3 (P=0.10), CD8+ T-cells (P=0.02), and lower live CD4+Foxp3+PD1+ T-regulatory (T-reg) cells (P=0.01) infiltrate in BM. Patients who had a response had progressive increase in BM CD3+ cells and BM CD8+ cells, with increased ICOS (activation) marker on BM CD4-effector cells at EOC 1 and EOC 2 as compared to those who had no response. The CTLA4 on CD8 T-cells went up in both responders and non-responders after PD1 based therapy. (Figure Presented) Summary/Conclusions: Full dose AZA and nivolumab are tolerable and produce an encouraging response rate with durable responses in relapsed AML with poor risk features. Immune mediated toxicities occur and may be adequately managed with early recognition and systemic steroids. Up-regulation of CTLA4 may be a mechanism of resistance to PD1 based therapies in AML and suggest role for combination therapy.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/204/CN-01399204/frame.html


Record #59 of 144
ID: CN-01296109
AU: Graff JN
AU: Alumkal JJ
AU: Drake CG
AU: Thomas GV
AU: Redmond WL
AU: Farhad M
AU: Slottke R
AU: Beer TM
TI: First evidence of significant clinical activity of PD-1 inhibitors in metastatic castration resistant prostate cancer (mCRPC)
SO: Annals of oncology. Conference: 41st european society for medical oncology congress, ESMO 2016. Denmark. Conference start: 20161007. Conference end: 20161011
YR: 2016
VL: 27
NO: no pagination
XR: EMBASE 613911489
PT: Journal: Conference Abstract
KY: adverse drug reaction; antineoplastic activity; *castration resistant prostate cancer; clinical trial; colitis; controlled clinical trial; controlled study; drug resistance; drug therapy; follow up; gene expression regulation; gene inactivation; human; human tissue; hypothyroidism; immune response; immunohistochemistry; leukocyte; liver disease; lymph node; major clinical study; male; microsatellite instability; myositis; overall survival; pain; patient history of chemotherapy; phase 2 clinical trial; progression free survival; sample size; side effect; tumor biopsy; androgen; androgen receptor antagonist; CD3 antigen; endogenous compound; enzalutamide; opiate; pembrolizumab; programmed death 1 ligand 1; *programmed death 1 receptor; prostate specific antigen
DOI: 10.1093/annonc/mdw372.3
AB: Background: PD-1 inhibition has demonstrated improved survival for patients with various solid tumors, but its role in prostate cancer has yet to be defined. Based on observations that PD-L1 expression is increased upon resistance to enzalutamide and androgen inhibition modulates the immune response to prostate cancer, we hypothesized that the addition of the PD-1 inhibitor pembrolizumab to enzalutamide at resistance could result in clinically important anti-tumor activity. Methods:We treated men with mCRPC progressing on the androgen receptor antagonist enzalutamide on a phase II study of pembrolizumab 200 mg IV every 3 weeks for 4 doses with continued enzalutamide. Prior chemotherapy for mCRPC was prohibited. The primary endpoint is the proportion of men with a prostate specific antigen (PSA) response > 50%. The secondary endpoints are objective disease response, PSA progression free survival, and overall survival. The sample size sufficient to detect a 25% response rate served as the basis for the statistical design. Tissue biopsy is performed if feasible. Results: As of 22 July 2016, 20 patients have completed pembrolizumab treatment with a median follow up of 18 weeks. 4 of 20 subjects treated to date (20%) have achieved a confirmed PSA reduction > 50%, reached a serum PSA < 0.1 ng/ml, and remain progression free after 16-61 weeks. 7 have stable disease of 9-50 weeks. 8 patients had progressive disease. 2 of the 4 PSA responders had measurable disease (liver, lymph nodes) and are evaluable for objective response. Both achieved a partial response and remain in response status after 61 and 22 weeks of follow-up. Two of the responders were able to discontinue opioid analgesic after reporting resolution of cancer-related pain. 5 patients had significant immune-related adverse events (grade 2 myositis, grade 3 hypothyroidism, grade 2 hypothyroidism, 2 with grade 3 colitis). Immunohistochemistry from baseline biopsies of two responders showed the presence of CD3 + , CD8 + , and CD163+ leukocyte infiltrates and PD-L1 expression. 2 of the 4 responders had a tumor biopsy and 1 had microsatellite instability in the tumor. Conclusions: Early results demonstrate reproducible, profound, and - to date - durable responses to PD-1 inhibition with enzalutamide in men with mCRPC.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/109/CN-01296109/frame.html


Record #60 of 144
ID: CN-01286658
AU: Schmid TA
AU: Gore ME
TI: Sunitinib in the treatment of metastatic renal cell carcinoma
SO: Therapeutic advances in urology
YR: 2016
VL: 8
NO: 6
PG: 348-371
XR: EMBASE 613375206
PT: Journal: Review
KY: asthenia; clinical trial (topic); constipation/si [Side Effect]; diarrhea/si [Side Effect]; drug dose escalation; drug efficacy; drug tolerability; dysgeusia/si [Side Effect]; dyspepsia/si [Side Effect]; epistaxis/si [Side Effect]; fatigue/si [Side Effect]; hand foot syndrome/si [Side Effect]; headache/si [Side Effect]; hemolytic anemia/si [Side Effect]; human; hypertension/si [Side Effect]; hyponatremia/si [Side Effect]; hypothyroidism/si [Side Effect]; *kidney metastasis/dt [Drug Therapy]; kidney metastasis/dt [Drug Therapy]; nausea/si [Side Effect]; peripheral edema/si [Side Effect]; phase 1 clinical trial (topic); phase 2 clinical trial (topic); phase 3 clinical trial(topic); priority journal; proteinuria/si [Side Effect]; rash/si [Side Effect]; review; stomatitis/si [Side Effect]; thrombocytopenia/si [Side Effect]; thrombotic thrombocytopenic purpura/si [Side Effect]; toxicity/si [Side Effect]; tumor regression; alpha interferon/ae [Adverse Drug Reaction]; bevacizumab/ae [Adverse Drug Reaction]; bevacizumab/cb [Drug Combination]; bevacizumab/iv [Intravenous Drug Administration]; everolimus/cb [Drug Combination]; everolimus/po [Oral Drug Administration]; mammalian target of rapamycin inhibitor; nivolumab/ae [Adverse Drug Reaction]; nivolumab/cb [Drug Combination]; pazopanib; protein tyrosine kinase inhibitor; rocapuldencel T/cb [Drug Combination]; sorafenib; *sunitinib/ae [Adverse Drug Reaction]; *sunitinib/ct [Clinical Trial]; *sunitinib/dt [Drug Therapy]; *sunitinib/po [Oral Drug Administration]; temsirolimus/cb [Drug Combination]; temsirolimus/iv [Intravenous Drug Administration]; trebananib/cb [Drug Combination]; trebananib/iv [Intravenous Drug Administration]; vasculotropin receptor/ec [Endogenous Compound]; adverse drug reaction; clinical trial; comparative effectiveness; controlled clinical trial; controlled study; diarrhea; fatigue; human cell; hypertension; hypothyroidism; *kidney metastasis; *molecularly targeted therapy; nausea; phase 2 clinical trial; phase 3 clinical trial; remission; side effect; skin; toxicity; alpha interferon; endogenous compound; *pazopanib; *sunitinib
DOI: 10.1177/1756287216663979
AB: Sunitinib is an oral multi-targeted tyrosine kinase inhibitor (TKI) that targets various receptors, including vascular endothelial growth factor receptors (VEGFRs). Sunitinib received approval in 2006 and became a standard treatment option in the first-line treatment of metastatic renal cell cancer (mRCC) after a phase III trial showed superiority compared with interferon alpha (IFN-alpha). Sunitinib has also shown activity in second-line treatment in several trials. Most of the combination trials with sunitinib with various agents have led to considerable toxicity without improving efficacy. Sunitinib alone causes significant side effects and has a distinct profile with diarrhoea, hypertension, skin effects hypothyroidism, fatigue and nausea of special interest. The recommended dose of sunitinib in mRCC is 50 mg orally daily for 4 weeks, followed by 2 weeks off treatment (4/2 schedule). An alternative 2 weeks on, 1 week off schedule (2/1 schedule) seems to be of similar efficacy and better tolerability and could be more widely used in the future. An intermittent treatment strategy with a stop in remission and re-induction after progression showed efficacy in smaller trials and is currently being evaluated in a phase III trial. Direct comparison of sunitinib with pazopanib in first-line treatment showed a similar efficacy for both TKIs with a distinct toxicity profile. Data from two phase II trials showed that sunitinib has also activity in non-clear cell cancer and is an option due to a lack of better alternatives. Currently, after immune checkpoint inhibitors have shown very promising results in the second-line treatment of RCC, they are being tested in a number of phase III trials in the first-line setting. The future will show the position of sunitinib in the first-line treatment of RCC in the era of the immune checkpoint inhibitors. Copyright © SAGE Publications.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/658/CN-01286658/frame.html


Record #61 of 144
ID: CN-01244337
AU: Schmid TA
AU: Gore ME
TI: Sunitinib in the treatment of metastatic renal cell carcinoma
SO: Therapeutic advances in urology
YR: 2016
VL: 8
NO: 6
PG: 348-371
XR: EMBASE 613375206
PT: Journal: Review
KY: adverse drug reaction; clinical trial; comparative effectiveness; controlled clinical trial; controlled study; diarrhea; fatigue; human; human cell; hypertension; hypothyroidism; *kidney metastasis; *molecularly targeted therapy; nausea; phase 2 clinical trial; phase 3 clinical trial; remission; side effect; skin; toxicity; alpha interferon; endogenous compound; *pazopanib; *sunitinib
DOI: 10.1177/1756287216663979
AB: Sunitinib is an oral multi-targeted tyrosine kinase inhibitor (TKI) that targets various receptors, including vascular endothelial growth factor receptors (VEGFRs). Sunitinib received approval in 2006 and became a standard treatment option in the first-line treatment of metastatic renal cell cancer (mRCC) after a phase III trial showed superiority compared with interferon alpha (IFN-alpha). Sunitinib has also shown activity in second-line treatment in several trials. Most of the combination trials with sunitinib with various agents have led to considerable toxicity without improving efficacy. Sunitinib alone causes significant side effects and has a distinct profile with diarrhoea, hypertension, skin effects hypothyroidism, fatigue and nausea of special interest. The recommended dose of sunitinib in mRCC is 50 mg orally daily for 4 weeks, followed by 2 weeks off treatment (4/2 schedule). An alternative 2 weeks on, 1 week off schedule (2/1 schedule) seems to be of similar efficacy and better tolerability and could be more widely used in the future. An intermittent treatment strategy with a stop in remission and re-induction after progression showed efficacy in smaller trials and is currently being evaluated in a phase III trial. Direct comparison of sunitinib with pazopanib in first-line treatment showed a similar efficacy for both TKIs with a distinct toxicity profile. Data from two phase II trials showed that sunitinib has also activity in non-clear cell cancer and is an option due to a lack of better alternatives. Currently, after immune checkpoint inhibitors have shown very promising results in the second-line treatment of RCC, they are being tested in a number of phase III trials in the first-line setting. The future will show the position of sunitinib in the first-line treatment of RCC in the era of the immune checkpoint inhibitors. Copyright © SAGE Publications.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/337/CN-01244337/frame.html


Record #62 of 144
ID: CN-01450300
AU: Flowers C
AU: Panizo C
AU: Isufi I
AU: Herrera AF
AU: Okada C
AU: Cull EH
AU: Kis B
AU: Chaves JM
AU: Bartlett NL
AU: Ai W
AU: Cruz-Merino L
AU: Bryan LJ
AU: Houot R
AU: Linton K
AU: Briones J
AU: Chau I
AU: Keudell GR
AU: Lu H
AU: Hsu FJ
AU: Halwani AS
TI: Intratumoral G100 induces systemic immunity and abscopal tumor regression in patients with follicular lymphoma: results of a phase 1/2 study examining g100 alone and in combination with pembrolizumab
SO: Blood. Conference: 59th annual meeting of the american society of hematology, ASH 2017. United states
YR: 2017
VL: 130
NO: Supplement 1) (no pagination
XR: EMBASE 620385431
PT: Conference Abstract
KY: adrenal insufficiency; adult; advertising; cancer size; colitis; congenital malformation; controlled study; death; disease free interval; drug therapy; female; flower; *follicular lymphoma; follow up; gene expression; human; human cell; hypothyroidism; immunotherapy; intratumoral drug administration; low energy radiation; major clinical study; male; monotherapy; pharmacokinetics; phase 1 clinical trial; randomized controlled trial; T lymphocyte; toxicity; tumor associated leukocyte; tumor biopsy; *tumor immunity; *tumor regression; CD4 antigen; CD8 antigen; endogenous compound; isobutylene; *pembrolizumab; programmed death 1 ligand 1; programmed death 1 receptor; conference abstract
AB: Background: Despite numerous treatment (Tx)options, follicular lymphoma (FL) remains incurable. G100 is a TLR-4 (toll-like receptor-4) agonist that activates both the innate and adaptive arms of the immune system. When given intratumorally (IT), G100 triggers an ANTI-tumor immune response that has led to systemic tumor shrinkage and long-lasting disease control in animal models and cancer patients (pts) and the combination of G100/ANTI-PD-1 antibodies has increased animal survival (Barfi ASH 2015, Bhatia ASCO 2016). We previously reported results of Part 1 dose escalation of IT G100 up to 20mu g in FL pts demonstrating that G100 was well tolerated and induced tumor responses in both the locally treated and untreated distal (abscopal) sites (Flowers ASCO 2017). We now present updated results of Part 1 and results of Part 2 which evaluated safety and efficacy of G100 alone and in combination with pembrolizumab (P) in FL pts in a randomized study. Methods: Previously treated (PTx) or Tx naive FL pts with >=2 tumor sites were eligible. Pts received 6-9 doses of IT G100 weekly to a site treated with low dose radiation (RT, 2 Gy x2 doses). A 2<sup>nd</sup> course of G100 could be given without RT to an additional site. In Part 2, pts were randomized to IT G100 (10 mu g/dose) or IT G100 + P 200 mg IV on Day 14 then q3wks for up to 2 years. Responses were evaluated by IrRC criteria based on bidimensional measurements (Wolchok ClCanRes 2009). Untreated sites were followed for abscopal response. Blood samples and tumor biopsies from treated and/or abscopal sites were obtained at baseline and post-G100. Results: As of 29June2017, 36 FL pts were treated (Part 1, 10 pts; Part 2, 26 pts: 13, G100 vs. 13, G100 + P). Pts included 19 Tx naive and 17 PTx (median # Tx 3, range 1-7, including 6 with Auto-SCT). G100 was well tolerated; related AEs were all grade (Gr) 1/2 with no G100-related DLTs or SAEs. For G100+P, 1 pt each experienced Gr 2 hypothyroidism, Gr 3 colitis/lab abnormalities/adrenal insufficiency (SAE). No deaths were reported. In Part 2 Randomized (n=26, median follow-up 5.1 mos) overall best responses were: G100 alone, 2 (15%) PRs (50-99% reduction), 4 (31%) MRs (minor response, 25-49% reduction), 5 (39%) SDs (<25% reduction), 2 (15%) PDs (>25% increase); and G100 + P, 4 (31%) PRs, 3 (23%) MRs, 5 (39%) SDs, 1 (7%) PD. Ongoing shrinkage of untreated sites has been observed, indicating that tumor MR may deepen over time. Abscopal tumor reduction occurred in 6 (46%) pts (range 19-52% reduction) on G100 and 8 (62%) pts (range 10-80%) on G100 + P. Abscopal tumor reductions of >10cm<sup>2</sup> were seen in 1 (8%) pt on G100 and 4 (31%) pts on G100 + P. For PR/MR pts, the median time to progression (TTP) for G100 alone and G100+P has not been reached. Overall best response to G100 monotherapy in Part 1 and 2 combined (n=23, median follow up 6.8 mos) was 6 (26%) PRs, 6 (26%) MRs, 9 (39%) SDs and 2 (9%) PDs. Abscopal tumor reduction occurred in 11 (48%) pts (range 11-78% reduction). For PR/MR pts, median TTP has not been reached (range: 1.9 to 11.5 mos). Responses were observed in both Tx naive [11 pts: 2 (18%) PRs, 4 (36%) MRs; 8 (73%) pts with abscopal shrinkage] and PTx pts [12 pts: 4 (33%) PRs, 2 (17%) MRs; 3 (25%) pts with abscopal shrinkage] including 1 PR in a pt with prior Auto-SCT. Tumor biopsies post-G100 exhibited increased CD8 infiltration as well as CD8/CD4 T cells co-expressing PD-L1 in both treated and distal abscopal sites. T cell repertoire s<sup>Ju</sup>tu<sup>m</sup>d<sup>p</sup>ie <sup>t</sup>s<sup>o</sup> revealed new and expanded clones of T cells in the tumor (tumor-infiltrating lymphocytes, TILs). Conclusions: G100 is a well tolerated active agent in FL with 52% pts experiencing clinical benefit (26% PR, 26% MR). The addition of P did not result in unexpected toxicity, and may have an effect on the degree and duration of tumor reduction. Longer follow-up will be required to determine the durability and depth of these responses. IT G100 therapy induced an inflammatory response locally that led to systemic ANTI-tumor responses with Advertisement tumor infiltration by activated CD8 T cells and expansion of TIL clones in treated and abscopal sites. Shrinkage of abscopal sites signified the induction or boosting of systemic ANTI-tumor immunity. With its unique mechanism of action, G100 may be an attractive option for FL pts in need of a low toxicity treatment that would not interfere/reduce the effectiveness of future therapies and could be combined with ANTI-PD-1 inhibitors or other immunotherapies. This study is ongoing and enrolling pts to examine the activity of 20mu g G100/dose.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/300/CN-01450300/frame.html


Record #63 of 144
ID: CN-01453036
AU: Flowers C
AU: Panizo C
AU: Isufi I
AU: Herrera AF
AU: Okada C
AU: Cull EH
AU: Kis B
AU: Chaves JM
AU: Bartlett NL
AU: Ai W
AU: Cruz-Merino L
AU: Bryan LJ
AU: Houot R
AU: Linton K
AU: Briones J
AU: Chau I
AU: Keudell GR
AU: Lu H
AU: Hsu FJ
AU: Halwani AS
TI: Intratumoral G100 induces systemic immunity and abscopal tumor regression in patients with follicular lymphoma: results of a phase 1/2 study examining g100 alone and in combination with pembrolizumab
SO: Blood. Conference: 59th annual meeting of the american society of hematology, ASH 2017. United states
YR: 2017
VL: 130
NO: Supplement 1) (no pagination
XR: EMBASE 620385431
PT: Conference Abstract
KY: adrenal insufficiency; adult; advertising; cancer size; colitis; congenital malformation; controlled study; death; disease free interval; drug therapy; female; flower; *follicular lymphoma; follow up; gene expression; human; human cell; hypothyroidism; immunotherapy; intratumoral drug administration; low energy radiation; major clinical study; male; monotherapy; pharmacokinetics; phase 1 clinical trial; randomized controlled trial; T lymphocyte; toxicity; tumor associated leukocyte; tumor biopsy; *tumor immunity; *tumor regression; CD4 antigen; CD8 antigen; endogenous compound; isobutylene; *pembrolizumab; programmed death 1 ligand 1; programmed death 1 receptor; conference abstract
AB: Background: Despite numerous treatment (Tx)options, follicular lymphoma (FL) remains incurable. G100 is a TLR-4 (toll-like receptor-4) agonist that activates both the innate and adaptive arms of the immune system. When given intratumorally (IT), G100 triggers an ANTI-tumor immune response that has led to systemic tumor shrinkage and long-lasting disease control in animal models and cancer patients (pts) and the combination of G100/ANTI-PD-1 antibodies has increased animal survival (Barfi ASH 2015, Bhatia ASCO 2016). We previously reported results of Part 1 dose escalation of IT G100 up to 20mu g in FL pts demonstrating that G100 was well tolerated and induced tumor responses in both the locally treated and untreated distal (abscopal) sites (Flowers ASCO 2017). We now present updated results of Part 1 and results of Part 2 which evaluated safety and efficacy of G100 alone and in combination with pembrolizumab (P) in FL pts in a randomized study. Methods: Previously treated (PTx) or Tx naive FL pts with >=2 tumor sites were eligible. Pts received 6-9 doses of IT G100 weekly to a site treated with low dose radiation (RT, 2 Gy x2 doses). A 2<sup>nd</sup> course of G100 could be given without RT to an additional site. In Part 2, pts were randomized to IT G100 (10 mu g/dose) or IT G100 + P 200 mg IV on Day 14 then q3wks for up to 2 years. Responses were evaluated by IrRC criteria based on bidimensional measurements (Wolchok ClCanRes 2009). Untreated sites were followed for abscopal response. Blood samples and tumor biopsies from treated and/or abscopal sites were obtained at baseline and post-G100. Results: As of 29June2017, 36 FL pts were treated (Part 1, 10 pts; Part 2, 26 pts: 13, G100 vs. 13, G100 + P). Pts included 19 Tx naive and 17 PTx (median # Tx 3, range 1-7, including 6 with Auto-SCT). G100 was well tolerated; related AEs were all grade (Gr) 1/2 with no G100-related DLTs or SAEs. For G100+P, 1 pt each experienced Gr 2 hypothyroidism, Gr 3 colitis/lab abnormalities/adrenal insufficiency (SAE). No deaths were reported. In Part 2 Randomized (n=26, median follow-up 5.1 mos) overall best responses were: G100 alone, 2 (15%) PRs (50-99% reduction), 4 (31%) MRs (minor response, 25-49% reduction), 5 (39%) SDs (<25% reduction), 2 (15%) PDs (>25% increase); and G100 + P, 4 (31%) PRs, 3 (23%) MRs, 5 (39%) SDs, 1 (7%) PD. Ongoing shrinkage of untreated sites has been observed, indicating that tumor MR may deepen over time. Abscopal tumor reduction occurred in 6 (46%) pts (range 19-52% reduction) on G100 and 8 (62%) pts (range 10-80%) on G100 + P. Abscopal tumor reductions of >10cm<sup>2</sup> were seen in 1 (8%) pt on G100 and 4 (31%) pts on G100 + P. For PR/MR pts, the median time to progression (TTP) for G100 alone and G100+P has not been reached. Overall best response to G100 monotherapy in Part 1 and 2 combined (n=23, median follow up 6.8 mos) was 6 (26%) PRs, 6 (26%) MRs, 9 (39%) SDs and 2 (9%) PDs. Abscopal tumor reduction occurred in 11 (48%) pts (range 11-78% reduction). For PR/MR pts, median TTP has not been reached (range: 1.9 to 11.5 mos). Responses were observed in both Tx naive [11 pts: 2 (18%) PRs, 4 (36%) MRs; 8 (73%) pts with abscopal shrinkage] and PTx pts [12 pts: 4 (33%) PRs, 2 (17%) MRs; 3 (25%) pts with abscopal shrinkage] including 1 PR in a pt with prior Auto-SCT. Tumor biopsies post-G100 exhibited increased CD8 infiltration as well as CD8/CD4 T cells co-expressing PD-L1 in both treated and distal abscopal sites. T cell repertoire s<sup>Ju</sup>tu<sup>m</sup>d<sup>p</sup>ie <sup>t</sup>s<sup>o</sup> revealed new and expanded clones of T cells in the tumor (tumor-infiltrating lymphocytes, TILs). Conclusions: G100 is a well tolerated active agent in FL with 52% pts experiencing clinical benefit (26% PR, 26% MR). The addition of P did not result in unexpected toxicity, and may have an effect on the degree and duration of tumor reduction. Longer follow-up will be required to determine the durability and depth of these responses. IT G100 therapy induced an inflammatory response locally that led to systemic ANTI-tumor responses with Advertisement tumor infiltration by activated CD8 T cells and expansion of TIL clones in treated and abscopal sites. Shrinkage of abscopal sites signified the induction or boosting of systemic ANTI-tumor immunity. With its unique mechanism of action, G100 may be an attractive option for FL pts in need of a low toxicity treatment that would not interfere/reduce the effectiveness of future therapies and could be combined with ANTI-PD-1 inhibitors or other immunotherapies. This study is ongoing and enrolling pts to examine the activity of 20mu g G100/dose.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/036/CN-01453036/frame.html


Record #64 of 144
ID: CN-01400068
AU: Roche L
AU: Murphy M
AU: Power DG
TI: Treatment of merkel cell carcinoma with pembrolizumab in a patient with psoriasis and psoriatic arthritis
SO: Journal of the european academy of dermatology and venereology. Conference: 13th congress of the european association of dermato-oncology, EADO 2017. Greece
YR: 2017
VL: 31
PG: 96
XR: EMBASE 617070172
PT: Conference Abstract
KY: adverse drug reaction; alopecia; cancer epidemiology; case report; chemotherapy; clinical trial; controlled clinical trial; controlled study; drug therapy; dry skin; erysipelas; *female; follow up; human; maculopapular rash; *male; *merkel cell carcinoma; phase 2 clinical trial; progression free survival; pruritus; *psoriatic arthritis; scar; side effect; squamous cell carcinoma; toxicity; treatment duration; avelumab; endogenous compound; *pembrolizumab; programmed death 1 ligand 1; programmed death 1 receptor
DOI: 10.1111/jdv.02-14275
AB: Merkel cell carcinoma is a rare and difficult to treat neuroendocrine skin cancer. Pembrolizumab, an anti T-cell programmed death-1 (PD1) antibody, has been shown to induce durable responses in metastatic disease in recent studies. Treatment with pembrolizumab has been reported to have an immune-stimulant effect with flares of inflammatory cutaneous diseases reported. We report a case of effective treatment of metastatic merkel cell carcinoma with pembrolizumab, initiated without a flare of pre-existing psoriasis and psoriatic arthritis. Our case highlights the efficacy of pembrolizumab treatment for metastatic MCC. Our case also highlights that such treatment can be safely initiated in patients with psoriasis and psoriatic arthritis. Long term data are lacking with pembrolizumab and avelumab in metastatic MCC, however from the 2 phase II trials median duration of follow-up is between 7-10 months and response rates from 31-56% are reported with progression free survival at 6 months is 40-67%. The pivotal pembrolizumab trial is a first-line study6 and the avelumab trial is a second-line trial after chemotherapy8. The optimum duration of treatment is as yet unclear and whether these agents are used optimally in first or second line is also unclear. Cutaneous toxicities from the pembrolizumab trial accounted for 15% of adverse events6 (alopecia - 7.7%, itching scar - 3.8%, pruritus - 3.8% and rash - 3.8%) and in the avelumab trial, 24% of adverse events8 (rash - 6.8%, maculopapular rash - 5.7%, pruritus - 4.5%, dry skin 2.3%, erysipelas - 1.1%, squamous cell carcinoma of the skin - 1.1%) all adverse events were manageable with no cutaneous adverse event classed higher than a Grade1-2 in either trial. It is very likely, that PD-1 and PD-L1 inhibitors will become a standard first line therapy in advanced MCC and chemotherapy will be moved to second line.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/068/CN-01400068/frame.html


Record #65 of 144
ID: CN-01294252
AU: Waterhouse DM
AU: George B
AU: Gutierrez M
AU: Otterson GA
AU: Ko A
AU: Ong TJ
AU: Stergiopoulos S
AU: Trunova N
AU: Kelly K
TI: Phase I study of nivolumab (nivo) + nab-Paclitaxel (nab-P) + carboplatin (C) in advanced NSCLC: safety and efficacy results
SO: Cancer research. Conference: 107th annual meeting of the american association for cancer research, AACR 2016. United states. Conference start: 20160416. Conference end: 20160420
YR: 2016
VL: 76
NO: 14 Supplement) (no pagination
XR: EMBASE 613610313
PT: Journal: Conference Abstract
KY: adenocarcinoma; adverse drug reaction; aged; antineoplastic activity; area under the curve; clinical article; clinical trial; controlled clinical trial; *controlled study; death; disease duration; drug therapy; drug withdrawal; female; human; hypokalemia; male; metastasis; monotherapy; neutropenia; *non small cell lung cancer; patient history of chemotherapy; pharmacokinetics; phase 1 clinical trial; pneumonia; *safety; side effect; squamous cell carcinoma; thyroid disease; toxicity; tumor volume; nivolumab; paclitaxel
DOI: 10.1158/1538-7445.AM2016-CT141
AB: Background: Chemotherapy leads to tumor lysis and release of tumor antigens, which may prime the immune system for checkpoint inhibitors. The combination of a taxane + immune checkpoint inhibitor has been reported to improve response in nonsmall cell lung cancer (NSCLC; Giaccone et al. ESMO 2015 [abstract 247]). This analysis provides interim results from the first of the 2 lung cohorts of a phase I study of nivo with the standard dose and schedule of nab-P/ C. Methods: The 2 lung cohorts (Arms C and D) were initiated sequentially in part 1 of the study. In Arm C, patients (pts) with stage IIIB/IV NSCLC and no prior chemotherapy for metastatic disease received 4 cycles of nab-P 100 mg/m2 on days 1, 8, and 15 + C area under the curve 6 on day 1 of a 21day cycle in combination with nivo 5 mg/kg on day 15 starting at cycle 1. Nivo was continued as monotherapy at cycle 5. The same regimen was administered in Arm D, with nivo starting at cycle 3.The primary objective of part 1 was the number of doselimiting toxicities (DLTs) in each treatment arm, including grade 3/4 treatmentemergent adverse events (TEAEs) and TEAEs leading to discontinuation. Pts treated with ? 2 cycles of nivo + nab-P/ C or who discontinued due to DLT after the start of nivo and prior to completing 2 cycles of nivo + nab-P/ C were considered DLT evaluable. If deemed safe per DLT evaluation, the treatment arms may be expanded to further assess safety, tolerability, and antitumor activity. Results: As of Nov 9, 2015, 12 pts had been enrolled in Arm C; of these, 9 received nivo + nab-P/ C before the data cut off date. Overall, most pts were aged ? 65 years (67%) and female (58%); 58% had adenocarcinoma, and 42% had squamous cell carcinoma. No DLTs were observed. The most frequent grade ? 3 TEAEs common to all treated pts and, separately, those treated with nivo + nab-P/ C were neutropenia (25% and 22%) and hypokalemia (17% and 22%, 2 out of 3 pts had history of thyroid disorder). No pneumonitis has been reported to date. Of the 9 nivotreated, response evaluable pts, 6 had a partial response, and 3 had stable disease (SD). In pts not receiving nivo, 1 patient had SD. Overall tumor burden decrease from baseline in total length of target lesions of responding pts ranged from 31% to 83%. Two pts discontinued treatment prior to nivo administration (1 due to AEs and 1 due to voluntary withdrawal); 1 additional pt received nivo after the data cut off date. One pt discontinued due to progression after 23 weeks of nivo + nab-P/ C. No treatmentrelated deaths have been reported to date. Conclusions: In Arm C of the lung cancer cohort, the addition of nivo on day 15 to the standard dose and schedule of nab-P/ C did not appear to result in added toxicity or raise new safety/tolerability concerns. Preliminary assessments of antitumor activity were encouraging. Expansion of this treatment arm to further assess safety and tolerability is underway and will be updated.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/252/CN-01294252/frame.html


Record #66 of 144
ID: CN-01378457
AU: Naing A
AU: Pant S
AU: Infante J
AU: Papadopoulos K
AU: Autio K
AU: Wong D
AU: Ott P
AU: Falchook G
AU: Patel M
AU: Whiteside M
AU: Colen R
AU: Bendell J
AU: Bauer T
AU: Janku F
AU: Javle M
AU: Tannir N
AU: Oft M
AU: Chan I
AU: Rasco D
AU: Hong D
AU: Patnaik A
AU: Moore K
AU: Korn M
AU: Vanvlasselaer P
AU: Brown G
TI: Anti-tumor activity of PEGylated human IL-10 (AM0010) in renal cancer alone and in combination with anti-PD1
SO: BJU international. Conference: 15th international kidney cancer symposium. United states
YR: 2016
VL: 118
PG: 25
XR: EMBASE 616030198
PT: Conference Abstract
KY: anemia; *antineoplastic activity; CD8+ T lymphocyte; cell clone; chemotherapy; clinical article; clinical trial; colitis; controlled clinical trial; controlled study; drug therapy; drug withdrawal; endocrine system; fatigue; female; gene expression; human; hypertriglyceridemia; *kidney cancer; male; monotherapy; phase 1 clinical trial; pneumonia; progression free survival; T lymphocyte activation; thrombocytopenia; CD8 antigen; endogenous compound; *interleukin 10; interleukin 10 receptor; pembrolizumab; programmed death 1 receptor; T lymphocyte receptor
DOI: 10.1111/bju.13694
AB: Immunotherapy as well as anti-inflammatory molecules (TOR inhibitors) have antitumor activity in kidney cancer. AM0010 is a PEGylated human Interleukin 10 (IL- 10). IL-10 is regarded as an anti-inflammatory cytokine but it enhances also the cytotoxicity and proliferation of antigen activated CD8 T cells. Activation of the T cell receptor induces the expression of IL- 10 receptors and PD-1 on CD8 T cells. This provides the mechanistic rationale for combining AM0010 and anti-PD1 for the treatment of cancer pts. Tolerability and anti-tumor activity of AM0010 alone and in combination with chemotherapies or immune checkpoint inhibitors was explored in a multi-basket phase 1 clinical trial. Nineteen pts. with RCC (15 evaluable), were treated with AMO010 alone (20 mg/kg) and eight were treated in combination with pembrolizumab (2 mg/kg). Both regimens were tolerated well (observation period 15 months). All TrAEs were transient and TrAEs leading to study discontinuation were not observed. There was no colitis, pneumonitis, or endocrine disruptions. G3/4 TrAEs in monotherapy included anemia (9), hypertriglyceridemia (3), thrombocytopenia (2), ALT/AST increase (2) and fatigue (2). AM0010 combination with pembrolizumab did not increase TrAEs. Four RCC patients treated with AM0010 monotherapy (n = 15) had a tumor response (Naing et al., JCO 2016). Four RCC patients treated with AM0010 and pembrolizumab (n = 8) had a tumor response (Naing et al., ASCO 2016). Median progression free survival (mPFS) was 3 months on AM0010 monotherapy and 9.4 months on AM0010 plus pembrolizumab. CD8+ T cells analysis in patients on AM0010 monotherapy showed an increase in activation markers, including PD-1 and Lag-3 as well as an increase of proliferating PD1+ Lag-3+ CD8 T cells. Several hundred rare, previously not detectable T cell clones were found expanded more than 10 fold in patients treated with AM0010 monotherapy or AM0010 and pembrolizumab.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/457/CN-01378457/frame.html


Record #67 of 144
ID: CN-01422407
AU: Haddad R
AU: Ferris RL
AU: Blumenschein G
AU: Fayette J
AU: Guigay J
AU: Colevas AD
AU: Licitra L
AU: Kasper S
AU: Vokes EE
AU: Worden F
AU: Saba NF
AU: Tahara M
AU: Monga M
AU: Lynch M
AU: Zhu J
AU: Shaw JW
AU: Gillison ML
AU: Harrington K
TI: Treatment beyond progression with nivolumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck in the phase 3 Checkmate 141 study
SO: Cancer research. Conference: american association for cancer research annual meeting 2017. United states
YR: 2017
VL: 77
NO: 13 Supplement 1) (no pagination
XR: EMBASE 618664435
PT: Conference Abstract
KY: adult; adverse event; *cancer recurrence; cancer size; controlled study; drug therapy; female; hazard ratio; *head and neck carcinoma; hormonal therapy; human; major clinical study; male; pharmacokinetics; phase 3 clinical trial; quality of life; randomization; randomized controlled trial; response evaluation criteria in solid tumors; skin disease; *squamous cell carcinoma; subcutaneous tissue; treatment duration; *nivolumab
CC: SR-ENT
DOI: 10.1158/1538-7445.AM2017-CT157
AB: Background: Responses in patients (pts) treated with immune checkpoint inhibitors may occur after initial evidence of radiological disease progression. In CheckMate 141, a randomized phase 3 study of nivolumab (nivo) vs investigator's choice (IC) of standard single-agent therapy in recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN), nivo demonstrated prolonged OS compared with IC therapy, hazard ratio = 0.70 (97.73% confidence interval [CI]: 0.51, 0.96). Grade 3-4 treatment-related adverse events (TRAEs) occurred in 13.1% of nivo-treated pts and 35.1% of IC-treated pts. Patient-reported quality of life was stable with nivo and worsened with IC therapy. Here we assessed safety and efficacy in pts treated beyond progression (TBP) with nivo in CheckMate 141. Methods: Treatment beyond investigator-assessed RECIST 1.1-defined progression was permitted in pts in the nivo arm if all criteria prespecified in the protocol were met. Otherwise, pts were not treated beyond progression and discontinued treatment after first progression. Pts without progression, or those who died or discontinued without a tumor assessment to determine progression, were excluded from this analysis. Results: Of the 240 pts randomized to nivo, 139 (58%) experienced RECIST-defined disease progression. Among these pts, 57 (41%) received >=1 subsequent dose of nivo after progression (TBP group), and 82 (59%) were not treated beyond progression (NTBP group). The mean duration of treatment beyond progression was 2.0 months (range: 0, 9). Median OS was 12.7 months (95% CI: 9.7, not reached) in the TBP group and 6.1 months (95% CI: 4.8, 7.8) in the NTBP group. The objective response rate from randomization to initial progression was 12.3% and 4.9% for the TBP and NTBP groups, respectively; 31.6% and 19.5% of pts, respectively, had stable disease. After initial progression, 13 pts (23%) in the TBP group had tumor burden reduction, with >30% reduction in 2 pts. Of these 13 pts, 7 were HPV+, 3 were PD-L1+, and 4 had >=20% tumor size increase at first progression. In the TBP and NTBP groups, select TRAEs were similar, with a higher frequency of skin/subcutaneous tissue disorders in the TBP group (29.8% and 11.0%; none were grade 3-4). Select endocrine TRAEs occurred in 10.5% (TBP) and 8.5% (NTBP) of pts; none were grade 3-4. Grade 3-4 TRAEs occurred in 12.3% and 13.4% of pts in the TBP and NTBP groups, respectively. Patient-reported quality of life from randomization through week 21 was generally stable in the TBP group, consistent with trends observed in the overall nivo-treated population. Additional analyses to further characterize TBP and NTBP pts will be presented. Conclusions: These results suggest that nivo treatment beyond RECIST-defined disease progression was tolerable in R/M SCCHN, with some pts experiencing tumor reduction after initial progression.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/407/CN-01422407/frame.html


Record #68 of 144
ID: CN-01424054
AU: Haddad R
AU: Ferris RL
AU: Blumenschein G
AU: Fayette J
AU: Guigay J
AU: Colevas AD
AU: Licitra L
AU: Kasper S
AU: Vokes EE
AU: Worden F
AU: Saba NF
AU: Tahara M
AU: Monga M
AU: Lynch M
AU: Zhu J
AU: Shaw JW
AU: Gillison ML
AU: Harrington K
TI: Treatment beyond progression with nivolumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck in the phase 3 Checkmate 141 study
SO: Cancer research. Conference: american association for cancer research annual meeting 2017. United states
YR: 2017
VL: 77
NO: 13 Supplement 1) (no pagination
XR: EMBASE 618664435
PT: Conference Abstract
KY: adult; adverse event; *cancer recurrence; cancer size; controlled study; drug therapy; female; hazard ratio; *head and neck carcinoma; hormonal therapy; human; major clinical study; male; pharmacokinetics; phase 3 clinical trial; quality of life; randomization; randomized controlled trial; response evaluation criteria in solid tumors; skin disease; *squamous cell carcinoma; subcutaneous tissue; treatment duration; *nivolumab
DOI: 10.1158/1538-7445.AM2017-CT157
AB: Background: Responses in patients (pts) treated with immune checkpoint inhibitors may occur after initial evidence of radiological disease progression. In CheckMate 141, a randomized phase 3 study of nivolumab (nivo) vs investigator's choice (IC) of standard single-agent therapy in recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN), nivo demonstrated prolonged OS compared with IC therapy, hazard ratio = 0.70 (97.73% confidence interval [CI]: 0.51, 0.96). Grade 3-4 treatment-related adverse events (TRAEs) occurred in 13.1% of nivo-treated pts and 35.1% of IC-treated pts. Patient-reported quality of life was stable with nivo and worsened with IC therapy. Here we assessed safety and efficacy in pts treated beyond progression (TBP) with nivo in CheckMate 141. Methods: Treatment beyond investigator-assessed RECIST 1.1-defined progression was permitted in pts in the nivo arm if all criteria prespecified in the protocol were met. Otherwise, pts were not treated beyond progression and discontinued treatment after first progression. Pts without progression, or those who died or discontinued without a tumor assessment to determine progression, were excluded from this analysis. Results: Of the 240 pts randomized to nivo, 139 (58%) experienced RECIST-defined disease progression. Among these pts, 57 (41%) received >=1 subsequent dose of nivo after progression (TBP group), and 82 (59%) were not treated beyond progression (NTBP group). The mean duration of treatment beyond progression was 2.0 months (range: 0, 9). Median OS was 12.7 months (95% CI: 9.7, not reached) in the TBP group and 6.1 months (95% CI: 4.8, 7.8) in the NTBP group. The objective response rate from randomization to initial progression was 12.3% and 4.9% for the TBP and NTBP groups, respectively; 31.6% and 19.5% of pts, respectively, had stable disease. After initial progression, 13 pts (23%) in the TBP group had tumor burden reduction, with >30% reduction in 2 pts. Of these 13 pts, 7 were HPV+, 3 were PD-L1+, and 4 had >=20% tumor size increase at first progression. In the TBP and NTBP groups, select TRAEs were similar, with a higher frequency of skin/subcutaneous tissue disorders in the TBP group (29.8% and 11.0%; none were grade 3-4). Select endocrine TRAEs occurred in 10.5% (TBP) and 8.5% (NTBP) of pts; none were grade 3-4. Grade 3-4 TRAEs occurred in 12.3% and 13.4% of pts in the TBP and NTBP groups, respectively. Patient-reported quality of life from randomization through week 21 was generally stable in the TBP group, consistent with trends observed in the overall nivo-treated population. Additional analyses to further characterize TBP and NTBP pts will be presented. Conclusions: These results suggest that nivo treatment beyond RECIST-defined disease progression was tolerable in R/M SCCHN, with some pts experiencing tumor reduction after initial progression.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/054/CN-01424054/frame.html


