Phase 1 Study of AMG 900, an Orally Administered Pan-Aurora Kinase Inhibitor, in Adult Patients (Pts) with Acute Myeloid Leukemia (AML)

Background: Aurora kinases form a family of highly conserved serine/threonine protein kinases that regulate key steps in mitosis. Aurora kinases A and B are amplified and/or overexpressed in many malignancies, including various types of leukemia, and are associated with high proliferation rates, poor prognosis, and therapeutic resistance. AMG 900 is an investigational, orally administered, highly potent, selective, small-molecule pan-aurora kinase inhibitor that has shown single-agent activity in heavily pretreated pts with chemotherapy-resistant/refractory solid tumors. This open-label, multicenter, sequential dose escalation study (NCT01380756) assessed AMG 900 in adult pts with AML.

Methods: The primary objectives of this study were to evaluate the safety and tolerability of AMG 900, to evaluate pharmacokinetics after multiple oral administrations, to determine the optimal dose schedule, and to determine the maximum tolerated dose (MTD). A secondary objective was to evaluate antitumor activity in pts with AML. Key inclusion criteria included definitively diagnosed AML that had failed standard treatments or for which no standard therapy was available, Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, and life expectancy > 3 months. Dose escalation included parallel evaluation of 2 schedules in separate groups. In group 1, AMG 900 was administered daily 4 days on/10 days off at doses of 15, 25, 40, 60, 80, 100, 125, and 150 mg. In group 2, AMG 900 was administered daily 7 days on/7 days off at doses of 30, 40, 50, 60, and 75 mg. Dose escalation was conducted using a 3+3+3 design; intrapatient dose escalation was not allowed. The relationship between gene expression at baseline and clinical response was an exploratory objective. RNA levels for preselected genes were measured by microarray in mononuclear cells obtained from bone marrow (BM) aspirates.

Results: A total of 35 pts were enrolled: 22 in group 1 and 13 in group 2. Twenty-three pts (65.7%) were male, 27 (77.1%) were white, and mean (SD) age was 66.1 (12.2) years. ECOG status was 0 in 7 pts (20.0%), 1 in 22 pts (62.9%), and 2 in 6 pts (17.1%). Pts received a median (min, max) of 14 (4, 49) doses of AMG 900. Mean maximum plasma concentration (C_max) and area under the concentration-time curve (AUC) increased with increasing dose. Thirty pts (85.7%) had treatment-related adverse events (AEs). The most common AEs (in ≥ 10% of pts overall) were nausea (31.4%), diarrhea (28.6%), febrile neutropenia (28.6%), fatigue (22.9%), vomiting (17.1%), alopecia (14.3%), dyspnea (11.4%), epistaxis (11.4%), mucosal inflammation (11.4%), and rash (11.4%). Nine pts (25.7%) died during the study from lung infection and respiratory failure (2 pts each) and acute respiratory failure, cardiorespiratory arrest, respiratory distress, sepsis, and septic shock (1 pt each). Only respiratory failure and septic shock (1 pt each) were considered potentially related to AMG 900 by the investigators. All 35 pts discontinued treatment. Reasons for discontinuation were disease progression (65.7%), AEs (11.4%), death (8.6%), withdrawal of consent (5.7%), other reasons (5.7%), and requirement for alternative therapy (2.9%). Two pts (5.7%) experienced dose-limiting toxicities: 1 pt from group 1 (40 mg) had grade 3 pancytopenia, and 1 pt from group 2 (50 mg) had febrile neutropenia and grade 3 abdominal pain. The MTD of AMG 900 was not formally reached in either dose schedule. Three pts (8.6%) from group 1 (40 mg [2 pts] and 60 mg [1 pt]) had a best response of complete response with incomplete count recovery (CRi). Overall, the objective response rate for CRi was 8.6% (80% confidence interval: 3%, 18%). Higher gene expression of BIRC5, AURKB, AURKA, TTK, and CCNB1 was associated with objective response in univariate logistic regression models (P < .02), and was still significant after adjusting for average dose and percentage of blasts in the BM in a multivariate model (P < .01). Expression profiles of responders were clustered together in a principal component analysis.

Conclusions: AMG 900 had an acceptable safety profile in this grievously ill population of adult pts with recurrent/refractory AML. Prolonged cytopenias hampered further dose escalation in this single-agent treatment setting. Combination of low doses of AMG 900 with other anticancer agents should be evaluated in future studies.