Temozolomide Plus Lomustine Followed by Radiation Therapy in Treating Patients With High-Grade Malignant Glioma

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. Combining more than one chemotherapy drug with radiation therapy may kill more tumor cells.

PURPOSE: Phase I trial to study the effectiveness of temozolomide plus lomustine followed by radiation therapy in treating patients who have high-grade malignant glioma.

OBJECTIVES:

* Determine the maximum tolerated dose of temozolomide when administered with lomustine in patients with high-grade malignant gliomas.
* Determine the dose-limiting toxic effects of this regimen in these patients.
* Evaluate the feasibility of radiotherapy after this treatment regimen in this patient population.
* Evaluate the radiographic responses in patients treated with this regimen.

OUTLINE: This is a multicenter, dose-escalation study of temozolomide.

Patients receive oral temozolomide on days 1-5 and oral lomustine on day 1. Treatment continues every 28 days, if blood counts have recovered, for 2 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo radiotherapy on days 1-5 weekly for 6 weeks. Patients continue the same chemotherapy regimen for up to 6 more courses beginning 4 weeks after completion of radiotherapy.

Cohorts of 3-6 patients receive escalating doses of temozolomide 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 dose-limiting toxicity.

Patients are followed for survival.

PROJECTED ACCRUAL: A total of 3-30 patients will be accrued for this study.

Eligibility Criteria:
DISEASE CHARACTERISTICS:

* Histologically confirmed high-grade malignant glioma of one of the following subtypes:

  * Glioblastoma
  * Anaplastic astrocytoma
  * Anaplastic oligoastrocytoma
  * Gliomatosis cerebri
* No disseminated disease or primary spinal cord malignancies
* Measurable intracranial residual disease by MRI

PATIENT CHARACTERISTICS:

Age:

* 3 and over
* Under 22 at time of diagnosis

Performance status:

* Karnofsky 50-100% if over 10 years of age
* Lansky 50-100% if 10 years of age or under

Life expectancy:

* At least 8 weeks

Hematopoietic:

* Absolute neutrophil count at least 1,000/mm\^3
* Platelet count at least 100,000/mm\^3 (transfusion independent)
* Hemoglobin at least 8.0 g/dL (RBC transfusions allowed)

Hepatic:

* Bilirubin no greater than 1.5 times normal for age
* SGPT no greater than 2.5 times normal for age
* Albumin at least 2 g/dL

Renal:

* Creatinine no greater than 1.5 times normal for age OR
* Creatinine clearance or radioisotope glomerular filtration rate at least lower limit of normal for age

Pulmonary:

* No dyspnea at rest
* No exercise intolerance
* Pulse oximetry at least 94%

Other:

* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* No uncontrolled infection

PRIOR CONCURRENT THERAPY:

Biologic therapy:

* No prior biologic therapy
* No concurrent prophylactic hematopoietic growth factors

Chemotherapy:

* No prior chemotherapy

Endocrine therapy:

* Prior corticosteroid therapy allowed
* No concurrent corticosteroids as antiemetic

Radiotherapy:

* No prior radiotherapy

Surgery:

* No more than 31 days since prior maximal neurosurgical procedure

Other:

* No concurrent phenobarbital or cimetidine