TY - JOUR
T1 - Pediatric phase I trial and pharmacokinetic study of MLN8237, an investigational oral selective small-molecule inhibitor of Aurora kinase A
T2 - A children's oncology group phase I consortium study
AU - Mossé, Yael P.
AU - Lipsitz, Emily
AU - Fox, Elizabeth
AU - Teachey, David T.
AU - Maris, John M.
AU - Weigel, Brenda
AU - Adamson, Peter C.
AU - Ingle, Mark A.
AU - Ahern, Charlotte H.
AU - Blaney, Susan M.
PY - 2012/11/1
Y1 - 2012/11/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-11-3251
DO - 10.1158/1078-0432.CCR-11-3251
M3 - Article
C2 - 22988055
AN - SCOPUS:84868542839
SN - 1078-0432
VL - 18
SP - 6058
EP - 6064
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -