A pediatric phase I trial and pharmacokinetic study of ispinesib: A Children's Oncology Group phase I consortium study

Purpose: To determine the maximum-tolerated dose, dose-limiting toxicities, and pharmacokinetics of the kinesin spindle protein inhibitor ispinesib in pediatric patients with recurrent or refractory solid tumors. Subjects and Methods: Ispinesib was administered as 1-hr intravenous infusion weekly×3, every 28 days. Cohorts of 3-6 patients were enrolled at 5, 7, 9, and 12mg/m ²/dose. Serial plasma samples for pharmacokinetic analyses were obtained after the first dose. Results: Twenty-four (13 females) patients with a median (range) age of 10 years (1-19) were enrolled in the study. At the 12mg/m ² dose level dose-limiting neutropenia occurred in 2/6 patients and hyperbilirubinemia in 1/6 patients, while at the 9mg/m ² dose level 1/6 patients had dose-limiting neutropenia. There were no objective responses, but three patients (diagnoses of anaplastic astrocytoma, alveolar soft part sarcoma, and ependymoblastoma) had stable disease for 4-7 courses. There was substantial interpatient variation in drug disposition. The median (range) terminal elimination half-life was 16 (8-44)hr and the plasma drug clearance was 5 (1-14)L/hr/m ². Conclusions: The maximum tolerated and recommended phase II dose for ispinesib administered weekly×3 every 28 days for children with solid tumors is 9mg/m ²/dose. Plans for a phase II trial in select pediatric solid tumors are in development.