Record #69 of 144
ID: CN-01297337
AU: Hellmann MD
AU: Rizvi NA
AU: Goldman JW
AU: Gettinger SN
AU: Borghaei H
AU: Brahmer JR
AU: Ready NE
AU: Gerber DE
AU: Chow LQ
AU: Juergens RA
AU: Shepherd FA
AU: Laurie SA
AU: Geese WJ
AU: Agrawal S
AU: Young TC
AU: Li X
AU: Antonia SJ
TI: Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study
SO: The lancet. Oncology
YR: 2017
VL: 18
NO: 1
PG: 31-41
PM: PUBMED 27932067
XR: EMBASE 613934515
PT: Clinical Trial, Phase I; Journal Article; Multicenter Study; Randomized Controlled Trial
KY: Adenocarcinoma [drug therapy] [pathology];Antibodies, Monoclonal [administration & dosage];Antineoplastic Combined Chemotherapy Protocols [therapeutic use];Carcinoma, Non-Small-Cell Lung [drug therapy] [pathology];Carcinoma, Squamous Cell [drug therapy] [pathology];Cohort Studies;Follow-Up Studies;Ipilimumab;Lung Neoplasms [drug therapy] [pathology];Neoplasm Staging;Prognosis;Survival Rate;Aged[checkword];Female[checkword];Humans[checkword];Male[checkword];Middle Aged[checkword];acute kidney failure/si [Side Effect]; adrenal insufficiency/si [Side Effect]; adult; advanced cancer/dt [Drug Therapy]; aged; alanine aminotransferase blood level; anemia/si [Side Effect]; arthralgia/si [Side Effect]; article; aspartate aminotransferase blood level; brain disease/si [Side Effect]; cancer staging; cataract/si [Side Effect]; cohort analysis; colitis/si [Side Effect]; controlled study; creatinine blood level; decreased appetite/si [Side Effect]; dehydration/si [Side Effect]; diabetes mellitus/si [Side Effect]; diarrhea/si [Side Effect]; dosage schedule comparison; drug dose comparison; drug efficacy; drug fatality/si [Side Effect]; drug safety; drug tolerability; drug withdrawal; dyspnea/si [Side Effect]; endocrine disease/si [Side Effect]; esophagitis/si [Side Effect]; facial nerve disease/si [Side Effect]; fatigue/si [Side Effect]; female; fever/si [Side Effect]; follow up; gastrointestinal symptom/si [Side Effect]; human; human tissue; hyperthyroidism/si [Side Effect]; hypertransaminasemia/si [Side Effect]; hypokalemia/si [Side Effect]; hyponatremia/si [Side Effect]; increased appetite/si [Side Effect]; infusion related reaction/si [Side Effect]; liver disease/si [Side Effect]; lung disease/si [Side Effect]; lung embolism/si [Side Effect]; lymphocyte count; maculopapular rash/si [Side Effect]; major clinical study; male; multicenter study; nausea/si [Side Effect]; nephrotoxicity/si [Side Effect]; *non small cell lung cancer/dt [Drug Therapy]; non small cell lung cancer/dt [Drug Therapy]; open study; outcome assessment; overall survival; pancreatitis/si [Side Effect]; phase 1 clinical trial; pneumonia/si [Side Effect]; priority journal; progression free survival; pruritus/si [Side Effect]; radiation necrosis/si [Side Effect]; randomized controlled trial; rash/si [Side Effect]; respiratory distress/si [Side Effect]; side effect/si [Side Effect]; skin disease/si [Side Effect]; skin toxicity/si [Side Effect]; survival time; treatment duration; treatment response; triacylglycerol lipase blood level; United States; vomiting/si [Side Effect]; alanine aminotransferase/ec [Endogenous Compound]; amylase/ec [Endogenous Compound]; aspartate aminotransferase/ec [Endogenous Compound]; creatinine/ec [Endogenous Compound]; *ipilimumab/ae [Adverse Drug Reaction]; *ipilimumab/ct [Clinical Trial]; *ipilimumab/cb [Drug Combination]; *ipilimumab/do [Drug Dose]; *ipilimumab/dt [Drug Therapy]; *nivolumab/ae [Adverse Drug Reaction]; *nivolumab/ct [Clinical Trial]; *nivolumab/cb [Drug Combination]; *nivolumab/do [Drug Dose]; *nivolumab/dt [Drug Therapy]; adrenal insufficiency; adverse drug reaction; appendix; chemotherapy; clinical trial; colitis; controlled clinical trial; death; disease duration; drug combination; drug therapy; funding; interactive voice response system; monotherapy; *non small cell lung cancer; pharmacokinetics; phase 3 clinical trial; pneumonia; safety; side effect; toxicity; young adult; endogenous compound; *ipilimumab; *nivolumab; programmed death 1 ligand 1; programmed death 1 receptor; triacylglycerol lipase
DOI: 10.1016/S1470-2045(16)30624-6
AB: METHODS: The open-label, phase 1, multicohort study (CheckMate 012) cohorts reported here were enrolled at eight US academic centres. Eligible patients were aged 18 years or older with histologically or cytologically confirmed recurrent stage IIIb or stage IV, chemotherapy-naive NSCLC. Patients were randomly assigned (1:1:1) by an interactive voice response system to receive nivolumab 1 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks, nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 12 weeks, or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks until disease progression, unacceptable toxicities, or withdrawal of consent. Data from the latter two cohorts, which were considered potentially suitable for further clinical development, are presented in this report; data from the other cohort (as well as several earlier cohorts) are described in the appendix. The primary outcome was safety and tolerability, assessed in all treated patients. This ongoing study is registered with ClinicalTrials.gov, number NCT01454102.FINDINGS: Between May 15, 2014, and March 25, 2015, 78 patients were randomly assigned to receive nivolumab every 2 weeks plus ipilimumab every 12 weeks (n=38) or nivolumab every 2 weeks plus ipilimumab every 6 weeks (n=40). One patient in the ipilimumab every-6-weeks cohort was excluded before treatment; therefore 77 patients actually received treatment (38 in the ipilimumab every-12-weeks cohort; 39 in the ipilimumab every-6-weeks cohort). At data cut-off on Jan 7, 2016, 29 (76%) patients in the ipilimumab every-12-weeks cohort and 32 (82%) in the ipilimumab every-6-weeks cohort had discontinued treatment. Grade 3-4 treatment-related adverse events occurred in 14 (37%) patients in the ipilimumab every-12-weeks cohort and 13 (33%) patients in the every-6-weeks cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (three [8%] and no patients), pneumonitis (two [5%] and one [3%] patients), adrenal insufficiency (one [3%] and two [5%] patients), and colitis (one [3%] and two [5%] patients). Treatment-related serious adverse events were reported in 12 (32%) patients in the ipilimumab every-12-weeks cohort and 11 (28%) patients in the every-6-weeks cohort. Treatment-related adverse events (any grade) prompted treatment discontinuation in four (11%) patients in the every-12-weeks cohort and five (13%) patients in the every-6-weeks cohort. No treatment-related deaths occurred. Confirmed objective responses were achieved in 18 (47% [95% CI 31-64]) patients in the ipilimumab every-12-weeks cohort and 15 (38% [95% CI 23-55]) patients in the ipilimumab every-6-weeks cohort; median duration of response was not reached in either cohort, with median follow-up times of 12·8 months (IQR 9·3-15·5) in the ipilimumab every-12-weeks cohort and 11·8 months (6·7-15·9) in the ipilimumab every-6-weeks cohort. In patients with PD-L1 of 1% or greater, confirmed objective responses were achieved in 12 (57%) of 21 patients in the ipilimumab every-12-weeks cohort and 13 (57%) of 23 patients in the ipilimumab every-6-weeks cohort.INTERPRETATION: In NSCLC, first-line nivolumab plus ipilimumab had a tolerable safety profile and showed encouraging clinical activity characterised by a high response rate and durable response. To our knowledge, the results of this study are the first suggestion of improved benefit compared with anti-PD-1 monotherapy in patients with NSCLC, supporting further assessment of this combination in a phase 3 study.FUNDING: Bristol-Myers Squibb.BACKGROUND: Nivolumab has shown improved survival in the treatment of advanced non-small-cell lung cancer (NSCLC) previously treated with chemotherapy. We assessed the safety and activity of combination nivolumab plus ipilimumab as first-line therapy for NSCLC.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/337/CN-01297337/frame.html


Record #70 of 144
ID: CN-01424034
AU: Fong L
AU: Morris M
AU: Armstrong A
AU: Petrylak D
AU: Vaishampayan U
AU: Alva A
AU: Hoffman-Censits J
AU: Sarkar I
AU: Carroll S
AU: Schiff C
AU: Sartor O
TI: A phase Ib trial to study the safety and tolerability of atezolizumab with radium-223 dichloride in patients with metastatic castrateresistant prostate cancer (mCRPC)
SO: Cancer research. Conference: american association for cancer research annual meeting 2017. United states
YR: 2017
VL: 77
NO: 13 Supplement 1) (no pagination
XR: EMBASE 618664810
PT: Conference Abstract
KY: adult; adverse drug reaction; antineoplastic activity; autoimmune disease; biopsy; bone metastasis; cancer patient; cancer survival; clinical article; controlled study; dendritic cell; drug combination; drug therapy; female; gene expression; human; human cell; human tissue; immune response; immunomodulation; incidence; ionizing radiation; lymphadenopathy; male; overall survival; pharmacokinetics; phase 1 clinical trial; preclinical study; *prostate cancer; radiation field; radiotherapy; randomization; randomized controlled trial; response evaluation criteria in solid tumors; side effect; soft tissue metastasis; T lymphocyte; toxicity; tumor growth; United States; androgen; *atezolizumab; B7 antigen; endogenous compound; programmed death 1 ligand 1; programmed death 1 receptor; *radium chloride ra 223; tumor antigen
DOI: 10.1158/1538-7445.AM2017-CT031
AB: Background: In patients (pts) with mCRPC, bone metastases (mets) occur up to 80% of the time and are a significant cause of morbidity and mortality. Radium-223 dichloride (Ra-223) is a targeted aemitter and extends overall survival (OS) in mCRPC pts with symptomatic bone mets. While several therapies, including Ra-223, have recently been approved for mCRPC, pts ultimately develop resistance and progressive disease. Therefore, there is a high unmet need for new treatments for mCRPC pts. Atezolizumab (atezo) is a humanized mAb that targets PD-L1 and blocks its interaction with its receptors, PD-1 and B7.1, which is expected to enhance T-cell responses and improve antitumor activity. A pre-clinical study found that tumor and dendritic cells have higher PD-L1 expression after ionizing radiation (IR) exposure and that combining anti-PD-L1 therapy with IR enhanced the inhibition of tumor growth. Radiotherapy leads to immune modulation and may help prime an immune response by releasing tumor-associated antigens that may target tumors distant from the local radiation field (i.e., abscopal effect). These data support the hypothesis that atezo + Ra-223 may be an effective therapy for CRPC pts with bone and soft tissue mets. Methods: A phase Ib clinical trial (NCT02814669) is being conducted to assess the safety and tolerability of atezo + Ra-223 in pts with mCRPC after progression on an androgen pathway inhibitor and to identify a recommended treatment schedule. Pts will have mCRPC with at least 2 bone mets and either measurable visceral (non-liver) mets or lymphadenopathy. Eligibility criteria include ECOG PS 0-1, progression on an androgen pathway inhibitor, and soft tissue disease amenable for serial biopsy. Exclusion criteria include small cell or neuroendocrine prostate cancer, autoimmune disease, eligible for and willing to receive treatment with taxanes, and prior treatment with Ra-223. Pts will receive atezo (840 mg q2w) and Ra-223 (55 kBq/kg q4w). The study includes a cohort phase, to evaluate a concurrent dosing regimen, and if safe and tolerable, a randomization phase to compare concurrent and staggered dosing. Regimens that are safe and tolerable may undergo expanded enrollment. A recommended schedule will be based on incidence of dose-limiting toxicities during first cycle of combination treatment. A preliminary assessment of efficacy will include ORR per RECIST v1.1, DOR, rPFS, OS, and PSA response rate. Approximately 45 pts will initially be enrolled in the United States.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/034/CN-01424034/frame.html


Record #71 of 144
ID: CN-01295841
AU: Naing A
AU: Papadopoulos KP
AU: Autio KA
AU: Ott PA
AU: Patel MR
AU: Wong DJ
AU: Falchook G
AU: Pant S
AU: Whiteside M
AU: Rasco D
AU: Patnaik A
AU: Bendell JC
AU: Bauer TM
AU: Colen RR
AU: Hong D
AU: Vlasselaer P
AU: Brown GL
AU: Oft M
AU: Tannir N
AU: Infante JR
TI: Anti-tumor activity of PEGylated human IL-10 (AM0010) in renal cancer alone and in combination with anti-PD1
SO: Annals of oncology. Conference: 41st european society for medical oncology congress, ESMO 2016. Denmark. Conference start: 20161007. Conference end: 20161011
YR: 2016
VL: 27
NO: no pagination
XR: EMBASE 613912141
PT: Journal: Conference Abstract
KY: anemia; *antineoplastic activity; cell clone; cell proliferation; chemotherapy; clinical article; clinical trial; clonal variation; colitis; controlled clinical trial; controlled study; drug therapy; drug withdrawal; endocrine system; fatigue; gene activation; human; human tissue; hypertriglyceridemia; immune response; *kidney carcinoma; lymphocyte count; monotherapy; phase 1 clinical trial; pneumonia; progression free survival; regulatory T lymphocyte; T lymphocyte activation; thrombocytopenia; CD8 antigen; endogenous compound; *interleukin 10; interleukin 18; interleukin 7; pembrolizumab; transforming growth factor beta
DOI: 10.1093/annonc/mdw368.7
AB: Background: IL-10 is regarded as an anti-inflammatory cytokine but it is also essential for the cytotoxicity and proliferation of antigen-activated CD8 T cells. Activation of the T cell receptor induces the expression of IL-10 receptors and PD-1 on CD8 T cells. This provides the mechanistic rationale for combining AM0010 and anti-PD1 for the treatment of cancer pts. Tolerability and anti-tumor activity of AM0010 alone and in combination with chemotherapies or immune checkpoint inhibitors was explored in a multi-basket phase 1 clinical trial. Methods: Pts with advanced renal cell cancer (RCC) were treated with AM0010 alone (daily SC) or in combination with pembrolizumab (q3wk IV). Tumor responses were monitored following irRC. Immune responses were measured by analysis of serum cytokines, activation of blood derived T cells, peripheral T cell clonality. Results: Nineteen pts. with RCC (15 evaluable), were treated with AMO010 alone (20 mg/kg) and eight were treated in combination with pembrolizumab (2mg/kg). Both regimens were tolerated well (observation period 15 months). All TrAEs were transient and TrAEs leading to study discontinuation were not observed. There was no colitis, pneumonitis, or endocrine disruptions. G3/4 TrAEs in monotherapy included anemia (9), hypertriglyceridemia (3), thrombocytopenia (2), ALT/AST increase (2) and fatigue (2). AM0010 combination with Pembrolizumab did not increase TrAEs. Objective responses (PR/CR) were observed in 4 of 15 evaluable RCC pts. in monotherapy (27%) and in 4 of 8 patients in AM0010 /pembrolizumab (50%). Progression free survival (PFS) was 3 and 9.4 months, respectively. AM0010 alone and in combination with anti-PD1 increased Th1 cytokines (IL-18, IFNg, IL-7) as well as the number and proliferation of PD1+ activated CD8 T cells while decreasing the proliferation of FoxP3 + Tregs and TGFb in the blood. AM0010 / anti-PD1 induced de-novo oligoclonal expansion of T cell clones in the blood without affecting total lymphocyte counts. Conclusions: AM0010 alone or in combination with anti-PD1 is well-tolerated. The clinical activity and the observed CD8 T cell activation encourages the continued exploration of AM0010 in combination with anti-PD1.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/841/CN-01295841/frame.html


Record #72 of 144
ID: CN-01422387
AU: Fong L
AU: Morris M
AU: Armstrong A
AU: Petrylak D
AU: Vaishampayan U
AU: Alva A
AU: Hoffman-Censits J
AU: Sarkar I
AU: Carroll S
AU: Schiff C
AU: Sartor O
TI: A phase Ib trial to study the safety and tolerability of atezolizumab with radium-223 dichloride in patients with metastatic castrateresistant prostate cancer (mCRPC)
SO: Cancer research. Conference: american association for cancer research annual meeting 2017. United states
YR: 2017
VL: 77
NO: 13 Supplement 1) (no pagination
XR: EMBASE 618664810
PT: Conference Abstract
KY: adult; adverse drug reaction; antineoplastic activity; autoimmune disease; biopsy; bone metastasis; cancer patient; cancer survival; clinical article; controlled study; dendritic cell; drug combination; drug therapy; female; gene expression; human; human cell; human tissue; immune response; immunomodulation; incidence; ionizing radiation; lymphadenopathy; male; overall survival; pharmacokinetics; phase 1 clinical trial; preclinical study; *prostate cancer; radiation field; radiotherapy; randomization; randomized controlled trial; response evaluation criteria in solid tumors; side effect; soft tissue metastasis; T lymphocyte; toxicity; tumor growth; United States; androgen; *atezolizumab; B7 antigen; endogenous compound; programmed death 1 ligand 1; programmed death 1 receptor; *radium chloride ra 223; tumor antigen
DOI: 10.1158/1538-7445.AM2017-CT031
AB: Background: In patients (pts) with mCRPC, bone metastases (mets) occur up to 80% of the time and are a significant cause of morbidity and mortality. Radium-223 dichloride (Ra-223) is a targeted aemitter and extends overall survival (OS) in mCRPC pts with symptomatic bone mets. While several therapies, including Ra-223, have recently been approved for mCRPC, pts ultimately develop resistance and progressive disease. Therefore, there is a high unmet need for new treatments for mCRPC pts. Atezolizumab (atezo) is a humanized mAb that targets PD-L1 and blocks its interaction with its receptors, PD-1 and B7.1, which is expected to enhance T-cell responses and improve antitumor activity. A pre-clinical study found that tumor and dendritic cells have higher PD-L1 expression after ionizing radiation (IR) exposure and that combining anti-PD-L1 therapy with IR enhanced the inhibition of tumor growth. Radiotherapy leads to immune modulation and may help prime an immune response by releasing tumor-associated antigens that may target tumors distant from the local radiation field (i.e., abscopal effect). These data support the hypothesis that atezo + Ra-223 may be an effective therapy for CRPC pts with bone and soft tissue mets. Methods: A phase Ib clinical trial (NCT02814669) is being conducted to assess the safety and tolerability of atezo + Ra-223 in pts with mCRPC after progression on an androgen pathway inhibitor and to identify a recommended treatment schedule. Pts will have mCRPC with at least 2 bone mets and either measurable visceral (non-liver) mets or lymphadenopathy. Eligibility criteria include ECOG PS 0-1, progression on an androgen pathway inhibitor, and soft tissue disease amenable for serial biopsy. Exclusion criteria include small cell or neuroendocrine prostate cancer, autoimmune disease, eligible for and willing to receive treatment with taxanes, and prior treatment with Ra-223. Pts will receive atezo (840 mg q2w) and Ra-223 (55 kBq/kg q4w). The study includes a cohort phase, to evaluate a concurrent dosing regimen, and if safe and tolerable, a randomization phase to compare concurrent and staggered dosing. Regimens that are safe and tolerable may undergo expanded enrollment. A recommended schedule will be based on incidence of dose-limiting toxicities during first cycle of combination treatment. A preliminary assessment of efficacy will include ORR per RECIST v1.1, DOR, rPFS, OS, and PSA response rate. Approximately 45 pts will initially be enrolled in the United States.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/387/CN-01422387/frame.html


Record #73 of 144
ID: CN-01363855
AU: Rugo H
AU: Tolaney S
AU: Dickler M
AU: Kabos P
AU: Ho C-L
AU: Wildiers H
AU: Jerusalem G
AU: Ales-Martinez JE
AU: Hossain A
AU: Johnston E
AU: Gianni L
TI: A phase 2 study of abemaciclib plus pembrolizumab for patients with hormone receptor positive (HR+), HER2 negative (HER2-) metastatic breast cancer (MBC)
SO: Cancer research. Conference: 39th annual CTRC-AACR san antonio breast cancer symposium. United states
YR: 2017
VL: 77
NO: 4 Supplement 1) (no pagination
XR: EMBASE 615274107
PT: Conference Abstract
KY: adult; cancer epidemiology; clinical trial; controlled clinical trial; *controlled study; disease control; drug combination; drug therapy; female; hormonal therapy; human; life expectancy; major clinical study; *metastatic breast cancer; monotherapy; non small cell lung cancer; oncology; oral drug administration; organ; overall survival; patient history of chemotherapy; pharmacokinetics; phase 1 clinical trial; phase 2 clinical trial; progression free survival; response evaluation criteria in solid tumors; safety; statistical analysis; study design; young adult; *abemaciclib; cyclin dependent kinase 4; cyclin dependent kinase 6; death receptor; endogenous compound; *epidermal growth factor receptor 2; *hormone receptor; *pembrolizumab; programmed death 1 ligand 1; programmed death 1 receptor
DOI: 10.1158/1538-7445.SABCS16-OT2-01-07
AB: Background: Abemaciclib is a small molecule inhibitor of both cyclin-dependent kinase (CDK) 4 and CDK6 administered orally twice daily on a continuous schedule. In I3Y-MC-JPBA, a phase I study, abemaciclib demonstrated acceptable safety, tolerability, and single-agent activity as monotherapy in different tumor types, including HR+ MBC (Patnaik A,et al. Cancer Discov 2016;6:1-14). In MONARCH 1, a phase 2 study, abemaciclib demonstrated a 19.7% objective response rate (ORR) with a median duration of response (DoR) of 8.6 months, median progression-free survival (PFS) of 6.0 months, and clinical benefit rate (CBR) of 42.4% in patients with HR+, HER2- MBC whose disease progressed on or after endocrine therapy and chemotherapy (Dickler, M. et al. American Society of Clinical Oncology (ASCO), abstract #510 (2016).). Pembrolizumab is a humanized monoclonal antibody against the programmed death receptor-1 (PD-1) protein that has shown preliminary efficacy in single-arm monotherapy trials in ER+/HER2- advanced breast cancer. Trial design: This open-label, phase 2 study will evaluate the safety and preliminary efficacy of abemaciclib 150 mg given orally every 12 hours on days 1-21 of a 21-day cycle in combination with intravenous pembrolizumab 200 mg on day 1 of a 21-day cycle in approximately 75 patients with stage IV non-small cell lung cancer or HR+, HER2- MBC (ClinicalTrials.gov NCT02779751). The study will include 3 disease-specific cohorts, each with approximately 25 patients. Only the HR+, HER2- MBC cohort will be presented here. Eligibility criteria: Eligible patients for the MBC cohort include women with confirmed HR+, HER2- MBC who have completed at least 1 but no more than 2 prior chemotherapy regimens in the metastatic setting; will provide tumor tissue prior to and after treatment (cycle 3, day 1); have measurable disease (RECIST v.1.1), adequate organ function, an ECOG performance status <1, and a life expectancy >12 weeks; are >18 yrs of age and able to swallow oral medications; and have not received treatment with any CDK 4 and 6 inhibitors or PD-1 or PD-L1 inhibitors. Specific aims: The primary objective is to characterize the safety profile of the combination of abemaciclib and pembrolizumab. Key secondary objectives include ORR, DoR, disease control rate (DCR), PFS, overall survival (OS), and characterization of pharmacokinetics. Statistical methods: The safety population includes patients who received at least one dose of study drug. ORR, DoR, DCR, and PFS analyses will be evaluated according to RECIST v.1.1 and irRECIST for disease progression. Time-toevent variables, such as DoR, PFS, and OS, will be estimated by Kaplan-Meier methodology. An interim analysis of safety and preliminary efficacy may occur for each cohort after all patients have completed (or discontinued from) approximately 24 weeks of treatment. The final analysis of OS will occur based on data collected for approximately 12 months after the last patient receives treatment.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/855/CN-01363855/frame.html


Record #74 of 144
ID: CN-01174396
AU: Macapinlac H
TI: Current and future trends for the utilization of positron emission tomography (PET) for treatment strategy
SO: Annals of oncology.
YR: 2015
VL: 26
PG: vii28
XR: EMBASE 72209232
PT: Journal: Conference Abstract
KY: *human; *positron emission tomography; *Japanese (people); *society; *oncology; imaging; therapy; neoplasm; cancer patient; prostate cancer; staging; radiotherapy; solid tumor; clinical trial (topic); prediction; clinical practice; surgery; survival; mortality; pilot study; tracer; copper 64; lutetium 177; somatostatin receptor; gallium 68; gastrin releasing peptide receptor; iodine 131; iodine 124; choline; yttrium 90; zirconium 89; carbon 11; fluorine 18; new drug
DOI: 10.1093/annonc/mdv422.1
AB: Today's cancer patients benefit from new drugs and therapies which are tailored to the molecular characteristics of each cancer patient. Better multimodality techniques including surgery and radiation therapy deliver more precise and effective treatments. These improvements in cancer care have reduced the death rate from cancer by 20% since the early 1990's. The recent changes in clinical practice have been partly due to improvement in accuracy of diagnosing and staging the extent of solid tumors primarily through FDG PET/CT imaging. Future applications of PET are mainly in the use of novel tracers when FDG is not as sensitive or accurate. Somatostatin receptor imaging of neuroendocrine type tumors with the use of Ga-68 tracers and most recently Cu-64 labeled somatostatin receptor analogs appear more sensitive in detecting the extent of disease and together with its Lu-177 or Y-90 labeled tracers provide a combined theranostic approach. Prostate cancer assessment utilizing Ga-68 PSMA appears to be more accurate when compared to F-18 or C-11 labeled choline, and recent pilot studies have demonstrated feasibility of PET imaging and therapy using I-124/I-131 PSMA. Gastrin releasing peptide receptor antagonist labeled with Cu-64 has demonstrated the possibility of PET imaging of prostate cancer and potentially delivering radiotherapy with Lu-177. The advent of immune checkpoint blockade therapy has provided an opportunity to utilize longer lived tracers like Zr-89 or Cu-64 to evaluate the biodistribution of these drugs which have demonstrated very strong potential in improving the survival of cancer patients. These may allow better staging and prognostic prediction of response to therapy and may allow better design of clinical trials with this new class of drugs.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/396/CN-01174396/frame.html


Record #75 of 144
ID: CN-01407349
AU: Fakhrejahani F
AU: Madan RA
AU: Dahut WL
AU: Karzai F
AU: Cordes LM
AU: Schlom J
AU: Gulley JL
TI: Avelumab in metastatic castration-resistant prostate cancer (mCRPC)
SO: Journal of clinical oncology. Conference: 2017 genitourinary cancers symposium. United states
YR: 2017
VL: 35
NO: 6 Supplement 1) (no pagination
XR: EMBASE 618006831
PT: Conference Abstract
KY: adverse drug reaction; aged; cancer epidemiology; *castration resistant prostate cancer; clinical article; clinical trial; controlled clinical trial; controlled study; disease course; drug therapy; fatigue; female; follow up; Gleason score; human; hypothyroidism; immune response; intravenous drug administration; *male; patient history of chemotherapy; pharmacokinetics; phase 1 clinical trial; safety; side effect; solid malignant neoplasm; amylase; androgen receptor antagonist; *avelumab; docetaxel; endogenous compound; enzalutamide; rilimogene galvacirepvec; sipuleucel T; triacylglycerol lipase
AB: Background: Despite recent progress, mCRPC remains a lethal disease. While programmed cell death 1 (PD-1) and PD-1 ligand (PD-L1) inhibitors have shown activity in variety of malignancies, to this point there is minimal evidence of activity in mCRPC. This is a report of avelumab, anti-PDL1 in mCRPC patients (pts). Methods: This is an expansion cohort of the first in human, phase I trial (JAVELIN Solid Tumor; EMR100070-001) that evaluated 10 mg/kg of avelumab in pts with mCRPC who had progressive disease (PD) on previous treatment. Pts who had PD on an androgen receptor antagonist (ARA) could enroll on trial and continue their ARA. Avelumab was administered as a 1-hour intravenous infusion every 2 weeks (w) with restaging scans every 6 w. Prostate cancer working group 2 criteria were used to determine PD. Results: 18 patients were enrolled on this cohort; the median age of pts was 67 years. Median on study PSA was 11ng/mL. 11 pts had Gleason score (GS) >= 8 and 7 had GS of 7. 3 pts had previous chemotherapy with docetaxel, 8 pts received previous vaccine treatment including 4 pts with sipuleucel-T and 4 pts with Prostvac. Overall avelumab treatment was safe and tolerable. 15 pts experienced grade <= 2 treatment related adverse events (TRAEs), fatigue being the most common one. 4 pts developed treatment related hypothyroidism, 3 with grade 2 and 1 with grade 1. In addition, 2 pts had grade 3 asymptomatic TRAEs (amylase & lipase elevations). 7 pts had stable disease (SD) > 24 w post treatment, 6 pts had PD after first restaging scans at 6 w which was reconfirmed in 2 restaging scan at 12 w. PSA doubling time (PSADT) prior to avelumab was compared with PSADT after 3 months (m) of treatment. Among 17 pts with available data, 3 pts had a prolonged PSADT which was defined at 3 m (twice as high as on-study PSADT), 7 pts had stable PSADT and 7 had decreased PSADT. 5 of 18 pts enrolled while on enzalutamide with a rising PSA. Among these pts 1 had prolonged PSADT, 2 had a stable PSADT and 2 with decreased PSADT after 3 m of follow up. 3 of 5 pts had SD > 24 m, 1 had SD for 13 w and 1 had PD at first restaging scans. Conclusions: These data provide safety data of avelumab on a population of pts with mCRPC. Immune analysis is under way to determine correlation with immune responses in the pts on this trial that had prolonged SD.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/349/CN-01407349/frame.html


Record #76 of 144
ID: CN-01296077
AU: Haddad R
AU: Seiwert T
AU: Pfister DG
AU: Worden F
AU: Liu SV
AU: Gilbert J
AU: Saba NF
AU: Weiss J
AU: Wirth LJ
AU: Sukari A
AU: Kang H
AU: Gibson MK
AU: Massarelli E
AU: Powell S
AU: Meister A
AU: Shu X
AU: Cheng J
AU: Bauml J
TI: Pembrolizumab after progression on platinum and cetuximab in head and neck squamous cell carcinoma (HNSCC): results from KEYNOTE-055
SO: Annals of oncology. Conference: 41st european society for medical oncology congress, ESMO 2016. Denmark. Conference start: 20161007. Conference end: 20161011
YR: 2016
VL: 27
NO: no pagination
XR: EMBASE 613911564
PT: Journal: Conference Abstract
KY: adult; adverse drug reaction; antineoplastic activity; clinical trial; controlled clinical trial; controlled study; disease duration; drug resistance; drug therapy; female; follow up; genetic marker; *head and neck squamous cell carcinoma; human; human tissue; hypothyroidism; imaging; immunohistochemistry; major clinical study; male; metastasis; middle aged; pharmacokinetics; phase 2 clinical trial; pneumonia; response evaluation criteria in solid tumors; safety; side effect; tumor resistance; biological marker; *cetuximab; endogenous compound; gamma interferon; *pembrolizumab; *platinum; programmed death 1 ligand 1
DOI: 10.1093/annonc/mdw376.9
AB: Background: There are few treatment options in recurrent/metastatic (R/M) HNSCC after progression on platinum and cetuximab, and their efficacy is disappointing. During KEYNOTE-012, pembrolizumab, an anti-PD-1 antibody that blocks the interaction between PD-1 and its ligands, showed promising antitumor activity in R/M HNSCC. The efficacy and safety of pembrolizumab in patients with R/M HNSCC after progression on platinum and cetuximab are being investigated in the phase 2, nonrandomized KEYNOTE-055 (NCT02255097) study. Methods: Pts receive pembrolizumab 200 mg every 3 weeks. Key eligibility criteria include R/M HNSCC resistant to platinum and cetuximab therapies, measurable disease, and ECOG PS 0-1. Primary outcomes include overall response rate (ORR, RECIST v1.1 by central imaging vendor) performed every 6-9 wk and safety. Adverse events (AEs) were graded using CTCAE, v4.0. Results: Of the 171 pts who received >1 dose of pembrolizumab, median age was 61 y, 81% were male, 75% had >2 prior lines of therapy for metastatic disease. As of Jan 29, 2016, median follow-up time was 4 mo (range, 0-14). Treatment-related AEs (TRAEs) occurred in 102 (60%) pts, with 20 (12%) pts experiencing a grade 3-5 TRAE. 4 (2%) pts discontinued and 1 (1%) pt died because of a TRAE. AEs of special immunologic interest occurred in 35 (20%) pts; hypothyroidism (n = 23; grade 1 or 2) and pneumonitis (n = 3, grade 1 or 2; n = 1, grade 3; n = 1, grade 5) were the most common. When confirmed responses were evaluated, the ORR was 15% (PR, n = 25; 95% CI, 10%-21%) with a median duration of response of 7 mo (range, 0-8+); the stable disease rate was 22% (n = 37; 95% CI, 16%-29%). When unconfirmed and confirmed responses were evaluated, the ORR was 22% (CR, n = 2; PR, n = 35; 95% CI, 16%-29%) and the stable disease rate was 15% (n = 25; 95% CI, 10%-21%). Conclusions: The clinically significant antitumor activity and safety profile of pembrolizumab in heavily pretreated R/M HNSCC shown here confirm findings from KEYNOTE-012 and support ongoing phase 3 trials in head and neck cancer. Further analyses of biomarker data including immunohistochemistry (PD-L1/PD-L2) and interferon gamma gene signatures will be presented.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/077/CN-01296077/frame.html


Record #77 of 144
ID: CN-01362785
AU: Zinzani PL
AU: Ribrag V
AU: Moskowitz CH
AU: Michot JM
AU: Kuruvilla J
AU: Balakumaran A
AU: Thompson S
AU: Marinello P
AU: Chlosta S
AU: Shipp MA
AU: Armand P
TI: Phase 1b study of pembrolizumab in patients with relapsed/ refractory primary mediastinal large B-cell lymphoma: keynote-013
SO: Haematologica. Conference: 21st congress of the european hematology association. Denmark
YR: 2016
VL: 101
PG: 320-321
XR: EMBASE 615559215
PT: Conference Abstract
KY: adult; antineoplastic activity; autologous stem cell transplantation; classical Hodgkin lymphoma; clinical article; clinical trial; controlled clinical trial; controlled study; coughing; death; decreased appetite; diarrhea; *diffuse large B cell lymphoma; drug therapy; fatigue; fever; follow up; human; hypothyroidism; imaging; informed consent; *mediastinum; nausea; neutropenia; pharmacokinetics; phase 1 clinical trial; physician; pneumonia; positron emission tomography; radiation; remission; safety; solid tumor; toxicity; endogenous compound; *pembrolizumab; programmed death 1 receptor
AB: Background: Primary mediastinal large B-cell lymphoma (PMBCL) frequently exhibits 9p24.1 alterations, leading to overexpression of the PD-1 ligands, PDL1 and PD-L2. This provides a possible mechanism of immune evasion and suggests that PMBCL could have a genetically determined vulnerability to PD- 1 blockade. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands. Pembrolizumab has already demonstrated robust antitumor activity in advanced solid tumors and in classical Hodgkin lymphoma. KEYNOTE-013 (NCT01953692) is a multicenter, multicohort phase 1b study designed to evaluate the safety and preliminary efficacy of pembrolizumab in patients with hematologic malignancies. Preliminary results of the PMBCL cohort of KEYNOTE-013 are reported. Aims: To determine the safety, tolerability, and antitumor activity of pembrolizumab in patients with relapsed/refractory (R/R) PMBCL. Methods: Patients with R/R disease who have relapsed after or are ineligible for autologous stem cell transplantation (ASCT) received pembrolizumab IV 10 mg/kg Q2W or 200 mg Q3W for up to 2 years or until confirmed disease progression or unacceptable toxicity. Primary end points were safety and ORR. Response was evaluated using computed tomography (CT) and positron emission tomography (PET) at weeks 6 and 12, and every 8 weeks thereafter, using IHP 2007 criteria. Other end points included complete remission rate and duration of response (DOR). Informed consent was obtained for all patients. Results: As of February 1, 2016, 16 patients were enrolled and treated in this cohort. The first 11 patients received pembrolizumab 10 mg/kg every 2 weeks; the next 5 patients received a fixed dose of 200 mg every 3 weeks, which has demonstrated equivalence based on PK/PD studies. Median age was 30 years (range, 22-62), 44% had >4 prior lines of therapy, 31% had prior ASCT, and 75% had prior radiation. 10 patients (62%) experienced treatment-related AEs, most commonly grade 1-2 decreased appetite, diarrhea, fatigue, hypothyroidism, nausea, and pyrexia (2 patients each). Only 1 patient experienced a grade 3 treatment-related AE (neutropenia), and there were no grade 4 treatment- related AEs or treatment-related deaths. 4 patients experienced serious AEs, including grade 3 pneumonia in 3 patients and grade 3 cough in 1 patient; all were unrelated to study drug. No patients discontinued for toxicity. Among the 16 treated patients, the median follow-up was 5.0 months (range, 0.8-22 months) and the objective response rate (ORR) was 37.5% (6/16), with 1 patient (6.25%) achieving a complete remission and 5 patients (31.25%) achieving a partial response. One subject discontinued treatment based on clinical progression before the first assessment and was considered a non-responder. The median DOR has not been reached (range, 0.03+-17+ months), with 5 responses ongoing at the time of data cutoff. 9 have discontinued treatment: 5 because of progressive disease based on imaging, 3 because of clinical progressive disease, and 1 because of physician decision. Summary/Conclusions: The preliminary results of KEYNOTE-013 indicate that PD-1 blockade with pembrolizumab is associated with a tolerable safety profile and a promising response rate in heavily pretreated patients with R/R PMBCL. These patients often have a very poor outcome with conventional therapy, justifying further studies of pembrolizumab in this population.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/785/CN-01362785/frame.html


Record #78 of 144
ID: CN-00906535
AU: Gardiner D
AU: Lalezari J
AU: Lawitz E
AU: DiMicco M
AU: Ghalib R
AU: Reddy KR
AU: Chang K-M
AU: Sulkowski M
AU: Marro SO
AU: Anderson J
AU: He B
AU: Kansra V
AU: McPhee F
AU: Wind-Rotolo M
AU: Grasela D
AU: Selby M
AU: Korman AJ
AU: Lowy I
TI: A Randomized, Double-Blind, Placebo-Controlled Assessment of BMS-936558, a Fully Human Monoclonal Antibody to Programmed Death-1 (PD-1), in Patients with Chronic Hepatitis C Virus Infection
SO: PloS one
YR: 2013
VL: 8
NO: 5
XR: EMBASE 368973621
PT: Journal: Article
KY: abdominal pain/si [Side Effect]; adult; area under the curve; article; autoimmune thyroiditis; CD4+ T lymphocyte; CD8+ T lymphocyte; controlled study; coughing/si [Side Effect]; diarrhea/si [Side Effect]; double blind procedure; drug safety; drug tolerability; enzyme linked immunosorbent assay; fatigue/si [Side Effect]; female; headache/si [Side Effect]; hepatitis C/dt [Drug Therapy]; *hepatitis C/dt [Drug Therapy]; *hepatitis C/et [Etiology]; Hepatitis C virus; human; hyperthyroidism/si [Side Effect]; hypothyroidism/si [Side Effect]; ligand binding; limit of quantitation; major clinical study; male; maximum plasma concentration; phenotype; protein expression; pruritus/si [Side Effect]; randomized controlled trial; side effect/si [Side Effect]; single drug dose; sore throat/si [Side Effect]; urticaria/si [Side Effect]; virus load; alpha interferon/dt [Drug Therapy]; CD19 antigen/ec [Endogenous Compound]; cytokine/ec [Endogenous Compound]; immunoglobulin/ec [Endogenous Compound]; *monoclonal antibody/ec [Endogenous Compound]; *nivolumab/ae [Adverse Drug Reaction]; *nivolumab/ct [Clinical Trial]; *nivolumab/dt [Drug Therapy]; *nivolumab/pk [Pharmacokinetics]; *nivolumab/pd [Pharmacology]; peginterferon alpha/dt [Drug Therapy]; placebo; *programmed death 1 receptor/ec [Endogenous Compound]; ribavirin/dt [Drug Therapy]; virus RNA/ec [Endogenous Compound]; *death; exposure; half life time; *hepatitis C; *Hepatitis C virus; *human; hyperthyroidism; immune deficiency; infection; infusion; memory; *patient; registration; T lymphocyte; *virus infection; alpha interferon; antivirus agent; CD4 antigen; CD8 antigen; cytokine; *human monoclonal antibody; immunoglobulin; ligand; nivolumab; paraprotein; *placebo; receptor; RNA
DOI: 10.1371/journal.pone.0063818
AB: Expression of the programmed death 1 (PD-1) receptor and its ligands are implicated in the T cell exhaustion phenotype which contributes to the persistence of several chronic viral infections, including human hepatitis C virus (HCV). The antiviral potential of BMS-936558 (MDX-1106) - a fully human anti-PD-1 monoclonal immunoglobulin-G4 that blocks ligand binding - was explored in a proof-of-concept, placebo-controlled single-ascending-dose study in patients (N = 54) with chronic HCV infection. Interferon-alfa treatment-experienced patients (n = 42) were randomized 5:1 to receive a single infusion of BMS-936558 (0.03, 0.1, 0.3, 1.0, 3.0 mg/kg [n = 5 each] or 10 mg/kg [n = 10]) or of placebo (n = 7). An additional 12 HCV treatment-naive patients were randomized to receive 10 mg/kg BMS-936558 (n = 10) or placebo (n = 2). Patients were followed for 85 days post-dose. Five patients who received BMS-936558 (0.1 [n = 1] or 10 mg/kg) and one placebo patient achieved the primary study endpoint of a reduction in HCV RNA >0.5 log<inf>10</inf> IU/mL on at least 2 consecutive visits; 3 (10 mg/kg) achieved a >4 log<inf>10</inf> reduction. Two patients (10 mg/kg) achieved HCV RNA below the lower limit of quantitation (25 IU/mL), one of whom (a prior null-responder) remained RNA-undetectable 1 year post-study. Transient reductions in CD4<sup>+</sup>, CD8<sup>+</sup> and CD19<sup>+</sup> cells, including both naive and memory CD4<sup>+</sup> and CD8<sup>+</sup> subsets, were observed at Day 2 without evidence of immune deficit. No clinically relevant changes in immunoglobulin subsets or treatment-related trends in circulating cytokines were noted. BMS-936558 exhibited dose-related exposure increases, with a half-life of 20-24 days. BMS-936558 was mostly well tolerated. One patient (10 mg/kg) experienced an asymptomatic grade 4 ALT elevation coincident with the onset of a 4-log viral load reduction. Six patients exhibited immune-related adverse events of mild-to-moderate intensity, including two cases of hyperthyroidism consistent with autoimmune thyroiditis. Further investigation of PD-1 pathway blockade in chronic viral disease is warranted.Trial Registration:ClinicalTrials.gov NCT00703469. © 2013 Gardiner et al.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/535/CN-00906535/frame.html


