Clinical Trial Finder

Inclusion Criteria:

• - 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.

• - 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.

• - No concurrent combination antiretroviral therapy for HIV-positive patients.

• - 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

PRIMARY OBJECTIVES:

• I. 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.

• II. Assess and describe the adverse events associated with this regimen in these patients.

• III. 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 OBJECTIVES:

• I. Determine the inhibition status of mTOR signaling pathways in peripheral blood mononuclear cells in patients treated with this regimen.

• II. Identify potential pharmacokinetic interactions between temozolomide and temsirolimus.

• III. 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.

Arms

Experimental: Treatment (temsirolimus, temozolomide, radiation therapy)

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 with stable or responding disease proceed to adjuvant therapy. 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 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.

Interventions

Other: - pharmacological study

Procedure: - adjuvant therapy

Radiation: - 3-dimensional conformal radiation therapy

Radiation: - intensity-modulated radiation therapy

Drug: - temsirolimus

Given IV

Drug: - temozolomide

Given orally