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Phase I/II Trial of Temsirolimus and Perifosine for Recurrent or Progressive Malignant Gliomas

Phase 1/Phase 2
18 Years
Open (Enrolling)
Adult Anaplastic Astrocytoma, Adult Anaplastic Oligodendroglioma, Adult Diffuse Astrocytoma, Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Adult Mixed Glioma, Adult Oligodendroglioma, Recurrent Adult Brain Tumor

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Trial Information

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.

Inclusion Criteria:

- Phase I and II: Histologically confirmed intracranial malignant glioma*, including
one of the following cell types:

- Glioblastoma

- Anaplastic astrocytoma

- Anaplastic oligodendroglioma

- Anaplastic oligoastrocytoma (also called anaplastic mixed gliomas)

- Malignant glioma not otherwise specified (NOS)

- Phase I: Histologically confirmed low-grade (WHO grade II) gliomas (e.g., low-grade
astrocytoma, low-grade oligodendroglioma, low-grade oligoastrocytoma [mixed gliomas],
or low-grade glioma NOS) allowed provided there is radiographic evidence of malignant
transformation by MRI or CT scan but histologic confirmation of high-grade
(malignant) transformation would not be otherwise undertaken for routine clinical
care (phase I)

- Unstained slides or tissue blocks available from ≥ 1 prior surgery

- Frozen tissue requested if available

- Mandatory for phase II

- Must have received prior radiotherapy and temozolomide

- Must have unequivocal evidence of tumor progression by baseline MRI or CT scan (in
comparison to a prior scan) OR have recently undergone resection for
recurrent/progressive disease

- Must be on a stable or decreasing dose of corticosteroids for ≥ 5 days before
baseline MRI/CT scan (and PET scan for patients enrolled in the phase II portion
of the study)

- Stable corticosteroids are not required for patients undergoing surgery on
the surgical substudy portion of the phase II study

- Measurable disease not required for patients who recently underwent resection as long
as progressive disease led to the surgery and the histology of the most recent
surgery documented recurrent/progressive/persistent malignant glioma

- If cytoreductive surgery is planned for tumor recurrence at the time of
enrollment, such patients may be eligible for the surgical substudy (Phase II
only), taking temsirolimus and perifosine pre-operatively and then re-initiating
such therapy after recovering from the effects of surgery

- Karnofsky performance status 60-100%

- Life expectancy > 8 weeks

- WBC ≥ 2,000/mm^3

- ANC ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Hemoglobin ≥ 10 g/dL (transfusion allowed)

- Bilirubin < 2 times upper limit of normal (ULN)

- SGOT and/or SGPT < 2 times ULN

- Calcium normal

- Phosphorus normal

- Creatinine < 1.5 mg/dL

- Cholesterol ≤ 350 mg/dL

- Triglycerides ≤ 400 mg/dL

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must agree to use effective contraception

- No history of any other cancer (except non-melanoma skin cancer or carcinoma in situ
of the cervix), unless in complete remission and off of all therapy for that disease
for a minimum of 3 years (phase II)

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to temsirolimus or perifosine

- No concurrent uncontrolled illness including, but not limited to, any of the

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness and/or social situation that would limit compliance with
study requirements

- No other concurrent anticancer therapy (including chemotherapy, radiotherapy,
hormonal therapy, or immunotherapy)

- Recovered from prior therapy

- At least 6 weeks since prior radiotherapy or nitrosoureas

- At least 4 weeks since prior temozolomide

- At least 4 weeks since prior direct inhibitors of VEGF/VEGFR (e.g., bevacizumab
[Avastin], aflibercept [VEGF Trap], cediranib [AZD2171], or XL-184 [BMS 907351])

- At least 4 weeks since prior investigational agents or cytotoxic therapy

- At least 3 weeks since prior procarbazine

- At least 2 weeks since prior vincristine

- At least 2 weeks since prior and no concurrent enzyme-inducing anti-epileptic drugs

- At least 1 week since prior non-cytotoxic agents (e.g., interferon, tamoxifen,
thalidomide, or cis-retinoic acid)

- No prior mTOR inhibitors (e.g., temsirolimus, sirolimus, or everolimus) (phase II)

- No prior perifosine or other AKT-targeting agents (phase II)

- No prior treatment with convection-enhanced delivery, other catheter-based
intra-tumoral treatment, or carmustine/Gliadel wafers (phase II)

- Prior stereotactic radiosurgery (including gamma-knife or cyber-knife) for newly
diagnosed or recurrent disease, or re-irradiation of any type allowed provided there
is confirmation of true progressive disease (rather than radiation necrosis) by
surgical documentation of recurrent/progressive disease (phase II)

- No other concurrent investigational agents

- No concurrent combination antiretroviral therapy for HIV-positive patients

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD defined as the dose at which fewer than one-third of patients experience a DLT according to CTCAE version 4.0 (Phase I)

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Thomas Kaley

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

January 2010

Completion Date:

Related Keywords:

  • Adult Anaplastic Astrocytoma
  • Adult Anaplastic Oligodendroglioma
  • Adult Diffuse Astrocytoma
  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Adult Mixed Glioma
  • Adult Oligodendroglioma
  • Recurrent Adult Brain Tumor
  • Astrocytoma
  • Brain Neoplasms
  • Glioblastoma
  • Glioma
  • Oligodendroglioma
  • Gliosarcoma



Memorial Sloan Kettering Cancer Center New York, New York  10021