• Progression-free survival at 1 year [ Designated as safety issue: No ]
  

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of tipifarnib when administered with radiotherapy in patients with non-disseminated, diffuse, intrinsic brainstem gliomas.
• Determine the efficacy of this regimen in these patients.

Secondary

• Determine the toxic effects of this regimen in these patients.
• Determine the radiographic changes of brainstem gliomas using MRI, perfusion and diffusion imaging, and positron-emission tomography scans in patients treated with this regimen.

OUTLINE: This is a phase I (closed to accrual as of 1/3/06), multicenter, dose-escalation study of tipifarnib followed by a phase II safety and efficacy study.

• Phase I (closed to accrual as of 1/3/06): Patients undergo radiotherapy 5 days a week for 6 weeks. Beginning 0-2 days before radiotherapy, patients receive oral tipifarnib twice daily until the completion of radiotherapy. Beginning 2 weeks after the completion of radiotherapy, patients receive oral tipifarnib twice daily in weeks 1-3. Treatment repeats every 4 weeks for up to 24 additional courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of tipifarnib during radiotherapy until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose level preceding that at which 2 of 6 patients experience dose-limiting toxicity.

• Phase II: Patients undergo radiotherapy and receive tipifarnib at the MTD as in phase I (closed to accrual as of 1/3/06) . Treatment continues for up to 24 months (26 courses) in the absence of disease progression or unacceptable toxicity.

Patients are followed for up to 1 year.

PROJECTED ACCRUAL: A total of 3-46 patients (3-12 patients for phase I [closed to accrual as of 1/3/06] and a total of 40 patients for phase II [including 6 patients treated in the dose-finding portion of phase I (closed to accrual as of 1/3/06)]) will be accrued for this study within 2.3 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed non-disseminated, intrinsic diffuse brainstem glioma

  • Newly diagnosed disease
  • No disseminated disease

PATIENT CHARACTERISTICS:

Age

• 3 to 21

Performance status

• Karnofsky 50-100% (patients 17 to 21 years of age) OR
• Lansky 50-100% (patients 3 to 16 years of age)

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,000/mm^3
• Platelet count ≥ 100,000/mm^3*
• Hemoglobin ≥ 8 g/dL* NOTE: *Transfusion independent

Hepatic

• ALT and AST < 2.5 times upper limit of normal (ULN)
• Bilirubin ≤ 1.5 ULN

Renal

• Creatinine < ULN OR
• Glomerular filtration rate > 70 mL/min

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for at least 6 months after study participation
• No other significant medical illness that would preclude study participation
• No uncontrolled infection
• No disease that would obscure toxicity or dangerously alter drug metabolism
• No known allergy to topical or systemic azoles (e.g., fluconazole, ketoconazole, or itraconazole)

PRIOR CONCURRENT THERAPY:

Biologic therapy

• More than 2 weeks since prior filgrastim (G-CSF), sargramostim (GM-CSF), or epoetin alfa
• No prior bone marrow transplantation

Chemotherapy

• No prior chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• No prior radiotherapy

Surgery

• Not specified

Other

• No concurrent enzyme-inducing anticonvulsant drugs (EIACD)

  • Patients switched from EIACD to non-EIACD for at least 7 days before study participation allowed
• No other concurrent anticancer therapy
• No other concurrent experimental drugs