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Phase 1 study of MLN8054, a selective inhibitor of Aurora A kinase in patients with advanced solid tumors.
- Source :
-
Cancer Chemotherapy & Pharmacology . Apr2011, Vol. 67 Issue 4, p945-954. 10p. - Publication Year :
- 2011
-
Abstract
- Purpose: Aurora A kinase is critical in assembly and function of the mitotic spindle. It is overexpressed in various tumor types and implicated in oncogenesis and tumor progression. This trial evaluated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of MLN8054, a selective small-molecule inhibitor of Aurora A kinase. Methods: In this first-in-human, dose-escalation study, MLN8054 was given orally for 7, 14, or 21 days followed by a 14-day treatment-free period. Escalating cohorts of 3-6 patients with advanced solid tumors were treated until DLT was seen in ≥2 patients in a cohort. Serial blood samples were collected for pharmacokinetics and skin biopsies were collected for pharmacodynamics. Results: Sixty-one patients received 5, 10, 20, 30, or 40 mg once daily for 7 days; 25, 35, 45, or 55 mg/day in four divided doses (QID) for 7 days; or 55, 60, 70, or 80 mg/day plus methylphenidate or modafinil with daytime doses (QID/M) for 7-21 days. DLTs of reversible grade 3 benzodiazepine-like effects defined the estimated MTD of 60 mg QID/M for 14 days. MLN8054 was absorbed rapidly, exposure was dose proportional, and terminal half-life was 30-40 h. Three patients had stable disease for >6 cycles. Conclusions: MLN8054 dosing for up to 14 days of a 28-day cycle was feasible. Reversible somnolence was dose limiting and prevented achievement of plasma concentrations predicted necessary for target modulation. A recommended dose for investigation in phase 2 trials was not established. A second-generation Aurora A kinase inhibitor is in development. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 03445704
- Volume :
- 67
- Issue :
- 4
- Database :
- Academic Search Index
- Journal :
- Cancer Chemotherapy & Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 59596510
- Full Text :
- https://doi.org/10.1007/s00280-010-1377-y