MLN8237 (ALISERTIB), An Investigational Aurora a Kinase (AAK) Inhibitor, in Patients with Advanced Solid Tumors Including Castration-Resistant Prostate Cancer (CRPC) Receiving a Standard Docetaxel Regimen: Preliminary Phase 1 Results

ABSTRACT Background AAK is a key mitotic regulator overexpressed/amplified in a variety of tumor types including prostate cancer. MLN8237 is an oral, selective AAK inhibitor. Here we report emerging data from the first clinical study of MLN8237 in combination with docetaxel in pts with solid tumors or CRPC. Methods Pts aged ≥18 y with ≤3 prior myelosuppressive chemotherapy regimens who were candidates for docetaxel received MLN8237 BID (days 1–5 or 1–7) in 3 + 3 dosing cohorts plus docetaxel on day 1 in 21-d cycles. Primary objectives were safety/tolerability and to determine a recommended phase 2 dose/schedule (RP2D); secondary objectives were pharmacokinetics (PK) and antitumor activity (RECIST v1.1 and/or PSA response by PCWG2). Results 22 pts in 5 dose cohorts received a median of 5 cycles (range 1–17); 9 pts remain on therapy. Median age was 63 y (36–87), 82% were male, and 14 had CRPC. 8 pts reported dose-limiting toxicities including G4 neutropenia >7 days (n = 5) and G3/4 febrile neutropenia (n = 3). MTD has not yet been reached. 21 pts reported drug-related AEs; G ≥ 3 in 20 pts, including neutropenia (86%), leukopenia (27%), and febrile neutropenia (23%). 11 pts had serious AEs and 3 discontinued due to AEs. There were 2 on-study deaths (due to disease progression). Steady-state systemic exposure of MLN8237 increased in an approx. dose proportional manner over 10–30 mg BID when administered with docetaxel 75 mg/m (n = 18). There was no consistent effect of MLN8237 dose on docetaxel exposure (n = 19). Of 20 response-evaluable pts, 3 with CRPC achieved PR plus a >50% decrease in PSA and 7 had stable disease including 3 pts who also had a >50% decrease in PSA; 1 pt with bladder cancer had a PR. Conclusions Myelosuppressive G ≥ 3 AEs were common, but 10 of 22 pts remained on study for ≥6 cycles. PK data from the expansion cohort are pending to support definitive conclusions regarding drug-drug interaction between docetaxel and MLN8237. Emerging data suggest this combination may have preliminary antitumor activity in pts with solid tumors/CRPC. Dose escalation/modification is ongoing to determine RP2D. Disclosure N.M. Hahn: Research Support to institution: Merck, Dendreon, Sanofi, Millennium, Exelexis, Novartis, Bristol-Myers Squibb, Celgene Consultant: Sanofi, Celgene Speakers Bureau Honoraria: Sanofi, Janssen Biotech, C. Higano: Amgen, Bayer, Dendreon, GTx, MPI, AZ, Pfizer, Cell Ther., Centocor, Perceptive Inform., Sanofi, TEVA, BMS, Aragon, Cell Genesys, Exelixis, Genentech, GSK, ImClone, OncoGenex, Mediv., Clin. Care Ops, Curatio, Medscape, RBC Capital Mkts Corp., Cougar, Endo, X. Zhou: Employment (Millennium Pharmaceuticals, Inc.), B. Zhang: Employment: Millennium Pharmaceuticals, Inc., E.J. Leonard: Employment (Millennium Pharmaceuticals, Inc.) Ownership interest (Millennium Pharmaceuticals, Inc.), E. Benaim: Employment (Millennium Pharmaceuticals, Inc.). All other authors have declared no conflicts of interest.