Capecitabine and Radiation Therapy in Treating Young Patients With Newly Diagnosed, Nonmetastatic Brain Stem Glioma or High-Grade Glioma

OBJECTIVES:

Primary

• Estimate the maximum tolerated dose of capecitabine rapidly disintegrating tablets (RDT) administered concurrently with radiotherapy in young patients with newly diagnosed, nondisseminated intrinsic brain stem glioma or high-grade glioma.
• Describe the dose-limiting toxicity in patients treated with this regimen.

Secondary

• Describe the safety profile of this regimen.
• Characterize the pharmacokinetics of capecitabine RDT in these patients.
• Explore the exposure-response relationship for measures of safety and effectiveness using pharmacokinetic and pharmacodynamic models.
• Describe the antitumor activity of this regimen observed in these patients.
• Estimate distributions of progression-free survival and survival in patients treated with this regimen.
• Characterize radiographic changes in tumor, using MRI, perfusion and diffusion MRI, and positron emission tomography (PET) scans, in patients treated with this regimen.

OUTLINE: This a multicenter, dose-escalation study of capecitabine rapidly disintegrating tablets (RDT).

Patients undergo radiotherapy once daily, 5 days a week, for approximately 6 weeks. Beginning within 24 hours of starting radiotherapy, patients also receive oral capecitabine RDT twice daily on days 1-21. Treatment with capecitabine RDT repeats every 21 days for 3 courses.

Cohorts of 3-6 patients receive escalating doses of capecitabine RDT 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.

Beginning in week 12, patients receive capecitabine RDT at a fixed dose twice daily on days 1-14. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo blood collection periodically during course 1 for pharmacokinetic correlative studies. Patients also undergo MRI, and rapid perfusion/diffusion MRI at baseline and periodically during study for radiographic correlative studies.

After completion of study treatment, patients are followed periodically for 2 years.

PROJECTED ACCRUAL: A total of 18 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• One of the following newly diagnosed, nondisseminated brain tumors:

• Intrinsic infiltrating brain stem glioma

• Histopathologic diagnosis not required
• Histopathologically confirmed high-grade glioma, meeting all of the following criteria:

• Underwent prior definitive surgery ≤ 28 days ago with incompletely resected disease
• Any of the following subtypes allowed:

• Anaplastic astrocytoma
• Glioblastoma multiforme
• Other high-grade glioma
• No anaplastic oligodendroglioma

PATIENT CHARACTERISTICS:

• Karnofsky performance scale (PS) 50-100% (if > 16 years of age) or Lansky PS 50-100% (if ≤ 16 years of age)
• Absolute neutrophil count ≥ 1,000/mm³
• Platelet count ≥ 100,000/mm³ (transfusion independent)
• Hemoglobin ≥ 8 g/dL (transfusion independent)
• Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR creatinine based on age as follows:

• No more than 0.8 mg/dL (for patients 5 years of age and under)
• No more than 1 mg/dL (for patients 6-10 years of age)
• No more than 1.2 mg/dL (for patients 11-15 years of age)
• No more than 1.5 mg/dL (for patients over 15 years of age)
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• ALT ≤ 5 times ULN
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No uncontrolled infection
• No significant cardiac, hepatic, gastrointestinal, renal, pulmonary, or other systemic disease
• No known hypersensitivity to capecitabine or any of its components
• No known dihydropyrimidine dehydrogenase (DPD) deficiency

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Prior dexamethasone and/or surgery allowed
• No prior chemotherapy, radiotherapy, immunotherapy, or bone marrow transplantation
• No other concurrent anticancer or experimental drug therapies or agents
• No concurrent warfarin or sorivudine or its chemically related analogues (e.g., brivudine)