Record #79 of 144
ID: CN-01422803
AU: Kasper S
AU: Haddad R
AU: Ferris RL
AU: Blumenschein G
AU: Fayette J
AU: Guigay J
AU: Colevas AD
AU: Licitra L
AU: Vokes EE
AU: Worden F
AU: Saba NF
AU: Tahara M
AU: Monga M
AU: Lynch M
AU: Zhu J
AU: Shaw JW
AU: Gillison ML
AU: Harrington KJ
TI: Treatment beyond progression with nivolumab (nivo) in patients with recurrent or metastatic (R/M) Squamous Cell Carcinoma of the Head and Neck (SCCHN) in the phase 3 CheckMate 141 study
SO: Oncology research and treatment. Conference: jahrestagung der deutschen, osterreichischen und schweizerischen gesellschaften fur hamatologie und medizinische onkologie 2017. Germany
YR: 2017
VL: 40
NO: Supplement 3
PG: 250-251
XR: EMBASE 618607509
PT: Conference Abstract
KY: adult; adverse event; *cancer recurrence; cancer size; clinical assessment; controlled study; drug therapy; female; *head and neck carcinoma; hormonal therapy; human; major clinical study; male; phase 3 clinical trial; quality of life; randomization; randomized controlled trial; response evaluation criteria in solid tumors; skin disease; *squamous cell carcinoma; treatment duration; endogenous compound; *nivolumab; programmed death 1 ligand 1
DOI: 10.1159/000479566
AB: Introduction: Responses in patients (pts) treated with immune checkpoint inhibitors may occur after initial evidence of radiological disease progression. In CheckMate 141, a randomized phase 3 study of nivo vs single agent of investigator's choice (IC) in R/M SCCHN, nivo prolonged OS vs IC therapy, HR = 0.70 (97.73% CI: 0.51, 0.96). Grade 3-4 treatment- related adverse events (TRAEs) occurred in 13.1% of nivo-treated pts and 35.1% of IC-treated pts. Pt-reported quality of life was stable with nivo and worsened with IC. We assessed outcomes in pts treated beyond progression (TBP) with nivo in CheckMate 141. Methods: Treatment beyond investigator-assessed RECIST 1.1-defined progression was permitted in pts in the nivo arm if all protocol-specified criteria were met. Otherwise, pts were not treated beyond progression and discontinued treatment after first progression. Pts without progression or without a tumor assessment to determine progression were excluded from analysis. Results: Of the 240 pts randomized to nivo, 139 (58%) experienced progression. Among them, 57 (41%) received >=1 dose of nivo after progression (TBP group), and 82 (59%) were not treated beyond progression (NTBP group). Mean duration of treatment beyond progression was 2.0 mo (range: 0-9). Median OS was 12.7 mo (95% CI: 9.7, not reached) in the TBP group and 6.1 mo (95% CI: 4.8, 7.8) in the NTBP group. The objective response rate from randomization to initial progression was 12.3% and 4.9% for the TBP and NTBP groups, respectively; 31.6% and 19.5% of pts, respectively, had stable disease. After initial progression, 13 pts (23%) in the TBP group had tumor burden reduction, with >30% reduction in 2 pts. Of these 13 pts, 7 were HPV+, 3 had PD-L1 >=1%, and 4 had >=20% tumor size increase at first progression. In the TBP and NTBP groups select TRAEs were similar, with a higher frequency of skin disorders in the TBP group (29.8% and 11.0%; 0 were grade 3-4). Select endocrine TRAEs occurred in 10.5% (TBP) and 8.5% (NTBP) of pts; 0 were grade 3-4. Grade 3-4 TRAEs occurred in 12.3% (TBP) and 13.4% (NTBP) of pts. Pt-reported quality of life from randomization through wk 21 was generally stable in the TBP group, consistent with the overall nivo-treated population. Additional analyses to characterize TBP and NTBP pts to be presented. Conclusions: Results suggest that nivo treatment beyond RECIST-defined progression was tolerable in R/M SCCHN, and some pts experienced tumor reduction after initial progression.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/803/CN-01422803/frame.html


Record #80 of 144
ID: CN-01050938
AU: Gardiner D
AU: Lalezari J
AU: Lawitz E
AU: DiMicco M
AU: Ghalib R
AU: Reddy KR
AU: Chang KM
AU: Sulkowski M
AU: Marro SO
AU: Anderson J
AU: He B
AU: Kansra V
AU: McPhee F
AU: Wind-Rotolo M
AU: Grasela D
AU: Selby M
AU: Korman AJ
AU: Lowy I
TI: A randomized, double-blind, placebo-controlled assessment of BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD-1), in patients with chronic hepatitis C virus infection
SO: Plos one
YR: 2013
VL: 8
NO: 5
PG: e63818
PM: PUBMED 23717490
PT: Clinical Trial; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't
KY: Antibodies, Monoclonal [adverse effects] [pharmacokinetics] [therapeutic use];Antiviral Agents [adverse effects] [therapeutic use];Double-Blind Method;Half-Life;Hepacivirus [drug effects] [genetics];Hepatitis C, Chronic [drug therapy];Interferon-alpha [therapeutic use];Programmed Cell Death 1 Receptor [antagonists & inhibitors] [metabolism];RNA, Viral [genetics];Viral Load [drug effects] [genetics];Adult[checkword];Female[checkword];Humans[checkword];Male[checkword];Middle Aged[checkword]
DOI: 10.1371/journal.pone.0063818
AB: TRIAL REGISTRATION: ClinicalTrials.gov NCT00703469.Expression of the programmed death 1 (PD-1) receptor and its ligands are implicated in the T cell exhaustion phenotype which contributes to the persistence of several chronic viral infections, including human hepatitis C virus (HCV). The antiviral potential of BMS-936558 (MDX-1106) - a fully human anti-PD-1 monoclonal immunoglobulin-G4 that blocks ligand binding - was explored in a proof-of-concept, placebo-controlled single-ascending-dose study in patients (N = 54) with chronic HCV infection. Interferon-alfa treatment-experienced patients (n = 42) were randomized 5∶1 to receive a single infusion of BMS-936558 (0.03, 0.1, 0.3, 1.0, 3.0 mg/kg [n = 5 each] or 10 mg/kg [n = 10]) or of placebo (n = 7). An additional 12 HCV treatment-naïve patients were randomized to receive 10 mg/kg BMS-936558 (n = 10) or placebo (n = 2). Patients were followed for 85 days post-dose. Five patients who received BMS-936558 (0.1 [n = 1] or 10 mg/kg) and one placebo patient achieved the primary study endpoint of a reduction in HCV RNA ≥0.5 log10 IU/mL on at least 2 consecutive visits; 3 (10 mg/kg) achieved a >4 log10 reduction. Two patients (10 mg/kg) achieved HCV RNA below the lower limit of quantitation (25 IU/mL), one of whom (a prior null-responder) remained RNA-undetectable 1 year post-study. Transient reductions in CD4(+), CD8(+) and CD19(+) cells, including both naïve and memory CD4(+) and CD8(+) subsets, were observed at Day 2 without evidence of immune deficit. No clinically relevant changes in immunoglobulin subsets or treatment-related trends in circulating cytokines were noted. BMS-936558 exhibited dose-related exposure increases, with a half-life of 20-24 days. BMS-936558 was mostly well tolerated. One patient (10 mg/kg) experienced an asymptomatic grade 4 ALT elevation coincident with the onset of a 4-log viral load reduction. Six patients exhibited immune-related adverse events of mild-to-moderate intensity, including two cases of hyperthyroidism consistent with autoimmune thyroiditis. Further investigation of PD-1 pathway blockade in chronic viral disease is warranted.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/938/CN-01050938/frame.html


Record #81 of 144
ID: CN-01287112
AU: Anonymous
TI: BRAF V600 mutation-negative metastatic or inoperable melanoma: survival advantage
SO: Prescrire international
YR: 2016
VL: 25
NO: 177
PG: 289-291
XR: EMBASE 613765884
PT: Journal: Review
KY: adverse drug reaction; *cancer epidemiology; clinical trial; colitis; controlled clinical trial; controlled study; death; double blind procedure; drug combination; drug therapy; encephalitis; Europe; *gene mutation; hepatitis; human; major clinical study; median survival time; *metastatic melanoma; monotherapy; mortality; organ; pneumonia; protein structure; randomized controlled trial; rash; side effect; thyroid disease; toxic epidermal necrolysis; uncertainty; visually impaired person; *B Raf kinase; cytotoxic agent; dacarbazine; endogenous compound; ipilimumab; new drug; nivolumab; trametinib
AB: * Existing drugs are poorly effective in patients with inoperable or metastatic melanoma without a mutation in the BRAF gene at position V600. The first-line treatment of choice for patients with BRAF V600-positive melanoma is a combination of dabrafenib (a BRAF inhibitor) and trametinib. * Nivolumab is a human monoclonal antibody designed to block receptors for PD-1 (programmed cell death-1) and thus to enhance T lymphocyte activity, especially against tumour cells. Nivolumab has been authorised in Europe as monotherapy for patients with inoperable or metastatic melanoma, regardless of BRAF V600 status. * Nivolumab has not been compared with the dabrafenib + trametinib combination in patients with BRAF V600-positive melanoma. * A randomised double-blind trial versus dacarbazine involved 418 patients with inoperable or metastatic BRAF V600-negative melanoma who had not yet received medication for this stage of the disease. The trial was halted prematurely when an unscheduled analysis showed an improvement in one-year survival with nivolumab compared to dacarbazine (73% versus 42%, p<0.0001). * A double-blind trial compared firstline treatment with nivolumab, ipilimumab or a combination of the two drugs. The mortality results are not yet available in mid-2016. The median time to melanoma aggravation or death was 6.9 months in the nivolumab group, 2.9 months in the ipilimumab group, and 11.5 months with the combination (p<0.001). * A comparative, randomised, unblinded trial included 405 patients with metastatic or inoperable melanoma in whom at least one drug had failed. An interim analysis conducted after about two years showed no statistically significant difference in median survival between patients who received nivolumab and those who received cytotoxic drugs. * As expected, given its protein structure and mechanism, the adverse effects of nivolumab are mainly due to immunological mechanisms. They are numerous and affect many organs: skin rash and toxic epidermal necrolysis, thyroid dysfunction, hepatitis, pneumonia, colitis and encephalitis. Adverse effects were serious in 9% of patients, and a few cases were fatal. * In practice, first-line nivolumab monotherapy was significantly more effective than dacarbazine in a trial in patients with BRAF V600-negative inoperable or metastatic melanoma. Although its evaluation must continue, nivolumab already seems to be a better option than dacarbazine and ipilimumab for treatment-naive patients, provided they receive detailed and balanced information on the uncertainties, efficacy and adverse effects of this new drug. For other patients, there is no evidence that nivolumab monotherapy represents an advantage over other available treatments.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/112/CN-01287112/frame.html


Record #82 of 144
ID: CN-01300514
AU: Anonymous
TI: BRAF V600 mutation-negative metastatic or inoperable melanoma: survival advantage
SO: Prescrire international
YR: 2016
VL: 25
NO: 177
PG: 289-291
XR: EMBASE 613765884
PT: Journal: Review
KY: adrenal insufficiency/si [Side Effect]; allergic reaction/si [Side Effect]; autoimmune hepatitis/si [Side Effect]; *BRAF gene; cancer growth; cancer mortality; *cancer survival; colitis/si [Side Effect]; creatinine blood level; demyelination/si [Side Effect]; diabetes mellitus/si [Side Effect]; diarrhea/si [Side Effect]; drug contraindication; drug efficacy; drug indication; drug safety; drug treatment failure; encephalitis/si [Side Effect]; enzyme blood level; fatigue/si [Side Effect]; *gene mutation; Guillain Barre syndrome/si [Side Effect]; hepatitis/si [Side Effect]; human; hypersensitivity/si [Side Effect]; hyperthyroidism/si [Side Effect]; hypopituitarism/si [Side Effect]; hypothyroidism/si [Side Effect]; kidney failure/si [Side Effect]; liver injury/si [Side Effect]; *metastatic melanoma/dt [Drug Therapy]; metastatic melanoma/dt [Drug Therapy]; monotherapy; motor dysfunction/si [Side Effect]; multiple cycle treatment; nausea/si [Side Effect]; neuropathy/si [Side Effect]; oncogene; pancreatitis/si [Side Effect]; paralysis/si [Side Effect]; pneumonia/si [Side Effect]; protein targeting; pruritus/si [Side Effect]; randomized controlled trial(topic); rash/si [Side Effect]; review; side effect/si [Side Effect]; thyroid disease/si [Side Effect]; toxic epidermal necrolysis/si [Side Effect]; treatment duration; vitiligo/si [Side Effect]; B Raf kinase/ec [Endogenous Compound]; carboplatin/ct [Clinical Trial]; carboplatin/cb [Drug Combination]; carboplatin/dt [Drug Therapy]; creatinine/ec [Endogenous Compound]; dacarbazine/ct [Clinical Trial]; dacarbazine/cm [Drug Comparison]; dacarbazine/cm [Drug Comparison]; dacarbazine/dt [Drug Therapy]; ipilimumab/ct [Clinical Trial]; ipilimumab/cb [Drug Combination]; ipilimumab/cm [Drug Comparison]; ipilimumab/dt [Drug Therapy]; liver enzyme/ec [Endogenous Compound]; *nivolumab/ae [Adverse Drug Reaction]; *nivolumab/ct [Clinical Trial]; *nivolumab/cb [Drug Combination]; *nivolumab/cm [Drug Comparison]; *nivolumab/cm [Drug Comparison]; *nivolumab/dt [Drug Therapy]; paclitaxel/ct [Clinical Trial]; paclitaxel/cb [Drug Combination]; paclitaxel/dt [Drug Therapy]; placebo; adverse drug reaction; *cancer epidemiology; clinical trial; colitis; controlled clinical trial; controlled study; death; double blind procedure; drug combination; drug therapy; encephalitis; Europe; hepatitis; major clinical study; median survival time; *metastatic melanoma; mortality; organ; pneumonia; protein structure; randomized controlled trial; rash; side effect; thyroid disease; toxic epidermal necrolysis; uncertainty; visually impaired person; *B Raf kinase; cytotoxic agent; dacarbazine; endogenous compound; ipilimumab; new drug; nivolumab; trametinib
AB: * Existing drugs are poorly effective in patients with inoperable or metastatic melanoma without a mutation in the BRAF gene at position V600. The first-line treatment of choice for patients with BRAF V600-positive melanoma is a combination of dabrafenib (a BRAF inhibitor) and trametinib. * Nivolumab is a human monoclonal antibody designed to block receptors for PD-1 (programmed cell death-1) and thus to enhance T lymphocyte activity, especially against tumour cells. Nivolumab has been authorised in Europe as monotherapy for patients with inoperable or metastatic melanoma, regardless of BRAF V600 status. * Nivolumab has not been compared with the dabrafenib + trametinib combination in patients with BRAF V600-positive melanoma. * A randomised double-blind trial versus dacarbazine involved 418 patients with inoperable or metastatic BRAF V600-negative melanoma who had not yet received medication for this stage of the disease. The trial was halted prematurely when an unscheduled analysis showed an improvement in one-year survival with nivolumab compared to dacarbazine (73% versus 42%, p<0.0001). * A double-blind trial compared firstline treatment with nivolumab, ipilimumab or a combination of the two drugs. The mortality results are not yet available in mid-2016. The median time to melanoma aggravation or death was 6.9 months in the nivolumab group, 2.9 months in the ipilimumab group, and 11.5 months with the combination (p<0.001). * A comparative, randomised, unblinded trial included 405 patients with metastatic or inoperable melanoma in whom at least one drug had failed. An interim analysis conducted after about two years showed no statistically significant difference in median survival between patients who received nivolumab and those who received cytotoxic drugs. * As expected, given its protein structure and mechanism, the adverse effects of nivolumab are mainly due to immunological mechanisms. They are numerous and affect many organs: skin rash and toxic epidermal necrolysis, thyroid dysfunction, hepatitis, pneumonia, colitis and encephalitis. Adverse effects were serious in 9% of patients, and a few cases were fatal. * In practice, first-line nivolumab monotherapy was significantly more effective than dacarbazine in a trial in patients with BRAF V600-negative inoperable or metastatic melanoma. Although its evaluation must continue, nivolumab already seems to be a better option than dacarbazine and ipilimumab for treatment-naive patients, provided they receive detailed and balanced information on the uncertainties, efficacy and adverse effects of this new drug. For other patients, there is no evidence that nivolumab monotherapy represents an advantage over other available treatments.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/514/CN-01300514/frame.html


Record #83 of 144
ID: CN-01375602
AU: Biasco E
AU: Sbrana A
AU: Farnesi A
AU: Marconcini R
AU: Paolieri F
AU: Bloise F
AU: Cianci C
AU: Antonuzzo A
AU: Galli L
TI: Small cohort of nivolumab expanded access programme (EAP) patients: data from a real-world population
SO: Anticancer research. Conference: 27th annual meeting of the italian society of uro-oncology, siuro 2017. Italy
YR: 2017
VL: 37
NO: 4
PG: 2071
XR: EMBASE 616404733
PT: Conference Abstract
KY: adult; adverse drug reaction; anemia; asthenia; clinical article; clinical practice; clinical trial; comparative effectiveness; *compassionate use; controlled study; disease control; disease course; drug therapy; fatigue; *female; follow up; human; hypothyroidism; intravenous drug administration; kidney metastasis; *male; nomenclature; randomized controlled trial; safety; side effect; stomatitis; systemic therapy; toxicity; young adult; *nivolumab
AB: Introduction: Nivolumab is the first checkpoint inhibitor, approved for the treatment of renal cell cancer, to show a survival benefit in a randomised phase III trial 1. The experience of patients and physicians in routine clinical practice is often different than that in a controlled clinical trial setting. The aim of this study was to retrospectively evaluate its efficacy and safety in real life patients. Patients and Methods: Nivolumab was available upon physician request for patients (pts) aged >=18 years who had relapsed after a minimum of one prior systemic treatment for stage IV renal cell cancer. Nivolumab 3 mg/kg was administered intravenously every 2 weeks. Pts included in the analysis had received >=1 dose of nivolumab and were monitored for adverse events using Common Terminology Criteria for Adverse Events. Results: In total, 15 pts referring to our centre, participated in the EAP. Table I shows pts' baseline characteristics. With a median follow-up of 4.3 months (range=0.9-6.3), the disease control rate (DCR) among 14 pts evaluable for response was 21.42%: 2 pts (14.29%) with partial response and 1 pt (7.14%) with stable disease. To date, median time of treatment is 3.67 months (range=0.5- 6.3), with 6 patients treated beyond progression, since we observed a clinical benefit. Among 15 pts, only 1 (6.67%) patient discontinued treatment due to severe toxicity, namely grade-4 asthenia. Treatment was well tolerated in most patients. Grade 3 or 4 treatment-related adverse events occurred just in 1 (6.67%) patient receiving nivolumab. The most common event with nivolumab was fatigue, observed in 6 (40%) patients, of which just one pt with grade-4 and the others with grade-1 fatigue. Other relevant adverse events were anemia in 2 pts (13.33%), both of which grade- 2, mild stomatitis in 1 pt (6.67%), and grade-2 hypothyroidism in 1 pt (6.67%). Discussion and Conclusion: Even if this is a limited, retrospective experience, it can be explicative of the use of Nivolumab in everyday clinical practice. Nivolumab was demonstrated to be a safe therapy for pre-treated pts with metastatic renal cell carcinoma. Despite a DCR of 21.42%, we observed a clinical benefit in the majority of treated patients (9 patients, that is 3 patients with an objective radiological response and 6 patients with a clinical benefit, despite a radiological progression). (Table presented).
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/602/CN-01375602/frame.html


Record #84 of 144
ID: CN-01294364
AU: Kelly K
AU: Patel M
AU: Infante JR
AU: Iannotti N
AU: Nikolinakos P
AU: Leach J
AU: Wang D
AU: Chandler J
AU: Jerusalem G
AU: Gurtler J
AU: Arkenau H-T
AU: Bajars M
AU: Heydebreck A
AU: Speit I
AU: Heery CR
AU: Gulley JL
TI: Safety of avelumab (MSB0010718C), an anti-PD-L1 antibody: updated analysis from the phase Ib JAVELIN Solid Tumor trial
SO: Cancer research. Conference: 107th annual meeting of the american association for cancer research, AACR 2016. United states. Conference start: 20160416. Conference end: 20160420
YR: 2016
VL: 76
NO: 14 Supplement) (no pagination
XR: EMBASE 613609459
PT: Journal: Conference Abstract
KY: acute liver failure; adult; adverse drug reaction; aged; anemia; autoimmune hepatitis; breast; cancer epidemiology; cancer therapy; cause of death; clinical trial; colitis; controlled clinical trial; controlled study; disease course; drug therapy; drug withdrawal; fatigue; female; gene expression; human; hypothyroidism; infusion; major clinical study; *non small cell lung cancer; ovary; pharmacokinetics; phase 1 clinical trial; phase 3 clinical trial; radiation pneumonia; respiratory distress; *safety; side effect; stomach; toxicity; treatment duration; *avelumab; endogenous compound; gamma glutamyltransferase; *programmed death 1 ligand 1; triacylglycerol lipase
DOI: 10.1158/1538-7445.AM2016-CT132
AB: Background: The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against multiple cancers. Avelumab* (MSB0010718C) is a fully human antiPD-L1 IgG1 antibody currently being investigated in clinical trials. The primary objective of this phase Ib, open-label expansion study (NCT01772004) was to assess the safety and tolerability of avelumab in patients (pts) with locally advanced or metastatic (LA/M) solid tumors. Methods: Pts from 16 different expansion cohorts (including NSCLC, gastric, ovarian, urothelial, and breast; ECOG performance status [PS] of 01 at trial entry) and unselected for PD-L1 expression were treated with avelumab at 10 mg/kg IV, Q2W until confirmed progression, unacceptable toxicity, or any criteria for withdrawal occurred. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Results: As of Aug 4, 2015, 900 pts were treated with avelumab and followed for ?4 wks. Median age was 62 years (range, 23-91), ECOG PS was 0 (39.1%), 1 (60.6%), or 23 (0.2%), and median number of prior lines of anticancer therapy was 2 (range, 113). Median duration of treatment with avelumab and number of administrations were 10.0 wks (range, 292) and 5 infusions (range, 143), respectively. Treatment-related (TR) AEs of any grade occurred in 585 pts (65.0%). Grade ?3 TRAEs occurred in 91 pts (10.1%). The most frequent (?0.5%) grade ?3 TRAEs were IRRs (n = 8, 0.9%), GGT elevation (n = 7, 0.8%), lipase elevation (n = 7, 0.8%), anemia (n = 7, 0.8%), and fatigue (n = 6, 0.7%). Seventyfive pts (8.3%) experienced potential immune-related (ir) TRAEs, with hypothyroidism (n = 34, 3.8%) and pneumonitis (n = 8, 0.9%) occurring most frequently (?0.5%). Grade ?3 potential irTRAEs were reported for 17 pts (1.9%); the most frequent (?0.3%) were autoimmune hepatitis (n = 4; 0.4%), colitis (n = 3; 0.3%), and pneumonitis (n = 3; 0.3%). TRAEs resulted in permanent treatment discontinuation for 64 pts (7.1%); 2.6% (n = 23) discontinued due to an IRR and 1.3% (n = 12) discontinued due to a potential irTRAE. TRAEs were considered the primary cause of death by the investigator for 4 pts (0.4%): radiation pneumonitis (1), autoimmune hepatitis (1), acute liver failure (1), and respiratory distress (1). Conclusion: Singleagent avelumab shows an acceptable safety profile in a heavily pretreated population of pts with LA/M malignancies. To date, >1,500 pts have been enrolled in the JAVELIN Solid Tumor clinical trial. Additional safety and efficacy analyses from this study are ongoing, and recruitment to several phase III trials is underway.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/364/CN-01294364/frame.html


Record #85 of 144
ID: CN-01397381
AU: Garcia IM
AU: Grande E
AU: Garcia-Carbonero R
AU: Lopez C
AU: Teule A
AU: Capdevila J
TI: A multicohort phase II study of durvalumab plus tremelimumab for the treatment of patients (PTS) with advanced neuroendocrine neoplasms (NENs) of gastroenteropancreatic (GEP) or lung origin (the DUNE trial-GETNE1601-)
SO: Journal of clinical oncology. Conference: 2017 annual meeting of the american society of clinical oncology, ASCO. United states
YR: 2017
VL: 35
NO: 15 Supplement 1) (no pagination
XR: EMBASE 617435711
PT: Conference Abstract
KY: blood; cancer epidemiology; chemotherapy; clinical trial; comparative effectiveness; controlled clinical trial; *controlled study; disease control; drug combination; drug therapy; *female; follow up; gastrointestinal tract; human; immunotherapy; *lung; major clinical study; *male; overall survival; *pancreas islet cell tumor; pharmacokinetics; phase 2 clinical trial; probability; progression free survival; remission; response evaluation criteria in solid tumors; retreatment; safety; tumor growth; cytotoxic T lymphocyte antigen 4; *durvalumab; endogenous compound; platinum; somatostatin derivative; *ticilimumab
AB: Background: NENs include a heterogeneous group of tumors with different behavior. Despite immunomodulators such as interferon are approved for the management of grade 1-2 NENs, the low mutation tumor load and PD-1/PDL-1 expression have limited the development of immune check-point inhibitors in this setting. The rational for immunotherapy in high grade NENs is stronger compared with low grade NENs based on the results observed in small cell lung cancer. However, the combination of an antiPDL-1 and antiCTLA-4 could increase the probability of success regardless of tumor growth rate, mutational tumor load or PDL-1 expression in low grade NENs. Methods: This prospective, multi-center, open label, phase II study (EudraCT:2016-002858-20) will evaluate the efficacy and safety of durvalumab plus tremelimumab in 126 pts within four different cohorts, including well-moderately differentiated lung NENs (Cohort 1), grade 1-2 gastrointestinal NENs (Cohort 2), grade 1-2 pancreatic NENs (Cohort 3) and grade 3 GEP NENs (Cohort 4). To optimize the efficacy of immunotherapy in low grade NENs, pts included in the trial must have progressed to all standard approved therapy in each setting, including somatostatin analogues, targeted agents and chemotherapy for lung and GEP grade 1-2 NENs up to 4 prior lines. For pts included in cohort 4, progression to standard platinum-based chemotherapy is mandatory. All pts will receive durvalumab 1500 mg every 28 days for 12 months, and tremelimumab 75 mg Q4W up to 4 doses/cycles. Retreatment is allowed after disease progression in the follow-up period. The primary endpoint of the study for cohorts 1-3 is disease control rate at 9 months including the percentage of pts achieving complete response, partial response, or stable disease according to RECIST v1.1; Median overall survival will be the primary endpoint for cohort 4. Primary endpoints will be assessed by investigators and confirmed by central radiological review. Secondary endpoints include median progression-free survival, safety and tolerability and a wide panel of biomarkers in blood samples and tumor tissue.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/381/CN-01397381/frame.html


Record #86 of 144
ID: CN-01398230
AU: Huang J
AU: Mo H
AU: Wu D
AU: Chen X
AU: Ma L
AU: Lan B
AU: Qu D
AU: Yang Q
AU: Xu B
TI: Phase I study of the anti-PD-1 antibody SHR-1210 in patients with advanced solid tumors
SO: Journal of clinical oncology. Conference: 2017 annual meeting of the american society of clinical oncology, ASCO. United states
YR: 2017
VL: 35
NO: 15 Supplement 1) (no pagination
XR: EMBASE 617538175
PT: Conference Abstract
KY: adverse drug reaction; antineoplastic activity; bladder cancer; cancer patient; capillary hemangioma; chronic obstructive lung disease; clinical trial; colorectal carcinoma; controlled clinical trial; *controlled study; diarrhea; disease control; disease exacerbation; *esophageal squamous cell carcinoma; fatigue; *female; fever; human; hypertransaminasemia; hypothyroidism; intravenous drug administration; liver cell carcinoma; lung cancer; major clinical study; *male; model; nasopharynx cancer; neutropenia; phase 1 clinical trial; pruritus; remission; safety; side effect; stomach cancer; thrombocytopenia; toxicity; *antibody; bilirubin; endogenous compound; *programmed death 1 receptor; troponin I
AB: Background: SHR-1210 is a humanized anti-PD-1 IgG4 antibody that blocks the binding of PD-L1 and PD-L2 to PD-1. SHR- 1210 binds to PD-1 with high affinity. Methods: This phase 1 study consisted of dose-escalation and expansion cohorts. We used a standard 3+3 design to assess safety in the dose escalation part. SHR-1210 was initially administered by intravenous (IV) infusion over 30 minutes on days 1 and 28, and repeated every 14 days thereafter. Based on pharmacologic models, disease-specific cohorts were enrolled to receive SHR-1210 at 200 mg IV every 2 weeks (Q2W). Results: Overall, a total of 58 patients were treated with SHR-1210 at 3 dose levels and schedules: 60 mg Q2W (12 patients); 200 mg Q2W (34 patients), and 400 mg Q2W (12 patients). 49/58 patients received > 2 cycles (each cycle was 28 days) while 36/58 patients were receiving ongoing treatment at the time of abstract preparation. No dose-limiting toxicity (DLT) was observed. The most common adverse events (AEs) related to SHR-1210 included: reactive capillary hemangiomas (79.3%), hypothyroidism (29.3%), pruritus (19.0%), elevated transaminase (13.8%), increased bilirubin (12.1%), fatigue (12.1%), fever (10.3%), and diarrhea (10.3%). Of the 46 cases of hemangiomas, only 5 patients were with grade 2, others were evaluated as grade 1. Of the 17 cases of hypothyroidism were asymptomatic and none exceeded grade 2 severity. Serious AEs suspected to be related to SHR-1210 included one grade 3 acute exacerbation of chronic obstructive pulmonary disease, one grade 3 elevated cardiac troponin I, one grade 4 thrombocytopenia and one grade 4 neutropenia. Overall, the objective response rate as assessed by central review was 31.0%, with a disease control rate of 46.5%. No patients achieved complete response. Eighteen patients had partial response, including 10 esophageal squamous cell carcinoma patients (10/29), three gastric cancer patients (3/8), one lung cancer patient (1/3), one nasopharynx cancer patient (1/3), one hepatocellular carcinoma patient (1/3), one colorectal carcinoma patient (1/3), and one bladder cancer patient (1/1). Conclusions: SHR-1210 was well-tolerated with encouraging antitumor activity and a safety profile.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/230/CN-01398230/frame.html


Record #87 of 144
ID: CN-01397842
AU: Kelly K
AU: Infante JR
AU: Taylor MH
AU: Patel MR
AU: Gordon MS
AU: Wong DJL
AU: Iannotti N
AU: Mehnert JM
AU: Loos A
AU: Koch H
AU: Speit I
AU: Gulley JL
TI: Safety profile of avelumab in patients with advanced solid tumors: a JAVELIN pooled analysis of phase 1 and 2 data
SO: Journal of clinical oncology. Conference: 2017 annual meeting of the american society of clinical oncology, ASCO. United states
YR: 2017
VL: 35
NO: 15 Supplement 1) (no pagination
XR: EMBASE 617434755
PT: Conference Abstract
KY: adrenal gland; adverse drug reaction; chill; colitis; controlled clinical trial; controlled study; drug therapy; drug withdrawal; fatigue; *female; fever; hepatitis; human; hypersensitivity; infusion rate; infusion related reaction; *male; Medical Dictionary for Regulatory Activities; *merkel cell carcinoma; meta analysis; myositis; nausea; pharmacokinetics; phase 1 clinical trial; pneumonia; post hoc analysis; rash; recurrence risk; *safety; side effect; symptom; thyroid disease; toxicity; *avelumab; endogenous compound; triacylglycerol lipase
AB: Background: Avelumab is a fully human IgG1 anti-PD-L1 antibody with clinical activity in several tumor types. Pooled safety data from a large phase 1 trial in various tumors and a phase 2 trial in Merkel cell carcinoma (NCT01772004, NCT02155647) were analyzed to further characterize the safety profile of avelumab. Methods: Patients (pts) received avelumab 10 mg/kg 1-hour IV Q2W until progression, unacceptable toxicity, or withdrawal. Treatment-related adverse events (TRAEs) were graded by NCI CTCAE. In post hoc analyses, immune-related adverse events (irAEs) were identified via an expanded AE list and medical review, and infusion-related reaction (IRR) events were identified based on prespecified MedDRA terms, occurring within 1 day or related symptoms that resolved within 2 days of infusion. Results: In 1,738 pts analyzed (phase 1, n = 1,650; phase 2, n = 88) who received >=1 dose of avelumab for a median of 12 weeks (range 2-138), the most common any grade TRAEs were fatigue (n = 307, 18%), IRR (n = 295, 17%), and nausea (n = 150, 9%). 177 pts (10%) had a grade >=3 TRAE; most common were fatigue and elevated lipase (17 [1%] each). TRAEs led to discontinuation in 107 pts (6%). Four pts (0.2%) died due to a TRAE. Any grade irAEs occurred in 247 pts (14%), which were grade >=3 in 39 pts (2%) and considered serious in 43 pts (2%). The most common any grade irAEs were thyroid disorder (n = 98, 6%) and rash (n = 90, 5%). Other irAEs (eg, colitis, hepatitis, pneumonitis, adrenal insuficiency, myositis) each occurred in < 2%. irAEs led to discontinuation in 34 pts (2%). IRR or related symptoms (eg, chills, pyrexia, hypersensitivity) occurred in 439 pts (25%), which were grade 3 in 9 pts (0.5%) and grade 4 in 3 pts (0.2%). An IRR occurred at first infusion in 79% and within first 4 doses in 99%; 63/439 pts (14%) had IRR recurrence in later cycles. IRR led to dose interruption in 152 (9%), infusion rate reduction in 124 (7%), and discontinuation in 35 pts (2%). Conclusions: This large pooled analysis confirms that avelumab has an acceptable safety profile. A minority of pts experienced a grade >=3 TRAE or irAE and discontinuation due to TRAEs was uncommon. IRRs mostly occurred at first infusion and the rate of recurrence was low.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/842/CN-01397842/frame.html


Record #88 of 144
ID: CN-01438362
AU: Ribas A
AU: Hodi FS
AU: Lawrence D
AU: Atkinson V
AU: Agarwal S
AU: Carlino MS
AU: Fisher R
AU: Long GV
AU: Miller WH
AU: Huang Y
AU: Homet Moreno B
AU: Ibrahim N
AU: Hamid O
TI: KEYNOTE-022 update: phase 1 study of first-line pembrolizumab (pembro) plus dabrafenib (D) and trametinib (T) for BRAF-mutant advanced melanoma
SO: Annals of oncology. Conference: 42nd ESMO congress, ESMO 2017. Spain
YR: 2017
VL: 28
NO: Supplement 5
PG: v430
XR: EMBASE 619623758
PT: Conference Abstract
KY: adult; antineoplastic activity; autoimmune hepatitis; brain metastasis; cancer staging; clinical article; drug therapy; erythema; female; fever; follow up; *gene mutation; human; hyperthyroidism; hypothyroidism; iridocyclitis; male; *melanoma; neutropenia; phase 1 clinical trial; pneumonia; randomized controlled trial; response evaluation criteria in solid tumors; response time; staining; *B Raf kinase; *dabrafenib; endogenous compound; gamma glutamyltransferase; *pembrolizumab; *trametinib
DOI: 10.1093/annonc/mdx377.003
AB: Background: Combination of anti-PD-1 agents with BRAF/MEK inhibitors (i) may provide synergistic antitumor effects in BRAF-mutant melanoma. The ph 1/2 KEYNOTE-022 study (NCT02130466) is assessing safety and antitumor activity of recommended doses of pembro + BRAFi D+ MEKi T; updated and additional ph 1 results are reported. Methods: Treatment-naive pts with BRAF<sup>V600E/K</sup>-mutant stage III/IV melanoma received pembro 2 mg/kg Q3W + D 150 mg BID + T 2 mg QD. Primary end point was safety; AEs were graded per CTCAE v4.0. Efficacy end points were ORR, PFS, and OS. Data cutoff: Mar 1, 2017. Results: Of the 15 pts enrolled, 10 (66.7%) had PD-L1+tumors (>=1% staining), 13 (86.7%)/2 (13.3%) had ECOG PS 0/1, and 1 (6.7%) had stable brain metastases. Median follow-up was 19.7 mo (range, 15.9-31.1). 3/15 (20.0%) pts had DLTs (pt 1 had gr 4 neutropenia; pt 2 had gr 4 ALT increase; and pt 3 had gr 4 ALT, gr 3 AST, and gr 3 GGT increase); all resolved. Thus, this dose was the MTD and recommended ph 2 regimen. 11 (73%) pts had gr 3-4 TRAEs; ALT increase, AST increase, and pyrexia occurred in>=20% of pts. 7 (46.7%) pts had immune-mediated AEs, most commonly hyperthyroidism in 3 pts (2 gr 1 and 1 gr 2) and hypothyroidism in 4 pts (all gr 1). Treatment was discontinued (d/c) for 2 events (1 gr 2 pneumonitis and 1 gr 3 autoimmune hepatitis) and was interrupted for 3 events (1 gr 1 hyperthyroidism, 1 gr 2 anterior uveitis, and 1 gr 3 erythematous rash); all resolved. ORR (RECIST v.1.1, investigator; confirmed + unconfirmed) was 67%; 1 pt had CR, 9 had PR; an additional 2 pts had SD and 3 had PD. ORR (RECIST v.1.1, investigator; confirmed only) was 53%; 8 pts had PR; an additional 3 pts had SD and 4 had PD. Median time to response was 2.8 mo (range, 2.2-3.0); median DOR was not reached (range, 2.8-26.5 mo). Among the 8 pts with confirmed ORR, 6 had ongoing responses and 2 had progression at data cutoff. 2 pts remained on triplet therapy, 2 d/c D + T, and 4 d/c pembro + D +T as of last follow- up. Conclusions: Updated results show that approved doses of pembro + D+ T continue to demonstrate promising antitumor activity for BRAF-mutant melanoma. A randomized ph 2 study is currently evaluating this triplet regimen as first-line therapy for BRAF-mutant melanoma.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/362/CN-01438362/frame.html


