489P - Food effect study of the investigational aurora a kinase (AAK) inhibitor MLN8237 (alisertib) in patients with advanced solid tumors

Date 01 October 2012
Event ESMO Congress 2012
Session Poster presentation III
Topics Drug Development
Presenter Gerald Falchook
Authors G.S. Falchook1, X. Zhou2, L.S. Rosen3, K. Venkatakrishnan2, R. Kurzrock1, D. Mahalingam4, J.W. Goldman5, J. Jung6, C. Milch2, J. Sarantopoulos7
  • 1Investigational Cancer Therapeutics, The University of Texas M. D. Anderson Cancer Center, 77030 - Houston/US
  • 2Clinical Pharmacology, Millennium Pharmaceuticals, Inc., 02139 - Cambridge/US
  • 3Medicine, Premiere Oncology, 90404 - Santa Monica/US
  • 4Oncology, Institute for Drug Development, Cancer Therapy and Research Center at University of Texas Health Science Center San Antonio, 78229 - San Antonio/US
  • 5Division Of Hematology Oncology, David Geffen School of Medicine, UCLA Medical Center, 90404 - Santa Monica/US
  • 6Biostatistics, Millennium Pharmaceuticals, Inc., 20139 - Cambridge/US
  • 7Medical Oncology, Institute for Drug Development, Cancer Therapy and Research Center at Universtiy of Texas Health Science Center San Antonio, 78229 - San Antonio/US

Abstract

Background

MLN8237 (alisertib) is an investigational, orally available, selective AAK inhibitor currently in clinical development for multiple oncology indications. The recommended phase 2 dose is 50 mg twice daily for 7 d in a 21-d cycle. This study was conducted to characterize the effects of food on single-dose pharmacokinetics (PK) of MLN8237 in pts with advanced solid tumors.

Methods

Eligible pts were aged ≥18 y and had ECOG PS 0–1. Following overnight fasting for at least 10 h, pts received a single 50 mg dose of MLN8237 (enteric-coated tablet) under either fasted or fed conditions with a standard high-fat meal using a 2-cycle, 2-way crossover design. PK samples were collected in Cycles 1 and 2 pre-dose and following Day 1 dosing up to 48 h post-Day 1 dose. Ratio of geometric mean Cmax and AUC0-last under fed conditions in reference to those under fasted conditions was calculated and the associated 90% CI were estimated using analysis of variances. Additional endpoints were safety and response.

Results

24 pts were enrolled: 33% male, 96% white, median age 58 y, and mean weight 64 kg. 14 pts were PK-evaluable (10 pts not PK-evaluable due to insufficient data). Following a single oral dose of MLN8237, median Tmax was 6 and 3 h for fed and fasted treatment, respectively. The geometric mean of AUC0-last following single dose under fed conditions was 106% of that under fasted conditions (90% CI: 82%, 137%). The geometric mean of Cmax under fed conditions was 83% of that under fasted conditions (90% CI: 66%, 106%). Following multiple dose administration, 23 (96%) pts had a drug-related adverse event (AE). Most common drug-related grade 3/4 AEs were neutropenia (50%), leukopenia (38%), and thrombocytopenia (21%). 3 pts had drug-related serious AEs. One pt died (non-drug-related respiratory arrest). Stable disease was achieved in 12 pts, including 1 pt with melanoma who received ∼11 cycles.

Conclusions

Systemic exposures achieved following a single 50 mg dose of MLN8237 administered following a high-fat meal are similar to those observed in the fasted state. These data support the conclusion that MLN8237 may be administered without regard for the timing of meals in future clinical studies.

Disclosure

G.S. Falchook: Research funding: Millennium Pharmaceuticals, Inc.

X. Zhou: Employment: Millennium Pharmaceuticals, Inc.

L.S. Rosen: Research support: Millennium Pharmaceuticals, Inc.

K. Venkatakrishnan: Employment: Millennium Pharmaceuticals, Inc.

R. Kurzrock: Research funding: Millennium Pharmaceuticals, Inc.

J. Jung: Employment: Millennium Pharmaceuticals, Inc.

C. Milch: Employment: Millennium Pharmaceuticals, Inc. Ownership interest: Takeda.

All other authors have declared no conflicts of interest.