AMG 900 in adult AML patients - A phase I dose escalation study

Aurora Kinases regulate critical steps in mitosis and meiosis. In Acute Myeloid Leukemia (AML) blasts, Aurora Kinases A and B are over expressed thus making them a therapeutic target.

In an article published in the American Journal of Hematology on 28^th March 2017, Hagop M. Kantarjian from the University of Texas, MD Anderson Cancer Center (MDACC), Houston, Texas, and colleagues discuss the results from their phase I sequential dose escalation study (NCT01380756), which investigated the safety and efficacy of orally administered AMG 900, a pan-Aurora Kinase inhibitor that inhibits both Aurora Kinases A and B, in adult patients with Relapsed or Refractory (R/R) AML.

Thirty-five AML patients (median age = 69 years), enrolled between October 2011–September 2014, received either 4/10 dose schedule (AMG 900 was administered daily 4 days on/10 days off at doses of 15–100 mg, n = 22) or 7/7 dose schedule (AMG 900 administered daily 7 days on/7 days off at doses of 30–50mg, n = 13).

The key results of the study were:

• Treatment related Adverse Events (AEs) occurred in 86% of patients (30/35); most common were nausea (31%), diarrhea (29%), febrile neutropenia (29%), and fatigue (23%)
• Death occurred in 26% of patients (n = 9) due to lung infection and respiratory failure (n = 2 each), as well as acute respiratory failure, cardiorespiratory arrest, respiratory distress, sepsis, and septic stock (n = 1 each)
• Three patients (9%) on the 4/10 dose schedule achieved a Complete Response with Incomplete Count Recovery (CRi)
• Higher gene expression of BIRC5, AURKA, TTK, CDC2, and CCNB1 were associated with the CRi responses in patients (n = 3); P < 0.021

The authors concluded by stating that “AMG 900 was associated with manageable extra-hematological toxicity and modest response in patients with R/R AML”. However, dose escalation of AMG 900 was hampered by prolonged cytopenia in R/R AML patients. The authors further suggested that low doses of AMG 900 in combination with other anti-cancer agent should be evaluated in future studies.

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 used: 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.