An exploratory phase 2 study of investigational Aurora A kinase inhibitor alisertib (MLN8237) in acute myelogenous leukemia and myelodysplastic syndromes Stuart L. Goldberg a,n , Pierre Fenaux b , Michael D. Craig c , Emmanuel Gyan d , John Lister e , Jeannine Kassis f , Arnaud Pigneux g , Gary J. Schiller h , JungAh Jung i , E. Jane Leonard i , Howard Fingert i , Peter Westervelt j a John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ, USA b Service d'hématologie Clinique, Hôpital Avicenne (AP-HP)/Université, Paris 13, Bobigny, France c Mary Babb Randolph Cancer Center, West Virginia University School of Medicine, Morgantown, WV, USA d Service d'hématologie et Thérapie Cellulaire, CNRS UMR 7292, CHRU de Tours, France e Division of Hematology and Cellular Therapy, Western Pennsylvania Cancer Institute, Pittsburgh, PA, USA f Hôpital Maisonneuve-Rosemont, Montreal, QC, Canada g Service d'hématologie CHU Bordeaux, Pessac, France h David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA i Takeda Pharmaceuticals International Co., Cambridge, MA, USA j Division of Oncology, Washington University Medical School, St. Louis, MO, USA article info Article history: Received 19 November 2013 Received in revised form 6 June 2014 Accepted 14 June 2014 Available online 5 July 2014 Keywords: Aurora A kinase inhibitor Alisertib Safety Acute myeloid leukemia (AML) Myelodysplastic syndrome (MDS) abstract Alisertib (MLN8237) is an investigational, oral, selective, Aurora A kinase (AAK) inhibitor. In this phase 2 trial, 57 patients with acute myeloid leukemia (AML) or high-grade myelodysplastic syndrome received alisertib 50mg BID for 7 days in 21-day cycles. Responses in 6/35 AML patients (17% response rate with an additional 49% stable disease, 34% transfusion independence) included 1 complete response lasting 41 year. No responses were observed in MDS patients. Adverse events 430% included diarrhea, fatigue, nausea, febrile neutropenia, and stomatitis. Results suggest modest activity in AML, supporting further research to better understand how AAK inhibition may induce leukemic cell senescence. & 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). 1. Introduction The Aurora kinases are serine/threonine protein kinases essen- tial for regulation of normal cell cycle mitosis. Aurora kinases A (AAK) and B are overexpressed in hematologic malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS); reduction of intracellular AAK results in mitotic inhibition, senescence, and apoptosis in human cell lines [1]. Alisertib (MLN8237) is an investigational, orally available, selective, small-molecule AAK inhibitor [1] with antitumor activity in preclinical leukemia models [2,3]. Here we report an exploratory phase 2 trial of alisertib in a heterogeneous patient population with AML or high-grade MDS (NCT00830518). The single-agent alisertib regimen administered in this study was determined by prior phase 1 studies [4,5]. 2. Methods AML patients ineligible for potentially curative treatment options, with 410% bone marrow (BM) or peripheral blood blasts at relapse, and who had failed to achieve complete response (CR) or relapsed after prior therapy were eligible. High-grade MDS patients were defined as follows: (a) International Prognostic Staging System (IPSS) risk Intermediate-2 or High; (b) 410% BM blasts; and (c) treatment failure from, or not a candidate for, standard therapies. Patients were aged Z18 years, with ECOG performance status 0–2, and adequate hepatic and renal function. The study was conducted according to the Declaration of Helsinki and Good Clinical Practice. Review boards at all partici- pating institutions approved the study protocol and all patients provided written informed consent. Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/lrr Leukemia Research Reports http://dx.doi.org/10.1016/j.lrr.2014.06.003 2213-0489/& 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). n Correspondence to: John Theurer Cancer Center at Hackensack University Medical Center, 92 Second Avenue, Suite 240, Hackensack, NJ 07601, USA. Tel.: þ551 996 5900; fax: þ551 996 0574. E-mail address: SGoldberg@hackensackumc.org (S.L. Goldberg). Leukemia Research Reports 3 (2014) 58–61