Pediatric Phase 1 Trial and Pharmacokinetic Study of MLN8237, an Investigational Oral Selective Small Molecule Inhibitor of Aurora Kinase A: A Children's Oncology Group Phase 1 Consortium study
Mené sur 37 patients pédiatriques atteints d'une tumeur solide récidivante ou réfractaire, cet essai de phase I évalue un composé appelé MLN8237, un inhibiteur de la kinase Aurora A
Purpose: MLN8237, a selective small molecule inhibitor of Aurora Kinase A, has activity in a broad range of preclinical pediatric cancer models. We performed a phase 1 trial in children with refractory/recurrent solid tumors to define the maximum tolerated dose, toxicities and pharmacokinetic properties of MLN8237. Experimental Design: MLN8237 was administered orally once daily or divided twice daily for 7 days, every 21 days. Using a rolling-six design, four dose levels (45, 60, 80, 100 mg/m2/day) were evaluated on the once daily schedule, and two dose levels (60, 80 mg/m2/day) on the twice-daily schedule. Pharmacokinetic studies were performed with initial dose and trough drug concentrations measured at steady state. Results: Thirty-seven patients were enrolled. On the once daily schedule, myelosuppression was dose limiting in 3/4 patients at 100 mg/m2 and 1/6 patients had dose-limiting mood alteration at 80 mg/m2. At 45 mg/m2, 1/6 patients experienced dose-limiting mucositis. Mucositis and myelosuppression were dose limiting at 80 mg/m2 on the twice-daily schedule, and 1/5 patients at 60 mg/m2 on the twice-daily schedule experienced a dose limiting alkaline phosphatase. 5/11 patients experienced hand-foot-skin syndrome with twice daily dosing versus 1/21 after once daily dosing. There was one partial response and six with prolonged stable disease among 33 evaluable subjects. Conclusions: 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 2 dose is 80 mg/m2/d once daily for 7 days.