Record #89 of 144
ID: CN-01303138
AU: Herrera AF
AU: Bartlett NL
AU: Ramchandren R
AU: Vose JM
AU: Moskowitz AJ
AU: Feldman TA
AU: LaCasce AS
AU: Ansell SM
AU: Moskowitz CH
AU: Fenton K
AU: Kato K
AU: Fong A
AU: Advani RH
TI: Preliminary results from a phase 1/2 study of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory hodgkin lymphoma
SO: Blood. Conference: 58th annual meeting of the american society of hematology, ASH 2016. United states. Conference start: 20161203. Conference end: 20161206
YR: 2016
VL: 128
NO: 22) (no pagination
XR: EMBASE 614224877
PT: Journal: Conference Abstract
KY: acute kidney failure; adult; adverse drug reaction; aged; antineoplastic activity; apheresis; CD4+ T lymphocyte; CD8 T lymphocyte; chemotherapy; *classical Hodgkin lymphoma; clinical article; clinical trial; controlled clinical trial; controlled study; dehydration; disease duration; drug combination; drug therapy; dyspnea; extract; fatigue; female; human; human cell; hypercalcemia; hypothyroidism; infusion related reaction; male; metabolism; myalgia; nausea; pharmacokinetics; phase 1 clinical trial; phase 2 clinical trial; pruritus; rash; recurrent disease; Reed Sternberg cell; regulatory T lymphocyte; relapse; safety; salvage therapy; side effect; staging; topical drug administration; toxicity; treatment failure; antihistaminic agent; biological marker; *brentuximab vedotin; CD30 antigen; CD34 antigen; CD4 antigen; corticosteroid; endogenous compound; *nivolumab
AB: Background Brentuximab vedotin (BV) is an antibody-drug conjugate directed against CD30, a receptor that engages the CD30 ligand expressed on immune cells in the tumor microenvironment, promoting tumor cell growth (Montanari 2014, Hansen 2014). Through disruption of the microtubule network, BV induces apoptotic cell death, and may initiate an antitumor immune response (i.e., immunogenic cell death) through the induction of endoplasmic reticulum (ER) stress (Gardai 2015). Nivolumab is a fully human monoclonal PD-1 blocking antibody that prevents tumor immune evasion. Both agents have independent high single-agent response rates in patients (pts) with relapsed or refractory (R/R) Hodgkin lymphoma (HL), and when used in combination, may exhibit mechanistic synergy. Given the demonstrated efficacy of both BV and nivolumab, together these agents could yield improved CR rates prior to ASCT in pts with R/R HL, and potentially better long-term outcomes. Methods A phase 1/2 study is ongoing to evaluate the safety and antitumor activity of BV administered in combination with nivolumab as first salvage therapy in pts with R/R classical HL after standard frontline chemotherapy (NCT02572167). Adult pts are treated in 21-day cycles for up to 4 cycles (12 weeks). Pts receive 1.8 mg/kg BV on Cycle 1 Day 1, and 3 mg/kg nivolumab on Cycle 1 Day 8. For cycles 2 through 4, BV and nivolumab are administered on Day 1 of each cycle at the same doses. After completion of the Cycle 4 response assessment, pts are eligible to undergo ASCT. Investigator assessment of lymphoma response and progression is per the Lugano Classification Revised Staging System for malignant lymphoma (Cheson 2014). Results Twenty-five pts (60% female) with a median age of 32 years (range, 18-69) have been enrolled to date. Sixty percent of pts have relapsed disease, 36% have primary refractory disease (failure to achieve CR with frontline therapy, or relapse within 3 months of completing frontline therapy), and 1 pt (4%) has unknown status. At the time of enrollment, 32% of pts presented with extranodal disease and 16% with bulky disease. At the time of the data extract, 23 pts had received treatment. An increased incidence of infusion-related reactions (IRRs) was observed at the start of combination treatment in Cycle 2 during the BV infusion leading to 1 dose delay. Premedication with corticosteroids (hydrocortisone 100 mg or equivalent) and antihistamines at Cycles 2-4 was instituted through a protocol amendment. Six pts have completed combination treatment, and all have achieved an objective response (ORR, 100%), with 3 of 6 achieving a complete metabolic response (CmR, 50%). All 6 pts have proceeded directly to ASCT. Median number of CD34+ cells collected was 12.9 x10 cells/kg (range, 5-26) in a mean number of 1.7 apheresis sessions (range, 1-2). Adverse events (AEs) for all pts are summarized prior to ASCT. Eighteen of the 23 treated pts (78%) experienced adverse events (AEs). Fifteen pts (65%) had AEs < Grade 2 in severity and 3 pts (13%) experienced Grade 3 AEs. No pts experienced Grade 4 AEs pre-ASCT. Fatigue was the most common AE occurring in 35% of pts, followed by nausea (26%), rash (22%), dyspnea, myalgia, and pruritus (17% each). One pt experienced a treatment-related serious adverse event (SAE) of dehydration, hypercalcemia, and acute kidney injury. Immune-related adverse events (IrAEs) were experienced by 3 pts; 2 pts who experienced Grade 1 rash treated with topical steroids, and 1 pt who experienced Grade 1 hypothyroidism. No pts have discontinued treatment prematurely. In addition to Reed-Sternberg cells, CD30 is expressed on activated T cells. Preliminary biomarker data indicate a BV-induced decrease in the percentage of CD4+ T regulatory (Treg) cells at C1D8, with no decrease in proliferating CD8+ T cells, and no significant decrease observed in the percentage of CD4+ Th1 cells compared to baseline for 5 of 6 pts (83%). Nivolumab induced a robust expansion of T cells at C1D15. Conclusions Early data suggest the combination of BV and nivolumab is an active and well-tolerated salvage therapy in pts with R/R HL. While an elevated incidence of IRRs has been observed, toxicities with this regimen appear to be tolerable overall. The preliminary antitumor activity suggests this combination may be a promising option for R/R HL pts. Updated results will be shared at the time of presentation.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/138/CN-01303138/frame.html


Record #90 of 144
ID: CN-01431448
AU: Chuk MK
AU: Chang JT
AU: Theoret MR
AU: Sampene E
AU: He K
AU: Weis SL
AU: Helms WS
AU: Jin R
AU: Li H
AU: Yu J
AU: Zhao H
AU: Zhao L
AU: Paciga M
AU: Schmiel D
AU: Rawat R
AU: Keegan P
AU: Pazdur R
TI: FDA Approval summary: accelerated approval of pembrolizumab for second-line treatment of metastatic melanoma
SO: Clinical cancer research
YR: 2017
VL: 23
NO: 19
PG: 5666-5670
XR: EMBASE 618870797
PT: Article
KY: adult; aged; arthralgia/si [Side Effect]; arthritis/si [Side Effect]; article; cancer growth; clinical effectiveness; colitis/si [Side Effect]; constipation/si [Side Effect]; controlled study; coughing/si [Side Effect]; decreased appetite/si [Side Effect]; dermatitis/si [Side Effect]; diarrhea/si [Side Effect]; *drug approval; fatigue/si [Side Effect]; female; fever/si [Side Effect]; focal epilepsy/si [Side Effect]; follow up; food and drug administration; hemolytic anemia/si [Side Effect]; hepatitis/si [Side Effect]; human; hyperthyroidism/si [Side Effect]; hypophysitis/si [Side Effect]; hypothyroidism/si [Side Effect]; major clinical study; male; *metastatic melanoma/di [Diagnosis]; *metastatic melanoma/dt [Drug Therapy]; metastatic melanoma/dt [Drug Therapy]; multicenter study; myalgia/si [Side Effect]; myositis/si [Side Effect]; nausea/si [Side Effect]; nephritis/si [Side Effect]; open study; pancreatitis/si [Side Effect]; pneumonia/si [Side Effect]; priority journal; pruritus/si [Side Effect]; randomized controlled trial; rash/si [Side Effect]; response evaluation criteria in solid tumors; *secondary health care; thyroid disease/si [Side Effect]; treatment outcome; treatment response; uveitis/si [Side Effect]; very elderly; vitiligo/si [Side Effect]; ipilimumab/dt [Drug Therapy]; *pembrolizumab/ae [Adverse Drug Reaction]; *pembrolizumab/ct [Clinical Trial]; *pembrolizumab/dt [Drug Therapy]; *pembrolizumab/iv [Intravenous Drug Administration]; *pembrolizumab/pk [Pharmacokinetics]; *pembrolizumab/pd [Pharmacology]; prednisone/ct [Clinical Trial]; prednisone/dt [Drug Therapy]
DOI: 10.1158/1078-0432.CCR-16-0663
AB: On September 4, 2014, the FDA approved pembrolizumab responses were ongoing. The most common (20%) adverse (KEYTRUDA; Merck Sharp & Dohme Corp.) with a recommended reactions were fatigue, cough, nausea, pruritus, rash, decreased dose of 2 mg/kg every 3 weeks by intravenous infusion for the appetite, constipation, arthralgia, and diarrhea. Immune-mediated treatment of patients with unresectable or metastatic melanoma adverse reactions included pneumonitis, colitis, hepatitis, hypo-who have progressed following treatment with ipilimumab and, if physitis, and thyroid disorders. The benefits of the observed ORR BRAF V600 mutation positive, a BRAF inhibitor. Approval was with prolonged duration of responses outweighed the risks of based on demonstration of objective tumor responses with pro-immune-mediated adverse reactions in this life-threatening dis-longed response durations in 89 patients enrolled in a random-ease and represented an improvement over available therapy. ized, multicenter, open-label, dose-finding, and activity-estimat-Important regulatory issues in this application were role of dura-ing phase 1 trial. The overall response rate (ORR) by blinded bility of response in the evaluation of ORR for accelerated approv-independent central review per RECIST v1.1 was 24% (95% al, reliance on data from a first-in-human trial, and strategies for confidence interval, 15-34); with 6 months of follow-up, 86% of dose selection. Copyright © 2017 American Association for Cancer Research.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/448/CN-01431448/frame.html


Record #91 of 144
ID: CN-01335640
AU: Anonymous
TI: Japanese Society of Medical Oncology 2016 Annual Meeting
SO: Annals of oncology. Conference: 14th annual meeting of the japanese society of medical oncology. Japan. Conference start: 20160728. Conference end: 20160730
YR: 2016
VL: 27
NO: no pagination
XR: EMBASE 615048790
PT: Journal: Conference Review
KY: animal model; antiangiogenic therapy; breast cancer; cancer epidemiology; cat; clinical outcome; clinical study; clinical trial; controlled clinical trial; controlled study; driver; drug resistance; drug therapy; feasibility study; female; hormonal therapy; human; human versus animal comparison; Japan; Japanese (citizen); lung cancer; metastatic colorectal cancer; molecularly targeted therapy; nonhuman; oncogene; *oncology; ovary cancer; palliative therapy; personalized medicine; phase 1 clinical trial; phase 2 clinical trial; screening; soft tissue sarcoma; stomach cancer; survival; thyroid medullary carcinoma; tumor resistance; bevacizumab; endogenous compound; epidermal growth factor receptor 2; hormone receptor; lenvatinib; mammalian target of rapamycin inhibitor; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor; pazopanib; phosphatidylinositol 3 kinase; placebo; programmed death 1 receptor; protein kinase B; ramucirumab; sorafenib; taselisib; tipiracil plus trifluridine; unclassified drug; vandetanib
AB: The proceedings contain 265 papers. The topics discussed include: personalized medicine in HER2-positive breast cancer; current status of lenvatinib for thyroid cancer; phase Ia/Ib study of taselisib in Japanese patients with solid tumors or hormone receptor positive breast cancer; HBOC management in PARP inhibitor development: Japanese perspective; ramucirumab for gastric cancer; phase II trial of sorafenib for advanced or metastatic medullary thyroid carcinoma and anaplastic thyroid carcinoma; development of a nationwide genomic screening network and clinical trial for lung cancer with rare driver oncogenes; vandetanib for thyroid cancer; overcoming endocrine therapy resistance in breast cancer, a cat and mouse game?; PD-1 signal inhibitors for ovarian cancer: perspectives and issues; the clinical outcome of pazopanib treatment for soft tissue sarcomas: a japanese musculoskeletal oncology group study; molecular-targeted therapies and genomic characterization in gynecologic cancers; new treatment options in gynecologic malignancy the PI3K/AKT/mTOR inhibitor in gynecologic malignancy; antiangiogenic therapy in gynecologic malignancy; current status and future perspective in metastatic colorectal cancer: SCRUM-Japan GI-SCREEN project in japan; early specialized palliative care in Japan: a feasibility study; subgroup analysis in RAISE: a phase III study of FOLFIRI 1 ramucirumab or placebo in patients with advanced mCRC; and final survival results of a multicenter phase i/ii study of tas-102 with bevacizumab for mCRC (C-TASK FORCE).
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/640/CN-01335640/frame.html


Record #92 of 144
ID: CN-01397905
AU: Giaccone G
AU: Thompson J
AU: McGuire C
AU: Manning M
AU: Kallakury B
AU: Chahine JJ
AU: Subramaniam DS
AU: Liu SV
AU: Gibney GT
AU: Kim C
AU: McCutcheon JN
TI: Pembrolizumab in patients with recurrent thymic carcinoma: results of a phase II study
SO: Journal of clinical oncology. Conference: 2017 annual meeting of the american society of clinical oncology, ASCO. United states
YR: 2017
VL: 35
NO: 15 Supplement 1) (no pagination
XR: EMBASE 617434606
PT: Conference Abstract
KY: adult; aged; bullous pemphigoid; Caucasian; chemotherapy; clinical article; controlled clinical trial; *controlled study; death; diarrhea; disease duration; drug therapy; fatigue; female; gene expression; hepatitis; human; human tissue; hyperthyroidism; hypothyroidism; insulin dependent diabetes mellitus; male; minimal residual disease; myasthenia gravis; myocarditis; myositis; organ culture; pacemaker; pancreatitis; phase 2 clinical trial; remission; response evaluation criteria in solid tumors; rhinorrhea; safety; side effect; *squamous cell carcinoma; staining; *thymus; treatment interruption; tumor cell; endogenous compound; *pembrolizumab; programmed death 1 ligand 1
AB: Background: There are few treatment options for thymic carcinoma after chemotherapy. We completed a single institution phase II study of pembrolizumab (P) in patients with recurrent thymic carcinomas. Methods: Main eligibility criteria included: progression after >= 1 chemotherapy line, ECOG PS 0-2, no history of autoimmune disease, and adequate organ function. P was given at 200mg IV every 3 weeks. The primary objective of the study was response rate (RR) by RECIST v1.1 criteria; secondary objectives were PFS and OS, and safety. Results: From 3/2015 to 12/2016 we accrued 41 patients. Of 40 eligible patients, 29 were male, 19 Caucasians, median age was 57 years (range 25-80), 14 had squamous carcinoma histology, and 19 ECOG PS 0. Median number of cycles delivered was 6 (range 1-31). The most common side effects were mild fatigue (10), diarrhea (4) and rhinorrhea (4). Six patients developed multiple grade 3-4 immune-relates AEs (irAEs): myocarditis/myositis (1), myositis/myocarditis/hepatitis/myasthenia gravis (1), myositis/hepatitis (1), bullous pemphigoid (1), hepatitis (1), hepatitis/pancreatitis/diabetes mellitus type 1 (1). There were no treatment related deaths. The 2 patients who developed myocarditis required a pacemaker. Three patients interrupted treatment because of irAEs (all responders) and 3 because of progression around the time of the irAE. irAEs were more frequent in females (4/6; p = .026). Five patients developed hypothyroidism and 1 hyperthyroidism. RR assessed in all 40 eligible patients was 22.5%: 1 complete response, 8 partial responses (plus 1 unconfirmed), 20 stable disease and with 11 progressions. Two partial responses show minimal residual disease with no PET uptake. Two responders have progressed and 5 responses are beyond 12 months duration. Of 29 cases tested for PD-L1 staining (Dako 22C3), high PD-L1 (>=50% tumor cells positive) was seen in 8 (28%); 6/9 responders had high PD-L1 expression. Targeted NGS in 15 cases did not show correlation between mutational burden and response. Conclusions: P has activity in patients with thymic carcinoma. irAEs are more frequent than in other tumors. Further analysis of NGS, Nanostring and PD-L1 expression and updated survival will be presented.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/905/CN-01397905/frame.html


Record #93 of 144
ID: CN-01397386
AU: Naing A
AU: Infante JR
AU: Wong DJL
AU: Korn WM
AU: Aljumaily R
AU: Papadopoulos KP
AU: Autio KA
AU: Pant S
AU: Bauer TM
AU: Drakaki A
AU: Daver NG
AU: Hung A
AU: Vlasselaer P
AU: Brown GL
AU: Oft M
AU: Tannir NM
TI: Emucacy and safety of pegylated human IL-10 (AM0010) in combination with an anti-PD-1 in renal cell cancer
SO: Journal of clinical oncology. Conference: 2017 annual meeting of the american society of clinical oncology, ASCO. United states
YR: 2017
VL: 35
NO: 15 Supplement 1) (no pagination
XR: EMBASE 617435703
PT: Conference Abstract
KY: anemia; cancer susceptibility; cell clone; cell phagocytosis; clinical article; clonal variation; colitis; controlled clinical trial; controlled study; cytokine release syndrome; disease course; drug therapy; endocrine disease; erythrocyte; female; follow up; gene activation; gene inactivation; genetic susceptibility; human; human cell; human tissue; hypertriglyceridemia; *kidney carcinoma; male; phase 1 clinical trial; pneumonia; *safety; splenomegaly; T lymphocyte activation; thrombocytopenia; CD8 antigen; endogenous compound; *interleukin 10; nivolumab; pembrolizumab; *programmed death 1 receptor; transforming growth factor beta; vasculotropin receptor
AB: Background: IL-10 has anti-inmuammatory activity and stimulates the cytotoxicity and proliferation of CD8+ T cells at higher concentrations. IL-10 receptors and PD1 are expressed on activated CD8 T cells, providing a rationale for combining AM0010 and an anti-PD1. The emucacy and safety promule for AM0010 alone was established in poor to intermediate risk RCC pts treated in 3 LOT. Objective responses were observed in 4 of 15 pts with RCC. In the dose escalation of AM0010 plus pembrolizumab, 4 of 8 patients had an objective response. The mPFS was 16.7 months and the mOS has not been reached, median follow up (mFU) is 19.3 mo. Methods: In this Phase 1b, 29 pts. with metastatic RCC were enrolled until Nov. 18 2016 on AM0010 (10 ug/kg daily SC) and nivolumab (3mg/kg, q2wk IV). 2 had favorable, 20 had intermediate and 4 had poor IMDC risk (3 were not available). Pts. had a median of 1 prior therapy (range 1-3). All pts. had received a VEGFR-TKI. Tumor responses were assessed with irRC. Immune responses were evaluated by serum cytokines, activation of blood derived T cells and peripheral T cell clonality. Results: AMO010 plus nivolumab was well tolerated. TrAEs were reversible. There were no autoimmune colitis, pneumonitis, or endocrine disorders. 14 patients had at least 1 G3/4 TrAE, including anemia (9), thrombocytopenia (5), hypertriglyceridaemia (4). 2 pts had a reversible cytokine release syndrome with splenomegaly and increased immune mediated red blood cell phagocytosis most likely precipitated by T-cell activation, as both pts had tumor responses. As of Jan 31 2017, partial responses (PR) were observed in 8 of 26 evaluable pts (31%). An additional 13 of 26 pts had stable disease (41%), 7 pts had tumor reductions of more than 30%. The mPFS and mOS has not been reached with a mFU of 5.2 mo. (range 0.3-10.3). AM0010 + anti-PD1 increased Th1 cytokines in the serum while decreasing TGFb, an expansion of proliferating PD1+ Lag3+ activated CD8 T cells and denovo oligoclonal expansion of T cell clones in the blood. Conclusions: AM0010 in combination with nivolumab is well-tolerated in RCC pts. The emucacy and the observed CD8 T cell activation is promising and encourages the continued study of AM0010 in combination with nivolumab.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/386/CN-01397386/frame.html


Record #94 of 144
ID: CN-01296308
AU: Bauman J
AU: Ferris RL
AU: Clump DA
AU: Ohr J
AU: Gooding W
AU: Kim S
AU: Karlovits B
AU: Duvvuri U
AU: Johnson JT
AU: Petro D
AU: Heron D
TI: Phase I trial of cetuximab, intensity modulated radiotherapy (IMRT), and ipilimumab in previously untreated, locally advanced head and neck squamous cell carcinoma (PULA HNSCC)
SO: Annals of oncology. Conference: 41st european society for medical oncology congress, ESMO 2016. Denmark. Conference start: 20161007. Conference end: 20161011
YR: 2016
VL: 27
NO: no pagination
XR: EMBASE 613910936
PT: Journal: Conference Abstract
KY: adverse drug reaction; colitis; controlled clinical trial; controlled study; disease course; folliculitis; *head and neck squamous cell carcinoma; hepatitis; human; hyperthyroidism; hypopharynx; hypophysitis; *intensity modulated radiation therapy; larynx; major clinical study; oropharynx; phase 1 clinical trial; phase 2 clinical trial; radiation dermatitis; side effect; smoking; toxicity; *cetuximab; cytotoxic T lymphocyte antigen 4; endogenous compound; *ipilimumab; steroid
DOI: 10.1093/annonc/mdw435.31
AB: Background: Concurrent IMRT with cetuximab (C), an EGFR-specific monoclonal antibody (mAb), provides suboptimal disease control in intermediate or high risk HNSCC. C induces cell-mediated immunity, but also immunosuppressive regulatory T cells (Treg) expressing CTLA-4, which correlate negatively with clinical outcomes. Thus, we conducted a phase I trial adding ipilimumab (ipi), an anti-CTLA-4 mAb, to standard C-IMRT. Methods: Key eligibility included: stage III-IVb PULA HNSCC ( pharynx, larynx); high risk (HPV-) or intermediate risk (HPV+ and either: > 10 pack-year tobacco and > N2 disease; or T4 or N3 disease). A 3 + 3 dose-escalation design was used to determine recommended phase II dose (RP2D, see Table). Dose limiting toxicity (DLT) was defined as any grade 4 adverse event (AE) except in-field radiation dermatitis or any immune-related (ir) AE requiring > 2 weeks of systemic steroids. Results: From July 2013-May 2016, 18 pts enrolled: 5 larynx, 3 hypopharynx, 3 HPVoropharynx, 7 HPV+ oropharynx; 14 smokers; 2 stage III, 13 stage IVa, 3 stage IVb. Two of 6 pts in cohort 1 experienced grade 3 ir-dermatologic DLT's, perforating folliculitis and autoimmune dermatitis, distinct from typical cetuximab-induced acneiform rash. No DLTs were observed in 6 pts completing treatment in cohort -1, which was expanded to N = 12. Among 16 pts who have completed treatment (2 ongoing), irAE included: grade 1, 2, and 3 dermatitis (2, 1, and 3 cases), grade 4 colitis (1; expansion cohort), and TPO auto-Ab-mediated, grade 1 hyperthyroidism (1). No hepatitis or hypophysitis was observed. Conclusions: The RP2D for ipi in combination with standard C-IMRT is 1mg/kg dosed weeks 5, 8, 11, and 14. Dermatologic irAEs were unique to this regimen and dose-limiting; the spectrum of irAEs was otherwise typical for ipi. (Table Presented).
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/308/CN-01296308/frame.html


Record #95 of 144
ID: CN-01250025
AU: Kurose K
AU: Ohue Y
AU: Wada H
AU: Doi T
AU: Nishikawa H
AU: Oka M
AU: Ueda R
TI: Phase la study of FoxP3+ CD4 Treg depletion by infusion of a humanized anti-CCR4 antibody, KW-0761, in cancer patients
SO: Cancer immunology research. Conference: CRI-CIMT-EATI-AACR inaugural international cancer immunotherapy conference: translating science into survival. United states. Conference start: 20150916. Conference end: 20150919
YR: 2016
VL: 4
NO: 1 Supplement) (no pagination
XR: EMBASE 613321687
PT: Journal: Conference Abstract
KY: *cancer patient; cell culture monitoring; clinical article; clinical trial; controlled clinical trial; controlled study; disease course; drug therapy; esophagus cancer; experimental design; gene inactivation; human; immune response; immunotherapy; *infusion; low drug dose; lung; lymphocyte subpopulation; peripheral blood mononuclear cell; phase 1 clinical trial; *regulatory T lymphocyte; survivor; toxicity; *autoantibody; cancer testis antigen; cancer vaccine; *CD4 antigen; CD8 antigen; endogenous compound; *mogamulizumab; thyroid peroxidase
DOI: 10.1158/2326-6074.CRICIMTEATIAACR15-A033
AB: Purpose: FoxP3<sup>+</sup> Tregs inhibit immune responses against tumors. KW-0761 is a humanized anti-human CCR4 monoclonal antibody (mAb) that has ADCC activity. Depletion of CCR4-expressing FoxP3<sup>+</sup> CD4 Tregs by KW-0761 infusion was investigated in solid cancer patients. Experimental Design: We conducted a phase Ia clinical trial of KW-0761 infusion in 7 lung and 3 esophageal cancer patients. Toxicity, clinical efficacy, changes in lymphocyte subpopulations, including Tregs, and induction of immune responses were analyzed. Results: The results showed that KW-0761 infusion at dose range between 0.1 mg/kg to 1.0 mg/kg was safe and well tolerated. No DLT was observed. Four of 10 patients showed stable disease during treatment and were long survivors. The monitoring of FoxP3<sup>+</sup> Tregs in the PBMCs during treatment indicated efficient depletion of those cells even at the lowest dose of 0.1 mg/kg used. The reduction in Th 1 CD4 T-cells and CD8 T-cells was limited, while a significant reduction was observed with Th 2 and Th 17 CD4 T-cells. Immune responses to cancer/testis (CT) antigens and an autoantibody response to thyroid peroxidase were observed in some patients. Conclusions: The findings showed Tregs depletion and the possible occurrence of an immune response following KW-0761 infusion. Combined use of KW-0761 to deplete FoxP3<sup>+</sup> Tregs with other immunotherapies, such as cancer vaccines or checkpoint inhibitors, is promising to augment immune responses.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/025/CN-01250025/frame.html


Record #96 of 144
ID: CN-01405756
AU: Weinstock C
AU: Khozin S
AU: Suzman D
AU: Zhang L
AU: Tang S
AU: Wahby S
AU: Goldberg KB
AU: Kim G
AU: Pazdur R
TI: U.S. Food and Drug Administration approval summary: atezolizumab for metastatic non-small cell lung cancer
SO: Clinical cancer research
YR: 2017
VL: 23
NO: 16
PG: 4534-4539
XR: EMBASE 617950226
PT: Article
KY: adverse drug reaction; anemia; arthralgia; case report; clinical trial; colitis; confidence interval; constipation; controlled clinical trial; controlled study; coughing; decreased appetite; drug therapy; dysphagia; dyspnea; fatigue; female; *food and drug administration; hazard ratio; hepatitis; human; hyponatremia; hypoxia; *lung cancer; male; musculoskeletal pain; nausea; nonhuman; overall survival; phase 2 clinical trial; phase 3 clinical trial; pneumonia; Populus; side effect; thyroid disease; alanine aminotransferase; aspartate aminotransferase; *atezolizumab; docetaxel; endogenous compound; platinum
DOI: 10.1158/1078-0432.CCR-17-0540
AB: On October 18, 2016, the FDA approved atezolizumab (TECENTRIQ; Genentech, Inc.) for treatment of patients with metastatic non-small cell lung cancer (mNSCLC) whose disease progressed during or following platinum-containing chemotherapy. Approval was based on demonstration of clinically meaningful improvements in overall survival (OS) and an acceptable safety profile in two randomized clinical trials (OAK and POPLAR). Median OS in OAK, a phase III trial, was 13.8 months [95% confidence interval (CI), 11.8-15.7] in the atezolizumab arm compared with 9.6 months (95% CI, 8.6-11.2) in the docetaxel arm [hazard ratio (HR) = 0.74; 95% CI, 0.63-0.87; P = 0.0004]. Median OS in POPLAR, a phase II trial, was 12.6 months (95% CI, 9.7-16.0) and 9.7 months (95% CI, 8.6-12.0; HR = 0.69; 95% CI, 0.52-0.92) for the atezolizumab and docetaxel arms, respectively. In patients treated with atezolizumab, the most common (>=20%) adverse reactions were fatigue, decreased appetite, dyspnea, cough, nausea, musculoskeletal pain, and constipation; the most common (>=2%) grade 3 to 4 adverse events were dyspnea, pneumonia, hypoxia, hyponatremia, fatigue, anemia, musculoskeletal pain, aspartate aminotransferase increase, alanine aminotransferase increase, dysphagia, and arthralgia. Clinically significant immune-related adverse events for patients receiving atezolizumab included 1.4% incidence each of grade 3 to 4 pneumonitis, hepatitis, colitis, and thyroid disease. Copyright ©2017 AACR.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/756/CN-01405756/frame.html


Record #97 of 144
ID: CN-01303995
AU: Reardon DA
AU: Kim T-M
AU: Frenel J-S
AU: Santoro A
AU: Lopez J
AU: Subramaniam DS
AU: Siu LL
AU: Rodon J
AU: Tamura K
AU: Saraf S
AU: Morosky A
AU: Stein K
AU: Soria J-C
TI: Results of the phase IB KEYNOTE-028 multicohort trial of pembrolizumab monotherapy in patients with recurrent PD-L1-positive glioblastoma multiforme (GBM)
SO: Neuro-oncology. Conference: 21st annual scientific meeting and education day of the society for neuro-oncology. United states. Conference start: 20161117. Conference end: 20161120
YR: 2016
VL: 18
PG: vi25-vi26
XR: EMBASE 613469140
PT: Journal: Conference Abstract
KY: adult; antineoplastic activity; arthritis; clinical article; clinical trial; controlled clinical trial; *controlled study; death; disease duration; doctor patient relation; drug therapy; drug withdrawal; faintness; fatigue; female; follow up; gene expression; *glioblastoma; human; human tissue; immunohistochemistry; male; middle aged; *monotherapy; non insulin dependent diabetes mellitus; patient history of chemotherapy; pharmacokinetics; phase 1 clinical trial; rash; response evaluation criteria in solid tumors; safety; stroma cell; toxicity; tumor cell; bevacizumab; endogenous compound; *pembrolizumab; *programmed death 1 ligand 1; programmed death 1 receptor
DOI: 10.1093/neuonc/now212.100
AB: Patients with recurrent GBM have limited treatment options and poor clinical outcome. Tumors, including GBM, use the PD-1 pathway to evade immune responses. KEYNOTE-028 (NCT02054806) evaluated the safety and efficacy of the anti-PD-1 monoclonal antibody pembrolizumab in 20 advanced solid tumor types. Results of the GBM cohort (N=26) are presented. Key inclusion criteria included advanced (unresectable and/ or metastatic) bevacizumab-naive GBM, failure of or inability to receive standard therapy, ECOG PS 0-1, and PD-L1 expression in >1% of tumor or stroma cells by immunohistochemistry. Patients received pembrolizumab 10 mg/kg every 2 weeks for up to 24 months or until confirmed progression, intolerable toxicity, death, withdrawal of consent, or physician decision. Response was assessed every 8 weeks for the first 6 months and every 12 weeks thereafter. The primary end point was ORR per RECIST v1.1 by investigator review. Median age was 55.5 years; 53.8% were male; 53.8% had an ECOG PS of 1; all had received prior chemotherapy. As of the February 17, 2016, data cutoff date, median followup duration was 60.9 weeks (range, 11.7-94.0) and 22 (84.6%) patients had discontinued pembrolizumab. Treatment-related AEs occurred in 19 (73.1%) patients, most commonly fatigue and rash (n=6 each, 23.1%). Four (15.4%) patients experienced grade 3-4 treatment-related AEs (lymDownloaded phopenia, type 2 diabetes mellitus, arthritis, and syncope). No patients died or discontinued pembrolizumab because of a treatment-related AE. There was 1 partial response (n=25; ORR, 4.0% [95% CI, 0.1-20.4]); an additional 12 (48.0%) patients experienced stable disease (SD). Median duration of SD was 39.4 weeks (range, 7.1+-85.9+). Median PFS was 2.8 months (95% CI, 1.9-9.1); median OS was 14.4 months (95% CI, 10.3-not reached). Treatment with pembrolizumab monotherapy was associated with a manageable safety profile, and consistent with that of other PD-1 agents, promising antitumor activity in patients with recurrent GBM.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/995/CN-01303995/frame.html


Record #98 of 144
ID: CN-01129917
AU: Hodi FS
AU: Postow MA
AU: Chesney JA
AU: Pavlick AC
AU: Robert C
AU: Grossmann KF
AU: McDermott DF
AU: Linette GP
AU: Meyer N
AU: Giguere JK
AU: Agarwala SS
AU: Shaheen MF
AU: Ernstoff MS
AU: Minor DR
AU: Salama A
AU: Taylor MH
AU: Ott PA
AU: Horak CE
AU: Gagnier P
AU: Wolchok JD
TI: Clinical response, progression-free survival (PFS), and safety in patients (pts) with advanced melanoma (MEL) receiving nivolumab (NIVO) combined with ipilimumab (IPI) vs IPI monotherapy in CheckMate 069 study
SO: Journal of clinical oncology
YR: 2015
VL: 33
NO: 15 SUPPL. 1
XR: EMBASE 72015041
PT: Journal: Conference Abstract
KY: *progression free survival; *safety; *patient; *human; *melanoma; *monotherapy; *American; *society; *oncology; overall survival; disease course; T lymphocyte; mutation; phase 1 clinical trial; phase 2 clinical trial; toxicity; wild type; drug therapy; data analysis; risk; *nivolumab; *ipilimumab; placebo; lactate dehydrogenase
AB: Background: Combined blockade of T-cell checkpoints by NIVO and IPI demonstrated a high objective response rate (ORR), promising overall survival (OS), and a manageable safety profile in pts with advanced MEL in a phase I study, based on which an appropriate dose was selected for registrational trials. We report efficacy and safety of the NIVO + IPI combination vs IPI alone in treatment-naive pts with advanced MEL, including pts with poor prognostic factors, in a phase II study. Methods: Pts (N = 142) with metastatic or unresectable MEL were randomized 2:1 to receive IPI 3 mg/kg combined with either NIVO 1 mg/kg or placebo Q3W x 4, followed by NIVO 3 mg/kg or placebo Q2W until disease progression or unacceptable toxicity. The primary endpoint was ORR in BRAF wild-type (WT) pts. Secondary and exploratory objectives included PFS in BRAF WT pts, ORR and PFS in BRAF V600 mutation-positive (MT) pts, and safety. Results: In BRAF WT pts (n = 109), ORR was 60% (43/72) for NIVO + IPI; 11% (4/37) for IPI alone (P < 0.0001); complete responses were reported in 12 (17%) and 0 pts, respectively. Median PFS was 8.9 months for the combination vs 4.7 months for IPI alone (P = 0.0012). Higher ORR was observed for NIVO + IPI vs IPI in predefined pt subgroups with poor prognostic factors, such as elevated baseline LDH (53% vs 0%) and M1c stage disease (62% vs 25%). Similar ORR and PFS results were observed in 33 BRAF MT pts. Grade 3-4 drug-related adverse events (AEs) were reported in 51% of pts receiving NIVO + IPI vs 20% for IPI alone. The safety profile of NIVO + IPI was similar across pt subgroups, including age. Select AEs related to the combination regimen were consistent with phase I reports and most resolved with immunosuppressive medication ( > 83% across organ categories) with the exception of endocrinopathies. Updated results from a planned data analysis in March 2015 will be presented. Conclusions: NIVO + IPI significantly improved ORR and PFS compared with IPI alone and had a manageable safety profile. The efficacy and safety of the combination was similar across pt subgroups and provided a favorable risk-benefit ratio in treatment- naive pts with advanced MEL. .
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/917/CN-01129917/frame.html


Record #99 of 144
ID: CN-01438394
AU: Cortinovis D
AU: Pawel J
AU: Syrigos K
AU: Mazieres J
AU: Dziadziuszko R
AU: Fehrenbacher L
AU: Conkling P
AU: Goldschmidt J
AU: Thomas CA
AU: Bordoni R
AU: Kosty M
AU: Braiteh FS
AU: He P
AU: Ballinger M
AU: Gandhi M
AU: Patel H
AU: Gandara DR
TI: Immune-related adverse events (irAEs) in advanced NSCLC patients treated with atezolizumab: safety population analyses from the Ph III study OAK
SO: Annals of oncology. Conference: 42nd ESMO congress, ESMO 2017. Spain
YR: 2017
VL: 28
NO: Supplement 5
PG: v468
XR: EMBASE 619623534
PT: Conference Abstract
KY: adult; adverse drug reaction; colitis; controlled study; corticosteroid therapy; diagnosis; diarrhea; drug therapy; drug withdrawal; female; gene expression; hepatitis; human; hypothyroidism; *immune-related gene; incidence; major clinical study; male; Medical Dictionary for Regulatory Activities; meningoencephalitis; *non small cell lung cancer; pharmacokinetics; pneumonia; randomized controlled trial; side effect; *atezolizumab; corticosteroid; docetaxel; endogenous compound; platinum; programmed death 1 ligand 1
DOI: 10.1093/annonc/mdx380.016
AB: Background: A superior survival benefit with atezolizumab (atezo; anti-PD-L1) vs docetaxel (doc; HR 0.73; 95% CI: 0.62, 0.87) has been demonstrated in OAK, the first randomized Ph III study of atezo in NSCLC patients (pts) who had failed prior platinum therapy. In the primary efficacy population (n=850), atezo benefit was seen regardless of PD-L1 expression levels on tumor cells (TC) or tumor-infiltrating immune cells (IC). Here, we present the analyses of irAEs in the safety population (N=1225) of OAK. Methods: Pts were randomized 1:1 to atezo (1200 mg) or doc (75 mg/m<sup>2</sup>) IV q3w. Coprimary endpoints were OS in ITT and in PD-L1 expression subgroups. Secondary endpoints included ORR and safety. irAEs were defined using MedDRA Preferred Terms that included both diagnosed immune conditions and signs and symptoms potentially representative of immune related events, regardless of investigator-assessed causality. Safety analyses conducted were incidence, nature and severity of irAEs, corticosteroid use and irAEs leading to atezo interruption/discontinuation. Data cutoff: July 7, 2016. Results: In the atezo arm, 6.2% of pts had grade 3-4 irAEs and 25.0% of pts had grade 1-2 irAEs. No grade 5 irAEs were reported. Low rates of any-grade hypothyroidism (3.9%), pneumonitis (1.5%), hepatitis, (1.1%), and colitis (0.3%) were observed. Grade 3-4 irAEs included pneumonitis (0.7%) and hepatitis (0.7%); no pts developed Grade 3-4 colitis. 36 (5.9%) atezo arm pts experienced irAEs requiring corticosteroid treatment. Majority of irAEs in the atezo arm were manageable; 13 pts (2.1%) discontinued atezo. Meningoencephalitis (0.7%) and AST/ALT elevation (0.3%/0.2%) were the most frequently reported irAEs leading to atezo discontinuation. 26 pts (4.3%) had dose interruptions due to irAEs. AST/ALT elevation (0.8%/0.8%) and diarrhea (0.8%) were the most frequently reported irAEs leading to dose interruption. Conclusions: The irAEs occurring in atezo-treated pts were mostly low grade and manageable, with few pts requiring dose interruption/discontinuation of atezo and corticosteroid treatment. Efficacy data based on irAE subgroups of OAK are presented separately.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/394/CN-01438394/frame.html


