The purpose of this study is to estimate the maximum-tolerated dose (MTD) and describe toxicities and preliminary clinical effects of tipifarnib, a farnesyltransferase (FTase) inhibitor, administered concurrently with radiation therapy in children with newly diagnosed intrinsic diffuse brainstem glioma (BSG). Children >or=3 and <or=21 years of age with newly diagnosed nondisseminated intrinsic diffuse BSG were treated with concurrent tipifarnib and radiation, followed by adjuvant tipifarnib. Escalating doses of tipifarnib were administered orally twice daily, continuously, for the entire duration of radiation, followed by a 2-week break. Postradiation tipifarnib, 200 mg/m(2)/dose, was administered twice daily for 21 consecutive days, in 28-day cycles. Seventeen patients, median age 5.9 years (range, 3.6-13.8), received external beam radiation therapy administered concurrently with tipifarnib at dose levels ranging from 100 to 150 mg/m(2)/dose, followed by adjuvant tipifarnib for up to 24 months in the absence of tumor progression or unacceptable toxicity. Dose-limiting toxicities were grade 3 skin rash in one patient at the 125 mg/m(2) dose level and two patients at the 150 mg/m(2) dose level, and grade 3 pneumonia with a normal absolute neutrophil count (ANC) in one patient at the 150 mg/m(2) dose level. One patient had isolated grade 4 neutropenia at the 150 mg/m(2) dose level. The MTD of tipifarnib administered was estimated as 125 mg/m(2)/dose b.i.d. When administered concurrently with radiation, the dose-limiting toxicities of tipifarnib are rash, infection with normal ANC, and neutropenia. The MTD of tipifarnib with concurrent radiation is 125 mg/m(2)/dose b.i.d. One-year survival and progression-free survival estimates are 36.4% (SE 16.7%) and 9.4% (SE 6.3%), respectively.