Phase I trial of the investigational aurora A kinase (AAK) inhibitor MLN8237 (alisertib) in combination with docetaxel (DTX) in patients (pts) with advanced solid tumors, including castration-resistant prostate cancer (CRPC).

217 Background: Overexpression of AAK, a key regulator of mitosis, is seen in various solid tumors, including prostate cancer. This open-label, Phase 1 trial investigated the safety/tolerability of MLN8237, an oral selective AAK inhibitor, combined with DTX in pts with advanced solid tumors, including CRPC. Methods: Previously treated pts aged ≥18 y who were candidates for DTX received 21-day cycles of MLN8237 10–50 mg BID on days 1–7, escalated in 3+3 dosing cohorts, plus DTX 60 or 75 mg/m2 on day 1. To manage toxicity, a 5-day MLN8237 regimen was later evaluated with DTX 60 or 75 mg/m2+ G-CSF support. Primary endpoints were safety/tolerability and recommended phase II dose/schedule (RP2D). Pharmacokinetics (PK) and antitumor activity (RECIST 1.1/PSA) were also assessed. Results: 35 pts (median age 63 y [25–87]; 71% male; 17 CRPC) recruited into 8 cohorts received a median of 3 (1–33) cycles; 15 pts (11 CRPC) had ≥6 cycles. 14 DLTs were seen in 11 pts (5 CRPC) in Cycle 1: G4 neutropenia >7 days (n=3), G3/4 febrile neutropenia (FN; n=7), G3 stomatitis (n=3), and G3 urinary tract infection (n=1). The RP2D was MLN8237 20 mg BID on Days 1–7 + DTX 75 mg/m2 in 21-day cycles without G-CSF. Common G≥3 drug-related AEs included neutropenia (86%), leukopenia (31%), FN (23%) and stomatitis (14%). 20 (57%) pts reported SAEs, most commonly FN (n=8). 2 pts withdrew due to AEs, inc. 1 death (G3 FN; G3 mucositis); 4 pts continue on study. On-study deaths (n=2; disease progression) were not considered drug-related. Steady-state MLN8237 exposure (AUCss) increased approximately dose-proportionally over 10–30 mg BID when combined with DTX (n=16). Analysis of the effect of MLN8237 on DTX PK at RP2D is ongoing. Among 11 evaluable CRPC pts, 6 had PR (4 had PSA50) and 6 had SD (4 with PSA50). 2 other pts (bladder cancer and angiosarcoma) also had PR. Conclusions: The RP2D was MLN8237 20 mg BID on days 1–7 + DTX 75 mg/m2 on day 1. Despite myelosuppression, the combination of MLN8237 and DTX had a generally manageable toxicity profile in pts with advanced solid tumors. Further clinical study of this combination, particularly in CRPC pts, is warranted. Clinical trial information: NCT01094288.