921P - MLN8237 (alisertib), an investigational aurora a kinase (AAK) inhibitor, in patients with advanced solid tumors including castration-resistant prost...

Date 29 September 2012
Event ESMO Congress 2012
Session Poster presentation I
Topics Clinical Research
Prostate Cancer
Basic Scientific Principles
Presenter Noah Hahn
Authors N.M. Hahn1, J. Sarantopoulos2, C. Higano3, X. Zhou4, B. Zhang5, E..J. Leonard4, E. Benaim6, J. Graff7
  • 1Department Of Medicine, Division Of Hematology/oncology, Indiana University Melvin and Bren Simon Cancer Center, 46202 - Indianapolis/US
  • 2Medical Oncology, Institute for Drug Development, Cancer Therapy Research Center at Universtiy of Texas Health Science Center, 78229 - San Antonio/US
  • 3Seattle Cancer Care Alliance, University of Washington, 98109 - Seattle/US
  • 4Clinical Pharmacology, Millennium Pharmaceuticals, Inc., 02139 - Cambridge/US
  • 5Biostatistics, Millennium Pharmaceuticals, Inc., 02139 - Cambridge/US
  • 6Clinical Development, Millennium Pharmaceuticals, Inc., 02139 - Cambridge/US
  • 7Medical Oncology, Oregon Health and Science University, 97239 - Portland/US



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.


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).


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.


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.


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.