Perifosine and Torisel (Temsirolimus) for Recurrent/Progressive Malignant Gliomas

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:

convection enhanced delivery, catheter based intra-tumoral treatment, or carmustine (BCNU)/Gliadel® wafers
stereotactic radiosurgery, or re-irradiation of any type
agent designed to inhibit mTOR or PI3K/AKT
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