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