A phase 1 study of ABT-751, an orally bioavailable tubulin inhibitor, administered daily for 7 days every 21 days in pediatric patients with solid tumors.

PURPOSE: To determine the toxicity profile, dose-limiting toxicities, and maximum tolerated dose of ABT-751 administered orally once daily for 7 days, repeated every 21 days. EXPERIMENTAL
DESIGN: Patients who were </=18 years of age, with relapsed or refractory solid tumors, and who were able to swallow capsules were eligible. The starting dose was 100 mg/m(2)/d (n = 3) and was escalated to 130 mg/m(2)/d (n = 6), 165 mg/m(2)/d (n = 6), 200 mg/m(2)/d (n = 6), and 250 mg/m(2)/d (n = 2) in cohorts of three to six patients. The maximum tolerated dose was determined from dose-limiting toxicities occurring during the first treatment cycle.
RESULTS: Twenty-four children (median age, 13 years; range, 4-18 years) were enrolled; 23 were evaluable for toxicity. Diagnoses included neuroblastoma (n = 8), sarcomas (n = 8), primary brain tumors (n = 2), Wilms' tumor (n = 2), and other solid tumors (n = 3). Dose-limiting toxicities (grade 3 sensory and motor neuropathy, grade 3 hypertension, and grade 3 fatigue) were observed in patients enrolled at the 250 mg/m(2)/d dose level. The maximum tolerated dose of ABT-751 administered daily for 7 days every 21 days was 200 mg/m(2)/d. Non-dose-limiting toxicities at the maximum tolerated dose included anemia, fatigue, peripheral sensory neuropathy, abdominal pain, nausea, constipation, anorexia, fever, and weight loss. Myelosuppression was minimal at the maximum tolerated dose. The median number of cycles administered is 2 (range, 1-50). No significant ABT-751-related cumulative toxicities were observed.
CONCLUSION: ABT-751 is well tolerated in children. The recommended dose for phase 2 trials in solid tumors is 200 mg/m(2)/d administered orally, daily for 7 days every 21 days. This dose is >40% higher than the maximum tolerated dose in adults receiving the same dosing schedule.