Radiation Therapy and Temsirolimus or Temozolomide in Treating Patients With Newly Diagnosed Glioblastoma

Study Overview
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Brief Summary
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RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether radiation therapy is more effective when given together with temsirolimus or temozolomide in treating patients with glioblastoma. PURPOSE: This randomized phase II trial is studying giving radiation therapy together with temsirolimus to see how well it works compared with giving radiation therapy together with temozolomide in treating patients with newly diagnosed glioblastoma.

Detailed Description
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OBJECTIVES: Primary Document the activity profile of temsirolimus by the evaluation of overall survival at 1 year in patients with newly diagnosed glioblastoma multiforme, without methylation of the MGMT gene promoter, treated with temsirolimus before and concomitantly with radiotherapy, followed by temsirolimus maintenance therapy. Secondary Investigate safety and tolerability of this therapy regimen in these patients. Assess progression-free survival and overall survival of these patients. Assess biomarkers in the tumor tissue relevant to temsirolimus and disease state, and their correlation to clinical outcome in these patients. OUTLINE: This is a multicenter study. Patients are stratified according to institution, age in years (< 50 vs ≥ 50), Karnofsky performance status (PS) (< 80% vs ≥ 80%) OR ECOG PS (0 or 1 vs 2), and corticosteroid use (yes vs no). Patients are randomized to 1 of 2 treatment arms. Arm I: Within 7 weeks after surgery or open biopsy, patients undergo radiotherapy 5 days a week for 6 weeks and receive oral temozolomide concurrently once daily for 6 weeks. Beginning 4 weeks after completion of concurrent chemoradiotherapy, patients receive adjuvant oral temozolomide once daily on days 1-5. Treatment with adjuvant temozolomide repeats every 28 days for up to 12 courses in the absence of disease progression and unacceptable toxicity. Arm II: Within 7 weeks after surgery or open biopsy, patients undergo radiotherapy 5 days a week for 6 weeks. Patients also receive temsirolimus IV over 30-60 minutes once weekly beginning 7 days before initiation of radiotherapy. After completion of chemoradiotherapy, patients receive maintenance temsirolimus IV once weekly in the absence of disease progression and unacceptable toxicity. Frozen tumor biopsies or paraffin-embedded tumor material obtained from surgery or open biopsy and blood samples are collected for analysis of molecular markers, determination of the methylation status of the MGMT gene promoter (before randomization and at a later time), and other studies. After completion of study therapy, patients are followed every 3 months.

Official Title
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Radiation Therapy and Concurrent Plus Adjuvant Temsirolimus (CCI-779) Versus Chemo-Irradiation With Temozolomide in Newly Diagnosed Glioblastoma Without Methylation of the MGMT Gene Promoter - A Randomized Multicenter, Open-Label, Phase II Study.

Conditions
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Brain and Central Nervous System Tumors

Intervention / Treatment
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* Drug: temozolomide
* Drug: temsirolimus


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed (by open brain biopsy or from a neurosurgical resection of the tumor) supratentorial glioblastoma multiforme (GBM) WHO grade IV disease Newly diagnosed disease Must provide demonstration of an unmethylated MGMT-promoter At least 2 weeks and no more than 6 weeks since surgery or open biopsy Tumor tissue specimens (paraffin-embedded and/or frozen) from the GBM surgery or open biopsy must be available for central pathology review, MGMT status determination, and exploratory analysis of PI3-K/Akt/mTOR targets (P70S6K) PATIENT CHARACTERISTICS: ECOG performance status 0-2 Life expectancy ≥ 12 weeks WBC ≥ 3.0 x 10^9/L Absolute neutrophil count ≥ 1.5 x10^9/L Platelet count ≥ 75.0 x 10^9/L Hemoglobin ≥ 10.0 g/dL Bilirubin ≤ 1.5 times the upper limit of normal (ULN) Alkaline phosphatase ≤ 2.5 x ULN AST and/or ALT ≤ 2.5 x ULN Serum creatinine < 1.5 x ULN PT and PTT normal Negative pregnancy test Not pregnant or nursing Fertile patients must use highly effective contraception No ischemic heart disease in the past 6 months 12-lead ECG normal No history of stroke No psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule No other malignancy within the past 5 years except adequately treated carcinoma in situ of the cervix or nonmelanoma skin cancer (with no subsequent evidence of recurrence) No serious concurrent systemic disorder including any of the following that, in the opinion of the investigator, would compromise the patient's ability to adhere to the protocol: Active infection HIV infection Cardiac disease QTc prolongation > 450/470 msec (males/females) No patients with a congenital long-QT-syndrome in their own or family medical history, unless eligible at the investigator's discretion No known hypersensitivity to the study treatment No known hypersensitivity to antihistamines or other medical reason that prohibits the intake of antihistamines No current alcohol dependence or drug abuse No legal incapacity or limited legal capacity Able to undergo a gadolinium-enhanced MRI of the brain PRIOR CONCURRENT THERAPY: See Disease Characteristics At least 4 weeks since prior and no concurrent investigational agent No prior stereotactic biopsy At least 30 days since prior drug therapy that has not received regulatory approval for any indication No chemotherapy within the past 5 years No prior chemotherapy for a brain tumor No prior radiotherapy to the head No other concurrent anticancer therapy No concurrent anticoagulation therapy except low-dose prophylactic low molecular weight heparin Concurrent steroid therapy allowed provided patient is on a stable or decreasing dose for ≥ 1 week At least 14 days since prior and no concurrent enzyme-inducing anticonvulsants (e.g., carbamazepine, phenobarbital, and phenytoin) No concurrent strong inducers or inhibitors of CYP3A4 No concurrent planned surgery for other diseases (e.g., dental extraction) No placement of Gliadel® wafer during prior surgery

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Temozolomide<br>TMZ will be given at 75 mg/m2 daily for the whole period of RT including weekends as registered. | Drug: temozolomide<br>* TMZ will be given at 75 mg/m2 daily for the whole period of RT including weekends as registered.<br>|
| Experimental: Temsirolimus<br>CCI-779 will be given i.v. once every week at 25 mg. Each treatment should be preceded by supportive medication with a histamine H2-receptor antagonist. A first dose of CCI-779, being 25 mg, will be given on day -7 from RT start. | Drug: temsirolimus<br>* CCI-779 will be given i.v. once every week at 25 mg. Each treatment should be preceded by supportive medication with a histamine H2-receptor antagonist. A first dose of CCI-779, being 25 mg, will be given on day -7 from RT start.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival at 1 year |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentages of worst Adverse Events or Laboratory Event grades as measured by CTCAEs Version 4.0 criteria |  | end of trial | 
| Progression-free survival (PFS) probability at 6 months and at 12 months, and overall survival (OS) probability at 2 years |  | end of trial | 
| Correlation between biomarkers relevant to temsirolimus and PFS and OS |  | end of trial | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult glioblastoma