Imatinib Mesylate in Treating Patients With Recurrent Malignant Glioma or Meningioma

OBJECTIVES:

- Determine the maximum tolerated dose of imatinib mesylate in patients with recurrent
malignant glioma or meningioma.

- Determine the safety profile of this drug in these patients.

- Determine the pharmacokinetics of this drug, with or without concurrent enzyme-inducing
anti-epileptic drugs (EIAEDs), in these patients. (Stratum of patients currently taking
EIAEDs closed to accrual as of 05/15/2003 for phase I and phase II)

- Determine angiogenic activity in vivo using functional neuro-imaging studies and in
vitro with assays of serum angiogenic peptides.

- Determine the efficacy of this drug, in terms of 6-month progression-free survival and
objective tumor response, in these patients.

OUTLINE: This is a multicenter, dose-escalation study. Patients are stratified according to
concurrent enzyme-inducing anti-epileptic drug use (yes [stratum closed to accrual as of
05/15/2003 for phase I and phase II] vs no).

- Phase I (patients with glioma or meningioma) Patients in cohorts 1 and 2 receive oral
imatinib mesylate (STI571) once daily on days 1-28. Patients in cohorts 3-5 receive oral
STI571 twice daily on days 1 and 3-28 of the first course and on days 1-28 of subsequent
courses. Courses repeat every 4 weeks in the absence of disease progression or
unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of STI571 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.

- Phase II (patients with glioma) (glioblastoma multiforme patients excluded as of
05/15/2003) Patients receive oral STI571 at the MTD determined in phase I, 1-2 times
daily for 4 weeks. Courses repeat every 4 weeks in the absence of disease progression or
unacceptable toxicity.

Patients are followed for survival.

PROJECTED ACCRUAL: A total of 36 patients will be accrued for phase I of the study within 6
months and a total of 39 patients will be accrued for phase II of the study within 6-8
months. (Glioblastoma multiforme patients excluded from phase II as of 05/13/2003).

DISEASE CHARACTERISTICS:

- Histologically confirmed recurrent or unresectable malignant glioma

- Glioblastoma multiforme (phase I only)

- Anaplastic astrocytoma

- Anaplastic oligodendroglioma

- Anaplastic mixed oligoastrocytoma

- Malignant astrocytoma not otherwise specified

- Gliosarcoma

- Low-grade histology with subsequent diagnosis of malignant glioma allowed (phase
I only) OR

- Histologically confirmed recurrent or unresectable benign or malignant meningioma
(phase I only)

- No prior intracranial hemorrhage

- Failed prior radiotherapy

- Progressive or recurrent disease by MRI or CT scan and/or resection

- PET or thallium scan, MR spectroscopy, or surgical documentation required in
patients who have received prior interstitial brachytherapy or stereotactic
radiosurgery

- Stable dose of steroids for 5-7 days prior to MRI or CT scan

PATIENT CHARACTERISTICS:

Age:

- 18 and over

Performance status:

- Karnofsky 60-100%

Life expectancy:

- More than 8 weeks

Hematopoietic:

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

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

- Hemoglobin at least 10 g/dL (transfusion allowed)

Hepatic:

- Bilirubin less than 2 times upper limit of normal (ULN)

- SGOT less than 2 times ULN

- No significant hepatic disease

Renal:

- Creatinine less than 1.5 mg/dL

- Creatinine clearance at least 60 mL/min

- No significant renal disease

Cardiovascular:

- No significant cardiac disease

- No deep venous or arterial thrombosis within the past 6 weeks

Pulmonary:

- No pulmonary embolism within the past 6 weeks

Other:

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective barrier contraception during and for up to 6
months after study participation

- No other serious concurrent medical illness

- No serious active infection

- No concurrent disease that would obscure toxicity or alter drug metabolism

- No other malignancy within the past 3 years except nonmelanoma skin cancer or
carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

Biologic therapy:

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

- No concurrent immunotherapy

- No concurrent prophylactic filgrastim (G-CSF)

Chemotherapy:

- Recovered from prior chemotherapy

- At least 4 weeks since prior cytotoxic therapy

- At least 2 weeks since prior vincristine

- At least 6 weeks since prior nitrosoureas

- At least 4 weeks since prior temozolomide

- At least 3 weeks since prior procarbazine

- Prior polifeprosan 20 with carmustine implant (Gliadel wafer) allowed

- Prior radiosensitizers allowed

- No other concurrent chemotherapy

- Phase I only:

- Prior chemotherapy required for anaplastic astrocytoma, anaplastic
oligodendroglioma, and anaplastic mixed oligoastrocytoma

- Prior treatment for up to 3 relapses allowed

- Phase II only:

- Prior chemotherapy not required

- Prior treatment for up to 2 relapses allowed

Endocrine therapy:

- See Disease Characteristics

- At least 1 week since prior tamoxifen and recovered

- No concurrent anticancer hormonal therapy

Radiotherapy:

- See Disease Characteristics

- At least 4 weeks since prior radiotherapy

- No concurrent radiotherapy

Surgery:

- See Disease Characteristics

- Recovered from prior surgical resection of recurrent or progressive disease

Other:

- At least 1 week since prior non-cytotoxic agents and recovered

- At least 1 week since prior tretinoin and recovered

- At least 2 weeks since prior drugs that affect hepatic metabolism

- No other concurrent investigational agents

- No concurrent warfarin