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