S0001 RT and Carmustine With or Without O6BG in Patients With New Glioblastoma Multiforme or Gliosarcoma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. O6-benzylguanine may help carmustine kill more tumor cells by making tumor cells more sensitive to the drug. It is not yet known whether radiation therapy and carmustine are more effective with or without O6-benzylguanine. PURPOSE: Randomized phase III trial to compare the effectiveness of radiation therapy plus carmustine with or without O6-benzylguanine in treating patients who have newly diagnosed glioblastoma multiforme or gliosarcoma.

Detailed Description
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OBJECTIVES: Compare the overall survival, failure-free survival, and progression-free survival of patients with newly diagnosed glioblastoma multiforme or gliosarcoma treated with radiotherapy and carmustine with or without O6-benzylguanine. Compare the frequency and severity of toxic effects of these regimens in these patients. Correlate the survival of these patients with the expression of O6-alkylguanine-DNA alkyltransferase. OUTLINE: This is a randomized study. Patients are stratified according to age (under 50 vs 50 and over), prior surgery (biopsy only vs resection), and Zubrod performance status (0-1 vs 2). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients undergo radiotherapy daily 5 days a week over 7 weeks for a total of 34 fractions. Patients also receive chemotherapy comprising O6-benzylguanine IV over 1 hour followed 6 hours later by carmustine IV over 1 hour on day 1 of radiotherapy. Chemotherapy repeats every 6 weeks for a maximum of 7 courses in the absence of disease progression or unacceptable toxicity. Arm II: Patients undergo radiotherapy as in arm I. Patients receive carmustine IV as in arm I. Patients are followed at week 48, every 4 months for 1 year, and then every 6 months for 4 years. PROJECTED ACCRUAL: A total of 375 patients will be accrued for this study within 5 years.

Official Title
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A Phase III Study of Radiation Therapy (RT) and O6-Benzylguanine (O6-BG) Plus BCNU Versus RT and BCNU Alone for Newly Diagnosed Glioblastoma Multiforme (GBM) and Gliosarcoma

Conditions
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Malignant Neoplasms of Eye, Brain and Other Parts of Central Nervous System

Intervention / Treatment
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* Drug: carmustine
* Radiation: radiation therapy
* Drug: O6-Benzylguanine


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed glioblastoma multiforme or gliosarcoma Biopsy or surgical resection within the past 28 days MRI* with gadolinium performed before registration Patients who undergo a simple biopsy only require preoperative MRI* with gadolinium No more than 2 noncontiguous tumor sites based on T2-weighted MRI (in 3 dimensions)* No prior radiotherapy-delivered cephalad to the interspace between the seventh cervical and the first thoracic vertebral body NOTE: *If an MRI is not medically feasible, patients may have a CT scan with contrast PATIENT CHARACTERISTICS: Age: 18 and over Performance status: Zubrod 0-2 Life expectancy: Not specified Hematopoietic: Absolute neutrophil count at least 3,000/mm^3 Platelet count at least 100,000/mm^3 Hemoglobin at least 8 g/dL Hepatic: Bilirubin no greater than 2 times upper limit of normal (ULN) SGOT/SGPT no greater than 2 times ULN Alkaline phosphatase no greater than 2 times ULN PT/PTT no greater than 1.2 times ULN Renal: Not specified Cardiac: No severe cardiac disease, including any of the following: Uncontrolled arrhythmias or conduction defects Major problems with edema (e.g., residual swelling in the legs from deep vein thrombosis) Recent coronary artery disease Poorly controlled hypertension (i.e., diastolic blood pressure greater than 110 mm Hg and/or systolic blood pressure greater than 180 mm Hg) Pulmonary: DLCO at least 70% of predicted No severe pulmonary disease Other: HIV negative No severe Cushing's syndrome No known allergies to any of the study drugs No major psychiatric illness No poorly controlled diabetes complicated by steroid treatment No other medical illness that cannot be adequately controlled or that would preclude study participation No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or adequately treated stage I or II cancer currently in complete remission Not pregnant or nursing Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: No prior chemotherapy No other concurrent antitumor chemotherapy Endocrine therapy: No concurrent hormonal therapy except postmenopausal estrogen replacement therapy Corticosteroids at stable or decreasing dose for tumor edema allowed Radiotherapy: See Disease Characteristics No prior radiotherapy No other concurrent radiotherapy (including intensity-modulated radiotherapy) to the index lesion(s) Surgery: See Disease Characteristics No concurrent antitumor surgery Other: No other concurrent investigational drugs No other concurrent antineoplastic drugs or therapy

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Experimental: O6-BG + BCNU + Radiation Therapy<br>O6-BG: 120 mg/m^2 IV over 1 hour on day 1 of each cycle BCNU: 40 mg/m^2 IV over 1 hour on day 1 of each cycle 6 hours after O6-BG dose. Radiation Therapy: 5 days/week using one fraction per day and a dose of 180 cGy per fraction. Initial target volume is dose of 5040 cGy in 28 fractions with boost target volume of 1080 cGy in 6 fractions. | Drug: carmustine<br>* 40 mg/m^2 IV over 1 hour on day 1 of each cycle 6 hours after O6-BG dose for experimental arm with O6=BG. 200 mg/m^2 IV over 1 hour on day 2 of each cycle for the active comparator arm.<br>Radiation: radiation therapy<br>* 5 days/week using one fraction per day and a dose of 180 cGy per fraction. Initial target volume is dose of 5040 cGy in 28 fractions with boost target volume of 1080 cGy in 6 fractions.<br>Drug: O6-Benzylguanine<br>* 120 mg/m^2 IV over 1 hour on day 1 of each cycle<br>* Other names: O6-BG;|
| Active Comparator: BCNU + Radiation Therapy<br>BCNU: 40 mg/m^2 IV over 1 hour on day 1 of each cycle. Radiation Therapy: 5 days/week using one fraction per day and a dose of 180 cGy per fraction. Initial target volume is dose of 5040 cGy in 28 fractions with boost target volume of 1080 cGy in 6 fractions. | Drug: carmustine<br>* 40 mg/m^2 IV over 1 hour on day 1 of each cycle 6 hours after O6-BG dose for experimental arm with O6=BG. 200 mg/m^2 IV over 1 hour on day 2 of each cycle for the active comparator arm.<br>Radiation: radiation therapy<br>* 5 days/week using one fraction per day and a dose of 180 cGy per fraction. Initial target volume is dose of 5040 cGy in 28 fractions with boost target volume of 1080 cGy in 6 fractions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival |  | assessed every 6 weeks for 42 weeks, then every 4 months for one year, followed by every 6 months for years 2 through 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival |  | assessed every 6 weeks for 42 weeks, then every 4 months for one year, followed by every 6 months for years 2 through 5 | 
| Time to treatment failure |  | assessed every 6 weeks for 42 weeks, then every 4 months for one year, followed by every 6 months for years 2 through 5 | 
| Toxicity |  | assessed weekly for 42 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult glioblastoma, adult giant cell glioblastoma, adult gliosarcoma