Lattice_grid_med
Powered by LatticeGrid

Search Enter term and hit return. Use '*' for as a wildcard.
Dees EC, Infante JR, Cohen RB, O'Neil BH, Jones S, von Mehren M, Danaee H, Lee Y, Ecsedy J, Manfredi M, Galvin K, Stringer B, Liu H, Eton O, Fingert H, Burris H
Phase 1 study of MLN8054, a selective inhibitor of Aurora A kinase in patients with advanced solid tumors
Cancer Chemotherapy and Pharmacology (2011) 67:945-54.
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.
Note
Publication Date: 2011-04-01.
PMCID: PMC3026871
Back
Last updated on Thursday, August 06, 2020