A phase 1 study of AMG 900, an orally administered pan-aurora kinase inhibitor, in adult patients with acute myeloid leukemia

Abstract

Aurora kinases are involved in the pathophysiology of several cancers including acute myeloid leukemia (AML). In this phase 1 study, we investigated the safety and efficacy of AMG 900, an orally administered, highly potent, selective, small-molecule inhibitor of both Aurora kinase A and B, in patients with AML . Patients with pathologically documented AML who either declined standard treatments or had relapsed from or were refractory to previous therapies were enrolled. Two every-2-week dose-escalation schedules using a modified 3 + 3 + 3 design were evaluated AMG 900 given daily for 4 days with 10 days off (4/10 schedule), and AMG 900 given daily for 7 days with 7 days off (7/7 schedule). Thirty-five patients were enrolled at 9 different dose levels: 22 patients on the 4/10 schedule (doses from 15 to 100 mg daily), and 13 patients on the 7/7 schedule (doses from 30 to 50 mg daily). Both schedules were tolerated; nausea (31%), diarrhea (29%), febrile neutropenia (29%), and fatigue (23%) were the most common treatment-related adverse events. Three patients (9%) achieved complete response with incomplete count recovery. Patients with higher baseline expression of a set of specific pathway-related genes (BIRC5, AURKA, TTK, CDC2, and CCNB1) were more likely to respond in an exploratory biomarker analysis. AMG 900 was tolerated in a general AML population, and pathway-specific biomarkers identified a potential target population. Future research efforts will be directed toward further exploration of biomarkers of response and combination of AMG 900 with other anticancer agents.

Conflict of interest statement

DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

Hagop M. Kantarjian reports research funding from BMS, Ariad, Pfizer, Amgen, and Novartis. Michael W. Schuster reports honoraria and speakers’ bureau participation from Amgen, and equity ownership in Amgen. Nitin Jain reports nothing to disclose. Anjali Advani reports research funding from Amgen. Elias Jabbour reports research funding and consultancy fees from Amgen. Mikkael A. Sekeres reports advisory board participation from Amgen and Celgene. Erik Rasmussen, Gloria Juan, Abraham Anderson, Vincent F. Chow, and Gregory Friberg are employees of Amgen and hold stock in Amgen. Erick Gamelin is a former employee of Amgen, a current employee of Pfizer, and holds stock in Amgen and Pfizer. Florian D. Vogl is a former employee of Amgen and holds stock in Amgen.

© 2017 Wiley Periodicals, Inc.

Figures

FIGURE 1

Mean plasma concentration-time profiles following multiple oral administrations for the 4 days on/10 days off schedule (A) or the 7 days on/7 days off schedule (B); area under the concentration-time curve by dose group after the first 4 days of the 4 days on/10 days off schedule (C) or after the first 7 days of the 7 days on/7 days off schedule (D). AUC4h, area under the concentration-time curve from time zero to 4 hours postdose