Record #1 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/273/CN-01332273/frame.html


Record #2 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/503/CN-01336503/frame.html


Record #3 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/539/CN-01294539/frame.html


Record #4 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/875/CN-01251875/frame.html


Record #5 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/922/CN-01303922/frame.html


Record #6 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/987/CN-01162987/frame.html


Record #7 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/977/CN-01377977/frame.html


Record #8 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/310/CN-01295310/frame.html


Record #9 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/797/CN-01333797/frame.html


Record #10 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/308/CN-01295308/frame.html


Record #11 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/794/CN-01362794/frame.html


Record #12 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/775/CN-01363775/frame.html


Record #13 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/454/CN-01378454/frame.html


Record #14 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/018/CN-01250018/frame.html


Record #15 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/497/CN-01173497/frame.html


Record #16 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/151/CN-01335151/frame.html


Record #17 of 92
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;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: 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.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.
US: http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/270/CN-01077270/frame.html


Record #18 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/361/CN-01295361/frame.html


Record #19 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/002/CN-01365002/frame.html


Record #20 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/555/CN-01250555/frame.html


Record #21 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/560/CN-01250560/frame.html


Record #22 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/321/CN-01295321/frame.html


Record #23 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/066/CN-01329066/frame.html


Record #24 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/117/CN-01303117/frame.html


Record #25 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/787/CN-01115787/frame.html


Record #26 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/118/CN-01367118/frame.html


Record #27 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/869/CN-01293869/frame.html


Record #28 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/127/CN-01303127/frame.html


Record #29 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/771/CN-01360771/frame.html


Record #30 of 92
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];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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/922/CN-00962922/frame.html


Record #31 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/208/CN-01247208/frame.html


Record #32 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/871/CN-01293871/frame.html


Record #33 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/336/CN-01295336/frame.html


Record #34 of 92
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;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 BRAF(V600) 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.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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/860/CN-01289860/frame.html


Record #35 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/372/CN-01294372/frame.html


Record #36 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/203/CN-01028203/frame.html


Record #37 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/094/CN-01303094/frame.html


Record #38 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/096/CN-01303096/frame.html


Record #39 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/109/CN-01296109/frame.html


Record #40 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/658/CN-01286658/frame.html


Record #41 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/337/CN-01244337/frame.html


Record #42 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/137/CN-01303137/frame.html


Record #43 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/457/CN-01378457/frame.html


Record #44 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/252/CN-01294252/frame.html


Record #45 of 92
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;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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/337/CN-01297337/frame.html


Record #46 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/841/CN-01295841/frame.html


Record #47 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/855/CN-01363855/frame.html


Record #48 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/077/CN-01296077/frame.html


Record #49 of 92
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. Conference: 13th Annual Meeting of the Japanese Society of Medical Oncology Sapporo Japan. Conference Start: 20150716 Conference End: 20150718. Conference Publication: (var.pagings)
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/396/CN-01174396/frame.html


Record #50 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/785/CN-01362785/frame.html


Record #51 of 92
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 2013328166
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/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]
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<sub>10</sub> IU/mL on at least 2 consecutive visits; 3 (10 mg/kg) achieved a >4 log<sub>10</sub> 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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/535/CN-00906535/frame.html


Record #52 of 92
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: UNLABELLED: 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.TRIAL REGISTRATION: ClinicalTrials.gov NCT00703469.
US: http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/938/CN-01050938/frame.html


Record #53 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/112/CN-01287112/frame.html


Record #54 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/514/CN-01300514/frame.html


Record #55 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/602/CN-01375602/frame.html


Record #56 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/364/CN-01294364/frame.html


Record #57 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/138/CN-01303138/frame.html


Record #58 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/995/CN-01303995/frame.html


Record #59 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/640/CN-01335640/frame.html


Record #60 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/025/CN-01250025/frame.html


Record #61 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/308/CN-01296308/frame.html


Record #62 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/917/CN-01129917/frame.html


Record #63 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/325/CN-01294325/frame.html


Record #64 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/703/CN-01020703/frame.html


Record #65 of 92
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: 1330-8
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/036/CN-01211036/frame.html


Record #66 of 92
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. Conference: 16th World Congress on Cancers of the Skin 2016. Austria. Conference Start: 20160831. Conference End: 20160903
YR: 2016
VL: 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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/986/CN-01212986/frame.html


Record #67 of 92
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: 4327-36
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/585/CN-01105585/frame.html


Record #68 of 92
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: 522-30
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;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: 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.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.
US: http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/654/CN-01081654/frame.html


Record #69 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/690/CN-01295690/frame.html


Record #70 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/709/CN-01364709/frame.html


Record #71 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/904/CN-01251904/frame.html


Record #72 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/994/CN-01333994/frame.html


Record #73 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/466/CN-01378466/frame.html


Record #74 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/563/CN-01249563/frame.html


Record #75 of 92
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;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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/685/CN-01335685/frame.html


Record #76 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/262/CN-01339262/frame.html


Record #77 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/884/CN-01363884/frame.html


Record #78 of 92
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];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 DESIGNWe 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.RESULTSRegressing 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.CONCLUSIONSOur 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.PURPOSEIpilimumab 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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/285/CN-00721285/frame.html


Record #79 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/862/CN-01295862/frame.html


Record #80 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/354/CN-01034354/frame.html


Record #81 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/154/CN-01060154/frame.html


Record #82 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/060/CN-01060060/frame.html


Record #83 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/031/CN-01296031/frame.html


Record #84 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/733/CN-01267733/frame.html


Record #85 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/558/CN-01249558/frame.html


Record #86 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/797/CN-01363797/frame.html


Record #87 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/788/CN-01377788/frame.html


Record #88 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/208/CN-01028208/frame.html


Record #89 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/845/CN-01361845/frame.html


Record #90 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/820/CN-01363820/frame.html


Record #91 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/217/CN-01296217/frame.html


Record #92 of 92
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://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/157/CN-01060157/frame.html