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.
Highlights
Aberrant activation of the pathway defined by phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin has been observed across a wide range of neoplastic diseases [1,2,3,4]
Evidence suggests that oncogenic alterations in the PI3K/Akt/mammalian target of rapamycin (mTOR) signaling cascade are associated with inferior prognoses in many pediatric cancers, including neuroblastoma, rhabdomyosarcoma, high-grade glioma, and medulloblastoma [8,9,10,11]
Secondary aims were to (1) determine whether pharmacokinetic serum levels of perifosine correlate with toxicity, (2) assess preliminary data on the efficacy of perifosine monotherapy, Phase I perifosine in children with central nervous system (CNS) and solid tumors and (3) determine whether molecular features of the tumor were associated with likelihood of response
Summary
Aberrant activation of the pathway defined by phosphatidylinositol 3-kinase (PI3K), Akt (protein kinase B), and mammalian target of rapamycin (mTOR) has been observed across a wide range of neoplastic diseases [1,2,3,4]. Rearrangements, and amplifications in this pathway lead to disordered control of cell growth and survival and are among the most frequently encountered genetic lesions in human cancers. They are estimated to be present in up to 30% of human malignancies, including pediatric solid and central nervous system (CNS) tumors [5,6,7]. Phosphorylated Akt in turn activates a number of cellular proteins and inactivates tuberous sclerosis complex 2 (TSC2) resulting in downstream activation of mTOR complex 1 (mTORC1) with a subsequent increase in cell growth, proliferation and survival. Aberrant stimulation of the PI3K/Akt/mTOR pathway can occur via a variety of mechanisms, including activating mutations in Ras, Akt, and receptor tyrosine kinases as well as loss of function of the inhibitory regulator phosphatase and tensin homologue (PTEN) [16,17,18]
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