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

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.

ALK2 inhibitors display beneficial effects in preclinical models of ACVR1 mutant diffuse intrinsic pontine glioma

“…Identification of co-segregation of ACVR1 mutation and dysregulation in the PI3K pathway potentially points the way towards combinatorial approaches which may be tested in this subgroup of tumours. The Akt inhibitor perifosine was one of the earliest compounds evaluated in DIPG models 40 and translated to the clinic 41 ; sensitivity to the mTOR inhibitor TAK228 (MLN0128) 42 and dual PI3K-mTOR inhibitor BKM120 36 have also recently been reported and an ongoing stratified medicine trial in DIPG patients includes everolimus as one of three investigational arms (NCT02233049). The genetic dependence and preclinical efficacy demonstrated here with inhibitors of ALK2 raises the prospect of another class of compounds entering the clinical trials toolkit for children with this devastating disease.…”

AKT as a Therapeutic Target for Cancer

“…In addition, perifosine markedly decreased the level of pAKT beginning at 10 minutes and lasting up to 24 hours and moderately decreased the level of pS6 from 1 to 24 hours in rats (55). This compound was demonstrated to have manageable or no toxicity from 25 to 125 mg/m 2 /day in a phase I clinical study (NCT00776867) in recurrent/refractory pediatric central nervous system and solid tumor patients (56). Perifosine combined with sorafenib showed promising activity against Hodgkin lymphoma in a phase I clinical study (NCT00019656; ref.…”

Randomized, placebo‐controlled, phase 3 study of perifosine combined with bortezomib and dexamethasone in patients with relapsed, refractory multiple myeloma previously treated with bortezomib

“…Nevertheless, the PI3K/Akt signaling cascade remains a rational target of interest in MM [29][30][31] and multiple other cancers [32][33][34][35], with several Akt inhibitors in ongoing clinical development either alone or in combination regimens [32,[36][37][38][39], and preclinical data demonstrating the validity of this mechanism of action with perifosine and other agents both in hematological malignancies and solid tumors [40][41][42][43].…”