Recommended phase (Ph) II dose (RP2D) selection for investigational Aurora A kinase (AAK) inhibitor MLN8237 (Alisertib; A) combined with paclitaxel (P): Clinical pharmacokinetics (PK), drug-drug interaction (DDI) assessment, and translational exposure-efficacy modeling.

2598 Background: Two maximum tolerated doses (MTDs) were reported for P/A combination in Ph 1 of NCT01091428 (Falchook, ASCO 2012). Here we report clinical PK/DDI results in the context of preclinical exposure-efficacy relationship for P/A to select RP2D. Methods: Pts with advanced ovarian/breast cancer received A (oral BID D1–3, 8–10, 15–17) with 60 or 80 mg/m2 P on D1, 8, 15 in 28-D cycles, with 3+3 dose escalation of A. PK of P was assessed on cycle 1 D1 (P+A); during cycle 2, A doses were withheld on D1–3 allowing for PK of P to be determined in the absence of A on D1. Isobolographic analysis of the response surface relating area under the plasma concentration-time curve (AUC) of A and P to tumor growth inhibition in mice bearing MDA-MB-231 xenografts incorporated mouse-human ratios of plasma free fraction and maximum tolerated exposures, allowing rank ordering of predicted antitumor activity for combined P and A. Results: MTDs were 80 mg/m2 P + 10 mg BID A (80P/10A) and 60 mg/m2 P + 40 mg BID A (60P/...