Journal article
A phase I study of single-agent perifosine for recurrent or refractory pediatric CNS and solid tumors
PloS one, Vol.12(6), pp.e0178593-e0178593
06/05/2017
DOI: 10.1371/journal.pone.0178593
PMCID: PMC5459446
PMID: 28582410
Abstract
The PI3K/Akt/mTOR signaling pathway is aberrantly activated in various pediatric tumors. We conducted a phase I study of the Akt inhibitor perifosine in patients with recurrent/refractory pediatric CNS and solid tumors. This was a standard 3+ 3 open-label dose-escalation study to assess pharmacokinetics, describe toxicities, and identify the MTD for single-agent perifosine. Five dose levels were investigated, ranging from 25 to 125 mg/m(2)/day for 28 days per cycle. Twenty-three patients (median age 10 years, range 4 -18 years) with CNS tumors (DIPG [n = 3], high-grade glioma [n = 5], medulloblastoma [n = 2], ependymoma [n = 3]), neuroblastoma (n = 8), Wilms tumor (n = 1), and Ewing sarcoma (n = 1) were treated. Only one DLT occurred (grade 4 hyperuricemia at dose level 4). The most common grade 3 or 4 toxicity at least possibly related to perifosine was neutropenia (8.7%), with the remaining grade 3 or 4 toxicities (fatigue, hyperglycemia, fever, hyperuricemia, and catheter-related infection) occurring in one patient each. Pharmacokinetics was dose-saturable at doses above 50 mg/m(2)/day with significant inter-patient variability, consistent with findings reported in adult studies. One patient with DIPG (dose level 5) and 4 of 5 patients with highgrade glioma (dose levels 2 and 3) experienced stable disease for two months. Five subjects with neuroblastoma (dose levels 1 through 4) achieved stable disease which was prolonged (>= 11 months) in three. No objective responses were noted. In conclusion, the use of perifosine was safe and feasible in patients with recurrent/refractory pediatric CNS and solid tumors. An MTD was not defined by the 5 dose levels investigated. Our RP2D is 50 mg/m(2)/day.
Details
- Title: Subtitle
- A phase I study of single-agent perifosine for recurrent or refractory pediatric CNS and solid tumors
- Creators
- Oren J. Becher - Memorial Sloan Kettering Cancer CenterNathan E. Millard - Memorial Sloan Kettering Cancer CenterShakeel Modak - Memorial Sloan Kettering Cancer CenterBrian H. Kushner - Memorial Sloan Kettering Cancer CenterSofia Haque - Cornell UniversityIvan Spasojevic - Duke Medical CenterTanya M. Trippett - Memorial Sloan Kettering Cancer CenterStephen W. Gilheeney - Memorial Sloan Kettering Cancer CenterYasmin Khakoo - Memorial Sloan Kettering Cancer CenterDavid C. Lyden - Cornell UniversityKevin C. De Braganca - Memorial Sloan Kettering Cancer CenterJill M. Kolesar - University of Wisconsin–MadisonJason T. Huse - Memorial Sloan Kettering Cancer CenterKim Kramer - Memorial Sloan Kettering Cancer CenterNai-Kong V. Cheung - Mem Sloan Kettering Canc Ctr, Dept Pediat, 1275 York Ave, New York, NY 10021 USAIra J. Dunkel - Cornell University
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.12(6), pp.e0178593-e0178593
- Publisher
- Public Library Science
- DOI
- 10.1371/journal.pone.0178593
- PMID
- 28582410
- PMCID
- PMC5459446
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Number of pages
- 15
- Grant note
- P30 CA008748 / Memorial Sloan Kettering Cancer Center Core Aeterna Zentaris P30CA008748 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 06/05/2017
- Academic Unit
- Pharmacy; Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984696546202771
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