Gefitinib Plus Temozolomide in Treating Patients With Malignant Primary Glioma

OBJECTIVES:

• Determine the maximum tolerated dose of gefitinib when given in combination with temozolomide in patients with malignant primary glioma.
• Determine the toxic effects of this regimen in these patients.
• Determine the pharmacokinetics of this regimen in these patients.

OUTLINE: This is a multicenter, dose-escalation study of gefitinib. Patients are stratified according to use of concurrent enzyme-inducing anti-epileptic drugs (yes vs no).

Patients receive oral gefitinib once daily on days 1-35 and oral temozolomide once daily on days 8-12 for the first course only. For the second and subsequent courses, patients receive oral gefitinib once daily on days 1-28 and oral temozolomide once daily on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of gefitinib 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 every 2 months for 1 year and then every 3-6 months thereafter.

PROJECTED ACCRUAL: Approximately 3-42 patients will be accrued for this study within 1-14 months.

DISEASE CHARACTERISTICS:

• Histologically confirmed malignant primary glioma

• Glioblastoma multiforme
• Anaplastic astrocytoma
• Anaplastic oligodendroglioma
• Anaplastic mixed oligoastrocytoma
• Malignant astrocytoma not otherwise specified
• Stable or progressive disease

• Progressive disease after interstitial brachytherapy or stereotactic radiosurgery must be confirmed by positron emission tomography or thallium scan, magnetic resonance spectroscopy, or surgical biopsy
• Prior treatment for no more than 3 prior relapses allowed

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Karnofsky 60-100%

Life expectancy:

• More than 8 weeks

Hematopoietic:

• WBC greater than 3,000/mm^3
• Absolute neutrophil count greater than 1,500/mm^3
• Platelet count greater than 120,000/mm^3
• Hemoglobin greater than 10 g/dL (transfusion allowed)

Hepatic:

• Bilirubin less than 1.5 times upper limit of normal (ULN)
• SGOT less than 1.5 times ULN

Renal:

• Creatinine less than 1.5 mg/dL OR
• Creatinine clearance greater than 60 mL/min

Other:

• Not pregnant
• Negative pregnancy test
• Fertile patients must use effective contraception
• No active infection
• No other concurrent significant medical illness that would preclude study participation
• No significant gastrointestinal risk factors (e.g., active ulcerative colitis) within the past 6 months
• No other malignancy within the past 3 years except non-melanoma skin cancer or carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• At least 1 week since prior interferon
• No concurrent filgrastim (G-CSF) during the first course of study therapy

Chemotherapy:

• At least 2 weeks since prior vincristine
• At least 3 weeks since prior procarbazine
• At least 6 weeks since prior nitrosoureas
• Prior or concurrent temozolomide allowed if there is no evidence of progression while receiving therapy

Endocrine therapy:

• At least 1 week since prior tamoxifen
• Must be on a stable dose of corticosteroids for at least 5 days

Radiotherapy:

• See Disease Characteristics
• At least 3 weeks since prior radiotherapy

Surgery:

• See Disease Characteristics
• At least 1 week since prior surgical resection

Other:

• Recovered from all prior therapy
• No prior gefitinib
• At least 1 week since prior non-cytotoxic agents except radiosensitizers
• At least 4 weeks since prior cytotoxic therapy
• At least 4 weeks since prior investigational agents
• At least 3 years since prior therapy for other malignancy
• Concurrent therapeutic agents allowed at stable dosage
• Concurrent enzyme-inducing anti-epileptic drugs allowed if continued during study participation