Temozolomide Plus Irinotecan in Treating Patients With Recurrent Malignant Glioma

OBJECTIVES:

- Determine the maximum tolerated dose and dose-limiting toxicity of irinotecan when
administered with temozolomide in patients with recurrent malignant glioma.

- Determine the safety profile of this regimen in this patient population.

- Determine the efficacy of this treatment regimen as measured by 6-month progression-free
survival and objective tumor response in these patients.

- Characterize the pharmacokinetics of this treatment regimen in these patients.

- Determine the antitumor activity of this treatment regimen in these patients.

OUTLINE: This is a multicenter, dose-escalation study of irinotecan. Patients are stratified
according to concurrent enzyme-inducing anti-epileptic drugs (EIAEDs) (e.g., phenytoin,
phenobarbital, carbamazepine, or primidone) (yes vs no).

In phase I of the study, patients receive oral temozolomide on days 1-5 and irinotecan IV
over 90 minutes on days 1 and 14. Treatment continues every 28 days for up to 1 year in the
absence of disease progression or unacceptable toxicity.

Patients concurrently on EIAEDs undergo dose escalation of irinotecan. Cohorts of 3 to 6
patients receive escalating doses of irinotecan until the maximum tolerated dose (MTD) is
determined. The MTD is defined as the dose preceding that at which 2 of 3 or 6 patients
experience dose-limiting toxicity.

In phase II of the study, patients receive the same treatment as in phase I at the MTD.

Patients are followed every 2 months for 1 year, every 3 months for 1 year, every 4 months
for 1 year, every 6 months until progression, and then every 4 months for survival.

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

DISEASE CHARACTERISTICS:

- Histologically confirmed supratentorial malignant primary glioma of one of the
following subtypes:

- Glioblastoma multiforme

- Anaplastic astrocytoma

- Anaplastic oligodendroglioma

- Mixed malignant glioma

- Original histology of low-grade glioma allowed if subsequent histological confirmation
of malignant glioma

- Measurable recurrent or residual primary disease by MRI

- Lesions with clearly defined margins

- Evidence of tumor recurrence or progression by MRI or CT scan

- Confirmation of true progressive disease by PET or thallium scan, magnetic resonance
spectroscopy, or surgical documentation after prior interstitial brachytherapy or
stereotactic radiosurgery

- No more than 3 relapses after prior chemotherapy/cytotoxic therapy (including
polifeprosan 20 with carmustine implant) for phase I and no more than 2 relapses for
phase II

PATIENT CHARACTERISTICS:

Age:

- 18 and over

Performance status:

- Karnofsky 60-100%

Life expectancy:

- Not specified

Hematopoietic:

- WBC at least 3,000/mm^3

- Absolute neutrophil count at least 1,500/mm^3

- Platelet count at least 100,000/mm^3

- Hemoglobin at least 10 g/dL

Hepatic:

- Bilirubin no greater than 1.5 mg/dL

- SGOT no greater than 2 times upper limit of normal

Renal:

- Creatinine no greater than 1.5 mg/dL

Cardiovascular:

- No uncontrolled hypertension, unstable angina, or symptomatic congestive heart failure

- No myocardial infarction within the past 6 months

- No serious uncontrolled cardiac arrhythmia

Other:

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No mental incapacitation

- HIV negative

- No AIDS-related disease

- No significant ongoing alcoholism or substance abuse

- No severe nonmalignant systemic disease

- No active infection

- No other severe disease that would preclude study

PRIOR CONCURRENT THERAPY:

Biologic therapy:

- At least 1 week since prior interferon or thalidomide and recovered

- No concurrent anticancer immunotherapy

- No concurrent sargramostim (GM-CSF)

- No concurrent prophylactic filgrastim (G-CSF) during first course of study therapy

Chemotherapy:

- See Disease Characteristics

- Recovered from prior chemotherapy

- At least 2 weeks since prior vincristine

- At least 3 weeks since prior procarbazine

- At least 4 weeks since prior cytotoxic chemotherapy (6 weeks for nitrosourea)

- Prior radiosensitizers allowed

- No prior temozolomide or irinotecan

- No other concurrent anticancer chemotherapy

Endocrine therapy:

- At least 1 week since prior tamoxifen and recovered

- No concurrent anticancer hormonal therapy

- Phase II:

- Non-increasing dose of corticosteroids allowed

Radiotherapy:

- See Disease Characteristics

- At least 4 weeks since prior radiotherapy and recovered

- No concurrent anticancer radiotherapy

Surgery:

- See Disease Characteristics

- At least 1-3 weeks since prior surgical resection and recovered

Other:

- At least 1 week since prior noncytotoxic agents (e.g., isotretinoin) and recovered

- Concurrent enzyme-inducing anti-epileptic drugs with or without steroids allowed

- No concurrent valproic acid as a single agent

- No concurrent medication that would preclude study (e.g., nonsteroidal
immunosuppressive agents)

- No other concurrent investigational drugs

- No concurrent participation in other clinical study