RATIONALE: Imatinib mesylate may interfere with the growth of tumor cells by blocking the enzymes necessary for their growth. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining imatinib mesylate with radiation therapy may kill more tumor cells.

PURPOSE: Phase I/II trial to compare the effectiveness of imatinib mesylate with or without radiation therapy in treating young patients who have newly diagnosed or recurrent glioma.

Condition	Treatment or Intervention	Phase
childhood central nervous system germ cell tumor high-grade childhood cerebral astrocytoma untreated childhood brain stem glioma recurrent childhood brain stem glioma recurrent childhood cerebral astrocytoma	Drug: imatinib mesylate  Procedure: adjuvant therapy  Procedure: enzyme inhibitor therapy  Procedure: protein tyrosine kinase inhibitor therapy  Procedure: radiation therapy	Phase I Phase II

Further Study Details: 

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.

• 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.
• (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.

Ages Eligible for Study:  3 Years   -   21 Years,  Genders Eligible for Study:  Both

Criteria

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)

California
      UCSF Comprehensive Cancer Center, San Francisco,  California,  94143,  United States; Recruiting
District of Columbia
      Children's National Medical Center, Washington,  District of Columbia,  20010-2970,  United States; Recruiting
Illinois
      Children's Memorial Hospital - Chicago, Chicago,  Illinois,  60614,  United States; Recruiting
Maryland
      Warren Grant Magnuson Clinical Center - NCI Clinical Studies Support, Bethesda,  Maryland,  20892-1182,  United States; Recruiting
Massachusetts
      Children's Hospital Boston, Boston,  Massachusetts,  02115,  United States; Recruiting
      Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute, Boston,  Massachusetts,  02115,  United States; Recruiting
North Carolina
      Duke Comprehensive Cancer Center, Durham,  North Carolina,  27710,  United States; Recruiting
Pennsylvania
      Children's Hospital of Philadelphia, Philadelphia,  Pennsylvania,  19104-4318,  United States; Recruiting
      Children's Hospital of Pittsburgh, Pittsburgh,  Pennsylvania,  15213,  United States; Recruiting
Tennessee
      St. Jude Children's Research Hospital, Memphis,  Tennessee,  38105-2794,  United States; Recruiting
Texas
      Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital, Houston,  Texas,  77030-2399,  United States; Recruiting
Washington
      Children's Hospital and Regional Medical Center - Seattle, Seattle,  Washington,  98105,  United States; Recruiting

Study chairs or principal investigators

Ian F. Pollack, MD,  Study Chair,  Children's Hospital of Pittsburgh   

Study ID Numbers:  CDR0000068761; PBTC-006; NCT00021229
Record last reviewed:  May 2004
Last Updated:  April 4, 2005
Record first received:  July 11, 2001
ClinicalTrials.gov Identifier:  NCT00021229
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08