Record #100 of 144
ID: CN-01430722
AU: Tawbi HA
AU: Burgess M
AU: Bolejack V
AU: Tine BA
AU: Schuetze SM
AU: Hu J
AU: D'Angelo S
AU: Attia S
AU: Riedel RF
AU: Priebat DA
AU: Movva S
AU: Davis LE
AU: Okuno SH
AU: Reed DR
AU: Crowley J
AU: Butterfield LH
AU: Salazar R
AU: Rodriguez-Canales J
AU: Lazar AJ
AU: Wistuba II
AU: Baker LH
AU: Maki RG
AU: Reinke D
AU: Patel S
TI: Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial
SO: The lancet. Oncology
YR: 2017
VL: 18
NO: 11
PG: 1493-1501
PM: PUBMED 28988646
XR: EMBASE 618618999
PT: Clinical Trial, Phase II; Journal Article; Multicenter Study; Randomized Controlled Trial
KY: Academic Medical Centers;Antibodies, Monoclonal, Humanized [adverse effects] [therapeutic use];Bone Neoplasms [drug therapy] [mortality] [pathology];Confidence Intervals;Disease-Free Survival;Dose-Response Relationship, Drug;Drug Administration Schedule;Infusions, Intravenous;Kaplan-Meier Estimate;Maximum Tolerated Dose;Neoplasm Invasiveness [pathology];Neoplasm Staging;Patient Safety [statistics & numerical data];Prognosis;Sarcoma [drug therapy] [mortality] [pathology];Soft Tissue Neoplasms [drug therapy] [mortality] [pathology];Survival Analysis;Treatment Outcome;United States;Adult[checkword];Aged[checkword];Female[checkword];Humans[checkword];Male[checkword];Middle Aged[checkword];adrenal insufficiency/si [Side Effect]; adult; *advanced cancer/dt [Drug Therapy]; advanced cancer/dt [Drug Therapy]; article; bone pain/si [Side Effect]; clinical practice; clinical protocol; cohort analysis; controlled study; drug efficacy; drug safety; female; human; human tissue; hypoxia/si [Side Effect]; immunogenicity; infectious pneumonia/si [Side Effect]; interstitial nephritis/si [Side Effect]; lung embolism/si [Side Effect]; lymphocyte count; major clinical study; male; multicenter study; *osteosarcoma/dt [Drug Therapy]; osteosarcoma/dt [Drug Therapy]; partial thromboplastin time; phase 2 clinical trial; pleura effusion/si [Side Effect]; pneumonia/si [Side Effect]; practice guideline; priority journal; progression free survival; randomized controlled trial; *soft tissue sarcoma/dt [Drug Therapy]; soft tissue sarcoma/dt [Drug Therapy]; thrombocyte count; treatment response; tumor biopsy; *pembrolizumab/ae [Adverse Drug Reaction]; *pembrolizumab/ct [Clinical Trial]; *pembrolizumab/dt [Drug Therapy]; *pembrolizumab/iv [Intravenous Drug Administration]
DOI: 10.1016/S1470-2045(17)30624-1
AB: METHODS: In this two-cohort, single-arm, open-label, phase 2 study, we enrolled patients with soft-tissue sarcoma or bone sarcoma from 12 academic centres in the USA that were members of the Sarcoma Alliance for Research through Collaboration (SARC). Patients with soft-tissue sarcoma had to be aged 18 years or older to enrol; patients with bone sarcoma could enrol if they were aged 12 years or older. Patients had histological evidence of metastatic or surgically unresectable locally advanced sarcoma, had received up to three previous lines of systemic anticancer therapy, had at least one measurable lesion according to the Response Evaluation Criteria In Solid Tumors version 1.1, and had at least one lesion accessible for biopsy. All patients were treated with 200 mg intravenous pembrolizumab every 3 weeks. The primary endpoint was investigator-assessed objective response. Patients who received at least one dose of pembrolizumab were included in the safety analysis and patients who progressed or reached at least one scan assessment were included in the activity analysis. Accrual is ongoing in some disease cohorts. This trial is registered with ClinicalTrials.gov, number NCT02301039.FINDINGS: Between March 13, 2015, and Feb 18, 2016, we enrolled 86 patients, 84 of whom received pembrolizumab (42 in each disease cohort) and 80 of whom were evaluable for response (40 in each disease cohort). Median follow-up was 17·8 months (IQR 12·3-19·3). Seven (18%) of 40 patients with soft-tissue sarcoma had an objective response, including four (40%) of ten patients with undifferentiated pleomorphic sarcoma, two (20%) of ten patients with liposarcoma, and one (10%) of ten patients with synovial sarcoma. No patients with leiomyosarcoma (n=10) had an objective response. Two (5%) of 40 patients with bone sarcoma had an objective response, including one (5%) of 22 patients with osteosarcoma and one (20%) of five patients with chondrosarcoma. None of the 13 patients with Ewing's sarcoma had an objective response. The most frequent grade 3 or worse adverse events were anaemia (six [14%]), decreased lymphocyte count (five [12%]), prolonged activated partial thromboplastin time (four [10%]), and decreased platelet count (three [7%]) in the bone sarcoma group, and anaemia, decreased lymphocyte count, and prolonged activated partial thromboplastin time in the soft-tissue sarcoma group (three [7%] each). Nine (11%) patients (five [12%] in the bone sarcoma group and four [10%] in the soft-tissue sarcoma group) had treatment-emergent serious adverse events (SAEs), five of whom had immune-related SAEs, including two with adrenal insufficiency, two with pneumonitis, and one with nephritis.INTERPRETATION: The primary endpoint of overall response was not met for either cohort. However, pembrolizumab showed encouraging activity in patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma. Enrolment to expanded cohorts of those subtypes is ongoing to confirm and characterise the activity of pembrolizumab.FUNDING: Merck, SARC, Sarcoma Foundation of America, QuadW Foundation, Pittsburgh Cure Sarcoma, and Ewan McGregor.BACKGROUND: Patients with advanced sarcomas have a poor prognosis and few treatment options that improve overall survival. Chemotherapy and targeted therapies offer short-lived disease control. We assessed pembrolizumab, an anti-PD-1 antibody, for safety and activity in patients with advanced soft-tissue sarcoma or bone sarcoma.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/722/CN-01430722/frame.html


Record #101 of 144
ID: CN-01294325
AU: Infante JR
AU: Naing A
AU: Papadopoulos KP
AU: Autio KA
AU: Ott PA
AU: Wong DJ
AU: Falchook GS
AU: Patel M
AU: Pant S
AU: Whiteside M
AU: Mumm JB
AU: Chan IH
AU: Bendell JC
AU: Bauer TM
AU: Janku F
AU: Javle M
AU: Colen RR
AU: Tannir NM
AU: Oft M
TI: Anti-tumor activity of PEGylated human IL-10 (AM0010) in patients with advanced solid tumors
SO: Cancer research. Conference: 107th annual meeting of the american association for cancer research, AACR 2016. United states. Conference start: 20160416. Conference end: 20160420
YR: 2016
VL: 76
NO: 14 Supplement) (no pagination
XR: EMBASE 613609909
PT: Journal: Conference Abstract
KY: advanced cancer; adverse drug reaction; anemia; *antineoplastic activity; cancer patient; cell clone; cell proliferation; chemotherapy; clonal variation; colitis; colon cancer; controlled clinical trial; controlled study; disease course; drug therapy; dyslipidemia; fatigue; female; gene activation; gene inactivation; human; human tissue; hypertransaminasemia; immunohistochemistry; immunostimulation; injection site reaction; kidney carcinoma; major clinical study; male; monotherapy; ovary; pancreas cancer; phase 1 clinical trial; phase 2 clinical trial; pneumonia; prostate cancer; rash; regulatory T lymphocyte; side effect; thrombocytopenia; treatment duration; *uvea melanoma; CD8 antigen; endogenous compound; gamma interferon; *interleukin 10; interleukin 18; interleukin 7; programmed death 1 receptor; transcription factor FOXP3; transforming growth factor beta; triacylglycerol lipase
DOI: 10.1158/1538-7445.AM2016-CT098
AB: Purpose: IL-10 inhibits inflammation but stimulates cytotoxic CD8 T cells. In preclinical models, PEGylated IL-10 induces rejection of tumors and establishes CD8 T cell memory. PEG-IL-10 (AM0010) activates the antiapoptotic STAT3 in tumor infiltrating activated CD8 T cells. This leads to the expansion of tumor reactive memory CD8 T cells both in the tumor and the blood. The primary objective of this phase 1 study is to establish tolerability and anti-tumor activity of AM0010 alone and in combination with chemotherapy and anti PD1 immunotherapy. Here we report the results of AM0010 in the monotherapy dose escalation and one expansion cohort in renal cell cancer (RCC). Procedures: 33 patients (pts) with advanced cancers including melanoma, RCC, nonsmall cell lung, colorectal, ovarian, prostate and pancreatic cancer were enrolled in cohorts of 3-6 pts each, followed by disease specific expansion cohorts at the recommended phase 2 dose (RP2D). AM0010 was selfadministrated daily subcutaneously for the duration of treatment and responses were monitored following immune related response criteria (irRC). Immune responses were monitored through analysis of serum cytokines, activation of blood derived T cells, immunosequencing for peripheral T cell clonality and immunohistochemistry for the infiltration of tumors by CD8 T cells. Results: 33 pts were enrolled in dose escalation cohorts with AM0010 monotherapy at doses from 1 to 40 mug/kg. MTD was not established. The RP2D (20mug/kg) was determined based on tolerability, single agent anti-tumor activity and immune activation. Patients were heavily pretreated with a median of 5 prior treatments. Most treatment related adverse events (TrAE) were low grade and included anemia, thrombocytopenia, rash, injection site reaction, fatigue, increased lipase, dyslipidemia and transaminitis. G3/4 non-hematopoietic TrAEs were observed in 11 of 51 pts. G3/4 anemia or thrombocytopenia TrAEs were observed in 13 pts. Most TrAEs were transient with only one patient discontinuing treatment due to a TrAE. Immune related TrAEs such as colitis, pneumonitis and endocrine disruption were not observed. AM0010 induced a dose dependent Th1 cytokine signature (IL-18, IFNgamma, IL-7) and a reduction of TGFbeta in the serum of pts. AM0010 increased PD-1 positive activated CD8 T cells in the blood and the tumor and decreased proliferation of FoxP3 Tregs in the blood. AM0010 lead to an oligoclonal expansion of T cell clones in the blood without affecting the overall number of lymphocytes. Many of the expanded T cell clones were not detectable before treatment. Partial responses (PR) were observed in pts with RCC and uveal melanoma. Four of 15 RCC pts treated at RP2D (27%) had an objective response. Prolonged stable disease of 6 or more months was observed in several indications including colon cancer. Conclusion: AM0010 is well-tolerated and leads to sustained and systemic immune stimulation. The pharmacodynamics and clinical activity observed support the further exploration of AM0010 in monotherapy and in combination regimens with checkpoint inhibitors and with cytotoxic chemotherapies.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/325/CN-01294325/frame.html


Record #102 of 144
ID: CN-01020703
AU: Hersey P
AU: Wolchock JD
AU: Thomas L
AU: Bondarenko IN
AU: O'Day S
AU: Weber J
AU: Garbe C
AU: Francis S
AU: Ibrahim RA
AU: Hoos A
AU: Robert C
TI: A second randomised ipilimumab phase III trial shows significant survival improvement in metastatic melanoma
SO: Asia-pacific journal of clinical oncology.
YR: 2011
VL: 7
PG: 111
XR: EMBASE 70586769
PT: Journal: Conference Abstract
KY: *melanoma; *society; *Australia; *survival; patient; human; arm; therapy; death; bleeding; T lymphocyte activation; monotherapy; incidence; Australia and New Zealand; overall survival; diarrhea; rash; intestine perforation; hypophysitis; electrocorticography; *ipilimumab; dacarbazine; placebo; monoclonal antibody; glycoprotein gp 100
DOI: 10.1111/j.1743-7563.2011.01469.x
AB: Aims: Australia and New Zealand have the world's highest incidence rates for melanoma. Ipilimumab, a monoclonal antibody that augments T-cell activation, was recently approved by the TGA in Australia as monotherapy for the treatment of patients with unresectable or metastatic melanoma who have failed or are intolerant to prior therapy. A previous phase III trial demonstrated that patients treated with ipilimumabmonotherapy were almost twice as likely to be alive after 1 and 2 years compared to gp100. The aim of this phase III trial was to evaluate a combination of dacarbazine (DTIC) plus ipilimumab in first line metastatic melanoma. Methods: In this double-blind phase III trial, 502 patients with metastatic melanoma, ECOG PS 0/1 and no prior therapy for advanced disease, were randomised 1:1 to ipilimumab (10 mg/kg) plus DTIC (850 mg/m<sup>2</sup>) or placebo plus DTIC (850 mg/m<sup>2</sup>) at weeks 1, 4, 7, 10 followed by DTIC every 3 weeks through to week 22. Eligible patients received ipilimumab or placebo every 12 weeks as maintenance. The primary endpoint was overall survival (OS). Results: Ipilimumab plus DTIC resulted in a significant improvement in OS (HR = 0.72; P = 0.0009). 56% of patients in the ipilimumabplus DTIC arm (n = 247) and 27% in the DTIC alone arm (n = 251) had grade 3/4 adverse events (AEs), including elevated ALT (22% versus 1%), diarrhoea (4% versus 0%), rash (1% versus 0%). No intestinal perforations or hypophysitis were noted. There were no drug-related deaths in the ipilimumab plus DTIC arm and one in the DTIC alone arm (gastrointestinal haemorrhage).
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/703/CN-01020703/frame.html


Record #103 of 144
ID: CN-01397350
AU: Pollack M
AU: Betof AS
AU: Rappazzo K
AU: Valentine I
AU: Eroglu Z
AU: Johnson DB
AU: Shoushtari AN
TI: Safety of resuming anti-PD-1 (aPD1) in patients (pts) with immune-related adverse events (irAEs) during combined anti-CTLA-4 (aCTLA4) and aPD1 in metastatic melanoma (MM)
SO: Journal of clinical oncology. Conference: 2017 annual meeting of the american society of clinical oncology, ASCO. United states
YR: 2017
VL: 35
NO: 15 Supplement 1) (no pagination
XR: EMBASE 617435760
PT: Conference Abstract
KY: adverse drug reaction; clinical trial; colitis; controlled clinical trial; controlled study; death; dermatitis; disease duration; drug withdrawal; *female; hepatitis; human; hypophysitis; major clinical study; *male; *metastatic melanoma; monotherapy; multicenter study; nephritis; neurological complication; overall survival; pancreatitis; pneumonia; progression free survival; relapse; *safety; *side effect; toxic epidermal necrolysis; toxicity; *cytotoxic T lymphocyte antigen 4; endogenous compound; *programmed death 1 receptor
AB: Background: Combination aPD1 and aCTLA4 has demonstrated greater response rates (RR) than aPD1 alone in MM. However, aPD1 + aCTLA4 also leads to more frequent and severe irAEs compared to aPD1. The safety of resuming aPD1 following these irAEs is not known. We characterized the safety and efficacy of resuming aPD1 following severe irAEs during aPD1 + aCTLA4 in pts with MM. Methods: We retrospectively reviewed mm pts from 3 academic centers who had a severe irAE with aPD1 + aCTLA4 (defined as CTCAE v4.03 G3-4 or leading to early discontinuation of aPD1 + aCTLA4) and who resumed aPD1 thereafter. We assessed for frequency, timing, and spectrum of irAEs as well as RR, progression free survival (PFS) and overall survival (OS). Results: We identified 64 pts who received aPD1 + aCTLA4 for a median of 2 doses (range, 1-4). The most frequent irAEs that led to aPD1 + aCTLA4 discontinuation were: colitis (36%), hepatitis (23%), hypophysitis (8%), pneumonitis (5%), nephritis (3%), neurologic complications (3%), and pancreatitis (3%); eight pts (13%) had > 1 concurrent severe irAEs. aPD1 was resumed at a median of 55 days after last dose of aCTLA4 + aPD1 (range, 17-289); 23% experienced recurrence of the same irAE with aPD1 monotherapy, 16% experienced a distinct irAE, and 60% did not experience any severe irAE after resuming aPD1. Hepatitis recurred in 6 of 18 pts, pancreatitis in 2 of 2, dermatitis in 1 of 4, nephritis in 1 of 2, pneumonitis in 1 of 3, hypophysitis in 1 of 5, and colitis in 1 of 27; the grade of these recurrent irAEs was: 46% grade 1-2, 33% grade 3, 13% grade 4, and 7% grade 5 (n = 1). One death from irAEs occurred related to Toxic Epidermal Necrolysis (TEN). No difference was observed in time prior to resuming aPD1 in those that had recurrent irAEs vs. those without (median 56 days each). The RR in this cohort was 73% (30% CR; 44% PR); median PFS (range, 2.2-not reached (NR)) and OS (range, 2.4-NR) were not reached. Conclusions: In our experience, pts who resume aPD1 following irAEs with aPD1 + aCTLA4 exhibit variable toxicity profiles with most experiencing no irAEs, but a minority experiencing severe or life-threatening irAEs. We observed excellent efficacy in this cohort.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/350/CN-01397350/frame.html


Record #104 of 144
ID: CN-01399009
AU: Ribrag V
AU: Avigan DE
AU: Martinelli G
AU: Green DJ
AU: Wise-Draper T
AU: Posada JG
AU: Vij R
AU: Zhu Y
AU: Farooqui MZH
AU: Marinello P
AU: Siegel DS
TI: Pembrolizumab monotherapy for relapsed/refractory multiple myeloma: phase 1b keynote-013 study
SO: Haematologica. Conference: 22th congress of the european hematology association. Spain
YR: 2017
VL: 102
PG: 114
XR: EMBASE 617380926
PT: Conference Abstract
KY: adverse drug reaction; aged; antineoplastic activity; arthralgia; asthenia; blurred vision; clinical trial; controlled clinical trial; *controlled study; death; disease course; drug combination; drug therapy; exposure; fatigue; female; follow up; human; hyperglycemia; hypothyroidism; major clinical study; male; *monotherapy; *multiple myeloma; myalgia; pharmacokinetics; phase 1 clinical trial; pruritus; safety; side effect; treatment failure; aspartate aminotransferase; dexamethasone; endogenous compound; lenalidomide; *pembrolizumab; proteasome inhibitor
AB: Background: Treatment options are needed for patients with RRMM. PD-L1 is expressed in patients with multiple myeloma, and blocking the programmed death 1 (PD-1) pathway may provide antitumor activity. Pembrolizumab is a humanized, high-affinity monoclonal antibody directed against PD-1 with robust antitumor activity and favorable safety in several solid and hematologic malignancies. KEYNOTE-013 (NCT01953692) is a multicohort phase 1b study of pembrolizumab monotherapy in patients with hematologic malignancies; results are reported for patients with RRMM. Aims: To determine the safety, tolerability, and antitumor activity of pembrolizumab monotherapy in patients with RRMM. Methods: Patients with RRMM who have failed >=2 prior lines of therapy including a proteasome inhibitor and immunomodulatory drug (IMiD) received pembrolizumab 10 mg/kg every 2 weeks or 200 mg fixed dose every 3 weeks. Primary end points were safety, tolerability, and objective response rate (ORR) as determined by investigators, per International Myeloma Working Group 2006 criteria. Results:At data cutoff of January 2, 2017, 30 patients were treated. The median (range) duration of follow-up was 15 (1-32) months. 28 (93%) patients discontinued the study; the most common reason was disease progression in 14 (47%) patients and clinical progression in 9 (30%) patients. 2 (7%) patients are still on treatment. Median (range) age was 70 (56-81) years. 21 (70%) patients had an ECOG performance status of 1. Patients received a median (range) of 4 (2-10) prior lines of therapy. 20 (67%) patients were lenalidomide refractory, 10 (33%) were double-refractory, 9 (30%) were triple refractory, and 1 (3%) patient was quadruple refractory. Among patients who received pembrolizumab at 10 mg/kg, the median (range) of pembrolizumab exposure was 6 (2-15) cycles; among those who received 200-mg fixed dose of pembrolizumab, the exposure was 3 (2-6) cycles. No patient experienced a response. Seventeen (57%; 95% CI, 37-75%) patients had stable disease. 13 (43%; 95% CI, 26-63%) patients had progressive disease as their best response. Treatmentrelated adverse events (TRAEs) occurred in 12 (40%) patients. The most common TRAE was asthenia (n=5, 17%); arthralgia, aspartate aminotransferase increased, fatigue, hyperglycemia, hypothyroidism, myalgia, pruritus, and blurred vision occurred in 1 patient each. A grade 3 TRAE (myalgia) occurred in 1 (3%) patient. There were no grade 4 TRAEs and no deaths due to TRAEs. 1 (3%) patient had an immune-related adverse event (grade 1 pruritus). Summary/Conclusions: The safety profile of pembrolizumab in RRMM was consistent with that observed with other cancers. Best response observed while on pembrolizumab monotherapy was stable disease. Recent results of ongoing studies, such as KEYNOTE-023 (NCT02036502), demonstrate promising efficacy of pembrolizumab in combination with IMiDs (lenalidomide) and dexamethasone in patients with RRMM.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/009/CN-01399009/frame.html


Record #105 of 144
ID: CN-01211036
AU: Wilgenhof S
AU: Corthals J
AU: Heirman C
AU: Baren N
AU: Lucas S
AU: Kvistborg P
AU: Thielemans K
AU: Neyns B
TI: Phase II study of autologous monocyte-derived mRNA electroporated dendritic cells (TriMixDC-MEL) plus ipilimumab in patientswith pretreated advanced melanoma
SO: Journal of clinical oncology
YR: 2016
VL: 34
NO: 12
PG: 1330-1338
PM: PUBMED 26926680
XR: EMBASE 609745686
PT: Journal: Article
KY: adult; *advanced cancer/dt [Drug Therapy]; *advanced cancer/th [Therapy]; advanced cancer/dt [Drug Therapy]; *advanced melanoma/dt [Drug Therapy]; *advanced melanoma/th [Therapy]; advanced melanoma/dt [Drug Therapy]; article; *autologous monocyte derived mRNA electroporated dendritic cell; cancer control; cancer staging; *cell therapy; chill/co [Complication]; chill/dt [Drug Therapy]; clinical article; colitis/si [Side Effect]; controlled study; *dendritic cell; dermatitis/si [Side Effect]; diarrhea/si [Side Effect]; disease course; disease duration; drug safety; erythrocyte sedimentation rate; female; flu like syndrome/co [Complication]; flu like syndrome/dt [Drug Therapy]; follow up; hepatitis/co [Complication]; hepatitis/si [Side Effect]; hepatitis C/dt [Drug Therapy]; human; hypophysitis/si [Side Effect]; hypopituitarism/si [Side Effect]; injection site reaction/co [Complication]; injection site reaction/dt [Drug Therapy]; lactate dehydrogenase blood level; lymphadenopathy/si [Side Effect]; lymphocyte count; maintenance therapy; male; *melanoma/dt [Drug Therapy]; *melanoma/th [Therapy]; melanoma/dt [Drug Therapy]; *multimodality cancer therapy; myalgia/si [Side Effect]; Ogilvie syndrome/si [Side Effect]; peripheral blood mononuclear cell; phase 2 clinical trial; pneumonia/si [Side Effect]; polymerase chain reaction; priority journal; progression free survival; treatment duration; alpha2b interferon; B Raf kinase inhibitor; C reactive protein/ec [Endogenous Compound]; corticosteroid/dt [Drug Therapy]; *ipilimumab/ae [Adverse Drug Reaction]; *ipilimumab/dt [Drug Therapy]; *ipilimumab/iv [Intravenous Drug Administration]; lactate dehydrogenase/ec [Endogenous Compound]; messenger RNA/ec [Endogenous Compound]; mitogen activated protein kinase kinase inhibitor; mycophenolate mofetil/dt [Drug Therapy]; chill; clinical trial; colitis; controlled clinical trial; dermatitis; diarrhea; disease control; flu like syndrome; hepatitis; hypophysitis; infusion; injection site; melanoma; *monocyte; remission; skin manifestation; *ipilimumab; *messenger RNA
DOI: 10.1200/JCO.2015.63.4121
AB: Purpose Autologous monocyte-derived dendritic cells (DCs) electroporated with synthetic mRNA (TriMixDC-MEL) are immunogenic and have antitumor activity as a monotherapy in patients with pretreated advanced melanoma. Ipilimumab, an immunoglobulin G1 monoclonal antibody directed against the cytotoxic T-lymphocyte-associated protein 4 receptor that counteracts physiologic suppression of T-cell function, improves the overall survival of patients with advanced melanoma. This phase II study investigated the combination of TriMixDC-MEL and ipilimumab in patients with pretreated advanced melanoma. Patients and Methods Thirty-nine patients were treated with TriMixDC-MEL (4 3 106 cells administered intradermally and 20 3 106 cells administered intravenously) plus ipilimumab (10 mg/kg every 3 weeks for a total of four administrations, followed by maintenance therapy every 12 weeks in patients who remained progression free). Six-month disease control rate according to the immune-related response criteria served as the primary end point. Results The 6-month disease control rate was 51% (95% CI, 36% to 67%), and the overall tumor response rate was 38% (including eight complete and seven partial responses). Seven complete responses and one partial tumor response are ongoing after a median follow-up time of 36 months (range, 22 to 43 months). The most common treatment-related adverse events (all grades) consisted of local DC injection site skin reactions (100%), transient post-DC infusion chills (38%) and flu-like symptoms (84%), dermatitis (64%), hepatitis (13%), hypophysitis (15%), and diarrhea/colitis (15%). Grade 3 or 4 immune-related adverse events occurred in 36% of patients. There was no grade 5 adverse event. Conclusion The combination of TriMixDC-MEL and ipilimumab is tolerable and results in an encouraging rate of highly durable tumor responses in patients with pretreated advanced melanoma. Copyright © 2016 by American Society of Clinical Oncology.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/036/CN-01211036/frame.html


Record #106 of 144
ID: CN-01105585
AU: Kurose K
AU: Ohue Y
AU: Wada H
AU: Iida S
AU: Ishida T
AU: Kojima T
AU: Doi T
AU: Suzuki S
AU: Isobe M
AU: Funakoshi T
AU: Kakimi K
AU: Nishikawa H
AU: Udono H
AU: Oka M
AU: Ueda R
AU: Nakayama E
TI: Phase Ia Study of FoxP3+ CD4 Treg Depletion by Infusion of a Humanized Anti-CCR4 Antibody, KW-0761, in Cancer Patients
SO: Clinical cancer research
YR: 2015
VL: 21
NO: 19
PG: 4327-4336
XR: EMBASE 2015486168
PT: Journal: Article
KY: antibody response; article; cancer immunotherapy; *CD4+ T lymphocyte; CD8+ T lymphocyte; clinical article; controlled clinical trial; controlled study; dose response; drug dose escalation; drug efficacy; drug half life; drug safety; drug tolerability; *esophagus cancer/dt [Drug Therapy]; gamma glutamyl transferase blood level; human; leukopenia/si [Side Effect]; *lung cancer/dt [Drug Therapy]; lymphocyte subpopulation; lymphocytopenia/si [Side Effect]; maximum plasma concentration; neutropenia/si [Side Effect]; outcome assessment; overall survival; peripheral blood mononuclear cell; phase 1 clinical trial; priority journal; progression free survival; protein expression; rash/si [Side Effect]; *regulatory T lymphocyte; side effect/si [Side Effect]; skin biopsy; *T cell depletion; Th17 cell; Th2 cell; chemokine receptor CCR4/ec [Endogenous Compound]; gamma glutamyltransferase/ec [Endogenous Compound]; *mogamulizumab/ct [Clinical Trial]; *mogamulizumab/do [Drug Dose]; *mogamulizumab/pk [Pharmacokinetics]; *mogamulizumab/ae [Adverse Drug Reaction]; *mogamulizumab/iv [Intravenous Drug Administration]; *mogamulizumab/dt [Drug Therapy]; *transcription factor FOXP3/ec [Endogenous Compound]
DOI: 10.1158/1078-0432.CCR-15-0357
AB: Purpose: FoxP3<sup>+</sup> Tregs inhibit immune responses against tumors. KW-0761 is a humanized anti-human CCR4 monoclonal antibody (mAb) that has antibody-dependent cellular cytotoxicity activity. Depletion of CCR4-expressing FoxP3<sup>+</sup> CD4 Tregs by KW-0761 infusion was investigated in solid cancer patients. Experimental Design: We conducted a phase Ia clinical trial of KW-0761 infusion in 7 lung and 3 esophageal cancer patients. Toxicity, clinical efficacy, changes in lymphocyte subpopulations, includingTregs,andinductionofimmune responseswereanalyzed. Results: The results showed that KW-0761 infusion in a dose range between0.1mg/kg and 1.0mg/kgwas safe andwell tolerated. Nodose-limiting toxicitywas observed. Four of 10 patients showed stable disease during treatment and were long survivors. The monitoring of FoxP3<sup>+</sup> Tregs in the peripheral blood mononuclear cells during treatment indicated efficient depletion of those cells, even at the lowest dose of 0.1 mg/kg used. The reduction in Th 1 CD4 T cells and CD8 T cells was limited, whereas a significant reduction was observed with Th 2 and Th 17 CD4 T cells. Immune responses to cancer/testis (CT) antigens and an autoantibody response to thyroid peroxidase were observed in some patients. Conclusions: The findings showed Tregs depletion and the possible occurrence of an immune response following KW-0761 infusion. Combined use of KW-0761 to deplete FoxP3<sup>+</sup> Tregs with other immunotherapies, such as cancer vaccines or checkpoint inhibitors, is a promising approach to augment immune responses.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/585/CN-01105585/frame.html


Record #107 of 144
ID: CN-01212986
AU: Dummer R
AU: Gutzmer R
AU: Corrie P
AU: Millward M
AU: Murzhenko A
AU: Maio M
TI: Trial in progress: clinical trial of nivolumab combined with ipilimumab followed by nivolumab monotherapy as first-line therapy of patients with stage III (unresectable) or stage IV melanoma: checkMate 401
SO: Melanoma research
YR: 2016
VL: Conference: 16th World Congress on Cancers of the Skin 2016. Austria. Conference Start: 20160831. Conference End: 20160903. 26
PG: e43
XR: EMBASE 612247918
PT: Journal: Conference Abstract
KY: adult; adverse drug reaction; Australia; brain metastasis; clinical practice; clinical trial; controlled clinical trial; controlled study; diagnosis; disease course; drug therapy; endocrine system; Europe; gastrointestinal tract; human; lung; major clinical study; *melanoma; *monotherapy; pancreas; phase 2 clinical trial; phase 3 clinical trial; quality of life; response evaluation criteria in solid tumors; safety; side effect; skin; systemic therapy; toxicity; urinary tract; young adult; *ipilimumab; *nivolumab
DOI: 10.1097/CMR.0000000000000285
AB: Background: In the phase II CheckMate 069 and phase III CheckMate 067 studies, ORR and PFS were significantly improved with nivolumab + ipilimumab (NIVO + IPI) combination regimen compared with IPI monotherapy in patients (pts) with advanced melanoma (MEL; N Engl J Med 2015;372:2006; N Engl J Med 2015;373:23). Adverse event (AE) frequency increased with NIVO + IPI compared with IPI or NIVO monotherapy; most AEs were select AEs (ie, immunemediated AEs) and occurred in skin, gastrointestinal (GI), endocrine, or hepatic systems. CheckMate 401 was initiated to characterize the incidence of grade 3-5 treatment-related potentially immune-mediated select AEs observed with the FDA-approved NIVO +IPI regimen in pts with advanced MEL in a first-line, routine, clinical-practice setting. Methods: CheckMate 401 (NCT02599402) is a phase 3b study initiated in Europe and Australia. Main eligibility criteria are > 18 yrs of age, newly diagnosed and histologically confirmed unresectable stage III or IV MEL (including cutaneous, mucosal, or ocular), ECOG performance status < 2, no prior systemic therapy, and no active brain metastases. Pts receive NIVO 1 mg/kg + IPI 3 mg/kg IV every 3 weeks for 4 doses followed by NIVO 3 mg/kg IV every 2 weeks for up to 24 months of total treatment, until progression or unacceptable toxicity. Target enrollment is 615 pts. Safety is assessed for a minimum of 100 days after last dose. Tumor assessments are performed using RECIST v1.1. Pts are allowed to continue treatment beyond progression if protocol specified criteria are met. Quality of life is measured by the EORTC QLQ-C30. Pts are followed up to 5 years for OS. Primary endpoint is incidence of CTCAE grade 3-5 treatment-related select AEs in skin, GI, endocrine, hepatic, pancreatic, pulmonary, neurological, and renal systems. Secondary endpoints include incidence and characterization of all grade 3-5 select AEs (including median time to onset and resolution), OS, ORR, and PFS.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/986/CN-01212986/frame.html


Record #108 of 144
ID: CN-01451795
AU: Ahmed T
AU: Triozzi P
AU: Addo S
AU: Kooski M
AU: Petty W
AU: Ruiz J
AU: Grant S
AU: D'Agostino R
AU: Bonomi M
TI: Combination pembrolizumab and low dose weekly carboplatin/paclitaxel for patients with recurrent/ metastatic NSCLC and PS of 2
SO: Journal of thoracic oncology. Conference: 18th world conference on lung cancer of the international association for the study of lung cancer, IASLC 2017. Japan
YR: 2017
VL: 12
NO: 11 Supplement 2
PG: S1917
XR: EMBASE 620146855
PT: Conference Abstract
KY: adverse event; aged; allergic reaction; atrioventricular block; *cancer recurrence; clinical article; controlled study; drug combination; drug therapy; fatigue; female; hormone substitution; human; hypothyroidism; immune related gene; *immunotherapy; low drug dose; male; *non small cell lung cancer; pacemaker; randomized controlled trial; response evaluation criteria in solid tumors; toxicity; *carboplatin; *paclitaxel; *pembrolizumab
AB: Background: Chemotherapy and immunotherapy have been shown to be beneficial for patients with non-small cell lung cancer (NSCLC) and performance status (PS) of 0 or 1; there still is debate, however, regarding its efficacy for patients with a PS of 2 which comprises approximately 30% of the NSCLC population. Pre-clinical data have demonstrated that low dose carboplatin/paclitaxel have resulted in superior immune efficacy compared to the maximum tolerated dose regimen. Given the significant unmet need for treatment options in this patient population, our study evaluated low-dose weekly carboplatin/ paclitaxel combined with pembrolizumab in patients with NSCLC and a PS of 2. Method: Patients with metastatic or recurrent NSCLC and PS of 2 were randomized to single agent pembrolizumab at 200mg every 3 weeks or pembrolizumab plus weekly carboplatin AUC 1 and paclitaxel 25 mg/m<sup>2</sup> irrespective to PDL-1 status. Response was determined using immune-related RECIST, and toxicity was graded using CTCAE 4.0. Result: Between 6/2016 and 2/2017, 20 patients were enrolled, and 19 patients were evaluable for response. The median age was 69 years (54-83). All 19 patients (100%) had a PS of 2. Ten patients were randomized to the single agent arm and 9 patients to the combination arm. Six patients received the therapy as second line (2 combination arm and 4 single agent arm). Mean 3 week cycles per patient: 9 (4-16) in combination arm and 7 (2-14) in single arm group. Response at 9 weeks in the combination arm: partial response (PR) 6 (67%), stable disease (SD) 2 (22%), and progressive disease (PD) 1 (11%). Response at 9 weeks in the single agent arm, PR 2 (20%), SD 4 (40%), and PD 4 (40%). Adverse events in combination arm: 1 (11%) discontinued therapy due to grade 3 fatigue, 3 (33%) discontinued carboplatin due to allergic reactions at 7, 9, and 10 months of treatment but continued pembrolizumab and paclitaxel, and 1 (11%) on hormone replacement therapy due to treatment-induced hypothyroidism. Adverse events in single agent arm: 1 (10%) discontinued treatment due to complete A-V block successfully resolved with pacemaker insertion, and 2 (20%) are on hormone replacement therapy due to treatment-induced hypothyroidism. Conclusion: Combination pembrolizumab and weekly low dose carboplatin/paclitaxel is an active and well tolerated regimen in patients with advanced NSCLC with PS of 2.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/795/CN-01451795/frame.html


Record #109 of 144
ID: CN-01408474
AU: Palomba ML
AU: Till BG
AU: Park SI
AU: Morschhauser F
AU: Cartron G
AU: Marks R
AU: Penuel E
AU: Chitra S
AU: Kuhn M
AU: Popplewell L
TI: A phase Ib study evaluating the safety and clinical activity of atezolizumab combined with obinutuzumab in patients with relapsed or refractory non-Hodgkin lymphoma (NHL)
SO: Hematological oncology. Conference: 14th international conference on malignant lymphoma palazzo dei congressi. Switzerland
YR: 2017
VL: 35
PG: 137-138
XR: EMBASE 617732352
PT: Conference Abstract
KY: anemia; biopsy; CD8 T lymphocyte; cell infiltration; cell level; clinical article; clinical trial; controlled clinical trial; controlled study; death; diabetes mellitus; diffuse large B cell lymphoma; drug combination; drug therapy; drug withdrawal; *female; *follicular lymphoma; human; human tissue; immunohistochemistry; immunosurveillance; immunotherapy; *male; neutropenia; pain; patient history of chemotherapy; pharmacokinetics; phase 1 clinical trial; positron emission tomography-computed tomography; *safety; x-ray computed tomography; *atezolizumab; biological marker; CD20 antigen; CD8 antigen; endogenous compound; *obinutuzumab; programmed death 1 ligand 1
DOI: 10.1002/hon.2437
AB: Introduction: Outcomes for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) pts remain poor with modern chemo-immunotherapies. DLBCL and FL may escape immune surveillance partly due to increased PD-L1/PD-1 expression. Atezolizumab (atezo; anti-PD-L1) has shown activity in many cancers, including NHL. Obinutuzumab (obi; anti-CD20) also has activity in NHL. Here we report data from a Ph Ib study to determine if atezo + obi can reinvigorate immunity to enhance antitumor responses in R/ R NHL (NCT02220842). Methods: All pts had measurable disease and >=1 prior chemo-immunotherapy regimen. Primary endpoints were safety and tolerability; secondary endpoints were PK and clinical activity. Pts received obi IV on days 1 (100 mg), 2 (900 mg), 8 and 15 (1000 mg) of Cycle 1. In Cycles 2-8, atezo 1200 mg IV + obi 1000 mg IV were given on day 1 q3w. Maintenance with atezo followed for 6 mo. Response was reported by PET-CT or CT scan using the Lugano 2014 criteria. Biopsies (FL) were collected to assess PD-L1 (SP142 assay), CD8 and MHCI expression using IHC. Results: As of Nov 21, 2016, 49 pts (23 DLBCL; 26 FL) were safety evaluable (baseline characteristics in table). Pts were heavily pretreated, with 87% of DLBCL pts refractory to last therapy. 30 pts had >=1 any-grade TEAE. The most common Gr 3-4 TEAEs were pain (8.2%), anemia and neutropenia (6.1% each). AEs led to study drug interruptions in 13 pts.1 pt had atezo-related AEs leading to treatment discontinuation (Gr 2 diabetes mellitus and pain). of 17 reported deaths, 15 were due to progression and 2 to unknown causes. At the end of induction assessment (after Cycle 10), 42 pts were efficacy evaluable (treatment characteristics in table). ORR (CR + PR) was 57% for FL and 16% for DLBCL. Most pts with CR/PR had CD8+ T-cell levels above the median. All FL pts with increased tumor-infiltrating CD8+ T cells after atezo + obi had a response; obi alone increased CD8+ T-cell infiltration in 5 of 6 pts. Loss of MHCI was detected in 2 of 35 evaluable pts (both DLBCL); median MHCI expression was similar in FL and DLBCL. PD-L1 and MHCI expression did not correlate with response. Conclusions: Atezo + obi was well tolerated and exhibited activity in R/R NHL. Biomarker analyses point to a more immune-rich environment in FL and suggest that established mechanisms of immune surveillance for DLBCL alone do not account for differences in activity. Changes in biomarker levels upon treatment demonstrate the dynamic nature of immune functionality biomarkers. (Table Presented).
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/474/CN-01408474/frame.html


Record #110 of 144
ID: CN-01295862
AU: Lopez Martin JA
AU: Cruz Merino L
AU: Arance Fernandez AM
AU: Illescas A
AU: Valduviecu Ruiz I
AU: Berrocal A
AU: Lopez-Torrecilla J
AU: Marquez Rodas I
AU: Soriano Teruel MV
AU: Alvarez Gonzalez A
AU: Chust Vicente ML
AU: Rodriguez Abreu D
AU: Cabrera R
AU: Penas Sanchez MC
AU: Curiel T
AU: Munoz Couselo E
AU: Aristu JJ
AU: Gomez-Caamano A
AU: Medina Martinez J
AU: Martin-Algarra S
TI: GRAY-B: an open label multicenter phase-2 GEM study on ipilimumab and radiation in patients with melanoma and brain metastases
SO: Annals of oncology. Conference: 41st european society for medical oncology congress, ESMO 2016. Denmark. Conference start: 20161007. Conference end: 20161011
YR: 2016
VL: 27
NO: no pagination
XR: EMBASE 613912096
PT: Journal: Conference Abstract
KY: adverse drug reaction; asthenia; Barthel index; *brain metastasis; *brain radiation; clinical trial; controlled clinical trial; controlled study; death; deterioration; drug therapy; erythema; exposure; feasibility study; headache; hemiparesis; human; human tissue; hypothyroidism; liver toxicity; major clinical study; *melanoma; overall survival; pharmacokinetics; phase 2 clinical trial; progression free survival; radical reaction; safety; sample size; scalp; side effect; survival rate; vomiting; dexamethasone; *ipilimumab; radical
DOI: 10.1093/annonc/mdw379.13
AB: Background: Estimated median overall survival (OS) in patients ( pts) with brain metastases (BM) ranges between 1.8-10.5 months (mo). Ipilimumab (IPI) has shown activity against mel-BM. Radiation (RT) might be synergistic to anti-CTLA-4 blockade through an 'abscopal' effect. Methods: Open label single stage multicenter phase 2 study, assuming a historical 20% 1-year survival rate (1y SR) with RT. Target sample size: 56 evaluable pts. Target 1y SR: 35% (alpha= 0.05, beta= 0.2). Objectives: Primary: 1y SR; Secondary: progression free survival (PFS); OS; objective response rate (mWHO); safety and feasibility. Treatment: IPI 3 mg/Kg iv q 3 weeks (4 cycles); whole brain RT (WBRT) 30 Gy in 10 fractions (or equivalent), started between C1 and C2. Main eligibility: First episode of BM in mel pts; Karnofsky PS > 70%; Barthel Index > 10; RTOG-RPA class 2; measurable disease; LDH < 2 x ULN; not eligible for radical therapy; not experiencing rapid clinical deterioration; not requiring dexamethasone > 16 mg/d (or equivalent). Results: This is a preliminary analysis after recruiting 43/56 pts (Apr 2014 - Mar 2016). Demographical characteristics are shown in the table. (Table presented) Treatment exposure: IPI: 19 pts completed 4 cycles; RT: 3 pts had early termination. Efficacy: Estimated 1y SR: 31.4% (95%CI 14.0;48.8%), median OS 5.2 mo (95%CI 3.1;6.3); median PFS: 3.21 mo (95%CI 1.7;4.7). Safety: Serious AEs were reported for 23 pts (53.5%), 4 were treatment-related, G3 hepatic toxicity (IPI), G3 cephalalgia and vomiting (RT), G2 scalp erythema (RT) and G3 left hemiparesis. Treatment-related G3 toxicities were seen in 6 pts (14%): asthenia, skin rash, cephalalgia, emesis, hypothyroidism, liver toxicity, hemiparesia. A total of 22 pts died; none of the deaths were study-related. Conclusions: Concomitant IPI + WBRT is feasible. There were no unexpected safety issues. Despite the frequent need for costicosteroids at baseline, interim 1y SR is 31.4%. The trial is ongoing. Updated results will be presented.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/862/CN-01295862/frame.html


