Temsirolimus and Perifosine in Treating Patients With Recurrent or Progressive Malignant Glioma

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 following:

  • 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