Phase I/II study of the investigational aurora A kinase (AAK) inhibitor MLN8237 (alisertib) in patients (pts) with non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), breast cancer (BrC), head/neck cancer (H&N), and gastroesophageal (GE) adenocarcinoma: Preliminary phase II results.

Abstract

3010 Background: AAK is a key mitotic regulator that is amplified or overexpressed in multiple tumor types. MLN8237 is an investigational oral, selective AAK inhibitor being studied in both hematologic (phase III) and nonhematologic malignancies. In the phase 1 part of this study, MLN8237 was generally well tolerated in pts with solid tumors. The maximum tolerated dose was 50 mg BID for 7d + 2 wks rest in 21-d cycles; this dose was recommended for phase II evaluation. Here we report preliminary data from the 5-arm phase 2 part (NCT01045421). Methods: 20 pts each with one of 5 tumor types in the relapsed/refractory setting were enrolled in phase II for efficacy evaluation: NSCLC (inc. 8–10 pts with mainly squamous-cell histology), SCLC (inc. 8–12 chemotherapy refractory pts), BrC (inc. 8–10 pts with a basal-like intrinsic subtype, and 8–10 HER2+ pts), H&N (inc. 8–12 pts with tonsillar or base-of-tongue disease), or GE adenocarcinoma. Pts were aged ≥18 y, and had ECOG PS 0–1, measurable disease by RECIST, and ≤2 prior cytotoxic chemotherapy regimens (≤4 in BrC). Oral MLN8237 was administered as an enteric-coated tablet at 50 mg BID for 7d + 2 wks rest in 21-d cycles. The primary endpoint was overall response rate. Response was determined by RECIST v1.1. Each arm with ≥2 partial responses (PR) is being expanded with 25 additional pts. Results: In 100 efficacy-evaluable pts, median age was 59 y (range 33–88) and 89% were caucasian. Pts received a median of 3 cycles (range 1–9). PRs were observed in 11 pts: H&N, SCLC (each n=3), BrC, GE adenocarcinoma (each n=2), and NSCLC (n=1). 45 pts had a best response of stable disease. In the safety population (n=196), most frequent grade ≥3 drug-related AEs were neutropenia (37%), leukopenia (12%), fatigue, anemia, stomatitis, and thrombocytopenia (each 6%). Updated data will be presented. Conclusions: Preliminary phase II data suggest that oral MLN8237 is tolerable and has antineoplastic activity in a range of solid tumors studied. This study is currently ongoing to further evaluate MLN8237 in the expansion cohorts.