Record #111 of 144
ID: CN-00862030
AU: Ribas A
AU: Kefford R
AU: Marshall MA
AU: Punt CJ
AU: Haanen JB
AU: Marmol M
AU: Garbe C
AU: Gogas H
AU: Schachter J
AU: Linette G
AU: Lorigan P
AU: Kendra KL
AU: Maio M
AU: Trefzer U
AU: Smylie M
AU: McArthur GA
AU: Dreno B
AU: Nathan PD
AU: Mackiewicz J
AU: Kirkwood JM
AU: Gomez-Navarro J
AU: Huang B
AU: Pavlov D
AU: Hauschild A
TI: Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma
SO: Journal of clinical oncology
YR: 2013
VL: 31
NO: 5
PG: 616-622
PM: PUBMED 23295794
PT: Clinical Trial, Phase III; Comparative Study; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't
KY: Antibodies, Monoclonal [adverse effects] [therapeutic use];Antineoplastic Agents [adverse effects] [therapeutic use];Antineoplastic Combined Chemotherapy Protocols [therapeutic use];Colitis [chemically induced];Diarrhea [chemically induced];Drug Administration Schedule;Drug Eruptions [etiology];Fatigue [chemically induced];Ipilimumab;Kaplan-Meier Estimate;Melanoma [drug therapy] [pathology];Nausea [chemically induced];Pruritus [chemically induced];Salvage Therapy [methods];Skin Neoplasms [drug therapy] [pathology];Treatment Outcome;Adult[checkword];Aged[checkword];Female[checkword];Humans[checkword];Male[checkword];Middle Aged[checkword]
DOI: 10.1200/JCO.2012.44.6112
AB: PATIENTS AND METHODS: Patients with treatment-naive, unresectable stage IIIc or IV melanoma were randomly assigned at a ratio of one to one to tremelimumab (15 mg/kg once every 90 days) or physician's choice of standard-of-care chemotherapy (temozolomide or dacarbazine).RESULTS: In all, 655 patients were enrolled and randomly assigned. The test statistic crossed the prespecified futility boundary at second interim analysis after 340 deaths, but survival follow-up continued. At final analysis with 534 events, median OS by intent to treat was 12.6 months (95% CI, 10.8 to 14.3) for tremelimumab and 10.7 months (95% CI, 9.36 to 11.96) for chemotherapy (hazard ratio, 0.88; P = .127). Objective response rates were similar in the two arms: 10.7% in the tremelimumab arm and 9.8% in the chemotherapy arm. However, response duration (measured from date of random assignment) was significantly longer after tremelimumab (35.8 v 13.7 months; P = .0011). Diarrhea, pruritus, and rash were the most common treatment-related adverse events in the tremelimumab arm; 7.4% had endocrine toxicities. Seven deaths in the tremelimumab arm and one in the chemotherapy arm were considered treatment related by either investigators or sponsor.CONCLUSION: This study failed to demonstrate a statistically significant survival advantage of treatment with tremelimumab over standard-of-care chemotherapy in first-line treatment of patients with metastatic melanoma.PURPOSE: In phase I/II trials, the cytotoxic T lymphocyte-associated antigen-4-blocking monoclonal antibody tremelimumab induced durable responses in a subset of patients with advanced melanoma. This phase III study evaluated overall survival (OS) and other safety and efficacy end points in patients with advanced melanoma treated with tremelimumab or standard-of-care chemotherapy.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/030/CN-00862030/frame.html


Record #112 of 144
ID: CN-01081654
AU: Eggermont AM
AU: Chiarion-Sileni V
AU: Grob JJ
AU: Dummer R
AU: Wolchok JD
AU: Schmidt H
AU: Hamid O
AU: Robert C
AU: Ascierto PA
AU: Richards JM
AU: Lebbé C
AU: Ferraresi V
AU: Smylie M
AU: Weber JS
AU: Maio M
AU: Konto C
AU: Hoos A
AU: Pril V
AU: Gurunath RK
AU: Schaetzen G
AU: Suciu S
AU: Testori A
TI: Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial
SO: The lancet. Oncology
YR: 2015
VL: 16
NO: 5
PG: 522-530
PM: PUBMED 25840693
PT: Clinical Trial, Phase III; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't
KY: Adjuvants, Immunologic [administration & dosage];Antibodies, Monoclonal [administration & dosage] [adverse effects];Combined Modality Therapy;Disease-Free Survival;Double-Blind Method;Ipilimumab;Lymphatic Metastasis;Melanoma [drug therapy] [pathology] [surgery];Neoplasm Recurrence, Local [drug therapy] [pathology] [surgery];Adult[checkword];Aged[checkword];Female[checkword];Humans[checkword];Male[checkword];Middle Aged[checkword]
DOI: 10.1016/S1470-2045(15)70122-1
AB: METHODS: We did a double-blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168.FINDINGS: Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2·74 years (IQR 2·28-3·22), there were 528 recurrence-free survival events (234 in the ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26·1 months (95% CI 19·3-39·3) in the ipilimumab group versus 17·1 months (95% CI 13·4-21·6) in the placebo group (hazard ratio 0·75; 95% CI 0·64-0·90; p=0·0013); 3-year recurrence-free survival was 46·5% (95% CI 41·5-51·3) in the ipilimumab group versus 34·8% (30·1-39·5) in the placebo group. The most common grade 3-4 immune-related adverse events in the ipilimumab group were gastrointestinal (75 [16%] vs four [<1%] in the placebo group), hepatic (50 [11%] vs one [<1%]), and endocrine (40 [8%] vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started ipilimumab (182 [39%] during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barré syndrome.INTERPRETATION: Adjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk-benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value.FUNDING: Bristol-Myers Squibb.BACKGROUND: Ipilimumab is an approved treatment for patients with advanced melanoma. We aimed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/654/CN-01081654/frame.html


Record #113 of 144
ID: CN-01295690
AU: Sznol M
AU: Ferrucci PF
AU: Hogg D
AU: Atkins M
AU: Wolter P
AU: Guidoboni M
AU: Lebbe C
AU: Kirkwood J
AU: Schachter J
AU: Daniels G
AU: Hassel J
AU: Cebon J
AU: Gerritsen W
AU: Atkinson V
AU: Thomas L
AU: McCaffrey J
AU: Power D
AU: Jiang J
AU: Hodi FS
AU: Wolchok J
TI: Safety profile of nivolumab (NIVO) and ipilimumab (IPI) combination therapy in patients (pts) with advanced melanoma (MEL)
SO: Annals of oncology. Conference: 41st european society for medical oncology congress, ESMO 2016. Denmark. Conference start: 20161007. Conference end: 20161011
YR: 2016
VL: 27
NO: no pagination
XR: EMBASE 613912419
PT: Journal: Conference Abstract
KY: adult; adverse drug reaction; aged; cancer epidemiology; consensus development; controlled clinical trial; controlled study; death; disease course; drug combination; drug therapy; drug withdrawal; endocrine system; follow up; gastrointestinal tract; human; lung; *melanoma; meta analysis; monotherapy; organ; pharmacokinetics; phase 1 clinical trial; *safety; side effect; skin; toxicity; *ipilimumab; *nivolumab
DOI: 10.1093/annonc/mdw379.18
AB: Background: Cumulative data indicate greater tumor response from the addition of IPI (anti-CTLA-4 antibody) to NIVO (anti-PD-1 antibody) in MEL pts, but with a higher frequency of adverse events (AEs) than observed with either agent alone. The objective of this pooled analysis is to describe the safety profile of NIVO + IPI across MEL studies in which established guidelines for AE management were utilized. Methods: A retrospective safety review was conducted for three phase 1-3 trials in which all MEL pts who received at least 1 dose of the standard regimen, NIVO 1 mg/ kg + IPI 3 mg/kg Q3W x 4, then NIVO 3 mg/kg Q2W until disease progression or unacceptable toxicity. Analyses included AEs, select (immune-related) AEs, time to onset and resolution, use of immune-modulating agents (IMs) for management of toxicity, and effect of IMs on outcome. Results: Among 448 pts, median age was 61 (range:18-87) and 25% had ECOG PS > 0. Median duration of follow-up was 13.2 months. Treatment-related grade 3-4 AEs occurred in 55% of pts, and led to discontinuation in 28%. The most frequent treatment-related select AEs of any grade were skin (64%) and gastrointestinal (47%); the most frequent grade 3-4 select AEs were hepatic (17%) and gastrointestinal (16%; Table). 30% developed a grade 2-4 select AE in >1 organ category. Median time to onset of grade 3-4 treatment-related select AEs ranged from 3.1 wks (skin) to 16.3 wks (renal). Excluding endocrine AEs, median time to resolution of grade 3-4 select AEs with IMs ranged from 1.1 wks (renal) to 7.3 wks (pulmonary). Resolution rates for non-endocrine grade 3-4 select AEs ranged between 79-100% using IMs. 4 (<1%) deaths were attributed to therapy. Conclusions: The frequency of grade 3-4 treatment-related AEs was higher with NIVO + IPI and time to onset of select AEs occurred earlier than with either agent alone. Resolution rates of select AEs were similar to those previously reported with IPI monotherapy. (Table presented).
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/690/CN-01295690/frame.html


Record #114 of 144
ID: CN-01251904
AU: Lukas K
AU: Scheibenbogen C
AU: Asemissen AM
AU: Busse A
AU: Ochsenreither S
AU: Blau I
AU: Baldus C
AU: Thiel E
AU: Keilholz U
AU: Letsch A
TI: Long term efficacy of WT1 peptide vaccination in patients with WT1 expressing AML /MDS and solid malignancies
SO: Oncology research and treatment. Conference: jahrestagung der deutschen, osterreichischen und schweizerischen gesellschaften fur hamatologie und medizinische onkologie 2016. Germany. Conference start: 20161014. Conference end: 20161018
YR: 2016
VL: 39
PG: 85
XR: EMBASE 613153080
PT: Journal: Conference Abstract
KY: adverse drug reaction; astrocytoma; breast; cancer susceptibility; chemotherapy; clinical article; controlled clinical trial; controlled study; disease control; drug therapy; drug withdrawal; feasibility study; female; *gene overexpression; histology; human; immunogenicity; larynx cancer; *mesothelioma; myelodysplastic syndrome; normal human; ovary cancer; phase 2 clinical trial; remission; side effect; stomach; toxicity; *vaccination; cancer vaccine; endogenous compound; granulocyte macrophage colony stimulating factor; *peptide; tumor antigen; *WT1 protein
DOI: 10.1159/000449050
AB: Immunotherapy is a novel strategy for generating antitumor immunity as part of cancer treatments. The present study aims to assess the feasibility, immunogenicity and clinical effects of WT1 peptide vaccination based on the growing evidence that Wilms' tumor protein 1 (WT1) is a promising tumor antigen for the development of universal cancer vaccines. In this light, we conducted two separate phase-II proof of principle vaccine trial in patients with active AML/MDS and with WT1 overexpressing solid tumors. Here we concentrate on patients remaining on vaccination for at least one year in order to analyze characteristics for long-term vaccination success. The vaccination schedule was identical for both trials: 0.2mg HLA-A*0201-restricted WT1.126-134 peptide admixed with 1 mg KLH (day 3), and 62.5mug GM-CSF (day 1-4) every two weeks x 4 s.c./i.d., followed by either biweekly or every four weeks for 10 months and at increased intervals of up to 3-monthly thereafter. The two trials included patients with active AML and high-risk MDS (n = 20), patients with AML in high risk complete remission (n = 9), as well as with mostly heavily pretreated ovarian (n = 7), thyroid (n = 2), breast (n = 1), gastric (n = 1), and larynx cancer (n = 1), astrocytoma (n = 1) and mesothelioma (n = 4). Standard criteria were used for response assessment. Patients remained on study in absence of limiting toxicity and disease progression.Toxicity to treatment was mild , and no patient went off protocol for adverse events or consent withdrawal. Eleven patients remained on study for more than 1 year with disease control, including 3/19 patients with active AML, 4/9 with AML in complete remission, 2/7 patients with ovarian cancer and 2/4 with mesothelioma. Of these 11 patients four remained on study for more than 3 years, including 3 patients with AML (75, 70+ and 114+ months) and one mesothelioma patient (84+ months). We could demonstrate remarkable longterm responses induced by WT1 vaccination in patients with AML and solid tumors. Further vaccine development, especially in combination with checkpoint inhibitors seem promising. Overall, no correlation between prior treatment and duration on vaccine was observed, since 2/4 patients in long-term disease control had previously aggressive chemotherapy. Of the solid tumor patients, chemotherapy-pretreated ovarian cancer and mesothelioma appear to be sensitive to WT1 vaccine, although other histologies cannot be excluded due to low patient numbers.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/904/CN-01251904/frame.html


Record #115 of 144
ID: CN-01364709
AU: Calagua C
AU: Shaw K
AU: Russo J
AU: Schaefer R
AU: Lis R
AU: Zhang Z
AU: Loda M
AU: Taplin M-E
AU: Balk SP
AU: Sun Y
AU: Ye H
TI: Effect of neoadjuvant intense androgen deprivation therapy in PD-l1 expression in prostate cancer
SO: Laboratory investigation. Conference: 106th annual meeting of the united states and canadian academy of pathology, USCAP 2017. United states
YR: 2017
VL: 97
PG: 217A
XR: EMBASE 615115004
PT: Conference Abstract
KY: aggressiveness; *androgen deprivation therapy; clinical trial; controlled clinical trial; controlled study; differentiation; drug therapy; gene deletion; *gene expression regulation; gene inactivation; genetic susceptibility; human; human tissue; immunocompetent cell; immunohistochemistry; immunotherapy; *male; minimal residual disease; neoadjuvant therapy; phase 2 clinical trial; population based case control study; *prostate cancer; prostatectomy; T lymphocyte; therapy effect; tumor cell; abiraterone acetate; CD3 antigen; chromogranin; endogenous compound; leuprorelin; pembrolizumab; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; prednisone; *programmed death 1 ligand 1; programmed death 1 receptor; synaptophysin
DOI: 10.1038/labinvest.2016.169
AB: Background: Although prostate cancer (PCa) is thought to be resistant to PD-1/ PD-L1 immunotherapies, recent studies reported that Enzalutimide treatment induced PD-L1 expression in PCa and anti-PD-1 antibody pembrolizumab showed anti-tumor efficacy in a subset of patients with Enzalutimide-resistant PCa. It is not clear if intense androgen deprivation therapy (IADT) has a similar immune modulation effect. In this study, we examined PD-L1 expression in residual tumors post neoadjuvant treatment with leuprolide with abiraterone acetate plus prednisone in a phase II clinical trial. Design: Representative tumor sections from 43 trial cases and 53 grade- and stage-matched untreated control radical prostatectomy cases were subject to immunohistochemistry to evaluate PD-L1 expression. Additional immunostains were performed on all cases to examine tumor ERG and PTEN status and extent of neuroendocrine differentiation, to investigate potential mechanisms of PD-L1 expression. PD-L1-positive tumors were also stained for CD3 and PD-1 to characterize tumor-associated immune cells. Results: Surprisingly, IADT-treated tumors showed a trend of reduced PD-L1 expression compared to untreated tumors. 7.0% of treated and 9.4% of untreated cases showed PD-L1 expression in >5% of tumor cells, respectively (p=0.73). 11.6% of treated and 24.5% of untreated cases showed PD-L1 expression in >1% of tumor cells, respectively (p=0.12). In addition, tumor PD-L1 expression had no significant association with PTEN deletion, ERG fusion status, or immunopositivity for chromogranin and synaptophysin. PD-L1-positive tumor cells were closely associated with CD3- and PD-1-positive immune cells, independent of treatment status. Conclusions: Neoadjuvant IADT using leuprolide with abiraterone acetate plus prednisone reduces PD-L1 expression in PCa, indicating the addition of PD-1/PD-L1 immunotherapies to IADT may not increase the therapeutic effect in the neoadjuvant setting. PD-L1 expression in PCa is likely to be an adaptive response to tumor-infiltrating T-cells, and less likely a direct result of tumor genetic alterations such as PTEN deletion. PD-L1 expression in a large cohort of untreated PCa is currently under investigation to check its association with tumor aggressiveness.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/709/CN-01364709/frame.html


Record #116 of 144
ID: CN-01333994
AU: Kiyohara Y
AU: Uhara H
AU: Ito Y
AU: Matsumoto N
AU: Yamazaki N
TI: Safety profile of nivolumab in Japanese patients with unresectable malignant melanoma: interim results from prospective post-marketing surveillance in Japan
SO: Pigment cell and melanoma research. Conference: 27th annual meeting of the japanese society for pigment cell research. Japan. Conference start: 20161112. Conference end: 20161113
YR: 2017
VL: 30
NO: 1
PG: 111
XR: EMBASE 614350366
PT: Journal: Conference Abstract
KY: adverse drug reaction; autoimmune disease; *cancer epidemiology; clinical trial; colitis; controlled clinical trial; controlled study; *cutaneous melanoma; data analysis; diarrhea; drug therapy; female; follow up; gender; human; insulin dependent diabetes mellitus; interstitial lung disease; *Japan; *Japanese (citizen); major clinical study; male; mucosal melanoma; myasthenia gravis; myositis; pharmacokinetics; phase 4 clinical trial; *postmarketing surveillance; *safety; side effect; *nivolumab
DOI: 10.1111/pcmr.12547
AB: Nivolumab is an indispensable agent at present for unresectable malignant melanoma (MM) treatment, but the real world evidence after launch is insufficient. Since July 2014, when nivolumab was approved in Japan, prospective post-marketing surveillance (PMS) that is a system specific to Japan is being conducted for all MM patients treated with nivolumab in Japan. PMS data were collected from all MM patients treated with nivolumab in Japan in the period from July 2014 to May 2016 (data cut-off). The surveillance data on follow-up for 6 months or longer (maximum 458 days) were available on 680 patients. Interim data analysis was conducted. Of 680 MM patients, 389 cutaneous melanomas (57.2%) and 208 mucosal melanomas (30.6%) were recorded. Patients with ECOG performance status (PS) of 2-4 and patients with preexisting autoimmune disorders, who are not able to participate in most clinical trials, accounted for 16.9% (n = 115) and 11.8% (n = 80), respectively. The incidences of drug-related adverse events (AEs) in any grade was 53.5% (n = 364) and grade 3-5 was 12.4% (n = 84). Notable drug-related AEs included colitis/diarrhea (n = 34), interstitial lung disease (ILD) (n = 22), type 1 diabetes mellitus (T1DM) (n = 5), myasthenia gravis (MG) and myositis (n = 4). In terms of the patient characteristics, there was no difference in incidence of drug-related AEs when stratified according to age, gender, PS, pre-LDH and preexisting autoimmune disorders. Based on the surveillance data collected at this time, the tolerability of nivolumab in Japanese patients with MM was largely favorable despite the fact that patients with preexisting autoimmune disorders and patients with PS 2 or higher were included. However, serious immune-related AEs such as colitis, ILD, T1DM and MG should be carefully monitored.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/994/CN-01333994/frame.html


Record #117 of 144
ID: CN-01407244
AU: Apolo AB
AU: Mortazavi A
AU: Stein MN
AU: Pal SK
AU: Davarpanah NN
AU: Parnes HL
AU: Ning YM
AU: Francis DC
AU: Cordes LM
AU: Monk P
AU: Lancaster T
AU: Costello R
AU: Nanda S
AU: Bottaro DP
AU: Wright JJ
AU: Streicher H
AU: Steinberg SM
AU: Berninger M
AU: Lindenberg L
AU: Dahut WL
TI: A phase I study of cabozantinib plus nivolumab (CaboNivo) and ipilimumab (CaboNivoIpi) in patients (pts) with refractory metastatic urothelial carcinoma (mUC) and other genitourinary (GU) tumors
SO: Journal of clinical oncology. Conference: 2017 genitourinary cancers symposium. United states
YR: 2017
VL: 35
NO: 6 Supplement 1) (no pagination
XR: EMBASE 618007261
PT: Conference Abstract
KY: adult; adverse drug reaction; aged; aseptic meningitis; *bladder metastasis; clinical article; colitis; controlled clinical trial; *controlled study; dehydration; diarrhea; drug combination; fatigue; female; germ cell tumor; human; hyponatremia; hypophosphatemia; kidney carcinoma; male; *penis cancer; phase 1 clinical trial; prostate cancer; proteinuria; pyelonephritis; rash; response evaluation criteria in solid tumors; Sertoli cell tumor; side effect; *squamous cell carcinoma; thorax pain; thrombocytopenia; thromboembolism; toxicity; trophoblastic tumor; *tumor resistance; urachus; amylase; *cabozantinib; endogenous compound; *ipilimumab; *nivolumab; triacylglycerol lipase
AB: Background: We report the safety and clinical activity of CaboNivo and CaboNivoIpi in pts with mUC and other GU tumors. Methods: Part I included 4 dose levels (DLs) (Cabo PO daily and Nivo IV q2wk): DL1 Cabo40/Nivo1, DL2 Cabo40/Nivo3, DL3 Cabo60/Nivo1, DL4 Cabo 60/Nivo3. Part II included 3 DLs (Cabo PO daily, plus NivoIpi IV q3 wk x 4 doses then Nivo q2wk): DL5 Cabo 40/Nivo1/Ipi1, DL6 Cabo40/Nivo3/Ipi1, DL7 Cabo 60/Nivo3/Ipi 1. Tumors were assessed for overall response rate (ORR) by RECIST 1.1. Adverse events (AEs) were graded (G) by NCI-CTCAE v4.0. Results: From 7/22/15-10/14/16, 40pts [mUC N=14/(plasmacytoid N=1); bladder urachal N=4; bladder squamous cell carcinoma (bSCC) N=2; germ cell tumor (GCT) N=4; castrate-resistant prostate cancer (CRPC) N=9/(neuroendocrine prostate N=1); sarcomatoid renal cell carcinoma (sRCC) N=1; trophoblastic tumor N=1); sertoli cell tumor N=1; and penile SCC N=4] were treated. Median age was 58 (range 31-77); 36 (90%) were male. AEs related to study drugs with [1] CaboNivo included G3 hyponatremia 4/24 (17%), hypophosphatemia 4/24 (17%), lipase increase 3/24 (13%), dehydration 2/24 (8%), diarrhea 2/24 (8%), fatigue 2/24 (8%), HTN 2/24 (8%), thromboembolic event 1/24 (4%), rash 1/24 (4%), chest pain 1/24 (4%), amylase increase 1/24 (4%), hyperthyroid 1/24 (4%), proteinuria 1/24 (4%), thrombocytopenia 1/24 (4%); and G4 pyelonephritis 1/24 (4%); [2] CaboNivoIpi included G3 hypophosphatemia 2/16 (13%), lipase increase 2/16 (13%), fatigue 1/16 (6%), ALT increase 1/16 (6%), and HTN 1/16 (6%). There were 2/40 (5%) G3 immunerelated AEs: 1 aseptic meningitis/CaboNivo; and 1 colitis/CaboNivoIpi. There were no G5 toxicities, or DLTs. 38 pts were evaluable for response. ORR was 12/38 (32%): 1 CR (bSCC); 11 PRs (5 mUC, 1 sRCC, 1 urachal, 1 bSCC, 1 CRPC, 2 penile). SD 20/38 (53%); 9/11 responses were ongoing and 26/39 (67%) pts remain on study. Conclusions: CaboNivo and CaboNivoIpi were well tolerated with no DLTs. Responses were seen at all DLs. The recommended dose for Part I is Cabo40/Nivo3 and for Part II is Cabo40/Nivo3/Ipi1. Rare tumors such as bSCC, urachal, and penile cancer demonstrated responses.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/244/CN-01407244/frame.html


Record #118 of 144
ID: CN-01249563
AU: Sznol M
AU: Ferrucci P
AU: Hogg D
AU: Atkins M
AU: Wolter P
AU: Guidoboni M
AU: Lebbe C
AU: Kirkwood J
AU: Schachter J
AU: Daniels G
AU: Hassel J
AU: Cebon J
AU: Gerritsen W
AU: Atkinson V
AU: Thomas L
AU: Mccaffrey J
AU: Power D
AU: Jiang J
AU: Hodi S
AU: Wolchok J
TI: Safety profile of nivolumab (NIVO) and ipilimumab (IPI) combination therapy in patients with advanced melanoma (MEL)
SO: Asia-pacific journal of clinical oncology. Conference: 43rd annual scientific meeting of the clinical oncological society of australia, COSA 2016. Australia. Conference start: 20161115. Conference end: 20161117
YR: 2016
VL: 12
PG: 118
XR: EMBASE 613440237
PT: Journal: Conference Abstract
KY: adult; adverse drug reaction; consensus development; controlled clinical trial; controlled study; death; disease course; drug combination; drug therapy; drug withdrawal; endocrine system; follow up; gastrointestinal tract; human; lung; *melanoma; meta analysis; middle aged; monotherapy; organ; pharmacokinetics; phase 1 clinical trial; *safety; side effect; skin; toxicity; *ipilimumab; *nivolumab
AB: Aims: Cumulative data indicate greater tumor response from the combination of nivolumab+ipilimumab (NIVO+IPI) in patients with melanoma (MEL), but with higher frequency of adverse events (AEs) compared with either agent alone. This pooled analysis of three studies describes the safety profile of NIVO+IPI utilizing established guidelines for AE management. Methods: A retrospective safety review was conducted for phase 1-3 trials in which patients received >1 dose of the standard regimen, NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4, then NIVO 3 mg/kg Q2W until progression or unacceptable toxicity. Analyses included AEs, select (immune-related) AEs, time to onset and resolution, use of immune-modulating agents (IMs) for toxicity management and effect of IMs on outcome. Results: Among 448 patients, median age was 61 years, and 25% had ECOG PS>0. Median duration of follow-up was 13.2 months. Treatment-related grade 3/4 AEs occurred in 55% of patients and led to discontinuation in 28%. The most frequent treatment-related select AEs of any grade were skin (64%) and gastrointestinal (47%), and of grade 3/4 were hepatic (17%) and gastrointestinal (16%); 30% developed a grade 2-4 select AE in>1 organ category. Median time to onset of grade 3/4 select AEs ranged from 3.1 (skin) to 16.3 weeks (renal). Excluding endocrine AEs, median time to resolution and resolution rates of grade 3/4 select AEs were 1.1 (renal) to 7.3 weeks (pulmonary) and 79-100%, respectively, using IMs. Four (<1%) deaths were attributed to therapy. Conclusions: The frequency of grade 3/4 treatment-related AEs was higher with NIVO+IPI, and time to onset of select AEs occurred earlier than with either agent alone. Resolution rates of select AEs were similar to those previously reported with IPI monotherapy.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/563/CN-01249563/frame.html


Record #119 of 144
ID: CN-01378466
AU: Plimack ER
AU: Motzer RJ
AU: Escudier B
AU: Sharma P
AU: Mcdermott DF
AU: George S
AU: Hammers HJ
AU: Carducci M
AU: Tykodi SS
AU: Sosman JA
AU: Choueiri TK
AU: Donskov F
AU: Gurney H
AU: Gauler TC
AU: Ueda T
AU: Zhao H
AU: Berghorn E
AU: Wagstaff J
TI: Two-year efficacy and safety update from the phase III CheckMate 025 study of nivolumab versus everolimus in patients with advanced renal cell carcinoma (aRCC)
SO: BJU international. Conference: 15th international kidney cancer symposium. United states
YR: 2016
VL: 118
PG: 11-12
XR: EMBASE 616030174
PT: Conference Abstract
KY: adult; adverse drug reaction; antiangiogenic therapy; clinical article; clinical trial; controlled clinical trial; controlled study; drug therapy; endocrine system; female; follow up; hazard ratio; human; *kidney carcinoma; male; overall survival; pharmacokinetics; phase 3 clinical trial; progression free survival; randomized controlled trial; *safety; side effect; toxicity; *everolimus; *nivolumab
DOI: 10.1111/bju.13694
AB: Background: The primary analysis of CheckMate 025, based on 14 months' minimum follow-up, demonstrated superior overall survival (OS) with nivolumab vs everolimus (25.0 vs 19.6 months) and a higher objective response rate (ORR; 25% vs 5%) in previously treated patients with aRCC (N Engl J Med 2015;373:1803-13). Here, we report updated 2-year efficacy and safety. Methods: Adults with clear-cell aRCC that had progressed after 1-2 prior anti-angiogenic therapies were randomized (1:1) to nivolumab 3 mg/kg IV every 2 weeks or everolimus 10 mg orally once daily until progression or unacceptable toxicity. The primary endpoint was OS. Key secondary endpoints were ORR and progression-free survival, and incidence of adverse events (AEs). Results: At a minimum follow-up of 26 months, the median OS was 26.0 months with nivolumab and 19.7 months with everolimus (hazard ratio = 0.73; p = 0.0006), with 1- and 2- year OS rates of 76% and 52% with nivolumab and 67% and 42% with everolimus, respectively. ORR remained consistent with the primary analysis, at 26% and 5%. Median duration of response was 12.0 months for the 105 nivolumab responders and 12.0 months for the 22 everolimus responders. Ongoing response was noted in 29% (30/105) of responders on nivolumab and 14% (3/22) of responders on everolimus. Incidence and type of treatment-related AEs were consistent with the primary analysis and remained lower with nivolumab (79%; grade 3-4, 20%) vs everolimus (88%; grade 3-4, 37%). The majority of treatment-related select AEs with nivolumab resolved (63-89%, depending on AE category), with the exception of endocrine AEs (37%). An analysis of potential prognostic features for OS for both treatments will be presented as well as characteristics of patients based on response status at 2 years. Conclusions: In this 2-year update, nivolumab continues to demonstrate durable responses and a survival benefit over everolimus in previously treated patients with aRCC. The safety profile is consistent with the primary analysis, and most patients' AEs resolved. (Table Presented) .
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/466/CN-01378466/frame.html


Record #120 of 144
ID: CN-01397700
AU: Boutros C
AU: Mateus C
AU: Lanoy E
AU: Routier E
AU: Chouaib S
AU: Schwob D
AU: Vagner S
AU: Girault I
AU: Caramella C
AU: Hibat S
AU: Gan Tao Y
AU: Cao K
AU: Chaput N
AU: Adam J
AU: Soria J-C
AU: Eggermont AM
AU: Deutsch E
AU: Robert C
TI: A dose escalation phase 1 study of radiotherapy (RT) in combination with anticytotoxic- T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody ipilimumab in patients (pts) with metastatic melanoma
SO: Journal of clinical oncology. Conference: 2017 annual meeting of the american society of clinical oncology, ASCO. United states
YR: 2017
VL: 35
NO: 15 Supplement 1) (no pagination
XR: EMBASE 617435073
PT: Conference Abstract
KY: adverse drug reaction; anemia; antineoplastic activity; asthenia; clinical article; clinical trial; colitis; controlled clinical trial; *controlled study; death; diarrhea; drug combination; drug eruption; drug therapy; eosinophilia; *female; fever; hepatitis; human; *male; maximum tolerated dose; *metastatic melanoma; nausea and vomiting; overall survival; pain; pharmacokinetics; phase 1 clinical trial; progression free survival; radiotherapy; safety; side effect; thyroid disease; toxicity; *cytotoxic T lymphocyte antigen 4; endogenous compound; *ipilimumab
AB: Background: Preclinical ndings have shown a synergy between RT and anti-CTLA-4 monoclonal antibody in several tumor animal models for both local tumor control and distant effects. Preliminary clinical data suggest that it could be due to an abscopal effect of RT. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD) and safety pro le of RT combined with ipilimumab in pts with metastatic melanoma. Methods: A 3+3 dose escalation design was used with 9, 15, 18 and 24 Gy dose of RT (in 3 fractions) at week 4 combined with 10 mg/kg ipilimumab (every 3 weeks for 4 doses). Pts with evidence of clinical bene t at week 12 were eligible for maintenance ipilimumab at 10 mg/kg every 12 weeks starting at week 24 until severe toxicity or disease progression based on immune-related response criteria (irRC). Results: 19 pts with advanced melanoma received ipilimumab between August 2011 and July 2015. Nine pts received the 4 doses of ipilimumab and 2 pts received maintenance ipilimumab (1 and 2 cycles respectively). All pts received the combined RT at week 4 in 3 fractions. All pts presented at least one AE of any grade. The most common AEs were asthenia, diarrhea, desease-related pain and fever. Grade 3 AEs occurred in 8 pts. They included colitis (n = 3), hepatitis (n = 2), anemia (n = 2), asthenia (n = 1), thyroid disorders (n = 1) and nausea/vomiting (n = 1). Nine pts discontinued the study owing to treatment-related adverse events including colitis (n = 6), hepatitis (n = 2) and DRESS (Drug Rash with Eosinophilia and systemic syndrome) (n = 1). DLT occurred in 2/6 pts in the cohort receiving 15 Gy. No drug-related death occurred. According to irRC, 4 partial responses (ORR: 21%) and 4 stable diseases were observed at week 24. The MTD was 9 Gy dose. One pt out of 12 treated in the 9 Gy cohort presented a DLT (grade 3 colitis). The median progression-free survival [95% CI] was 7.2 months [2.4 - 16.8]. The median overall survival [95% CI] was 14.4 months [7.2 - 20.4]. Conclusions: When combined with ipilimumab at 10 mg/kg, in the present design, the MTD of RT was 9 Gy. This combination appears to be associated with antitumor activity.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/700/CN-01397700/frame.html


Record #121 of 144
ID: CN-01397802
AU: Boutros C
AU: Mateus C
AU: Lanoy E
AU: Routier E
AU: Chouaib S
AU: Schwob D
AU: Vagner S
AU: Girault I
AU: Caramella C
AU: Hibat S
AU: Gan Tao Y
AU: Cao K
AU: Chaput N
AU: Adam J
AU: Soria J-C
AU: Eggermont AM
AU: Deutsch E
AU: Robert C
TI: A dose escalation phase 1 study of radiotherapy (RT) in combination with anticytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody ipilimumab in patients (pts) with metastatic melanoma
SO: Journal of clinical oncology. Conference: 2017 annual meeting of the american society of clinical oncology, ASCO. United states
YR: 2017
VL: 35
NO: 15 Supplement 1) (no pagination
XR: EMBASE 617434857
PT: Conference Abstract
KY: adverse drug reaction; anemia; antineoplastic activity; asthenia; clinical article; clinical trial; colitis; controlled clinical trial; *controlled study; death; diarrhea; drug combination; drug eruption; drug therapy; eosinophilia; *female; fever; hepatitis; human; *male; maximum tolerated dose; *metastatic melanoma; nausea and vomiting; overall survival; pain; pharmacokinetics; phase 1 clinical trial; progression free survival; radiotherapy; safety; side effect; thyroid disease; toxicity; *cytotoxic T lymphocyte antigen 4; endogenous compound; *ipilimumab
AB: Background: Preclinical ndings have shown a synergy between RT and anti-CTLA-4 monoclonal antibody in several tumor animal models for both local tumor control and distant effects. Preliminary clinical data suggest that it could be due to an abscopal effect of RT. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD) and safety pro le of RT combined with ipilimumab in pts with metastatic melanoma. Methods: A 3+3 dose escalation design was used with 9, 15, 18 and 24 Gy dose of RT (in 3 fractions) at week 4 combined with 10 mg/kg ipilimumab (every 3 weeks for 4 doses). Pts with evidence of clinical benefit at week 12 were eligible for maintenance ipilimumab at 10 mg/kg every 12 weeks starting at week 24 until severe toxicity or disease progression based on immune-related response criteria (irRC). Results: 19 pts with advanced melanoma received ipilimumab between August 2011 and July 2015. Nine pts received the 4 doses of ipilimumab and 2 pts received maintenance ipilimumab (1 and 2 cycles respectively). All pts received the combined RT at week 4 in 3 fractions. All pts presented at least one AE of any grade. The most common AEs were asthenia, diarrhea, desease-related pain and fever. Grade 3 AEs occurred in 8 pts. They included colitis (n = 3), hepatitis (n = 2), anemia (n = 2), asthenia (n = 1), thyroid disorders (n = 1) and nausea/vomiting (n = 1). Nine pts discontinued the study owing to treatment-related adverse events including colitis (n = 6), hepatitis (n = 2) and DRESS (Drug Rash with Eosinophilia and systemic syndrome) (n = 1). DLT occurred in 2/6 pts in the cohort receiving 15 Gy. No drug-related death occurred. According to irRC, 4 partial responses (ORR: 21%) and 4 stable diseases were observed at week 24. The MTD was 9 Gy dose. One pt out of 12 treated in the 9 Gy cohort presented a DLT (grade 3 colitis). The median progression-free survival [95% CI] was 7.2 months [2.4 - 16.8]. The median overall survival [95% CI] was 14.4 months [7.2 - 20.4]. Conclusions: When combined with ipilimumab at 10 mg/kg, in the present design, the MTD of RT was 9 Gy. This combination appears to be associated with antitumor activity.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/802/CN-01397802/frame.html


Record #122 of 144
ID: CN-01335685
AU: Coens C
AU: Suciu S
AU: Chiarion-Sileni V
AU: Grob JJ
AU: Dummer R
AU: Wolchok JD
AU: Schmidt H
AU: Hamid O
AU: Robert C
AU: Ascierto PA
AU: Richards JM
AU: Lebbé C
AU: Ferraresi V
AU: Smylie M
AU: Weber JS
AU: Maio M
AU: Bottomley A
AU: Kotapati S
AU: Pril V
AU: Testori A
AU: Eggermont AM
TI: Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial
SO: The lancet. Oncology
YR: 2017
VL: 18
NO: 3
PG: 393-403
PM: PUBMED 28162999
XR: EMBASE 614299805
PT: Clinical Trial, Phase III; Comparative Study; Journal Article; Multicenter Study; Randomized Controlled Trial
KY: Adjuvants, Immunologic [therapeutic use];Adolescent;Antibodies, Monoclonal [therapeutic use];Double-Blind Method;Follow-Up Studies;International Agencies;Ipilimumab;Melanoma [drug therapy] [pathology] [surgery];Neoplasm Staging;Prognosis;Quality of Life;Adult[checkword];Aged[checkword];Aged, 80 and over[checkword];Female[checkword];Humans[checkword];Male[checkword];Middle Aged[checkword];Young Adult[checkword];adult; aged; article; cancer adjuvant therapy; *cancer staging; *cancer surgery; cancer survival; controlled study; *cutaneous melanoma/dm [Disease Management]; *cutaneous melanoma/dt [Drug Therapy]; *cutaneous melanoma/su [Surgery]; cutaneous melanoma/dt [Drug Therapy]; diarrhea/si [Side Effect]; double blind procedure; drug efficacy; drug safety; drug tolerability; drug withdrawal; EORTC QLQ C30; fatigue/si [Side Effect]; female; geographic distribution; high risk population; human; insomnia/si [Side Effect]; longitudinal study; loss of appetite/si [Side Effect]; major clinical study; male; multicenter study; nausea/si [Side Effect]; patient compliance; patient reported outcome; phase 3 clinical trial; *quality of life; quality of life assessment; randomized controlled trial; recurrence free survival; treatment duration; vomiting/si [Side Effect]; *ipilimumab/ae [Adverse Drug Reaction]; *ipilimumab/ct [Clinical Trial]; *ipilimumab/cm [Drug Comparison]; *ipilimumab/dt [Drug Therapy]; *ipilimumab/iv [Intravenous Drug Administration]; placebo; adverse drug reaction; *cancer susceptibility; clinical trial; controlled clinical trial; *cutaneous melanoma; deterioration; diarrhea; doctor patient relation; drug therapy; endocrine system; food and drug administration; funding; gastrointestinal tract; in-transit metastasis; insomnia; interactive voice response system; lymph node metastasis; questionnaire; randomization; side effect; skin; symptom; toxicity; visually impaired person; *adjuvant; *ipilimumab; *placebo
DOI: 10.1016/S1470-2045(17)30015-3
AB: METHODS: EORTC 18071 was a multinational, double-blind, randomised, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) in 19 countries worldwide. Participants were randomly assigned (1:1) centrally by an interactive voice response system, to receive either ipilimumab 10 mg/kg or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. HRQoL was assessed with the EORTC QLQ-C30 quality-of-life instrument at baseline, weeks 4, 7, 10, and 24, and every 12 weeks thereafter up to 2 years, irrespective of disease progression. Results were summarised by timepoint and in a longitudinal manner in the intention-to-treat population. Two summary scores were calculated for each HRQoL scale: the average score reported during induction (ipilimumab or placebo at a dose of 10 mg/kg, administered as one single dose at the start of days 1, 22, 43, and 64-ie, four doses in 3 weeks), and the average score reported after induction. A predefined threshold of a 10 point difference between arms was considered clinically relevant. The primary HRQoL endpoint was the global health scale, with the predefined hypothesis of no clinically relevant differences after induction between groups. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168.FINDINGS: Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to treatment: 475 in the ipilimumab group and 476 in the placebo group. Compliance with completing the HRQoL questionnaire was 893 (94%) of 951 patients at baseline, 693 (75%) of 924 at week 24, and 354 (51%) of 697 at week 108. Patient mean global health scores during (77·32 [SD 17·36] vs 72·96 [17·82]; p=0·00011) and after induction (76·48 [17·52] vs 72·32 [18·60]; p=0·00067) were statistically significantly different between groups but were not clinically relevant. Mean global health scores differed most between the groups at week 7 (77 [SD 19] in the placebo group vs 72 [22] in the ipilimumab group) and week 10 (77 [20] vs 70 [23]). Mean HRQoL scores differed by more than 10 points at week 10 between treatment groups for diarrhoea (7·67 [SD 17·05] for placebo vs 18·17 [28·35] for ipilimumab) and insomnia (15·17 [22·53] vs 25·60 [29·19]).INTERPRETATION: Despite increased toxicity, which led to treatment discontinuation for most patients during the induction phase of ipilimumab administration, overall HRQoL, as measured by the EORTC QLQ-C30, was similar between groups, as no clinically relevant differences (10 points or more) in global health status scores were observed during or after induction. Clinically relevant deterioration for some symptoms was observed at week 10, but after induction, no clinically relevant differences remained. Together with the primary analysis, results from this trial show that treatment with ipilimumab results in longer recurrence-free survival compared with that for treatment with placebo, with little impairment in HRQoL despite grade 3-4 investigator-reported adverse events.FUNDING: Bristol-Myers Squibb.BACKGROUND: The EORTC 18071 phase 3 trial compared adjuvant ipilimumab with placebo in patients with stage III melanoma. The primary endpoint, recurrence-free survival, was significantly longer in the ipilimumab group than in the placebo group. Investigator-reported toxic effects of ipilimumab consisted mainly of skin, gastrointestinal, endocrine, and hepatic immune-related adverse events. Adjuvant treatment with ipilimumab in this setting was approved in October, 2014, by the US Food and Drug Administration based on the results of the primary outcome of this trial. Here, we report the results of the secondary endpoint, health-related quality of life (HRQoL), of this trial.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/685/CN-01335685/frame.html


