The purpose of this study is to test the effectiveness of a drug called temsirolimus in combination with a drug called perifosine in treating brain tumors that have continued to grow after previous treatment. Temsirolimus is an intravenous drug approved by the FDA for treatment of other cancers (kidney cancer, certain types of lymphoma) but not for brain tumors. Perifosine is a pill that has not been approved by the FDA which blocks a messenger that tells cancer cells to grow. Research suggests that combined treatment with both drugs is better than either alone, and that it is reasonably safe.

Malignant gliomas are the most common primary brain tumors, and glioblastoma (GBM) is the most common subtype in adults, representing more than 50% of gliomas. Standard initial treatment for newly diagnosed GBM consists of maximal surgical resection followed by radiotherapy to the tumor bed and chemotherapy with an oral DNA alkylator, temozolomide. However, recurrence is nearly universal despite standard therapy. There is no standard treatment at recurrence. Median survival is about 15 months from diagnosis and 6 months from recurrence. Once patients develop tumor progression, conventional chemotherapy is generally ineffective.

Inclusion Criteria:

• Histologically confirmed intracranial glioblastoma (GBM), including sub variants
• At least 15 unstained slides or at least 1 tissue blocks must be collected from at least one prior surgery.
• Received prior radiotherapy and prior temozolomide as treatment for the malignant glioma
• Recovered from toxic effects of prior therapies and at least 2 weeks must have elapsed since any prior signaling pathway modulators; in general, at least 4 weeks must have elapsed from any other anticancer therapy
• Able to undergo contrast enhanced magnetic resonance imaging (MRI) scans or CT scans
• Shown unequivocal evidence for contrast enhancing tumor progression by MRI or CT in comparison to a prior scan
• Age > or = 18 years
• Karnofsky Performance Status > or = 70
• Life expectancy of > 8 weeks
• Normal organ and marrow function, adequate liver function, and adequate renal function before starting therapy
• Platelet count of at least 100,000/mm3 on at least 2 consecutive blood draws at least 1 week apart with results stable or trending upward
• Normal coagulation
• Cholesterol level < or = 350 mg/dl and triglycerides level < or = 400 mg/dl
• Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation
• Women of childbearing potential must have a negative beta-human chorionic gonadotropin (B-hCG) pregnancy test documented within 7 days prior to treatment
• Women must agree not to breast feed
• Ability to understand and the willingness to sign a written informed consent document
• Ability to swallow tablets

Group A (medical) specific inclusion criteria:

• Fulfill all of the general inclusion criteria
• At least 3 months between any prior brain radiotherapy and initiation of study therapy
• MRI/CT must demonstrate measurable enhancing tumor of at least 1cm squared in cross-sectional area to allow assessment of radiographic response
• On stable or decreasing dose of corticosteroids for a minimum of 5 days before the baseline MRI/CT
• The baseline brain MRI/CT must be performed less than 15 days prior to initiation of study treatment. Otherwise it must be repeated

Group B (surgical) specific inclusion criteria:

• Fulfill all of the general inclusion criteria
• Have cytoreductive surgery as part of their routine care for recurrent tumor
• Have cytoreductive surgery as part of their routine care for recurrent tumor
• A brain MRI/CT must be performed less than 15 days prior to initiation of study treatment. Otherwise it must be repeated

Exclusion Criteria:

• There is no limit on the number or type of prior chemotherapies except:

  1. convection enhanced delivery, catheter based intra-tumoral treatment, or carmustine (BCNU)/Gliadel® wafers
  2. stereotactic radiosurgery, or re-irradiation of any type
  3. agent designed to inhibit mTOR or PI3K/AKT
  4. direct Vascular Endothelial Growth Factor (VEGF)/Vascular Endothelial Growth Factor Receptors (VEGFR) inhibitors

• Smoking or plan to smoke tobacco or marijuana during study therapy

• Plan to eat grapefruit or drink grapefruit juice during study therapy

• Receiving any other investigational agents concurrently with study treatment

• Taking hepatic Enzyme Inducing Anti-Epileptic Drug (EIAED)

• Taking medications that are inducers or inhibitors of Cytochrome P450 3A4 (CYP3A4) for at least two weeks prior to study treatment

• Uncontrolled intercurrent illness

• HIV-positive patients on combination antiretroviral therapy

• Other active concurrent malignancy

• History of gout which can be exacerbated by perifosine

• Known history of allergic reactions attributed to compounds of similar chemical or biologic composition to temsirolimus or perifosine

• Therapeutic anticoagulation

• History of hemorrhagic or ischemic stroke

• Prior intratumoral bleeding must be evaluated with a non-contrast head CT to exclude acute blood prior to start of treatment

No Masking