OBJECTIVES:

Primary

• Determine the maximum tolerated dose of imatinib mesylate with or without radiotherapy in children with newly diagnosed poor prognosis brainstem glioma or recurrent high-grade intracranial glioma stratified according to the use of enzyme-inducing anticonvulsant drugs (EIACDs). (Phase I) (Phase I, strata I and IIA closed to accrual as of 5/10/04.)
• Determine the safety and efficacy of this drug in patients with diffuse intrinsic brainstem gliomas. (Phase II)

Secondary

• Determine the therapeutic activity of this regimen in these patients. (Phase II)
• Determine the pharmacokinetics of these regimens in these patients. (Phase I) (Phase I, strata I and IIA closed to accrual as of 5/10/04.)
• Compare the effects of EIACD use in these patients when treated with this drug. (Phase I) (Phase I, strata I and IIA closed to accrual as of 5/10/04.)
• Determine the progression-free survival and overall survival of patients treated with this drug. (Phase II)

OUTLINE: This is a phase I dose-escalation, multicenter study followed by a phase II. Patients are stratified according to tumor type (newly diagnosed intrinsic brainstem glioma vs recurrent/refractory intracranial high-grade glioma). Patients in stratum II (phase I only) are further stratified according to concurrent use of enzyme-inducing anticonvulsant drugs (EIACDs) (yes vs no). Patients are assigned to one of two strata in the phase I study.

• Phase I

  • Stratum I (newly diagnosed brainstem glioma): Patients undergo radiotherapy once daily five days a week for 6 weeks. Beginning 2-3 weeks after completion of radiotherapy, patients without evidence of intratumoral bleed receive oral imatinib mesylate twice daily. Imatinib mesylate treatment repeats every 4 weeks for up to 13 courses in the absence of disease progression or unacceptable toxicity. (Closed to accrual as of 5/10/04.)
  • Stratum II A (recurrent or refractory high-grade intracranial gliomas/no concurrent EIACs): Patients receive imatinib mesylate as in stratum I. (Closed to accrual as of 5/10/04).
  • Stratum II B (recurrent or refractory high-grade intracranial gliomas and concurrent EIACs): Patients receive imatinib mesylate as in stratum I.

Cohorts of 3-6 patients receive escalating doses of imatinib mesylate until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which at least 5 of 6 patients experience no dose-limiting toxicity.

• Phase II: (Open to accrual as of 5/10/04.)

  • Stratum I only: Patients undergo radiotherapy as in phase I. Patients receive imatinib mesylate at the MTD established in phase I.

Patients are followed every 3 months for 1 year, every 6 months for 4 years, and then annually thereafter.

PROJECTED ACCRUAL: Approximately 140 patients will be accrued for this study within 2 years.

DISEASE CHARACTERISTICS:

• Stratum I:

  • Newly diagnosed diffuse intrinsic brainstem malignant glioma
  • No disseminated disease
  • No radiographic evidence of intratumoral hemorrhage before or after radiotherapy

• Stratum II (A- no concurrent enzyme-inducing anticonvulsant drugs [EIACDs] vs B-concurrent use of EIACDs [closed to accrual as of 5/10/04]):

  • Histologically confirmed recurrent or refractory anaplastic astrocytoma, glioblastoma multiforme, or other high-grade glioma (including recurrent brain stem glioma
  • No intratumoral hemorrhage unrelated to prior surgical procedure

PATIENT CHARACTERISTICS:

Age:

• 3 to 21

Performance status:

• Karnofsky 50-100% OR
• Lansky 50-100%

Life expectancy:

• Not specified

Hematopoietic:

• Absolute neutrophil count greater than 1,000/mm^3
• Platelet count greater than 100,000/mm^3 (transfusion independent)
• Hemoglobin greater than 8 g/dL (transfusion allowed)

Hepatic:

• Bilirubin no greater than 1.5 times normal for age
• SGPT less than 3 times normal for age
• Albumin at least 2 g/dL
• No significant hepatic disease

Renal:

• Creatinine less than 1.5 times normal for age OR
• Glomerular filtration rate greater than 70 mL/min
• No significant renal disease

Cardiovascular:

• No significant cardiac disease
• No deep venous or arterial thrombosis within the past 6 weeks

Pulmonary:

• No significant pulmonary disease

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective barrier contraception during and for 6 months after study participation
• No uncontrolled infection
• No significant gastrointestinal disease
• No significant psychiatric disease
• Neurological deficits allowed if stable for at least 1 week prior to study (stratum II)

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• More than 2 weeks since prior colony-stimulating growth factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF], or epoetin alfa)
• At least 3 months since prior bone marrow transplantation (stratum II)

Chemotherapy:

• No prior chemotherapy (stratum I)
• At least 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas) and recovered (stratum II)

Endocrine therapy:

• Prior routine corticosteroids allowed
• Concurrent corticosteroids allowed if on stable or decreasing dose for at least 1 week prior to study

Radiotherapy:

• Stratum I:

  • No prior radiotherapy

• Stratum II:

  • At least 3 months since prior craniospinal radiotherapy (18 Gy or more)
  • At least 8 weeks since prior local radiotherapy to primary tumor
  • At least 2 weeks since prior focal radiotherapy for symptomatic metastases

Surgery:

• See Disease Characteristics

Other:

• No prior imatinib mesylate (stratum II)
• At least 2 weeks since beginning or discontinuing medications affecting cytochrome P450 3A4, 5, and 7 isoenzyme metabolism
• No other concurrent anticancer drug
• No other concurrent experimental drug
• No concurrent warfarin
• No concurrent enzyme-inducing anticonvulsant drugs (stratum I)