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The objectives of this trial were to define the toxicity profile, dose, pharmacokinetics, and pharmacodynamics of the farnesyl transferase (FTase) inhibitor, tipifarnib, in children and adolescents with hematological malignancies.Tipifarnib was administered twice daily for 21 days, repeated every 28 days starting at a dose of 300 mg/m2/dose. Pharmacokinetic sampling was performed for 36 hr after the first dose and leukemic blasts were collected pre-treatment and at steady state for determination of FTase activity.Of 29 patients enrolled, 18 were fully evaluable for toxicity, and 23 for response; 26 had pharmacokinetic and pharmacodynamic sampling. The recommended dose is 300 mg/m2/dose and toxicities included skin rash, mucositis, nausea, vomiting, and diarrhea. Neurotoxicity, which was dose-limiting in adults at doses exceeding 600 mg/dose, was infrequent and mild. The plasma pharmacokinetics of tipifarnib were highly variable but comparable to adults with acute leukemia and children with solid tumors. The median apparent clearance of tipifarnib was 630 ml/min/m2 and the median half-life was 4.7 hr. At steady state on 300 mg/m2/dose, FTase activity was inhibited by 82% in leukemic blasts. No objective responses were observed.Oral tipifarnib is well tolerated in children with leukemia on a twice daily for 21days schedule at 300 mg/m2/dose. Pediatr Blood Cancer 2011;56:226-233. © 2010 Wiley-Liss, Inc.