Irinotecan in Treating Patients With Progressive or Recurrent Malignant Glioma

Phase I/II Trial of Irinotecan (CPT-11) in Patients With Recurrent Malignant Glioma

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die.

PURPOSE: Phase I/II trial to study the effectiveness of irinotecan in treating patients who have progressive or recurrent malignant glioma.

OBJECTIVES: I. Determine the maximum tolerated dose and the dose limiting toxicities of irinotecan in patients with progressive or recurrent malignant glioma. II. Define the safety profile of every 3 week dosing of irinotecan in these patients. III. Characterize the pharmacokinetic profile of this regimen in these patients. IV. Assess evidence of antitumor activity in these patients. V. Determine the efficacy of irinotecan in these patients as measured by 6 month progression-free survival and objective tumor response. VI. Evaluate further the safety profile of irinotecan in these patients during phase II study.

OUTLINE: This is a dose escalation study. Patients are stratified according to concurrent enzyme-inducing antiepileptic drugs (EIAEDs)(yes vs no). Group A (without EIAEDs): Patients receive irinotecan IV over 90 minutes on day 1, followed by up to 3 weeks of rest. Group B (with EIAEDs): Patients receive the same treatment but dose escalation is performed in cohorts of 3 patients. The maximum tolerated dose (MTD) is defined as the dose below that at which 2 of 6 patients experience dose limiting toxicities. The Phase I MTD is the starting dose recommended for use in the Phase II portion of the study. Treatment continues every 3 weeks for up to 12 months in the absence of disease progression or unacceptable toxicity. Patients are followed every 2 months for 1 year, every 3 months for 1 year, every 4 months for 1 year, then every 6 months until disease progression. Patients are then followed every 4 months for survival.

PROJECTED ACCRUAL: Up to 30 patients will be accrued for phase I within 10 months. A total of 48 patients will be accrued for phase II within 6-8 months.

DISEASE CHARACTERISTICS: Histologically proven progressive or recurrent primary malignant glioma Phase I (excluding group A patients): No more than 2 prior chemotherapy regimens, including 1 prior adjuvant therapy and 1 prior regimen for recurrent or progressive tumor, or 2 prior regimens for progressive tumor Phase II and/or group A patients: No more than 1 prior chemotherapy regimen, either as adjuvant or for recurrent disease Measurable disease by MRI or CT scan

PATIENT CHARACTERISTICS: Age: 18 and over Performance status: Karnofsky 60-100% Life expectancy: Not specified Hematopoietic: Neutrophil count at least 1,500/mm3 Platelet count at least 100,000/mm3 Hepatic: Bilirubin no greater than 1.5 mg/dL SGOT no greater than 3 times upper limit of normal Renal: Creatinine no greater than 1.5 mg/dL Cardiovascular: No uncontrolled hypertension No unstable angina No symptomatic congestive heart failure No myocardial infarction within 6 months No serious uncontrolled cardiac arrhythmia Other: Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No severe nonmalignant systemic disease or active infection No concurrent alcoholism or drug abuse No psychosis HIV negative

PRIOR CONCURRENT THERAPY: Biologic therapy: No concurrent immunotherapy No concurrent sargramostim (GM-CSF) Chemotherapy: See Disease Characteristics At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas, mitomycin, or suramin) No prior irinotecan, topotecan, or other topotecan 1 inhibitors No other concurrent chemotherapy Endocrine therapy: Stable or decreasing dosage of corticosteroids within 72 hours of study entry (phase II only) No other concurrent immunosuppressive agents No concurrent hormonal therapy Radiotherapy: At least 4 weeks since prior radiotherapy Patients with prior interstitial brachytherapy or stereotactic radiosurgery must have confirmation of progressive disease No concurrent radiotherapy Surgery: At least 3 weeks since prior resection Other: Acute toxic effects (excluding neurotoxicity or alopecia) of any prior therapy must be resolved No concurrent valproic acid as a single agent Concurrent enzyme-inducing antiepileptic drugs (EIAED) with or without steroids are allowed No concurrent investigational drugs