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Clinical Trial
. 2017 Jun 5;12(6):e0178593.
doi: 10.1371/journal.pone.0178593. eCollection 2017.

A phase I study of single-agent perifosine for recurrent or refractory pediatric CNS and solid tumors

Oren J Becher  1   2 , Nathan E Millard  1 , Shakeel Modak  1 , Brian H Kushner  1 , Sofia Haque  3   4 , Ivan Spasojevic  5 , Tanya M Trippett  1 , Stephen W Gilheeney  1 , Yasmin Khakoo  1   6 , David C Lyden  1   6 , Kevin C De Braganca  1 , Jill M Kolesar  7 , Jason T Huse  8 , Kim Kramer  1 , Nai-Kong V Cheung  1 , Ira J Dunkel  1   6
Affiliations
Clinical Trial

A phase I study of single-agent perifosine for recurrent or refractory pediatric CNS and solid tumors

Oren J Becher et al. PLoS One. .

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/m2/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/m2/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 high-grade 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/m2/day.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Diagram of study participants.
Fig 2
Fig 2. Steady state plasma concentration of perifosine at weeks 2, 3, and 4.
Concentrations were plotted for each study subject whose samples were available for calculation (patients 1–22) across the dose groups; enumerated individual subject trace; grey, semi-transparent thick line represents the arithmetic mean of the plasma concentration at the corresponding time-point for the given dose group. Saturable dose exposure above 50 mg/m2/day dose is evident albeit large inter-patient variability, consistent with findings reported in previous adult studies.
Fig 3
Fig 3. Correlation plot of perifosine steady state plasma concentration versus daily dose (actually administered).
Error bars represent single standard deviation; enumerated dose groups. Saturable dose exposure above 50 mg/m2/day is observed in pediatric patients.
See this image and copyright information in PMC

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