A phase I study of perifosine with temsirolimus for recurrent pediatric solid tumors
dc.contributor.author | Becher, Oren J. | |
dc.contributor.author | Gilheeney, Stephen W. | |
dc.contributor.author | Khakoo, Yasmin | |
dc.contributor.author | Lyden, David C. | |
dc.contributor.author | Haque, Sofia | |
dc.contributor.author | Braganca, Kevin C. | |
dc.contributor.author | Kolesar, Jill M. | |
dc.contributor.author | Huse, Jason T. | |
dc.contributor.author | Modak, Shakeel | |
dc.contributor.author | Wexler, Leonard H. | |
dc.contributor.author | Kramer, Kim | |
dc.contributor.author | Spasojevic, Ivan | |
dc.contributor.author | Dunkel, Ira J. | |
dc.date.accessioned | 2017-06-16T20:09:43Z | |
dc.date.available | 2018-08-28T15:28:59Z | en |
dc.date.issued | 2017-07 | |
dc.identifier.citation | Becher, Oren J.; Gilheeney, Stephen W.; Khakoo, Yasmin; Lyden, David C.; Haque, Sofia; Braganca, Kevin C.; Kolesar, Jill M.; Huse, Jason T.; Modak, Shakeel; Wexler, Leonard H.; Kramer, Kim; Spasojevic, Ivan; Dunkel, Ira J. (2017). "A phase I study of perifosine with temsirolimus for recurrent pediatric solid tumors." Pediatric Blood & Cancer 64(7): n/a-n/a. | |
dc.identifier.issn | 1545-5009 | |
dc.identifier.issn | 1545-5017 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/137302 | |
dc.description.abstract | BackgroundThe PI3K/AKT/mTOR pathway is aberrantly activated in many pediatric solid tumors including gliomas and medulloblastomas. Preclinical data in a pediatric glioma model demonstrated that the combination of perifosine (AKT inhibitor) and temsirolimus (mTOR inhibitor) is more potent at inhibiting the axis than either agent alone. We conducted this study to assess pharmacokinetics and identify the maximum tolerated dose for the combination.ProcedureWe performed a standard 3+3 phase I, open‐label, dose‐escalation study in patients with recurrent/refractory pediatric solid tumors. Four dose levels of perifosine (25–75 mg/m2/day) and temsirolimus (25–75 mg/m2 IV weekly) were investigated.ResultsTwenty‐three patients (median age 8.5 years) with brain tumors (diffuse intrinsic pontine glioma [DIPG] n = 8, high‐grade glioma n = 6, medulloblastoma n = 2, ependymoma n = 1), neuroblastoma (n = 4), or rhabdomyosarcoma (n = 2) were treated. The combination was generally well tolerated and no dose‐limiting toxicity was encountered. The most common grade 3 or 4 toxicities (at least possibly related) were thrombocytopenia (38.1%), neutropenia (23.8%), lymphopenia (23.8%), and hypercholesterolemia (19.0%). Pharmacokinetic findings for temsirolimus were similar to those observed in the temsirolimus single‐agent phase II pediatric study and pharmacokinetic findings for perifosine were similar to those in adults. Stable disease was seen in 9 of 11 subjects with DIPG or high‐grade glioma; no partial or complete responses were achieved.ConclusionsThe combination of these AKT and mTOR inhibitors was safe and feasible in patients with recurrent/refractory pediatric solid tumors. | |
dc.publisher | Wiley Periodicals, Inc. | |
dc.subject.other | AKT | |
dc.subject.other | mTOR | |
dc.subject.other | perifosine | |
dc.subject.other | phase I clinical trials | |
dc.subject.other | temsirolimus | |
dc.title | A phase I study of perifosine with temsirolimus for recurrent pediatric solid tumors | |
dc.type | Article | en_US |
dc.rights.robots | IndexNoFollow | |
