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 x 3 every 28 days Cohorts of 3-6 patients were enrolled at 5 7, 9 and 12 mg/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 12 mg/m(2) dose level dose limiting neutropenia occurred in 2/6 patients and hyperbilirubinemia in 1/6 patients while at the 9 mg/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 x 3 every 28 days for children with solid tumors is 9 mg/m(2)/dose Plans for a phase II trial in select pediatric solid tumors are in development Pediatr Blood Cancer 2010 55 1323-1328 (C) 2010 Wiley Liss Inc