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.

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Figures

Figure 1

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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References

    1. Nigg EA. Mitotic kinases as regulators of cell division and its checkpoints. Nat Rev Mol Cell Biol. 2001;2:21–32. - PubMed
    1. Macurek L, Lindqvist A, Lim D, Lampson MA, Klompmaker R, Freire R, et al. Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery. Nature. 2008;455:119–23. - PubMed
    1. Sasai K, Parant JM, Brandt ME, Carter J, Adams HP, Stass SA, et al. Targeted disruption of Aurora A causes abnormal mitotic spindle assembly, chromosome misalignment and embryonic lethality. Oncogene. 2008;27:4122–7. - PubMed
    1. Yang G, Chang B, Yang F, Guo X, Cai KQ, Xiao XS, et al. Aurora kinase A promotes ovarian tumorigenesis through dysregulation of the cell cycle and suppression of BRCA2. Clin Cancer Res. 2010;16:3171–81. - PMC - PubMed
    1. Macarulla T, Ramos FJ, Tabernero J. Aurora kinase family: a new target for anticancer drug. Recent Pat Anticancer Drug Discov. 2008;3:114–22. - PubMed

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