dc.subject.hlbsecondlevel | Pediatrics | |
dc.subject.hlbtoplevel | Health Sciences | |
dc.description.peerreviewed | Peer Reviewed | |
dc.description.bitstreamurl | https://deepblue.lib.umich.edu/bitstream/2027.42/137302/1/pbc26409.pdf | |
dc.description.bitstreamurl | https://deepblue.lib.umich.edu/bitstream/2027.42/137302/2/pbc26409_am.pdf | |
dc.identifier.doi | 10.1002/pbc.26409 | |
dc.identifier.source | Pediatric Blood & Cancer | |
dc.identifier.citedreference | Pitter KL, Galban CJ, Galban S, et al. Perifosine and CCI 779 co‐operate to induce cell death and decrease proliferation in PTEN‐intact and PTEN‐deficient PDGF‐driven murine glioblastoma. PLoS ONE. 2011; 6: e14545. | |
dc.identifier.citedreference | Chandarlapaty S, Sawai A, Scaltriti M, et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell. 2011; 19: 58 – 71. | |
dc.identifier.citedreference | Martini M, De Santis MC, Braccini L, Gulluni F, Hirsch E. PI3K/AKT signaling pathway and cancer: an updated review. Ann Med. 2014; 46: 372 – 383. | |
dc.identifier.citedreference | Zarghooni M, Bartels U, Lee E, et al. Whole‐genome profiling of pediatric diffuse intrinsic pontine gliomas highlights platelet‐derived growth factor receptor alpha and poly (ADP‐ribose) polymerase as potential therapeutic targets. J Clin Oncol. 2010; 28: 1337 – 1344. | |
dc.identifier.citedreference | Shukla N, Ameur N, Yilmaz I, et al. Oncogene mutation profiling of pediatric solid tumors reveals significant subsets of embryonal rhabdomyosarcoma and neuroblastoma with mutated genes in growth signaling pathways. Clin Cancer Res. 2012; 18: 748 – 757. | |
dc.identifier.citedreference | Parsons DW, Li M, Zhang X, et al. The genetic landscape of the childhood cancer medulloblastoma. Science. 2011; 331: 435 – 439. | |
dc.identifier.citedreference | Paugh BS, Zhu X, Qu C, et al. Novel oncogenic PDGFRA mutations in pediatric high‐grade gliomas. Cancer Res. 2013; 73: 6219 – 6229. | |
dc.identifier.citedreference | Mosse YP, Laudenslager M, Longo L, et al. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature. 2008; 455: 930 – 935. | |
dc.identifier.citedreference | Jones DT, Hutter B, Jager N, et al. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet. 2013; 45: 927 – 932. | |
dc.identifier.citedreference | Opel D, Poremba C, Simon T, Debatin KM, Fulda S. Activation of AKT predicts poor outcome in neuroblastoma. Cancer Res. 2007; 67: 735 – 745. | |
dc.identifier.citedreference | Thorarinsdottir HK, Santi M, McCarter R, et al. Protein expression of platelet‐derived growth factor receptor correlates with malignant histology and PTEN with survival in childhood gliomas. Clin Cancer Res. 2008; 14: 3386 – 3394. | |
dc.identifier.citedreference | Castellino RC, Barwick BG, Schniederjan M, et al. Heterozygosity for Pten promotes tumorigenesis in a mouse model of medulloblastoma. PLoS ONE. 2010; 5: e10849. | |
dc.identifier.citedreference | Hambardzumyan D, Becher OJ, Rosenblum MK, Pandolfi PP, Manova‐Todorova K, Holland EC. PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev. 2008; 22: 436 – 448. | |
dc.identifier.citedreference | Li Z, Oh DY, Nakamura K, Thiele CJ. Perifosine‐induced inhibition of AKT attenuates brain‐derived neurotrophic factor/TrkB‐induced chemoresistance in neuroblastoma in vivo. Cancer. 2011; 117: 5412 – 5422. | |
dc.identifier.citedreference | van Blitterswijk WJ, Verheij M. Anticancer mechanisms and clinical application of alkylphospholipids. Biochim Biophys Acta. 2013; 1831: 663 – 674. | |
dc.identifier.citedreference | Fensterle J, Aicher B, Seipelt I, Teifel M, Engel J. Current view on the mechanism of action of perifosine in cancer. Anticancer Agents Med Chem. 2014; 14: 629 – 635. | |
dc.identifier.citedreference | Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011; 12: 21 – 35. | |
dc.identifier.citedreference | Geoerger B, Kieran MW, Grupp S, et al. Phase II trial of temsirolimus in children with high‐grade glioma, neuroblastoma and rhabdomyosarcoma. Eur J Cancer. 2012; 48: 253 – 262. | |
dc.identifier.citedreference | O’Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates AKT. Cancer Res. 2006; 66: 1500 – 1508. | |
dc.identifier.citedreference | Wan X, Harkavy B, Shen N, Grohar P, Helman LJ. Rapamycin induces feedback activation of AKT signaling through an IGF‐1R‐dependent mechanism. Oncogene. 2007; 26: 1932 – 1940. | |
dc.identifier.citedreference | Carracedo A, Ma L, Teruya‐Feldstein J, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K‐dependent feedback loop in human cancer. J Clin Invest. 2008; 118: 3065 – 3074. | |
dc.identifier.citedreference | Woo EW, Messmann R, Sausville EA, Figg WD. Quantitative determination of perifosine, a novel alkylphosphocholine anticancer agent, in human plasma by reversed‐phase liquid chromatography‐electrospray mass spectrometry. J Chromatogr B Biomed Sci Appl. 2001; 759: 247 – 257. | |
dc.identifier.citedreference | Therasse P, Arbuck S, Eisenhauer E, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000; 92: 205 – 216. | |
dc.identifier.citedreference | Brodeur GM, Pritchard J, Berthold F, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993; 11: 1466 – 1477. | |
dc.identifier.citedreference | Figg WD, Monga M, Headlee D, et al. A phase I and pharmacokinetic study of oral perifosine with different loading schedules in patients with refractory neoplasms. Cancer Chemother Pharmacol. 2014; 74: 955 – 967. | |
dc.identifier.citedreference | Spunt SL, Grupp SA, Vik TA, et al. Phase I study of temsirolimus in pediatric patients with recurrent/refractory solid tumors. J Clin Oncol. 2011; 29: 2933 – 2940. | |
dc.identifier.citedreference | Fouladi M, Perentesis JP, Phillips CL, et al. A phase I trial of MK‐2206 in children with refractory malignancies: a Children’s Oncology Group study. Pediatr Blood Cancer. 2014; 61: 1246 – 1251. | |
dc.identifier.citedreference | Kaley TJ, Pentsova E, Omuro AMP, et al. Phase I trial of temsirolimus and perifosine for recurrent or progressive malignant glioma [abstract]. J Clin Oncol. 2013; 31: 2095. | |
dc.identifier.citedreference | Van Ummersen L, Binger K, Volkman J, et al. A phase I trial of perifosine (NSC 639966) on a loading dose/maintenance dose schedule in patients with advanced cancer. Clin Cancer Res. 2004; 10: 7450 – 7456. | |
dc.identifier.citedreference | Cole DE, Lester‐McCully CM, Widemann BC, Warren KE. Plasma and cerebrospinal fluid pharmacokinetics of the AKT inhibitor, perifosine, in a non‐human primate model. Cancer Chemother Pharmacol. 2015; 75: 923 – 928. | |
dc.identifier.citedreference | Nguyen LN, Ma D, Shui G, et al. Mfsd2a is a transporter for the essential omega‐3 fatty acid docosahexaenoic acid. Nature. 2014; 509: 503 – 506. | |
dc.owningcollname | Interdisciplinary and Peer-Reviewed |
Files in this item
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.