Record #123 of 144
ID: CN-01339262
AU: Alley EW
AU: Lopez J
AU: Santoro A
AU: Morosky A
AU: Saraf S
AU: Piperdi B
AU: Brummelen E
TI: Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial
SO: Lancet oncology
YR: 2017
VL: (no pagination)
XR: EMBASE 614767417
PT: Journal: Article In Press
KY: adverse drug reaction; antineoplastic activity; apoptosis; arthralgia; clinical article; clinical trial; controlled clinical trial; controlled study; disease course; drug therapy; drug withdrawal; erythema multiforme; fatigue; funding; gene expression; human; human tissue; hypothyroidism; immunohistochemistry; infusion related reaction; iridocyclitis; multicenter study; nausea; oncology; pharmacokinetics; *pleura mesothelioma; population model; randomized controlled trial; response evaluation criteria in solid tumors; rhabdomyolysis; *safety; side effect; solid tumor; toxicity; treatment failure; tumor cell; death receptor; endogenous compound; ligand; *pembrolizumab; platinum; programmed death 1 ligand 1; programmed death 1 receptor
DOI: 10.1016/S1470-2045%2817%2930169-9
AB: Background: Malignant pleural mesothelioma is a highly aggressive cancer with poor prognosis and few treatment options following progression on platinum-containing chemotherapy. We assessed the safety and efficacy of pembrolizumab (an anti-programmed cell death receptor 1 [PD-1] antibody) in advanced solid tumours expressing programmed cell death ligand 1 (PD-L1) and report here on the interim analysis of the malignant pleural mesothelioma cohort. Methods: Previously treated patients with PD-L1-positive malignant pleural mesothelioma were enrolled from 13 centres in six countries. Patients received pembrolizumab (10 mg/kg every 2 weeks) for up to 2 years or until confirmed progression or unacceptable toxicity. Key eligibility criteria included measurable disease, failure of standard therapy, and Eastern Cooperative Oncology Group performance status of 0 or 1. PD-L1 positivity was defined as expression in 1% or more of tumour cells by immunohistochemistry. Response was assessed based on investigator review using the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). Primary endpoints were safety and tolerability, analysed in the all-patients-as-treated population, and objective response, analysed for the full-analysis set. This trial is registered with ClinicalTrials.gov, number NCT02054806, and is ongoing but not recruiting participants. Findings: As of June 20, 2016, 25 patients received pembrolizumab. 16 (64%) patients reported a treatment-related adverse event; the most common adverse event were fatigue (six [24%]), nausea (six [24%]), and arthralgia (five [20%]). Five (20%) patients reported grade 3 treatment-related adverse events. Three (12%) patients required dose interruption because of immune-related adverse events: one (4%) of 25 each had grade 3 rhabdomyolysis and grade 2 hypothyroidism; grade 3 iridocyclitis, grade 1 erythema multiforme, and grade 3 erythema; and grade 2 infusion-related reaction. No treatment-related deaths or discontinuations occurred. Five (20%) patients had a partial response, for an objective response of 20% (95% CI 6.8-40.7), and 13 (52%) of 25 had stable disease. Responses were durable (median response duration 12.0 months [95% CI 3.7 to not reached]); two patients remained on treatment at data cutoff. Interpretation: Pembrolizumab appears to be well tolerated and might confer anti-tumour activity in patients with PD-L1-positive malignant pleural mesothelioma. Response durability and efficacy in this patient population warrants further investigation. Funding: Merck. Copyright © 2017 Elsevier Ltd.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/262/CN-01339262/frame.html


Record #124 of 144
ID: CN-01407012
AU: Falkowitz D
AU: Lee D
AU: Nogar J
TI: Fatality secondary to nivolumab induced hepatitis: a medication error
SO: Clinical toxicology. Conference: 2017 annual meeting of the north american congress of clinical toxicology, NACCT 2017. Canada
YR: 2017
VL: 55
NO: 7
PG: 724
XR: EMBASE 617812182
PT: Conference Abstract
KY: abdomen; adverse drug reaction; aged; blood clotting disorder; *case fatality rate; case report; clinical trial; controlled clinical trial; controlled study; coronary artery disease; diabetes mellitus; drug combination; drug therapy; drug withdrawal; emergency ward; exercise; fever; fulminant hepatic failure; gallbladder; *hepatitis A; hospice; human; hypertension; hypertransaminasemia; hypotension; immunotherapy; infusion; international normalized ratio; liver injury; liver support; male; *medication error; melanoma; multiple drug dose; oncology; palliative therapy; patent; phase 3 clinical trial; sepsis; side effect; ultrasound; vascularization; vital sign; acetylcysteine; acetylsalicylic acid; ammonia; bilirubin; dobutamine; endogenous compound; enoxaparin; escitalopram; hydrocortisone; insulin; lisinopril; metformin plus sitagliptin; metoprolol; *nivolumab; omeprazole; oxycodone; oxygen; prednisone; risperidone; triacylglycerol lipase; vitamin K group
DOI: 10.1080/15563650.2017.1348043
AB: Background: Nivolumab is a human monoclonal antibody that is used in a variety of cancer treatments to modulate T cell immune reactivity. Nivolumab-induced hepatitis has been well documented but management of these patients is not clear. Fatalities have been reported in patients in which treatment with corticosteroids was delayed and/or had continued exposure following an initial hepatic injury. We present a case fatality and medication error in a patient who received a second dose of nivolumab despite preexisting signs of hepatitis. Case report: A 70-year-old male with a history of hypertension, coronary artery disease, diabetes mellitus, and malignant melanoma undergoing immunotherapy, presented to the emergency department for hypotension and fever 4 d after his second nivolumab infusion. His presenting vital signs: HR-75 bpm, BP-103/ 57mmHg, RR-20/min, O2 sat-98%, Temp-97.8 degreeF orally. His medications included: insulin,metformin, sitagliptin, enoxaparin, oxycodone, lisinopril, aspirin, escitalopram, risperidone, metoprolol, omeprazole, and prednisone. He had an unremarkable physical exam. Initial laboratory analysis revealed a lactate-7.2mmol/ L. The patient was also found to have transaminitis with an AST-1506 U/L, ALT-3190 U/L, and total bilirubin 1.0mg/dL. CT of the abdomen was normal and a right upper quadrant ultrasound and duplex demonstrated diffuse non-specific mild gall bladder wall thickening. The hepatic vasculature was patent. Five hours after admission the patient's AST and ALT rose to 2844U/L and 4388 U/L, respectively. Lipase was 50 U/L. INR was 1.36 with a lactate of 7.2mmol/L. He continued to deteriorate and his AST/ALT peaked at 5458 and 9400 U/L with an ammonia of 97 umol/L and an INR of 5.93 on hospital day #5. He was treated with intravenous hydrocortisone 100mg every 8 h and N-acetylcysteine (dosed at typical 21-h protocol with continued phase 3 dosing). The patient also received multiple doses of vitamin K as needed for coagulopathy. His sepsis workup and cultures were all negative. He required dobutamine continuous infusion for hypotension. The patient expired on hospital day #6 after he was enrolled in hospice/ palliative care. One month prior to presentation the patient experienced transaminitis following his initial infusion of nivolumab. His AST and ALT were 275 U/L and 1138 U/L at their peak and trended back down to 76 U/L and 553 U/L 5 d prior to admission after treatment with prednisone. Oncology recommended discontinuation of the monoclonal antibody to avoid worsening hepatic injury. However, the patient received an additional infusion of the nivolumab in error, 4 d prior to when he presented to the emergency department. Case discussion: We present a case fatality secondary to nivolumab-induced hepatitis following a medication error. Despite proper treatment with hydrocortisone and additional liver support with N-acetylcysteine, our patient died from fulminant hepatic failure. Conclusions: Patients who suffer from a hepatic injury secondary to treatment with nivolumab need to be closely monitored, treated with corticosteroids, and consideration given to discontinuation of the treatment. Providers need to exercise caution when re-administering nivolumab, and ensure that it is appropriately discontinued after an initial hepatic injury due to this medication (Table presented).
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/012/CN-01407012/frame.html


Record #125 of 144
ID: CN-01451043
AU: Eroglu Z
AU: Kim Y
AU: Gibney G
AU: Kudchadkar R
AU: Chen Y
AU: Markowitz J
AU: Brohl A
AU: McCormick L
AU: Bellamy D
AU: Richards A
AU: Weber J
AU: Khushalani N
TI: Mature results of combination nivolumab (NIVO) plus ipilimumab (IPI) as adjuvant therapy in stage IIIC/IV melanoma (MEL)
SO: Pigment cell and melanoma research. Conference: society for melanoma research 2017 congress. Australia
YR: 2018
VL: 31
NO: 1
PG: 153
XR: EMBASE 620214929
PT: Conference Abstract
KY: *adjuvant chemotherapy; adult; cancer recurrence; *cancer staging; cancer surgery; cancer survival; cancer susceptibility; clinical article; cohort analysis; colitis; comparative effectiveness; controlled study; death; disease free survival; drug combination; drug therapy; female; follow up; hepatitis; human; hyperglycemia; hypophysitis; male; *metastatic melanoma; middle aged; pharmacokinetics; randomized controlled trial; recurrence free survival; vomiting; adjuvant; amylase; endogenous compound; interferon; *ipilimumab; *nivolumab; triacylglycerol lipase
DOI: 10.1111/pcmr.12656
AB: Background: Adjuvant therapy in melanoma continues to evolve rap-idly. Results from trials comparing anti-PD1 agents with interferon and/or IPI are pending. In a single center trial, we examined the safety & efficacy of 2 dose cohorts of NIVO + IPI in patients (pts) with re-sected stage IIIC/IV MEL. Methods: Eligible pts rendered disease free by surgery were treated with NIVO (1 mg/kg) + IPI (3 mg/kg) Q3 wks X 4 doses (induction) followed by 2 years of NIVO (3 mg/kg Q2 wks; Cohort A). Cohort B examined NIVO (3 mg/kg) + IPI (1 mg/kg) Q3 wks X 4 doses followed by the same maintenance. Results: Forty patients (20 in each cohort) were treated. Median age was 50 (22-78) in cohort A and 55 (29-77) in cohort B. Half the pts in both cohorts had resected stage 4 MEL (4 M1a, 8 each M1b and M1c.) More pts in cohort B completed all 4 induction doses (65% versus 50%); 6 pts in each completed all planned therapy. Most common grade 3/4 AEs in cohort A were lipase (n = 8), ALT/AST (8/5), colitis (3); in cohort B, lipase/amylase (8/5), hyperglycemia and vomiting (4 each), colitis (2). Hepatitis and hypophysitis were significantly higher in cohort A in induction. At median follow-up of 40 and 29 months respectively for cohort A and B, median RFS and OS have not been reached; 2-year relapse-free survival (RFS) rates are 80% (95% CI: 55-92), and 75% (50-89); 3-year RFS is 70% (45-85) in cohort A. There were 6 relapses in cohort A and 5 in cohort B, with 1 death from recurrence in the former. In pts with stage 4 MEL, the 3-yr RFS is 73% (46-88). Correlative analyses are ongoing. Conclusion: Adjuvant NIVO + IPI followed by maintenance NIVO in stage IIIC/IV MEL is feasible with promising efficacy in high-risk re-sected MEL compared to historical data. IPI (1 mg/kg Q6 weeks) plus fixed dose NIVO is being compared to NIVO alone as adjuvant MEL therapy in a randomized trial (NCT03068455).
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/043/CN-01451043/frame.html


Record #126 of 144
ID: CN-01363884
AU: Yuan Y
AU: Frankel P
AU: Synold T
AU: Yost S
AU: Lee P
AU: Waisman J
AU: Somlo G
AU: Hurria A
AU: Mortimer J
TI: Phase II Trial of the addition of pembrolizumab to letrozole and palbociclib in patients with metastatic estrogen receptor positive breast cancer who have stable disease on letrozole and palbociclib
SO: Cancer research. Conference: 39th annual CTRC-AACR san antonio breast cancer symposium. United states
YR: 2017
VL: 77
NO: 4 Supplement 1) (no pagination
XR: EMBASE 615274012
PT: Conference Abstract
KY: central nervous system metastasis; chemotherapy; clinical article; clinical trial; combination drug therapy; comparative effectiveness; controlled clinical trial; controlled study; *disease duration; drug combination; drug therapy; *estrogen receptor positive breast cancer; *female; heart disease; hormonal therapy; human; immune deficiency; interstitial lung disease; major surgery; metastatic breast cancer; pharmacokinetics; phase 2 clinical trial; postmenopause; probability; progression free survival; response evaluation criteria in solid tumors; safety; study design; systemic therapy; tuberculosis; endogenous compound; estrogen receptor; *letrozole; *palbociclib; *pembrolizumab; programmed death 1 ligand 1; steroid
DOI: 10.1158/1538-7445.SABCS16-OT2-01-03
AB: Background: The combination of palbociclib and letrozole has become the standard of care for patients with newly diagnosed estrogen receptor positive (ER+) metastatic breast cancer (MBC), with promising prolongation of progression free survival (PFS). However, nearly half of all patients achieved stable disease only after the first 6 months of therapy. Check-point inhibitor pembrolizumab was effective in ER+ MBC with a response rate of 13-17%, this study will evaluate the efficacy of adding pembrolizumab for patients with ER+ MBC who have achieved stable disease (SD) on letrozole and palbociclib. Trial Design:This is an open-label single institutional study. Patient will receive letrozole (2.5 mg) once a day and palbociclib (125 mg, 100 mg, or 75 mg as established tolerated dose) once a day for 3 weeks on and 1 week off. Pembrolizumab will be given at 200 mg IV every 3 weeks. Eligibility Criteria: Eligible patients must be postmenopausal women with ER+ MBC with measurable disease by RECIST1.1, ECOG performance status 0-1; must have received letrozole and palbociclib for at least 6 months, and have documented SD per RECIST 1.1. Up to3 lines of previous systemic therapy including endocrine therapy and/or chemotherapy are allowed. Patients are excluded if they had prior treatment with anti-PD1 or anti-PD-L1therapy, immunodeficiency; currently using systemic steroids active tuberculosis infection; major surgery within 28 days; active or untreated CNS metastases; history of interstitial lung disease; active infection requiring systemic therapy; or active cardiac disease. Specific Aims: The primary objective is to evaluate the objective response rate(ORR). The secondary objective is to determine the safety and tolerability of pembrolizumab plus the letrozole/palbociclib combination. We will use clinical benefit rate (CBR), duration of response (DOR), PFS, and OS to test the efficacy of this novel drug combination. Statistical Design: We will employ a three-at-risk design (modified rolling design) for the initial cohort of this Phase II study to insure the triplet is well-tolerated. This design permits only 3 patients to be a risk for DLT at any one time during the "safety lead-in" .When the first 6 patients have completed the observation period and treatment with <1 DLT, the safety lead-in for the triplet will be considered successful, and accrual will proceed to a total of 18 patients. Response (CR or PR by RECIST version 1.1) in patients who have demonstrated only SD on letrozole and palbociclib can be reasonably attributed to the addition of pembrolizumab. As a result, we set the probability of a response occurring without the addition of pembrolizumab as 3% or less. With 18 patients, a true response rate of 20% would result in at least 2 responders with 90% power and a type I error of 10%. With 18 patients, the response can be estimated with a 95% CI half-width of 23%. Target Accrual: 18.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/884/CN-01363884/frame.html


Record #127 of 144
ID: CN-01443175
AU: Balar AV
AU: Castellano D
AU: O'Donnell PH
AU: Grivas P
AU: Vuky J
AU: Powles T
AU: Plimack ER
AU: Hahn NM
AU: Wit R
AU: Pang L
AU: Savage MJ
AU: Perini RF
AU: Keefe SM
AU: Bajorin D
AU: Bellmunt J
TI: First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study
SO: The lancet. Oncology
YR: 2017
VL: 18
NO: 11
PG: 1483-1492
PM: PUBMED 28967485
PT: Clinical Trial, Phase II; Comparative Study; Journal Article; Multicenter Study; Randomized Controlled Trial
KY: Antibodies, Monoclonal, Humanized [adverse effects] [therapeutic use];Carcinoma, Transitional Cell [drug therapy] [mortality] [pathology];Cisplatin;Disease-Free Survival;Dose-Response Relationship, Drug;Drug Administration Schedule;Infusions, Intravenous;Internationality;Maximum Tolerated Dose;Neoplasm Invasiveness [pathology];Neoplasm Staging;Patient Safety;Prognosis;Prospective Studies;Single-Blind Method;Survival Analysis;Treatment Outcome;Urologic Neoplasms [drug therapy] [mortality] [pathology];Aged[checkword];Aged, 80 and over[checkword];Humans[checkword];Middle Aged[checkword]
DOI: 10.1016/S1470-2045(17)30616-2
AB: METHODS: In this multicentre, single-arm, phase 2 study (KEYNOTE-052), cisplatin-ineligible patients with advanced urothelial cancer who had not been previously treated with systemic chemotherapy were recruited from 91 academic medical centres in 20 countries. Enrolled patients received intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was objective response (the proportion of patients who achieved complete or partial response) in all patients and by PD-L1 expression status according to the Response Evaluation Criteria in Solid Tumors, version 1.1, as assessed by independent central review. PD-L1 expression was assessed in tumour and inflammatory cells from tumour biopsies provided at study entry. Activity and safety were analysed in all patients who received at least one dose of pembrolizumab (all-patients-treated population). This study is registered with ClinicalTrials.gov, number NCT02335424, and follow-up is ongoing.FINDINGS: Between Feb 24, 2015, and Aug 8, 2016, 374 patients were enrolled and 370 patients received at least one dose of pembrolizumab. 89 (24%, 95% CI 20-29) of 370 patients had a centrally assessed objective response, and as of Sept 1, 2016 (data cutoff), 74 (83%) of 89 responses were ongoing. Median follow-up was 5 months (IQR 3·0-8·6). A PD-L1-expression cutoff of 10% was associated with a higher frequency of response to pembrolizumab; 42 (38%, 95% CI 29-48) of 110 patients with a combined positive score of 10% or more had a centrally assessed objective response. The most common grade 3 or 4 treatment-related adverse events were fatigue (eight [2%] of 370 patients), alkaline phosphatase increase (five [1%]), colitis, and muscle weakness (both four [1%]). 36 (10%) of 370 patients had a serious treatment-related adverse event. 17 (5%) of 370 patients died from non-treatment-related adverse events associated with death, and one patient died from treatment-related adverse events (myositis in addition to grade 3 thyroiditis, grade 3 hepatitis, grade 3 pneumonia, and grade 4 myocarditis).INTERPRETATION: First-line pembrolizumab has antitumour activity and acceptable tolerability in cisplatin-ineligible patients with urothelial cancer, most of whom were elderly, had poor prognostic factors, or had serious comorbidities. In view of this result, pembrolizumab has become a new treatment option for patients who are cisplatin-ineligible or not suitable candidates for chemotherapy. Pembrolizumab in the first-line setting is being further assessed in the phase 3 KEYNOTE-361 trial (ClinicalTrials.gov, NCT02335424).FUNDING: Merck & Co.BACKGROUND: More than half of all patients with advanced urothelial cancer cannot receive standard, first-line cisplatin-based chemotherapy because of renal dysfunction, poor performance status, or other comorbidities. We assessed the activity and safety of first-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/175/CN-01443175/frame.html


Record #128 of 144
ID: CN-00721285
AU: Klein O
AU: Ebert LM
AU: Nicholaou T
AU: Browning J
AU: Russell SE
AU: Zuber M
AU: Jackson HM
AU: Dimopoulos N
AU: Tan BS
AU: Hoos A
AU: Luescher IF
AU: Davis ID
AU: Chen W
AU: Cebon J
TI: Melan-A-specific cytotoxic T cells are associated with tumor regression and autoimmunity following treatment with anti-CTLA-4
SO: Clinical cancer research
YR: 2009
VL: 15
NO: 7
PG: 2507-2513
PM: PUBMED 19318477
PT: Clinical Trial, Phase II; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't
KY: Antibodies, Monoclonal [therapeutic use];Antigens, Neoplasm [immunology];Antineoplastic Agents [therapeutic use];Autoimmunity;Cytotoxicity, Immunologic;Double-Blind Method;Exanthema [chemically induced] [immunology];Ipilimumab;Lymphocytes, Tumor-Infiltrating [immunology];MART-1 Antigen;Melanoma [diagnostic imaging] [drug therapy] [immunology];Neoplasm Proteins [immunology];Skin Neoplasms [diagnostic imaging] [drug therapy] [immunology];T-Lymphocytes, Cytotoxic [immunology];Tomography, X-Ray Computed;Humans[checkword]
DOI: 10.1158/1078-0432.CCR-08-2424
AB: EXPERIMENTAL DESIGN: We enrolled patients with advanced melanoma in a phase II study with ipilimumab. One of these patients experienced a complete remission of his tumor. The specificity and functional properties of CD8-positive T cells in his peripheral blood, in regressing tumor tissue, and at the site of an immune-mediated skin rash were investigated.RESULTS: Regressing tumor tissue was infiltrated with CD8-positive T cells, a high proportion of which were specific for Melan-A. The skin rash was similarly infiltrated with Melan-A-specific CD8-positive T cells, and a dramatic (>30-fold) increase in Melan-A-specific CD8-positive T cells was apparent in peripheral blood. These cells had an effector phenotype and lysed Melan-A-expressing tumor cells.CONCLUSIONS: Our results show that Melan-A may be a major target for both the autoimmune and antitumor reactions in patients treated with anti-CTLA-4, and describe for the first time the antigen specificity of CD8-positive T cells that mediate tumor rejection in a patient undergoing treatment with an anti-CTLA-4 antibody. These findings may allow a better integration of ipilimumab into other forms of immunotherapy.PURPOSE: Ipilimumab is a monoclonal antibody that blocks the immune-inhibitory interaction between CTL antigen 4 (CTLA-4) and its ligands on T cells. Clinical trials in cancer patients with ipilimumab have shown promising antitumor activity, particularly in patients with advanced melanoma. Often, tumor regressions in these patients are correlated with immune-related side effects such as dermatitis, enterocolitis, and hypophysitis. Although these reactions are believed to be immune-mediated, the antigenic targets for the cellular or humoral immune response are not known.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/285/CN-00721285/frame.html


Record #129 of 144
ID: CN-01397397
AU: Piulats JM
AU: Cruz-Merino L
AU: Garcia MTC
AU: Berrocal A
AU: Alonso-Carrion L
AU: Espinosa E
AU: Castro RL
AU: Rodriguez-Abreu D
AU: Fra PL
AU: Martin-Algarra S
TI: Phase II multicenter, single arm, open label study of nivolumab (NIVO) in combination with ipilimumab (IPI) as first line in adult patients (pts) with metastatic uveal melanoma (MUM): gEM1402 NCT02626962
SO: Journal of clinical oncology. Conference: 2017 annual meeting of the american society of clinical oncology, ASCO. United states
YR: 2017
VL: 35
NO: 15 Supplement 1) (no pagination
XR: EMBASE 617435688
PT: Conference Abstract
KY: adult; adverse drug reaction; anemia; cancer epidemiology; clinical article; clinical trial; consensus development; controlled clinical trial; controlled study; cutaneous melanoma; diarrhea; drug combination; drug therapy; drug withdrawal; female; follow up; human; hypertransaminasemia; male; *metastatic uvea melanoma; middle aged; multicenter study; *open study; overall survival; phase 2 clinical trial; progression free survival; response evaluation criteria in solid tumors; safety; side effect; Spain; systemic therapy; thyroiditis; toxicity; *ipilimumab; *nivolumab
AB: Background: Uveal melanoma is the most common primary intraocular malignant tumor in adults. Overall Survival (OS) at 5 years(y) is 62% due high incidence of liver metastasis, fatal within 4-9 months(m) from diagnosis. No standard treatment exists for MUM. NIVO+IPI combination has shown efficacy in metastatic cutaneous melanoma. However, MUM pts were excluded in these trials. Methods: GEM1402 is a phase-2 trial evaluating NIVO+IPI in untreated adult pts with MUM; is being conducted in 10 centers in Spain, leading by the Spanish Melanoma Group. Eligible pts had histologically-confirmed MUM, ECOG-PS 0/1, and no prior systemic treatment for MUM. Treatment consisted in NIVO (1mg/kg, iv, q3 weeks [wk]) and 4 doses of IPI (3mg/kg iv q3wk) followed by NIVO (3mg/kg q2wk) until progressive disease (PD), toxicity or withdrawal. Primary endpoint is OS and secondary progression free survival (PFS), Overall Response Rate (ORR) (per RECIST 1.1) and safety. Radiologic evaluations q6wk. Interim analysis (n = 19) was planned per protocol to assess safety and ORR. Intention to treat analysis includes pts with PD at first radiological evaluation. Safety population includes all pts receiving at least one dose of study treatment. Results: 19 pts enrolled from April to July 2016: Median age 62y (43y-82y), 63% male, liver M1 84% pts and extra-liver M1 42% pts, 31% elevated baseline LDH. 11 pts completed cycle 2 and 8 pts stopped after 1 dose (6 PD, 2 toxicity). Treatment-related adverse events were reported in 12 pts and lead to end of treatment in 2 pts. Grade >=3 toxicities were seen in 7 pts (36.8%): diarrhea, transaminitis, dermatological events, anemia, acute thyroiditis. All G3/4 were resolved following the toxicity guideline. One G5 acute thyroiditis related to NIVO+IPI was reported. ORR was observed in 15.8% and disease stabilization in 47.4%. With a median followup of 4.6m, PFS was 4.99m. Median OS was not reached at time of this analysis. Conclusions: Combination of NIVO+IPI is feasible for MUM. In this INTERIM ANALYSIS, ORR did not reach yet 20%, but PFS seems promising. The clinical trial is ongoing. Final results will be updated.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/397/CN-01397397/frame.html


Record #130 of 144
ID: CN-01397576
AU: Apolo AB
AU: Mortazavi A
AU: Stein MN
AU: Davarpanah NN
AU: Nadal RM
AU: Parnes HL
AU: Ning YM
AU: Francis DC
AU: Cordes LM
AU: Berniger MA
AU: Steinberg SM
AU: Agarwal PK
AU: Bagheri MH
AU: Nanda S
AU: Monk P
AU: Lancaster T
AU: Moore T
AU: Costello R
AU: Bottaro DP
AU: Pal SK
TI: A phase I study of cabozantinib plus nivolumab (CaboNivo) and cabonivo plus ipilimumab (CaboNivoIpi) in patients (pts) with refractory metastatic (m) urothelial carcinoma (UC) and other genitourinary (GU) tumors
SO: Journal of clinical oncology. Conference: 2017 annual meeting of the american society of clinical oncology, ASCO. United states
YR: 2017
VL: 35
NO: 15 Supplement 1) (no pagination
XR: EMBASE 617435323
PT: Conference Abstract
KY: adult; adverse drug reaction; aged; anorexia; aseptic meningitis; cell cycle G1 phase; clinical article; colitis; controlled clinical trial; *controlled study; diarrhea; disease course; drug combination; fatigue; female; germ cell tumor; human; hypertension; hyponatremia; hypophosphatemia; hypothyroidism; kidney carcinoma; male; nausea; neutropenia; *penis cancer; phase 1 clinical trial; prostate cancer; response evaluation criteria in solid tumors; Sertoli cell; side effect; squamous cell carcinoma; thrombocytopenia; toxicity; *transitional cell carcinoma; trophoblastic tumor; *tumor resistance; urachus; *cabozantinib; endogenous compound; *ipilimumab; *nivolumab; ribonuclease L; triacylglycerol lipase
AB: Background: We report the safety and clinical activity of the combination of CaboNivo and CaboNivoIpi in pts with mUC and other mGU tumors (NCT02496208). Methods: In this phase I trial 30 pts were treated in 4 dose levels (DL) for part 1 (CaboNivo) and 18 pts were treated in 3 DL for part 2 (CaboNivoIpi). Pts received Cabo PO daily and Nivo IV (part 1) with Ipi 1mg/kg x 4 doses q3wks (part 2). A mUC and a renal cell carcinoma (RCC) expansion cohort of CaboNivo has initiated enrollment. Tumors were assessed for overall response rate (ORR) q8wks (RECIST 1.1). Adverse events (AEs) were graded (G) by NCI-CTCAE v4.0. Results: From 7/22/15 to 12/31/2016, 48pts (CaboNivo N = 30; CaboNivoIpi N = 18) (mUC N = 19; bladder urachal N = 4; bladder squamous cell carcinoma (bSCC) N = 2; germ cell tumor (GCT) N = 4; castrate-resistant prostate cancer (CRPC) N = 9; RCC N = 2, sarcomatoid RCC N = 2, Sertoli cell N = 1, and trophoblastic tumor N = 1 were treated. Median age was 58 (range 35-77), 41 (85%) were male. Common treatment-related G1/2 AEs for CaboNivo: ALT increase (67%), fatigue (63%), diarrhea (60%), hypothyroidism (57%); CaboNivoIpi: fatigue (72%), diarrhea (61%), anorexia (61%); Grade 3 AEs for CaboNivo: hypertension (23%), neutropenia (17%), hypophosphatemia (13%), lipase increase (10%), fatigue (7%), aseptic meningitis (3%); CaboNivoIpi: hypophosphatemia (19%), hypertension (19%), fatigue (13%), hyponatremia (13%), nausea (13%), lipase increase (11%), colitis (6%); G4 CaboNivo: lipase increase (7%) thrombocytopenia (3%); CaboNivoIpi lipase increase (6%) There were no G5 toxicities, no DLTs. 43 pts were evaluable for response: ORR was 30% 13/43 [3 CR (2 mUC, 1 bSCC); 10 PRs (4 mUC, 2 penile, 1 sarcomatoid RCC, 1 urachal, 1 CRPC, 1 bSCC)]. ORR for CaboNivo 39% (mUC 44%); CaboNivoIpi 18% (mUC 29%). 11/13 (85%) of responses were ongoing at cutoff. Conclusions: CaboNivo and CaboNivoIpi combinations were well tolerated with no DLTs and have durable efficacy in mGU tumors particularly mUC. Rare tumors such as bSCC, urachal, and penile cancers demonstrated response to the combination. Larger cohorts of mUC and rare GU tumors are ongoing.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/576/CN-01397576/frame.html


Record #131 of 144
ID: CN-01397166
AU: Schadendorf D
AU: Ascierto PA
AU: Haanen JBAG
AU: Espinosa E
AU: Demidov LV
AU: Garbe C
AU: Lorigan P
AU: Gogas H
AU: Hoeller C
AU: Guren TK
AU: Rorive A
AU: Rutkowski P
AU: Munoz-Couselo E
AU: Dummer R
AU: Carneiro A
AU: Hospers G
AU: Grigoryeva EB
AU: Bhore R
AU: Nathan P
TI: Efficacy and safety of nivolumab (NIVO) in patients with advanced melanoma (MEL) and poor prognostic factors who progressed on or after ipilimumab (IPI): results from a phase II study (CheckMate 172)
SO: Journal of clinical oncology. Conference: 2017 annual meeting of the american society of clinical oncology, ASCO. United states
YR: 2017
VL: 35
NO: 15 Supplement 1) (no pagination
XR: EMBASE 617436130
PT: Conference Abstract
KY: adverse drug reaction; brain metastasis; cancer epidemiology; chemotherapy; clinical trial; controlled clinical trial; controlled study; data base; diarrhea; disease duration; drug therapy; *female; follow up; human; hypothyroidism; major clinical study; *male; *mucosal melanoma; multicenter study; overall survival; pharmacokinetics; phase 2 clinical trial; phase 3 clinical trial; progression free survival; pruritus; remission; *safety; side effect; toxicity; uvea; *ipilimumab; *nivolumab
AB: Background: In the phase III CheckMate 037 study, NIVO improved the objective response rate and progression-free survival with less toxicity vs chemotherapy in patients (pts) with MEL who progressed after prior IPI treatment. We report the first efficacy and updated safety data from pts with MEL in CheckMate 172, including those with rare melanoma subtypes (uveal, mucosal), brain metastases, or an ECOG performance status (PS) of 2. Methods: In this ongoing phase II, single-arm, open-label, multicenter study, pts with MEL who progressed on or after IPI were treated with NIVO 3 mg/kg Q2W for up to 2 years until progression or unacceptable toxicity (NCT02156804). We report efficacy and updated safety data from 734 treated pts with >=1 year of follow-up (database lock: November 2016). Results: Of 734 pts, 50% had LDH>ULN, 7% ECOG PS 2, 66% M1c disease, 15% a history of brain metastases, and 23% received >=3 prior therapies. Overall, 593 pts (81%) received more than 4 doses of NIVO. Overall, response rate at 12 weeks was 32%, with a complete response in 1% (Table). The 1-year overall survival (OS) rate was 63%. Any grade and grade 3/4 treatment-related adverse events (AEs) occurred in 66% and 17% of pts, respectively. Discontinuations due to treatment-related AEs occurred in 4% of pts. The most common treatment-related select (potentially immune-related) AEs were diarrhea (12%), hypothyroidism (9%), and pruritus (7%). Conclusions: CheckMate 172 is the largest study of NIVO efficacy and safety in pts with MEL who progressed on or after IPI. NIVO demonstrated a safety profile consistent with that of prior clinical trials. Efficacy outcomes were encouraging in some difficult-to-treat subgroups of pts with poor prognostic factors, such as mucosal melanoma and brain metastases. (Table Presented).
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/166/CN-01397166/frame.html


Record #132 of 144
ID: CN-01034354
AU: Wolchok JD
AU: Thomas L
AU: Bondarenko IN
AU: O'Day S
AU: Weber JS
AU: Garbe C
AU: Francis S
AU: Ibrahim RA
AU: Hoos A
AU: Robert C
TI: Phase III randomized study of ipilimumab (IPI) plus dacarbazine (DTIC) versus DTIC alone as first-line treatment in patients with unresectable stage III or IV melanoma
SO: Journal of clinical oncology
YR: 2011
VL: 29
NO: 18 SUPPL. 1
XR: EMBASE 70708008
PT: Journal: Conference Abstract
KY: *patient; *human; *melanoma; phase 3 clinical trial; arm; death; electrocorticography; rash; perforation; survival; follow up; hypertransaminasemia; gastrointestinal hemorrhage; log rank test; monotherapy; adjuvant therapy; survival rate; diarrhea; intestine perforation; hypophysitis; overall survival; health care quality; therapy; *dacarbazine; *ipilimumab; placebo; lactate dehydrogenase
AB: Background: IPI monotherapy (3mg/kg) improved overall survival (OS) in a phase III study of previously treated, unresectable or metastatic melanoma. Current study in 1st line metastatic melanoma evaluates combination of DTIC (a global standard of care) plus IPI. Methods: In this double-blind phase 3 study, patients (pts) with metastatic melanoma, ECOG PS 0/1, and no prior therapy for advanced disease, were randomized 1:1 to IPI (10 mg/kg) + DTIC (850 mg/m2) or placebo + DTIC (850 mg/m2) at Wks 1, 4, 7, 10 followed by DTIC q3 wks through Wk 22 (induction). Eligible pts received IPI or placebo q12 wks as maintenance. Primary endpoint was OS; 2-sided log-rank test was performed, stratified by baseline M stage and ECOG PS. Results: Of 502 pts, 56% had M1c disease, 40% elevated LDH, and 26% adjuvant therapy. 37% in IPI + DTIC and 65% in DTIC alone arms received 4 induction doses. A significant improvement in OS (HR=0.72; P=0.0009) and higher estimated 1, 2 and 3 yr survival rates were seen with IPI + DTIC (Table). 56% in IPI +DTIC (n=247) and 27% in DTIC alone (n=251) arms had grade 3/4 adverse events (AEs, regardless of attribution), including: elevated ALT (22% vs 1%); diarrhea (4% vs 0%); rash (1% vs 0%). No intestinal perforations or hypophysitis were noted. There were no drug-related deaths in IPI + DTIC and one in DTIC alone arm [gastrointestinal (GI) hemorrhage]. Conclusions: IPI (10mg/kg) + DTIC significantly improved OS in 1st line metastatic melanoma vs DTIC alone; durable survival and objective responses were noted in some pts after follow-up for up to 4yrs. Type of AEs was consistent with prior IPI studies; however, frequencies of some AEs differed with a higher transaminitis and lower diarrhea/colitis/ GI perforation rates than expected. No drug-related deaths were noted in IPI arm. OS benefit of IPI is confirmed in treatment-naive metastatic melanoma.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/354/CN-01034354/frame.html


Record #133 of 144
ID: CN-01060154
AU: Eggermont AM
AU: Chiarion-Sileni V
AU: Grob JJ
AU: Dummer R
AU: Wolchok JD
AU: Schmidt H
AU: Hamid O
AU: Robert C
AU: Ascierto PA
AU: Richards JM
AU: Lebbe C
AU: Ferraresi V
AU: Smylie M
AU: Weber JS
AU: Maio M
AU: Konto C
AU: Gurunath RK
AU: Pril V
AU: Suciu S
AU: Testori A
TI: Ipilimumab versus placebo after complete resection of stage III melanoma: initial efficacy and safety results from the EORTC 18071 phase III trial
SO: Journal of clinical oncology
YR: 2014
VL: 32
NO: 15 SUPPL. 1
XR: EMBASE 71526756
PT: Journal: Conference Abstract
KY: *melanoma; *safety; *human; *society; *oncology; *surgery; adjuvant therapy; risk; in-transit metastasis; lymph node metastasis; cutaneous melanoma; lymph node; follow up; algorithm; patient; recurrent disease; toxicity; hazard ratio; death; population; double blind procedure; intention to treat analysis; immune response; recurrence free survival; arm; *ipilimumab; *placebo; cytotoxic T lymphocyte antigen 4; human monoclonal antibody
AB: Background: Ipilimumab (Ipi), a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to augment antitumor immune responses, is an approved treatment for advanced melanoma. Here, we report the results of a phase III trial designed to evaluate Ipi as an adjuvant therapy for resected stage III melanoma at high risk of recurrence. Methods: In this randomized, double-blind trial, eligible patients (pts) included those >18 yrs of age who underwent complete resection of stage III cutaneous melanoma (excluding lymph node metastasis <1 mm or in-transit metastasis). 951 pts were randomized (stratified by stage and region) 1:1 to receive Ipi 10 mg/kg (n=475) or placebo (Pbo, n=476) every 3 wks for 4 doses, then every 3 mos for up to 3 yrs until completion, disease recurrence, or unacceptable toxicity. The primary endpoint was recurrence-free survival (RFS), analyzed on the intent-to-treat population. 512 RFS events (recurrence or death) were needed to provide 90% power to detect an Ipi vs Pbo hazard ratio (HR) of 0.75 (2-sided alpha=5%). Results: Overall, 20%/44%/36% of pts had stage IIIA/IIIB/IIIC, 42% ulcerated primary, and 58% macroscopic lymph node involvement. At a median follow-up of 2.7 yrs, Ipi significantly improved RFS vs Pbo. RFS benefit was consistent across subgroups (e.g., stage IIIB or IIIC, ulcerated primary). Most common grade 3/4 immune-related adverse events (irAEs) in the Ipi and Pbo arms were gastrointestinal (15.9% vs 0.8%), hepatic (10.6% vs 0.2%), and endocrine (8.5% vs 0%). Most irAEs were managed and resolved using established algorithms. Of 471 pts who started Ipi, 245 (52%) discontinued treatment due to AEs [182 (38.6%) within 12 weeks]; 5 (1.1%) died due to drug-related AEs. Conclusions: In this phase III trial, Ipi as adjuvant therapy provided a clinically and statistically significant improvement in RFS vs Pbo for pts with stage III melanoma at high risk of recurrence. AE profile was generally consistent with that observed in advanced melanoma, although with a higher incidence of endocrinopathies.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/154/CN-01060154/frame.html


