title: 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.
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA.
authors.forename: Hagop M
authors.identifier: http://orcid.org/0000-0002-1908-3307
authors.initials: HM
authors.lastname: Kantarjian
authors.affiliation: Medical Hematology/Oncology Stony Brook University School of Medicine, Stony Brook, New York, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Schuster
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA.
authors.forename: Nitin
authors.initials: N
authors.lastname: Jain
authors.affiliation: Leukemia Program, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Anjali
authors.initials: A
authors.lastname: Advani
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA.
authors.forename: Elias
authors.identifier: http://orcid.org/0000-0003-4465-6119
authors.initials: E
authors.lastname: Jabbour
authors.affiliation: Research and Development, Amgen Inc., Thousand Oaks, California, USA.
authors.forename: Erick
authors.initials: E
authors.lastname: Gamelin
authors.affiliation: Research and Development, Amgen Inc., Thousand Oaks, California, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Rasmussen
authors.affiliation: Research and Development, Amgen Inc., Thousand Oaks, California, USA.
authors.forename: Gloria
authors.initials: G
authors.lastname: Juan
authors.affiliation: Research and Development, Amgen Inc., Thousand Oaks, California, USA.
authors.forename: Abraham
authors.initials: A
authors.lastname: Anderson
authors.affiliation: Research and Development, Amgen Inc., Thousand Oaks, California, USA.
authors.forename: Vincent F
authors.initials: VF
authors.lastname: Chow
authors.affiliation: Research and Development, Amgen Inc., Thousand Oaks, California, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Friberg
authors.affiliation: Research and Development, Amgen Inc., Thousand Oaks, California, USA.
authors.forename: Florian D
authors.initials: FD
authors.lastname: Vogl
authors.affiliation: Leukemia Program, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Mikkael A
authors.initials: MA
authors.lastname: Sekeres
mesh_terms: D000284:Administration, Oral; D000368:Aged; D064127:Aurora Kinases / Q000037:antagonists & inhibitors*; D015415:Biomarkers; D018450:Disease Progression; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010793:Phthalazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019233:Retreatment; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; C555658:N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D064127:Aurora Kinases