Phase 1 Pharmacokinetic/Pharmacodynamic Study of MLN8237 - An Investigational, Oral, Selective Aurora A Kinase Inhibitor - In Patients With Advanced Solid Tumors
Mené sur 59 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue l'activité antitumorale et la toxicité de l'alisertib, un inhibiteur de la kinase Aurora A
Purpose: Aurora A kinase (AAK) is a key regulator of mitosis and a target for anti-cancer drug development. This phase 1 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 (QD) or twice daily (BID) for 7, 14, or 21 consecutive days, followed by 14 days recovery, in 21-, 28-, or 35-day cycles. Dose-limiting toxicities (DLTs) and the 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 BID and 50 mg QD, 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 demonstrated 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. Conclusion: The recommended phase 2 dose of MLN8237 is 50 mg BID on the 7-day schedule, which is being evaluated further in a variety of malignancies, including in a phase 3 trial in peripheral T-cell lymphoma.