Pediatric Phase I Trial and Pharmacokinetic Study of MLN8237, an Investigational Oral Selective Small-Molecule Inhibitor of Aurora Kinase A: A Children's Oncology Group Phase I Consortium Study

Abstract

MLN8237, a selective small-molecule inhibitor of Aurora kinase A, has activity in a broad range of preclinical pediatric cancer models. We conducted a phase I trial in children with refractory/recurrent solid tumors to define the maximum-tolerated dose, toxicities, and pharmacokinetic properties of MLN8237. MLN8237 was administered orally either once daily or divided twice daily for seven days, every 21 days. Using a rolling-six design, four dose levels (45, 60, 80, and 100 mg/m(2)/day) were evaluated on the once-daily schedule, and two dose levels (60 and 80 mg/m(2)/d) on the twice-daily schedule. Pharmacokinetic studies were conducted with the initial dose and trough drug concentrations also measured at the steady state. Thirty-seven patients were enrolled. On the once-daily dosing schedule, myelosuppression was dose limiting in three of four patients at 100 mg/m(2), and one of six patients had dose-limiting mood alteration at 80 mg/m(2). At 45 mg/m(2), one of six patients experienced dose-limiting mucositis. Mucositis and myelosuppression were dose limiting at 80 mg/m(2) on the twice-daily schedule, and one of five patients at 60 mg/m(2) on the twice-daily schedule experienced a dose-limiting alkaline phosphatase. Five of 11 patients experienced hand-foot-skin syndrome with twice-daily dosing versus one of 21 after once-daily dosing. There was one partial response and six with prolonged stable disease among 33 evaluable subjects. The twice-daily dose regimen is well tolerated in adults; however, children experienced a greater frequency of myelosuppression and hand-foot-skin syndrome on this schedule. Children tolerated a higher dose and the recommended pediatric phase II dose is 80 mg/m(2)/d once daily for seven days.