Record #134 of 144
ID: CN-01060060
AU: Eggermont AM
AU: Chiarion-Sileni V
AU: Grob JJ
AU: Dummer R
AU: Wolchok JD
AU: Schmidt H
AU: Hamid O
AU: Robert C
AU: Ascierto PA
AU: Richards JM
AU: Lebbe C
AU: Ferraresi V
AU: Smylie M
AU: Weber JS
AU: Maio M
AU: Konto C
AU: Gurunath RK
AU: Pril V
AU: Suciu S
AU: Testori A
TI: Ipilimumab versus placebo after complete resection of stage III melanoma: initial efficacy and safety results from the eortc 18071 phase III trial
SO: Journal of clinical oncology
YR: 2014
VL: 32
NO: 18 SUPPL. 1
XR: EMBASE 71530716
PT: Journal: Conference Abstract
KY: *melanoma; *safety; *human; *society; *oncology; *surgery; adjuvant therapy; risk; in-transit metastasis; lymph node metastasis; cutaneous melanoma; lymph node; follow up; algorithm; patient; recurrent disease; toxicity; hazard ratio; death; population; double blind procedure; intention to treat analysis; immune response; recurrence free survival; arm; *ipilimumab; *placebo; cytotoxic T lymphocyte antigen 4; human monoclonal antibody
AB: Background: Ipilimumab (Ipi), a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to augment antitumor immune responses, is an approved treatment for advanced melanoma. Here, we report the results of a phase III trial designed to evaluate Ipi as an adjuvant therapy for resected stage III melanoma at high risk of recurrence. Methods: In this randomized, double-blind trial, eligible patients (pts) included those >18 yrs of age who underwent complete resection of stage III cutaneous melanoma (excluding lymph node metastasis <1 mm or in-transit metastasis). 951 pts were randomized (stratified by stage and region) 1:1 to receive Ipi 10 mg/kg (n=475) or placebo (Pbo, n=476) every 3 wks for 4 doses, then every 3 mos for up to 3 yrs until completion, disease recurrence, or unacceptable toxicity. The primary endpoint was recurrence-free survival (RFS), analyzed on the intent-to-treat population. 512 RFS events (recurrence or death) were needed to provide 90% power to detect an Ipi vs Pbo hazard ratio (HR) of 0.75 (2-sided alpha=5%). Results: Overall, 20%/44%/36% of pts had stage IIIA/IIIB/IIIC, 42% ulcerated primary, and 58% macroscopic lymph node involvement. At a median follow-up of 2.7 yrs, Ipi significantly improved RFS vs Pbo. RFS benefit was consistent across subgroups (e.g., stage IIIB or IIIC, ulcerated primary). Most common grade 3/4 immune-related adverse events (irAEs) in the Ipi and Pbo arms were gastrointestinal (15.9% vs 0.8%), hepatic (10.6% vs 0.2%), and endocrine (8.5% vs 0%). Most irAEs were managed and resolved using established algorithms. Of 471 pts who started Ipi, 245 (52%) discontinued treatment due to AEs [182 (38.6%) within 12 weeks]; 5 (1.1%) died due to drug-related AEs. Conclusions: In this phase III trial, Ipi as adjuvant therapy provided a clinically and statistically significant improvement in RFS vs Pbo for pts with stage III melanoma at high risk of recurrence. AE profile was generally consistent with that observed in advanced melanoma, although with a higher incidence of endocrinopathies.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/060/CN-01060060/frame.html


Record #135 of 144
ID: CN-01296031
AU: Herbst RS
AU: Martin-Liberal J
AU: Calvo E
AU: Isambert N
AU: Bendell JC
AU: Cassier P
AU: Perez-Gracia JL
AU: Yang J
AU: Rege J
AU: Mi G
AU: Ferry D
AU: Paz-Ares L
TI: Interim safety and clinical activity in patients with advanced NSCLC from a multi-cohort phase 1 study of ramucirumab (R) plus pembrolizumab (P)
SO: Annals of oncology. Conference: 41st european society for medical oncology congress, ESMO 2016. Denmark. Conference start: 20161007. Conference end: 20161011
YR: 2016
VL: 27
NO: no pagination
XR: EMBASE 613911670
PT: Journal: Conference Abstract
KY: adenocarcinoma; adrenal insufficiency; aged; asthenia; biliary tract cancer; clinical trial; colitis; controlled clinical trial; *controlled study; death; delirium; disease control; female; gastroesophageal junction; human; human tissue; hypertension; hyponatremia; immunohistochemistry; infusion related reaction; major clinical study; male; multiple cancer; *non small cell lung cancer; pharmacokinetics; phase 1 clinical trial; Pneumocystis pneumonia; response time; *safety; sepsis; smoking; squamous cell carcinoma; systemic therapy; transitional cell carcinoma; treatment duration; endogenous compound; isobutylene; *pembrolizumab; programmed death 1 ligand 1; programmed death 1 receptor; *ramucirumab; vasculotropin receptor 2
DOI: 10.1093/annonc/mdw435.34
AB: Background: Hallmarks of tumor growth include angiogenesis and immunosuppression. This is the first study to combine R (VEGFR2 antibody) with P (PD-1 antibody) to target both processes simultaneously. R and P have both shown clinical activity in multiple tumor types. Methods: This ongoing phase 1a/b study (NCT02443324) enrolled pts with gastric or gastroesophageal junction (G/GEJ), NSCLC, urothelial carcinoma (UC), or biliary tract cancer (BTC) following progression on systemic therapy. The primary end point was to define safety and tolerability of adding R to P; preliminary efficacy will be examined. The DAKO PD-L1 22C3 IHC pharmDx assay was used to classify PD-L1 as strong pos (>50%), weak pos (1-49%), or neg for NSCLC pts. Results: As of data cut-off on 23-June-2016, 91 pts have been enrolled with G/GEJ, UC or NSCLC and 66 (73%) experienced a treatment-related AE (TRAE). Fifteen (16%) pts experienced grade 3-4 TRAEs, most commonly colitis (4%) and hypertension (4%). One treatment related death occurred in the G/GEJ cohort (pneumocystis pneumonia and pulmonary sepsis). Pts with previously treated advanced NSCLC (n = 27) received R at 10 mg/kg on Day 1 with P 200 mg on Day 1 q3W. The median age was 65, 78% were male, 96% had a history of smoking, 78% had adenocarcinoma and 15% had squamous-cell carcinoma. Sixteen (59%) pts received >2 and 4 (15%) pts received >3 prior treatment regimens for their disease. Overall, 22 (81%) pts experienced a TRAE, most commonly asthenia (19%) and hypertension (19%). Two (7%) pts experienced grade 3-4 TRAEs (adrenal insufficiency, hyponatremia, delirium, and infusion related reaction). Eight (30%) pts had an objective response (1 unconfirmed). Responses occurred in both histological subtypes and all PD-L1 groups. The disease control rate was 85%. Median time to response was 1.45mo and median duration of response has not been reached. Median PFS has not been reached (95% CI, 3.98 to NR). Median duration of treatment is 6.8mo or longer. Objective responses were still ongoing in all responders. Conclusions: R + P generated no new safety signals and demonstrated promising clinical activity in pts with previously treated advanced NSCLC, including PD-L1 neg pts.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/031/CN-01296031/frame.html


Record #136 of 144
ID: CN-01267733
AU: Hodi FS
AU: Postow MA
AU: Chesney JA
AU: Pavlick AC
AU: Robert C
AU: Grossmann KF
AU: McDermott DF
AU: Linette GP
AU: Meyer N
AU: Giguere JK
AU: Agarwala S
AU: Shaheen MF
AU: Ernstoff MS
AU: Minor DR
AU: Salama AK
AU: Taylor MH
AU: Ott PA
AU: Jiang J
AU: Gagnier P
AU: Wolchok JD
TI: Overall survival in patients with advanced melanoma (MEL) who discontinued treatment with nivolumab (NIVO) plus ipilimumab (IPI) due to toxicity in a phase II trial (CheckMate 069)
SO: Journal of clinical oncology. Conference: 2016 annual meeting of the american society of clinical oncology, ASCO 2016. United states. Conference start: 20160603. Conference end: 20160607
YR: 2016
VL: 34
NO: no pagination
XR: EMBASE 611754187
PT: Journal: Conference Abstract
KY: adverse drug reaction; clinical trial; controlled study; *drug therapy; drug toxicity; drug withdrawal; endocrine system; follow up; human; major clinical study; *melanoma; *overall survival; post hoc analysis; progression free survival; remission; *toxicity; wild type; B Raf kinase; *ipilimumab; *nivolumab; placebo
AB: Background: Results from CheckMate 069 demonstrated a significant improvement in objective response rate (ORR) and progression-free survival (PFS) with NIVO+IPI vs IPI alone in treatment-naive patients (pts) with BRAF wild-type MEL (N Engl J Med 2015;372:2006). We evaluated overall survival (OS) in pts who discontinued treatment due to toxicity in this study. Methods: Pts (N = 142) were randomized 2:1 to receive NIVO 1 mg/kg plus IPI 3 mg/kg or IPI 3 mg/kg plus placebo every 3 weeks x 4 doses, followed by NIVO 3 mg/kg or placebo, respectively, every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was ORR in pts with BRAF wild-type tumors. Secondary and exploratory endpoints included PFS and OS. A post-hoc analysis was performed to evaluate OS in pts who discontinued treatment due to toxicity. Results: At a follow-up of 18 months, median OS in pts who discontinued treatment was not reached with NIVO+IPI and was 11.2 months for IPI alone (Table). Similar 18-month OS rates were observed in pts who discontinued NIVO+IPI due to toxicity and in the overall treatment group (Table). Among pts who discontinued NIVO+IPI, ORR was 68% (27% achieved a complete response). Median duration of response was not reached and 21 of 30 pts (70%) remain in response. Grade 3/4 treatment-related adverse events (AEs) occurred in 55% of pts in the NIVO+IPI group vs 22% with IPI, and led to discontinuation in 30% and 9% of pts, respectively. In pts who discontinued NIVO+IPI due to toxicity, resolution rates of treatment-related select AEs ranged from 89% to 100% (40% for endocrine AEs). Efficacy updates, including 2-year OS rates, will be presented for these pts. Conclusions: These data suggest that pts who discontinue NIVO+IPI treatment due to drug toxicity derive an OS benefit similar to that observed in the overall population.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/733/CN-01267733/frame.html


Record #137 of 144
ID: CN-01249558
AU: Chapman PB
AU: Sznol M
AU: Lao CD
AU: Gonzalez R
AU: Daniels GA
AU: Thompson JA
AU: Kudchadkar RR
AU: Sharfman WH
AU: Atkins MB
AU: Pavlick AC
AU: Infante JR
AU: Kim KB
AU: Weber JS
AU: Nair S
AU: Cowey L
AU: Lipson EJ
AU: Lee S
AU: Avila A
AU: Hodi S
TI: Safety data from an expanded access program (EAP) of nivolumab (NIVO) in combination with ipilimumab (IPI) in patients with advanced melanoma (MEL)
SO: Asia-pacific journal of clinical oncology. Conference: 43rd annual scientific meeting of the clinical oncological society of australia, COSA 2016. Australia. Conference start: 20161115. Conference end: 20161117
YR: 2016
VL: 12
PG: 119
XR: EMBASE 613440275
PT: Journal: Conference Abstract
KY: adult; adverse drug reaction; cancer epidemiology; clinical trial; *compassionate use; controlled clinical trial; controlled study; data base; death; drug combination; drug withdrawal; endocrine system; female; gastrointestinal tract; human; major clinical study; male; *melanoma; middle aged; pancreatitis; pharmacokinetics; phase 3 clinical trial; pneumonia; progression free survival; *safety; side effect; skin; *ipilimumab; *nivolumab
AB: Aims: In a phase 3 trial (CheckMate 067), NIVO and IPI combination showed longer progression-free survival in patients with MEL, although treatmentrelated grade 3/4 adverse events (AEs) were more common with NIVO+IPI than with NIVO or IPI. We report safety data from an EAP of NIVO+IPI in MEL patients (CheckMate 218). Methods: Patients received NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4, then NIVO 3 mg/kg Q2W until progression or up to 48 weeks. Assessments included incidence of treatment-related AEs and select (immune-related) AEs from the first 6 months (database lock: November 2015). Results: Among 252 patients, median age was 59 years, 68% were male, 29% received >1 prior therapy, 98% had ECOG PS of 0-1, 77% had stage IV MEL, and 50% had M1c. Median number of NIVO and IPI doses received were 3.5 (1-22) and 3 (1-4), respectively. After treatment with NIVO+IPI, 39% patients continued to receive NIVO alone. 106/252 pts (42%) are still on treatment. Treatment-related AEs of any grade were reported in 93% patients and grade 3/4 in 52%. The most common grade 3/4 select AEs were gastrointestinal (18%) and hepatic (14%). Less common were skin (3%), renal (2%), and endocrine (2%) AEs; pancreatitis and pneumonitis occurred at <1%. No treatment-related deaths were reported. Median time to onset for treatment-related grade 3/4 gastrointestinal and hepatic AEs was 6.6 (0.4- 16.1) and 8.6 (1.0-17.0) weeks, respectively. Treatment-related grade 3/4 AEs leading to discontinuation were reported in 23% patients. Conclusions: In this EAP, patient demographics were similar to those reported in CheckMate 067, except that there were patients in the EAP who received prior therapies for MEL. The overall safety profile was consistent with prior clinical trial.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/558/CN-01249558/frame.html


Record #138 of 144
ID: CN-01363797
AU: Goncalves A
AU: Bachelot T
AU: Lusque A
AU: Arnedos M
AU: Campone M
AU: Bieche I
AU: Lacroix L
AU: Pierron G
AU: Dalenc F
AU: Filleron T
AU: Sablin M-P
AU: Jimenez M
AU: Ferrero J-M
AU: Lefeuvre-Plesse C
AU: Bonnefoi H
AU: Attignon V
AU: Soubeyran I
AU: Jezequel P
AU: Commo F
AU: Andre F
TI: High-throughput genome analysis and therapeutic decision for patients with HER2-negative metastatic breast cancer: first feasibility and molecular results of the randomized phase II study SAFIR02 BREAST (UCBG-0105/1304)
SO: Cancer research. Conference: 39th annual CTRC-AACR san antonio breast cancer symposium. United states
YR: 2017
VL: 77
NO: 4 Supplement 1) (no pagination
XR: EMBASE 615274278
PT: Conference Abstract
KY: bone metastasis; cancer patient; chemotherapy; chi square test; controlled clinical trial; controlled study; death; disease course; doctor patient relation; drug therapy; endocrine system; exploratory research; *feasibility study; *female; *genome analysis; human; human tissue; major clinical study; *metastatic breast cancer; molecularly targeted therapy; oncogene N ras; organ culture; randomization; randomized controlled trial; response evaluation criteria in solid tumors; toxicity; triple negative breast cancer; tumor biopsy; 4 amino n [1 (4 chlorophenyl) 3 hydroxypropyl] 1 (7h pyrrolo[2,3 d]pyrimidin 4 yl) 4 piperidinecarboxamide; azd 4547; B Raf kinase; bicalutamide; BRCA1 protein; BRCA2 protein; durvalumab; endogenous compound; epidermal growth factor receptor; *epidermal growth factor receptor 2; fibroblast growth factor receptor 1; fibroblast growth factor receptor 2; hormone receptor; ion; K ras protein; mammalian target of rapamycin; olaparib; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; programmed death 1 ligand 1; protein kinase B; protein kinase LKB1; sapitinib; selumetinib; somatomedin C receptor; tuberin; vandetanib; vistusertib
DOI: 10.1158/1538-7445.SABCS16-PD1-08
AB: Background A genomic-driven therapeutic strategy in metastatic breast cancer (MBC) was recently demonstrated as feasible in the clinical practice, but its actual impact on patient outcome remains elusive. SAFIR02 study is an ongoing national multicentric phase II randomized trial evaluating targeted therapies matching specific genomic alterations (GA) administered as maintenance after objective response and/or stable disease obtained with chemotherapy in HER2-negative MBC patients. This analysis reports on feasibility of the procedure and the rate of identified actionable targets. Methods Eligible MBC patients (PS=0/1, first- or second-line of chemotherapy, HER2-negative/hormone receptor (HR)-negative or endocrine resistant HR-positive; measurable per RECIST 1.1; accessible to tumor biopsy; no bone metastases-only disease, no major organ dysfunction) were subjected to tumor biopsy for genomic analysis (CGH arrays, Affymetrix Cytoscan; NGS, Ion Torrent PGM, AmpliSeq, panel of around 50 genes). Actionable GA were identified and corresponding targeted therapies were proposed by a multidisciplinary tumor board (MTB). Patients received cytotoxic-based treatment at physician's choice and those with stable or responding disease after 6 to 8 cycles (or at least 4 if stopped for toxicity reason) and targetable GA, were offered randomization between targeted therapy or chemotherapy maintenance until progression or intolerance (main study). Since January 2016, an amendment was made to propose to patients without targetable alteration a randomization between anti-PD-L1 (MEDI4736) or standard chemotherapy maintenance (substudy). Results Between March 2014 and May 2016, 457 patients have been enrolled at 21 centers. Genomic analyses could not be obtained in 107 cases (23%) due to either biopsy failure (n= 40; 9%) or low cellularity (n=67; 14%). Of the 307 patients reviewed by the MTB, 197 (64%) had an actionable GA, including PIK3CA-PIK3CB-PIK3R1 (n=51), FGF4 or FGFR1/2 (n= 42), BRCA1/2 (n=15), AKT1/2/3 (n=13), BRAF/KRAS/NRAS (n=13), HER2/3 (n=10), NF1-FRS2 (n=10), MTOR-RPTOR-TSC2 (n=8), PTEN (n=7), STK11 (n=7), IGF1R (n=7), EGFR (n=5). Therapeutic proposals by MTB included AZD5363 (n=71), AZD4547 (n=42), AZD2014 (n=23), selumetinib (n=23), olaparib (n=16), AZD8931 (n=15), vandetanib (n=5), bicalutamide (n=2). In an exploratory analysis involving 157 patients, the rate of targeted therapy proposal by MTB markedly differed between triple-negative patients (TNBC; 24 of 48, 50%) and HER2-negative/HR-positive patients (92 of 109, 84%; p=6.14. 10<sup>-6</sup>, Chi-2 test). At the time of the analysis, 85 patients have been randomized (main study, 68; substudy, 17). Causes of randomization failure (n=108) included disease progression (n=45) or death (n=25), non-eligibility criteria (n=27), patient/physician's decision (n=11). Conclusion A large number of patients had identified targetable GA. Of note, the rate of targeted therapeutic proposal was significantly lower in TNBC than in HER2-negative/HR-positive patients. Rapidly progressing disease may impede ultimate randomization.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/797/CN-01363797/frame.html


Record #139 of 144
ID: CN-01377788
AU: Goncalves A
AU: Bachelot T
AU: Lusque A
AU: Arnedos M
AU: Campone M
AU: Bieche I
AU: Lacroix L
AU: Pierron G
AU: Dalenc F
AU: Filleron T
AU: Sablin M-P
AU: Jimenez M
AU: Ferrero J-M
AU: Lefeuvre-Plesse C
AU: Bonnefoi H
AU: Attignon V
AU: Soubeyran I
AU: Jezequel P
AU: Commo F
AU: Andre F
TI: High-throughput genome analysis and therapeutic decision for patients with HER2-negative metastatic breast cancer: first feasibility and molecular results of the randomized phase II study SAFIR02 BREAST (UCBG-0105/1304)
SO: Cancer research. Conference: 39th annual CTRC-AACR san antonio breast cancer symposium. United states
YR: 2017
VL: 77
NO: 4 Supplement 1) (no pagination
XR: EMBASE 616063713
PT: Conference Abstract
KY: bone metastasis; cancer patient; chemotherapy; chi square test; clinical trial; controlled clinical trial; controlled study; death; disease course; doctor patient relation; drug therapy; endocrine system; exploratory research; *feasibility study; *female; *genome analysis; human; human tissue; major clinical study; *male; *metastatic breast cancer; molecularly targeted therapy; oncogene N ras; organ culture; randomization; randomized controlled trial; response evaluation criteria in solid tumors; toxicity; triple negative breast cancer; tumor biopsy; 4 amino n [1 (4 chlorophenyl) 3 hydroxypropyl] 1 (7h pyrrolo[2,3 d]pyrimidin 4 yl) 4 piperidinecarboxamide; azd 4547; B Raf kinase; bicalutamide; BRCA1 protein; BRCA2 protein; durvalumab; endogenous compound; epidermal growth factor receptor; *epidermal growth factor receptor 2; fibroblast growth factor receptor 1; fibroblast growth factor receptor 2; hormone receptor; ion; K ras protein; mammalian target of rapamycin; olaparib; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; programmed death 1 ligand 1; protein kinase B; protein kinase LKB1; sapitinib; selumetinib; somatomedin C receptor; tuberin; vandetanib; vistusertib
DOI: 10.1158/1538-7445.SABCS16-PD1-08
AB: Background A genomic-driven therapeutic strategy in metastatic breast cancer (MBC) was recently demonstrated as feasible in the clinical practice, but its actual impact on patient outcome remains elusive. SAFIR02 study is an ongoing national multicentric phase II randomized trial evaluating targeted therapies matching specific genomic alterations (GA) administered as maintenance after objective response and/or stable disease obtained with chemotherapy in HER2-negative MBC patients. This analysis reports on feasibility of the procedure and the rate of identified actionable targets. Methods Eligible MBC patients (PS=0/1, first-or second-line of chemotherapy, HER2-negative/hormone receptor (HR)-negative or endocrine resistant HR-positive; measurable per RECIST 1.1; accessible to tumor biopsy; no bone metastases-only disease, no major organ dysfunction) were subjected to tumor biopsy for genomic analysis (CGH arrays, Affymetrix Cytoscan; NGS, Ion Torrent PGM, AmpliSeq, panel of around 50 genes). Actionable GA were identified and corresponding targeted therapies were proposed by a multidisciplinary tumor board (MTB). Patients received cytotoxic-based treatment at physician's choice and those with stable or responding disease after 6 to 8 cycles (or at least 4 if stopped for toxicity reason) and targetable GA, were offered randomization between targeted therapy or chemotherapy maintenance until progression or intolerance (main study). Since January 2016, an amendment was made to propose to patients without targetable alteration a randomization between anti-PD-L1 (MEDI4736) or standard chemotherapy maintenance (substudy). Results Between March 2014 and May 2016, 457 patients have been enrolled at 21 centers. Genomic analyses could not be obtained in 107 cases (23%) due to either biopsy failure (n= 40; 9%) or low cellularity (n=67; 14%). Of the 307 patients reviewed by the MTB, 197 (64%) had an actionable GA, including PIK3CA-PIK3CB-PIK3R1 (n=51j, FGF4 or FGFR1/2 (n= 42), BRCA1/2 (n=15), AKT1/2/3 (n=13), BRAF/KRAS/NRAS (n=13), HER2/3 (n=10), NF1-FRS2 (n=10), MTOR-RPTOR-TSC2 (n=8), PTEN (n=7), STK11 (n=7), IGF1R (n=7), EGFR (n=5). Therapeutic proposals by MTB included AZD5363 (n=71), AZD4547 (n=42), AZD2014 (n=23), selumetinib (n=23), olaparib (n=16), AZD8931 (n=15), vandetanib (n=5), bicalutamide (n=2). In an exploratory analysis involving 157 patients, the rate of targeted therapy proposal by MTB markedly differed between triple-negative patients (TNBC; 24 of 48, 50%) and HER2-negative/HR-positive patients (92 of 109, 84%; p=6.14. 10"<sup>6</sup>, Chi-2 test). At the time of the analysis, 85 patients have been randomized (main study, 68; substudy, 17). Causes of randomization failure (n=108) included disease progression (n=45) or death (n=25), non-eligibility criteria (n=27), patient/physician's decision (n=11). Conclusion A large number of patients had identified targetable GA. Of note, the rate of targeted therapeutic proposal was significantly lower in TNBC than in HER2-negative/HR-positive patients. Rapidly progressing disease may impede ultimate randomization.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/788/CN-01377788/frame.html


Record #140 of 144
ID: CN-01028208
AU: Thomas L
AU: Wolchok JD
AU: Garbe C
AU: Lebbe C
AU: Bondarenko I
AU: Rodrigues K
AU: Konto C
AU: Chin KM
AU: Francis S
AU: Robert C
TI: Safety of ipilimumab in patients (pts) with untreated, advanced melanoma alive beyond 2 years: results from a phase III study
SO: Journal of clinical oncology
YR: 2012
VL: 30
NO: 15 SUPPL. 1
XR: EMBASE 71004862
PT: Journal: Conference Abstract
KY: *human; *safety; *patient; *melanoma; *society; *oncology; rash; pruritus; phase 3 clinical trial; population; overall survival; T lymphocyte; survival rate; exposure; hypopigmentation; risk assessment; *ipilimumab; dacarbazine; placebo; cytotoxic T lymphocyte antigen 4; human monoclonal antibody
AB: Background: Ipilimumab (IPI), a fully human monoclonal antibody, blocks cytotoxic T-lymphocyte antigen-4 to potentiate an antitumor T-cell response. In a phase 3 study (CA184-024) of previously untreated pts with stage III or IV melanoma, IPI + dacarbazine (DTIC) significantly improved overall survival (OS) vs. DTIC alone (Robert et al. NEJM 2011). We now report safety data of IPI in pts from this study alive > 2 yrs from study initiation. Methods: Pts with untreated advanced melanoma, were randomized to IPI (10 mg/kg) + DTIC (850 mg/m<sup>2</sup>) or placebo + DTIC (850 mg/m<sup>2</sup>) given at Wks 1, 4, 7, 10 followed by DTIC q 3 wks through Wk 22. Eligible pts (stable disease or better) received IPI or placebo q 12 wks as maintenance. In the population of subjects alive >2 yrs, the appearance of immune-related adverse events (irAEs) occurring after 2 yrs was evaluated. Within this group was a subset of subjects still receiving IPI dosing after 2 yrs; safety for these pts was evaluated to assess the impact of prolonged IPI exposure. Results: In the IPI + DTIC group 68 (28%) pts survived > 2 yrs compared to 44 (18%) in the DTIC alone group; 11 of the 68 continued IPI dosing for 2 yrs. Safety assessment beyond 2 yrs showed 3 of the 11 pts had any grade irAEs; 1 pt had grade 3/4 rash, pruritus while low grade events included rash, pruritus (n=2) and elevated ALT / AST (n=1). Overall among all 68 pts in the Ipi + DTIC group, there were 5 pts (7.4%) with any grade irAEs including grade 3/4 rash, pruritus (n=1) and low grade rash (n=3), pruritus (n=2), skin hypopigmentation, and elevated ALT / AST (n=1). No gastrointestinal or endocrine events (any grade) were observed. Conclusions: In Study 024, IPI + DTIC treatment improved OS pts with untreated, advanced melanoma with higher survival rates in the IPI + DTIC group at 1 yr (47.3% vs. 36.3%), 2 yrs (28.5% vs. 17.9%), and 3 yrs (20.8% vs. 12.2%) (HR 0.72, p<0.001). The safety profile of pts alive after 2 yrs suggests that treatment with IPI + DTIC is associated with low rates of irAEs in these pts. Furthermore, in pts still receiving active IPI treatment beyond 2 yrs, the safety profile appears to be consistent and medically manageable using established safety guidelines (Weber, Oncologist 2007).
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/208/CN-01028208/frame.html


Record #141 of 144
ID: CN-01361845
AU: Pan K
AU: Gonsalves C
AU: Eschelman D
AU: Orloff M
AU: Sato T
TI: Ipilimumab (IPI) and immunoembolization (IE) for treatment of metastatic uveal melanoma (UM) hepatic metastases
SO: Journal of vascular and interventional radiology. Conference: world conference on interventional oncology, WCIO 2016. United states
YR: 2016
VL: 27
NO: 6
PG: e90
XR: EMBASE 614675154
PT: Conference Abstract
KY: adverse drug reaction; artificial embolization; cancer epidemiology; cell cycle G1 phase; clinical article; controlled clinical trial; controlled study; diarrhea; drug combination; drug therapy; human; hypothyroidism; infusion; Kaplan Meier method; liver cell culture; *liver metastasis; liver toxicity; male; median survival time; *metastatic uvea melanoma; nomenclature; nuclear magnetic resonance imaging; overall survival; progression free survival; pruritus; randomized controlled trial; rash; remission; response evaluation criteria in solid tumors; retrospective study; side effect; tumor volume; adjuvant; cytotoxic T lymphocyte antigen 4; endogenous compound; ethiodized oil; gelfoam; granulocyte macrophage colony stimulating factor; interleukin 2; *ipilimumab
DOI: 10.1016/j.jvir.2016.04.006
AB: Objective: Previous reports have shown IE to be an effective treatment for UM hepatic metastases. The purpose of this study is to determine if the effectiveness of IE can be enhanced with adjuvant systemic Ipi, an anticytotoxic T-lymphocyte-associated protein-4 antibody. Methods: A retrospective review was performed of 26 patients (mean, 58 years [range 31 - 78]; 12 men) with UM hepatic metastases (<20% hepatic tumor burden) treated with systemic Ipi and IE between 2012 and 2015. Ipi was given at standard dosing and schedule (3mg/kg every 21 days, 4 infusions). Lobar IE was used as a first-line liver directed therapy and performed every 4 weeks with 1,500 mcg of granulocyte-macrophage-colony-stimulating factor emulsified in ethiodized oil, and 2 million IU interleukin-2, followed by gelfoam embolization. Best radiologic response (RECIST) for hepatic/extrahepatic metastases was determined using contrast- enhanced CT and MRI after every 2 IE treatments. Overall survival (OS) and progression-free survival of liver (PFS-L) and extrahepatic (PFS-S) metastases were evaluated with Kaplan-Meier analysis. Common Terminology Criteria for Adverse Events v4.0 was used to assess toxicity. Results: Twenty-six patients underwent 132 IEs (median 4; range 2-15). Eight patients (31%) had pre-existing extrahepatic metastases. Ten patients developed extrahepatic metastases (median, 7.3 months; range 2.8-25.0) during treatment. Median survival has not been reached, however, 12 patients (46%) expired during the observation period (median OS, 16.5 months; range 2.5-31.1); (95% CI, 6.4 to 22.5 months). Partial response with regression of hepatic metastases was observed in 3 patients (11.5%). Median PFS-L was 5.9 months (range, 1.7-12.2); (95% CI, 2.8 to 7.6 months). Median PFS-S was 6.9 months (range, 1.7-25.0); (95% CI, 3.5 to 12.8 months). No regression of extrahepatic metastases was observed in any patient. Most common toxicities noted included diarrhea >G2 (19.2%); rash/pruritus >G2, (19.2%); and hypothyroidism >G2, 4/26 (15.3%). Hepatic toxicity was observed in 4 patients: G1 (3.8%), G2 (7.7%) and G3 (3.8%). No G4/G5 toxicity was seen. Conclusions: Combination treatment with IE and Ipi is a feasible approach for patients with metastatic UM. However, compared to historical controls, the addition of Ipi did not appear to prolong PFS-L and PFS-S. In addition, toxicities not previously seen with IE alone were observed. Therefore, initial results do not support the use of Ipi in patients undergoing IE. However, future randomized studies comparing combination therapy versus IE alone may be warranted.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/845/CN-01361845/frame.html


Record #142 of 144
ID: CN-01363820
AU: Paoletti C
AU: Regan MM
AU: Liu MC
AU: Marcom PK
AU: Hart LL
AU: Smith JW
AU: Tedesco KL
AU: Amir E
AU: Krop IE
AU: DeMichele AM
AU: Goodwin PJ
AU: Block M
AU: Aung K
AU: Cannell EM
AU: Darga EP
AU: Baratta PJ
AU: Brown ME
AU: McCormack RT
AU: Hayes DF
TI: Circulating tumor cell number and CTC-endocrine therapy index predict clinical outcomes in ER positive metastatic breast cancer patients: results of the COMETI Phase 2 trial
SO: Cancer research. Conference: 39th annual CTRC-AACR san antonio breast cancer symposium. United states
YR: 2017
VL: 77
NO: 4 Supplement 1) (no pagination
XR: EMBASE 615274204
PT: Conference Abstract
KY: adult; adverse drug reaction; apoptosis; biopsy; *cancer patient; *cell count; *circulating tumor cell; clinical article; *clinical outcome; clinical trial; controlled clinical trial; controlled study; disease course; female; gene expression regulation; *hormonal therapy; human; human tissue; *metastatic breast cancer; middle aged; pharmacokinetics; randomized controlled trial; safety; side effect; toxicity; triple negative breast cancer; TUNEL assay; atezolizumab; biological marker; placebo
DOI: 10.1158/1538-7445.SABCS16-P1-01-01
AB: Resistance to standard taxane-based chemotherapy is common in triple-negative breast cancer (TNBC). Mutations and gene amplifications in the MAPK pathway that upregulate MAPK signaling are present in many TNBC tumors. Upregulation of the MAPK signaling pathway can result in degradation of the pro-apoptotic protein BIM and upregulation of anti-apoptotic proteins, including BCL-2, BCL-XL, and MCL-1, thus promoting cell survival and desensitizing tumor cells to the pro-apoptotic effects of taxane chemotherapy. Updated data on clinical safety and efficacy are presented along with biomarker data evaluating the effects of treatment on induction of apoptosis. The COLET study (ClinicalTrials.gov ID, NCT02322814; EudraCT number, 2014-002230-32) consisted of a safety run-in (n~12) followed by a blinded 1:1 randomized expansion stage (n~90) to C + P or placebo (PBO) + P. The safety stage is complete and the randomized stage is enrolling pts. Two additional cohorts investigating the effect of adding atezolizumab will be recruiting and are out of scope of this submission. Pts in cohort I were treated with P 80 mg/m<sup>2</sup> on days 1, 8, and 15 and C/PBO 60 mg/day on days 3-23 of each 28-day cycle until disease progression or unacceptable toxicity. Gene expression and apoptotic index were measured by RNA-Seq and TUNEL staining, respectively, to assess the biologic activity of C + P. Sixteen women (median age, 55.5 years) were enrolled in the safety run-in stage. At data snapshot (April 22, 2016), all 16 pts had received >1 dose of study treatment. Median time on treatment was 116 days (range, 7-336) for C and 84 days (range, 0-351) for P. Fifteen (94%) pts had >1 adverse event (AE); 5 (31%) pts had grade 1/2 AEs and 10 (63%) pts had grade 3 AEs (Table). No pts experienced grade 4-5 AEs. Among the 16 safety run-in patients, responses to date include partial response (PR; n = 8 [50.0%]), stable disease (SD, n = 4 [25.0%]), and progressive disease (n = 2 [12.5%]), as well as 2 pts with no postbaseline tumor assessment. Six pts maintained a PR at ~20 weeks and three maintained a PR at >40 weeks. To date, matched pre- and ontreatment biopsies were evaluable for 2 pts, 1 with a PR and 1 with SD. In the patient who attained a PR, increased expression of pro-apoptosis genes, including BIM, was observed; but this was not seen in the patient experiencing SD. The PR patient also had an increase in apoptotic index. Updated biomarker data will be reported. This is the first study to evaluate C + P in TNBC. The safety profile of C + P is consistent with that of known safety profiles. Efficacy and safety will be further evaluated in the ongoing randomized stage.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/820/CN-01363820/frame.html


Record #143 of 144
ID: CN-01296217
AU: Boutros C
AU: Mateus C
AU: Routier E
AU: Chouaib S
AU: Libenciuc C
AU: Reigneau M
AU: Girault I
AU: Caramella C
AU: Hibat S
AU: Vagner S
AU: Tao YG
AU: Chaput N
AU: Adam J
AU: Soria J-C
AU: Eggermont A
AU: Deutsch E
AU: Robert C
TI: A dose escalation phase 1 study of radiotherapy (RT) in combination with anti-cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody ipilimumab (Ipi) in patients (pts) with metastatic melanoma
SO: Annals of oncology. Conference: 41st european society for medical oncology congress, ESMO 2016. Denmark. Conference start: 20161007. Conference end: 20161011
YR: 2016
VL: 27
NO: no pagination
XR: EMBASE 613911210
PT: Journal: Conference Abstract
KY: adverse drug reaction; anemia; antineoplastic activity; asthenia; blood; clinical article; clinical trial; colitis; controlled clinical trial; *controlled study; death; diarrhea; disease course; DRESS syndrome; drug combination; drug therapy; fever; hepatitis; human; maximum tolerated dose; *metastatic melanoma; national health organization; nausea and vomiting; nomenclature; pharmacokinetics; phase 1 clinical trial; radiotherapy; safety; side effect; thyroid disease; toxicity; translational research; *cytotoxic T lymphocyte antigen 4; endogenous compound; *ipilimumab
DOI: 10.1093/annonc/mdw379.12
AB: Background: A synergy between RT and anti-CTLA-4 monoclonal antibody has been demonstrated preclinically and preliminary clinical data suggest that it could be due to an abscopal effect of RT. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD) and safety profile of RT combined with Ipi in pts with metastatic melanoma. Methods: A 3 + 3 dose escalation design was used with 9, 15, 18 and 24 Gy of RT (in 3 fractions) at week 4 combined with 10 mg/kg Ipi (every 3 weeks for 4 doses). Pts with evidence of clinical benefit at week 12 were eligible for maintenance Ipi at 10 mg/kg every 12 weeks starting at week 24 until severe toxicity or disease progression based on immune-related response criteria (irRC). The adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for AEs, version 4.0. Tumors and blood were collected before and during treatment for translational research analyses. Results: 19 pts received Ipi between August 2011 and July 2015. 9 pts received the 4 doses of Ipi and 2 pts received maintenance Ipi (1 and 2 cycles respectively). All pts received the combined RT at week 4 in 3 fractions. All pts presented at least one AE of any grade. The most common AEs were asthenia, diarrhea, fever, nausea and vomiting. Grade 3 AEs occurred in 8 pts. They included colitis (n = 3), hepatitis (n = 2), anemia (n = 2), asthenia (n = 1), thyroid disorders (n = 1) and nausea/vomiting (n = 1). 9 pts discontinued the study owing to treatment-related adverse events including colitis (n = 6), hepatitis (n = 2) and DRESS syndrome (Drug Rash with Eosinophilia and systemic syndrome) (n = 1). DLT occurred in 2/6 pts in the cohort receiving 15 Gy. No drug-related death occurred. According to irRC, 4 partial responses (ORR: 21%) and 4 stable diseases were observed at week 24. The MTD was 9 Gy. One pt out of 12 treated in the 9 Gy cohort presented a DLT (grade 3 colitis). Conclusions: When combined with Ipi at 10 mg/kg, in the present design, the MTD of RT was 9 Gy. This combination appears to be associated with antitumor activity. Translational research results will be available and presented.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/217/CN-01296217/frame.html


Record #144 of 144
ID: CN-01060157
AU: Jamal R
AU: Belanger K
AU: Friedmann JE
AU: Ayoub J-PM
AU: Cocolakis E
AU: Kazemi S
AU: Dionne J
AU: Lambert C
AU: Le HB
AU: Kempen L
AU: Spatz A
AU: Lapointe R
AU: Miller WH
TI: A randomized phase II study of ipilimumab (IPI) with carboplatin and paclitaxel (CP) in patients with unresectable stage III or IV metastatic melanoma (MM)
SO: Journal of clinical oncology
YR: 2014
VL: 32
NO: 15 SUPPL. 1
XR: EMBASE 71526672
PT: Journal: Conference Abstract
KY: *human; *society; *patient; *metastatic melanoma; *oncology; *phase 2 clinical trial; toxicity; arm; safety; therapy; immunocompetent cell; overall survival; follow up; wild type; epidemiology; colitis; antineoplastic activity; neoplasm; cancer of unknown primary site; melanoma; disease course; febrile neutropenia; disease control; death; electrolyte disturbance; bone marrow suppression; infection; anemia; thrombocytopenia; endocrine disease; rash; *ipilimumab; *paclitaxel; *carboplatin; biological marker; monoclonal antibody; cytotoxic T lymphocyte antigen 4; tumor antigen; vemurafenib; steroid
AB: Background: MM has been one of the most treatment-resistant human malignancies. Recently, IPI, a fully human anti-CTLA4 monoclonal antibody has been widely approved for patients (pts) with MM on the basis of increased overall survival (OS). CP is one of few therapies available to pts with BRAF wild type MM that is progressing rapidly. We hypothesized that cytoreduction by CP might both provide time for IPI response, as well as expose immune cells to tumor antigens. In addition to safety and anti-tumor activity, immune biomarker studies were performed. Methods: Thirty pts with no prior treatment or one BRAF targeted regimen were randomized in a 1:2 ratio to either concurrent (arm A) or sequential (arm B) CP (AUC6 + 175mg/m<sup>2</sup> x 5) with IPI (3mg/kg x 4) given every 3 weeks either concurrently or delayed by one week. Tumor assessments were conducted at week 8, 16 and 24. Results: We enrolled 24 cutaneous, 2 mucosal, 3 ocular and 1 unknown primary melanoma. Median age was 55 years and 6 of 8 BRAF mutated pts previously received vemurafenib. Twenty-five pts (83%) received all 5 cycles of CP while 28 pts (93%) completed IPI induction. Two pts died prior to week 16 of disease progression, while 3 patients discontinued CP because of toxicity. Overall median follow-up was 24 weeks (8-24). Response rates (RR) and disease control rates (DCR) for 14 evaluable patients at 24 weeks were 21.4% and 42.9% by mWHO, and 35.7% and 64.3% by irRC, respectively. There were no treatment-related deaths on trial. Grade 3-4 AEs regardless of causality were seen in 63% of pts. CP-related Grade 3-4 AEs were found in 47% of pts in the form of hepatotoxity, electrolyte imbalances, myelosuppression and infections. Grade 3-4 anemia occurred in 3 pts while thrombocytopenia occurred in 2 pts. The rate of febrile neutropenia was 7% (2/30). Seventeen per cent (5/30) of patients received steroids for an immune-related (ir) AE: 2 pts with Grade 3 colitis, 2 pts with Grade 2 endocrinopathy, and 1 pt with Grade 2 rash. Conclusions: Safety results suggest manageable toxicity when CP is added to IPI, with most patients completing the full course of treatment. Updated ORR, DCR, 6 month OS, and immune biomarker studies will be presented.
US: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/157/CN-01060157/frame.html