General AML

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 28th 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.

References
  1. Kantarjian H.M. et al. A Phase 1 Study of AMG 900, an Orally Administered Pan-Aurora Kinase Inhibitor, in Adult Patients with Acute Myeloid Leukemia. Am J Hematol. 2017 Mar 28. DOI: 10.1002/ajh.24736. [Epub ahead of print].