• Tolerability (maximum tolerated dose) [ Designated as safety issue: Yes ]
  
• Time to treatment related toxicity as assessed by hematologic measures and CTC criteria [ Designated as safety issue: Yes ]
  
• Time to treatment related ≥ grade 3 toxicity [ Designated as safety issue: Yes ]
  
• Time to progression [ Designated as safety issue: No ]
  
• Time to treatment failure [ Designated as safety issue: No ]
  
• Early response as assessed by automated morphological MRI change detector and physiological MRI techniques, including diffusion-weighted imaging, perfusion-weighted imaging, and chemical shift imaging [ Designated as safety issue: No ]
  

• Inhibition status of mTOR signaling pathways in peripheral blood mononuclear cells [ Designated as safety issue: No ]
  
• Potential pharmacokinetic interactions [ Designated as safety issue: No ]
  
• Correlate survival, progression-free survival, and response with pre-treatment tumor tissue molecular markers [ Designated as safety issue: No ]
  

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of temsirolimus when administered with temozolomide in combination with radiotherapy followed by adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme.
• Assess and describe the adverse events associated with this regimen in these patients.
• Evaluate the early response to therapy in these patients using an automated morphological MRI change detector and physiological MRI techniques, including diffusion-weighted imaging, perfusion-weighted imaging, and chemical shift imaging.

Secondary

• Determine the inhibition status of mTOR signaling pathways in peripheral blood mononuclear cells in patients treated with this regimen.
• Identify potential pharmacokinetic interactions between temozolomide and temsirolimus.
• Correlate, preliminarily, survival, progression-free survival, and response with pre-treatment tumor tissue molecular markers in these patients.

OUTLINE: This is a multicenter, dose-escalation study of temsirolimus. Patients are assigned to 1 of 2 treatment groups.

• Group 1 (temsirolimus with radiation and temozolomide): Patients receive temsirolimus IV over 30 minutes once weekly. Beginning 7-10 days later, patients also receive oral temozolomide daily and undergo concurrent 3-D conformal radiotherapy or intensity-modulated radiotherapy once daily, 5 days a week, for 6 weeks. Patients are evaluated 4-6 weeks after completion of chemoradiotherapy. Patients with stable or responding disease proceed to adjuvant therapy.

Cohorts of 3-6 patients receive escalating doses of temsirolimus until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience a dose-limiting toxicity. At least 6 patients are treated at the MTD.

• Group 2 (radiation and temozolomide): Patients receive oral temozolomide daily and undergo concurrent 3-D conformal radiotherapy or intensity-modulated radiotherapy once daily, 5 days a week, for 6 weeks. Patients are evaluated 4-6 weeks after completion of chemoradiotherapy. Patients with stable or responding disease proceed to adjuvant therapy.
• Adjuvant therapy: Beginning 4-6 weeks after the completion of chemoradiotherapy patients receive oral temozolomide on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Some patients undergo blood collection for immune monitoring and translational/pharmacologic studies.

After completion of study treatment, patients are followed periodically for 5 years.

PROJECTED ACCRUAL: A total of 46 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed glioblastoma multiforme (GBM)

  • Gliosarcoma and other grade 4 astrocytoma variants (e.g., giant cell glioblastoma) allowed

• Newly diagnosed disease

  • Has undergone surgical resection or biopsy of the tumor at least 1 week but no more than 6 weeks ago

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Absolute neutrophil count ≥ 1,500/mm^3
• Hemoglobin ≥ 9.0 g/dL
• Platelet count ≥ 100,000/mm^3
• Total bilirubin ≤ 2.5 times upper limit of normal (ULN)
• Cholesterol < 350 mg/dL
• Triglycerides < 400 mg/dL
• AST ≤ 2.5 times ULN
• Creatinine ≤ 1.5 times ULN
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No history of allergy or intolerance to dacarbazine
• No ongoing or active infection
• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia
• No psychiatric illness or social situation that would preclude study compliance
• No other uncontrolled illness
• No gastrointestinal tract disease affecting ability to take oral medication or requiring IV alimentation
• No significant traumatic injury within the past 21 days
• No active, uncontrolled peptic ulcer disease
• No other active cancers requiring therapy

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Willing and able to comply with antibiotic prophylaxis with either trimethoprim/sulfamethoxazole (daily or 3 times per week) or monthly IV pentamidine combined with daily levofloxacin
• No prior chemotherapy for any brain tumor
• No prior temozolomide or mTOR inhibitor therapies
• No prior cranial radiotherapy
• More than 21 days since prior major surgery (excluding neurosurgical biopsy or resection of GBM)
• No prior surgical procedures affecting absorption

• No concurrent enzyme-inducing anticonvulsants, including any of the following:

  • Carbamazepine
  • Phenytoin
  • Phenobarbital
  • Primidone
• No other concurrent investigational agents

• Not receiving warfarin prior to study registration

  • Concurrent warfarin allowed if patients develop an indication for it while enrolled on the protocol
• No concurrent combination antiretroviral therapy for HIV-positive patients