PURPOSE: Aurora A kinase (AAK) is a key regulator of mitosis and a target for 
anticancer drug development. This phase I study investigated the safety, 
pharmacokinetics, and pharmacodynamics of MLN8237 (alisertib), an 
investigational, oral, selective AAK inhibitor, in 59 adults with advanced solid 
tumors.
EXPERIMENTAL DESIGN: Patients received MLN8237 once daily or twice daily for 7, 
14, or 21 consecutive days, followed by 14 days recovery, in 21-, 28-, or 35-day 
cycles. Dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) for 
the 7- and 21-day schedules were determined. Pharmacokinetic parameters were 
derived from plasma concentration-time profiles. AAK inhibition in skin and 
tumor biopsies was evaluated and antitumor activity assessed.
RESULTS: Neutropenia and stomatitis were the most common DLTs. The MTD for the 
7- and 21-day schedules was 50 mg twice daily and 50 mg once daily, 
respectively. MLN8237 absorption was fast (median time to maximum concentration, 
2 hours). Mean terminal half-life was approximately 19 hours. At steady state, 
pharmacodynamic effects were shown by accumulation of mitotic and apoptotic 
cells in skin, and exposure-related increases in numbers of mitotic cells with 
characteristic spindle and chromosomal abnormalities in tumor specimens, 
supporting AAK inhibition by MLN8237. Stable disease was observed and was 
durable with repeat treatment cycles, administered over 6 months, in 6 patients, 
without notable cumulative toxicity.
CONCLUSIONS: The recommended phase II dose of MLN8237 is 50 mg twice daily on 
the 7-day schedule, which is being evaluated further in a variety of 
malignancies, including in a phase III trial in peripheral T-cell lymphoma.