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 - PubMed (original) (raw)
Clinical Trial
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
Yael P Mossé et al. Clin Cancer Res. 2012.
Abstract
Purpose: 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.
Experimental design: 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.
Results: 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.
Conclusion: 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.
©2012 AACR.
Figures
Figure 1
Average concentration × time curves for each dose level (mg/m2/dose). Plasma samples were obtained on cycle 1, day 1 for patients receiving once-daily dosing (45, 60, 80, and 100 mg/m2/dose) and twice-daily dosing (30 or 40 mg/m2/dose, twice daily). For patients receiving twice-daily dosing the second dose of MLN8237 on day 1 was not administered for accurate determination of pharmacokinetic parameters.
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