Phase I dose-escalation study of the investigational Aurora A kinase (AAK) inhibitor MLN8237 as an enteric-coated tablet (ECT) formulation in patients with nonhematologic malignancies.

3094 Background: The investigational drug MLN8237 is an orally available, selective AAK inhibitor with early clinical trials using a powder in capsule (PIC) formulation in a range of tumor types. This phase I/II study was conducted in pts with nonhematologic malignancies using an ECT formulation. Safety and PK from phase I are reported. Methods: Eligible pts were age ≥18 y with advanced, nonhematologic malignancies, ECOG PS 0–1, measurable disease by RECIST and ≤2 prior cytotoxic chemotherapy regimens. MLN8237 ECT was administered orally BID for 7 d + 14 d of rest (21-d cycles). Doses were escalated in a 3+3 design based on dose-limiting toxicities in cycle 1 until maximum tolerated dose (MTD). AEs were graded according to NCI-CTCAE v4.0. Results: 17 pts were treated, 5 are ongoing, and enrollment is complete. Median age was 58 y (range 34–81), and frequent tumor types included sarcoma (n=4), and ovarian (n=2). Pts received a median of 2 cycles (range 1–8) at either 10 (n=1), 20 (n=3), 40 (n=4), 50 (n=6), or 60 mg (n=3) BID. The MTD was identified as 50 mg BID. A DLT of G4 febrile neutropenia was reported at 50 mg BID. No further DLTs were reported, but at 60 mg BID, 3 pts had G4 neutropenia. The most common AEs were neutropenia (47%) and fatigue (47%). Neutropenia was the most common G≥3 AE (41%), and was generally reversible. There were 17 treatment-emergent SAEs in 9 pts; neutropenia was the only SAE to occur in >1 pt (n=2). Preliminary PK data were available in 14 pts. Following oral administration, MLN8237 ECT was absorbed at a moderate rate with an overall median Tmax of 3 h and dose-related increase in exposure over 10–50 mg BID. Mean t½ was ~20 h following multiple dosing. Conclusions: In pts with advanced non-hematologic malignancies, the data suggest that the toxicity profile of MLN8237 was predictable, generally tolerable, and manageable, and these results support a recommended phase II dose of 50 mg BID for 7 days in a 21-day cycle using the ECT formulation. The ongoing phase II portion is investigating MLN8237 in lung, breast, head/neck and gastroesophageal malignancies.