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01-04-2011 | Original Article

Phase 1 study of MLN8054, a selective inhibitor of Aurora A kinase in patients with advanced solid tumors

Authors: E. Claire Dees, Jeffrey R. Infante, Roger B. Cohen, Bert H. O’Neil, Suzanne Jones, Margaret von Mehren, Hadi Danaee, Yih Lee, Jeffrey Ecsedy, Mark Manfredi, Katherine Galvin, Bradley Stringer, Hua Liu, Omar Eton, Howard Fingert, Howard Burris

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2011

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.

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Title: Phase 1 study of MLN8054, a selective inhibitor of Aurora A kinase in patients with advanced solid tumors
Authors: E. Claire Dees
Jeffrey R. Infante
Roger B. Cohen
Bert H. O’Neil
Suzanne Jones
Margaret von Mehren
Hadi Danaee
Yih Lee
Jeffrey Ecsedy
Mark Manfredi
Katherine Galvin
Bradley Stringer
Hua Liu
Omar Eton
Howard Fingert
Howard Burris
Publication date: 01-04-2011
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 4/2011
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-010-1377-y

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