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, Emily Lipsitz, Elizabeth Fox, David T. Teachey, John M. Maris, Brenda Weigel, Peter C. Adamson, Mark A. Ingle, Charlotte H. Ahern, Susan M. Blaney

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

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/m2/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/m2, and one of six patients had dose-limiting mood alteration at 80 mg/m2. At 45 mg/m2, one of six patients experienced dose-limiting mucositis. Mucositis and myelosuppression were dose limiting at 80 mg/m2 on the twice-daily schedule, and one of five patients at 60 mg/m2 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/m2/d once daily for seven days.

Original languageEnglish (US)
Pages (from-to)6058-6064
Number of pages7
JournalClinical Cancer Research
Volume18
Issue number21
DOIs
StatePublished - Nov 1 2012

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