Radiation Therapy Combined With Chemotherapy in Treating Patients With Anaplastic Astrocytoma or Mixed Gliomas

Official Title: “A Phase III Randomized Study (Phase I Closed) of Radiation Therapy and Temozolomide Versus Radiation Therapy and Nitrosourea for Anaplastic Astrocytoma And Mixed Anaplastic Oligoastrocytoma (Astrocytoma Dominant)”

RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs used in chemotherapy, such as temozolomide, carmustine, and lomustine, use different ways to stop tumor cells from dividing so they stop growing or die. Combining radiation therapy with chemotherapy may kill more tumor cells.

PURPOSE: This randomized phase III trial is studying radiation therapy and temozolomide to see how well they work compared to radiation therapy and carmustine or lomustine in treating patients with anaplastic astrocytoma or mixed gliomas.

OBJECTIVES: - Compare the overall survival and time to tumor progression in patients with anaplastic astrocytoma or mixed gliomas treated with radiotherapy combined with temozolomide vs carmustine or lomustine vs temozolomide and carmustine (arm discontinued as of 8/15/02). - Compare the relative toxic effects of these regimens in these patients. - Correlate molecular analyses with overall survival and time to tumor progression in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age (under 50 vs 50 and over), Karnofsky performance status (60-80% vs 90-100%), and prior surgery (biopsy only vs resection).

Phase I (closed as of 8/15/02) - Prior to initiating the randomization to 1 of 3 treatment arms in phase III, 15 patients are accrued to arm III. If 2 or more of the first 15 patients experience grade 3 or worse pulmonary toxicity OR if 5 or more of the first 15 patients experience grade 4-5 thrombocytopenia/neutropenia, then arm III treatment is discontinued.

Phase III - Patients are randomized to 1 of 2 treatment arms. - Arm I: Patients undergo radiotherapy 5 days a week for 6 weeks. Patients receive oral temozolomide on days 1-5 of the first week of radiotherapy. Chemotherapy repeats every 4 weeks for a total of 12 courses. - Arm II: Patients undergo radiotherapy as in arm I. Patients receive carmustine IV or lomustine IV over 1-2 hours on days 1-3 of the first week of radiotherapy and a second course on days 56-58. Chemotherapy repeats every 8 weeks for a total of 6 courses. - Arm III (discontinued as of 8/15/02): Patients undergo radiotherapy as in arm I.

Patients receive carmustine IV or lomustine IV over 3 hours on day 5 and oral temozolomide (2 hours after completion of carmustine or lomustine infusion) on days 1-5 of the first week of radiotherapy. Combination chemotherapy repeats every 8 weeks for 6 courses.

Patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 30 patients will be accrued for phase I of the study and then a total of 454 patients (227 per treatment arm) will be accrued for phase III of the study within 4 years. (Phase I closed as of 8/15/02)

Intervention(s) in this Clinical Trial

• Drug: carmustine
• Drug: lomustine
• Drug: temozolomide
• Radiation: radiation therapy

Primary Measures

• Overall survival (OS)
  • Safety Issue?: No
• Time to tumor progression (TTP)
  • Safety Issue?: No
• Toxicity
  • Safety Issue?: Yes
• Correlation of molecular analyses with OS and TTP
  • Safety Issue?: No

DISEASE CHARACTERISTICS:

• Histologically proven unifocal anaplastic astrocytoma or mixed gliomas, including the following:
• Anaplastic oligoastrocytoma
• Mixed oligodendroglial/astrocytic tumors
• Oligodendroglial component must be no greater than 25%
• No vascular proliferation and necrosis
• Increased cellularity, pleomorphism, and nuclear atypia allowed
• No tumor predominantly located in the posterior fossa (i.e., brainstem or cerebellum)
• Patients with prior biopsy proven low grade astrocytoma who now have anaplastic astrocytoma and have had no prior radiotherapy or chemotherapy also eligible
• Study therapy must begin within 6 weeks of diagnosis
• No spinal cord tumors, spinal drop metastases, or metastases to noncontiguous meninges
• Pathologic evidence of local meningeal infiltration by underlying tumor allowed

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Karnofsky 60-100%

Life expectancy:

• At least 1 year

Hematopoietic:

• Hemoglobin at least 10 g/dL
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 150,000/mm^3

Hepatic:

• Bilirubin less than 2 times upper limit of normal (ULN)
• AST less than 2 times ULN
• Alkaline phosphatase less than 2 times ULN

Renal:

• Blood urea nitrogen no greater than 25 mg/dL
• Creatinine less than 1.5 times normal

Pulmonary:

• No pre-existing lung disease that, in the investigator's opinion, would preclude administration of carmustine or lomustine or completion of therapy

Other:

• No other major medical illness or psychiatric impairment that would preclude study compliance
• No other malignancy within the past 5 years except nonmelanomatous skin cancer or carcinoma in situ of the cervix
• No known hypersensitivity to 1 of the components of carmustine, lomustine, temozolomide, dacarbazine, or any other nitrosourea
• No active infection
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior biologic therapy

Chemotherapy:

• See Disease Characteristics
• No prior chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• See Disease Characteristics
• No prior radiotherapy to brain or head and neck

Surgery:

• Not specified

Other:

• No other concurrent anticancer treatment for anaplastic astrocytoma until a recurrence is detected

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Radiation Therapy Oncology Group Other

Overall Clinical Trial Officials and Contacts

Susan M. Chang, MD Study Chair University of California, San Francisco  

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00004259

Study ID Number: CDR0000067512

ClinicalTrials.gov Identifier: NCT00004259

Health Authority: United States: Federal Government

Clinical trial summary from the National Cancer Institute's PDQ® database