Phase I/II Trial of Temsirolimus and Perifosine for Recurrent or Progressive Malignant Gliomas
I. Define the maximum tolerated dose of temsirolimus in combination with perifosine in
patients with recurrent or progressive malignant glioma who are not taking enzyme-inducing
anti-epileptic drugs. (Phase I) II. Determine the efficacy of this regimen, as measured by
6-month progression-free survival and radiographic response rates, in these patients. (Phase
I. Characterize the safety profile of this regimen in these patients. II. Estimate the
median overall and progression-free survival of patients treated with this regimen.
III. Explore the association of pre-treatment molecular phenotype with response to
IV. Explore molecular effects during treatment, including PI3K/AKT/mTOR/S6K and RAS/MEK/ERK
signaling, proliferation, and apoptosis.
OUTLINE: This is a phase I dose-escalation study of temsirolimus, followed by a phase II
study. Patients are stratified according to study phase (I vs II), prior treatment with
direct VEGF/VEGFR inhibitor (yes vs no), histologically documented malignant glioma (yes vs
no), histology at study registration (glioblastoma [GBM] [GBM, gliosarcoma, GBM with
oligodendroglioma features, giant cell GBM] vs anaplastic glioma [anaplastic astrocytoma,
anaplastic oligodendroglioma, anaplastic oligoastrocytoma, or high-grade glioma not
otherwise specified]), enrollment in phase II surgical substudy (yes vs no), presence of
measurable disease (yes vs no), and molecular profile of baseline tissue (enriched [PDGF] vs
non-enriched [EGFR, NF1, or undetermined/other]).
PHASE I: Patients receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22 and oral
perifosine once daily on days 1-28. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity.
PHASE II: Patients receive temsirolimus (at the maximum-tolerated dose determined in phase
I) and perifosine as in phase I. Some patients may also undergo cytoreductive surgery.
Archived and resected tumor tissue samples are collected for correlative laboratory studies,
including molecular analysis of PI3K/AKT/mTOR/S6K and RAS/MEK/ERK signaling, proliferation,
and apoptosis by IHC, western blot, FISH, and TUNEL, and other molecular studies.
After completion of study therapy, patients are followed up every 3 months.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
MTD defined as the dose at which fewer than one-third of patients experience a DLT according to CTCAE version 4.0 (Phase I)
Memorial Sloan-Kettering Cancer Center
United States: Food and Drug Administration
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