Year: 2020
Type: article
Study design: Clinical Trial
Abstract: The mutant IDH1 (mIDH1) inhibitor BAY1436032 demonstrated robust activity in preclinical AML models, supporting clinical evaluation. In the current dose-escalation study, BAY1436032 was orally administered to 27 mIDH1 AML subjects across 4 doses ranging from 300 to 1500 mg twice-daily. BAY1436032 exhibited a relatively short half-life and apparent non-linear pharmacokinetics after continuous dosing. Most subjects experienced only partial target inhibition as indicated by plasma R-2HG levels. BAY1436032 was safe and a maximum tolerated dose was not identified. The median treatment duration for all subjects was 3.0 months (0.49-8.5). The overall response rate was 15% (4/27; 1 CRp, 1 PR, 2 MLFS), with responding subjects experiencing a median treatment duration of 6.0 months (3.9-8.5) and robust R-2HG decreases. Thirty percent (8/27) achieved SD, with a median treatment duration of 5.5 months (3.1-7.0). Degree of R-2HG inhibition and clinical benefit did not correlate with dose. Although BAY1436032 was safe and modestly effective as monotherapy, the low overall response rate and incomplete target inhibition achieved at even the highest dose tested do not support further clinical development of this investigational agent in AML.
Source: Leukemia
Authors: Michael Heuser, Neil Palmisiano, Ioannis Mantzaris, Alice Mims, Courtney DiNardo, Lewis R. Silverman, Eunice S. Wang, Walter Fiedler, Claudia Baldus, Sebastian Schwind, Timothy Pardee, Alexander E. Perl, Charles Cai, Stefan Kaulfuss, Eleni Lagkadinou, Christine Rentzsch, Markus Wagner, Gary Wilkinson, Bingyan Wu, Michael Jeffers, Isabelle Genvresse, Alwin Krämer
Institutions: Medizinische Hochschule Hannover, Thomas Jefferson University, Sidney Kimmel Cancer Center, Albert Einstein College of Medicine, Montefiore Medical Center, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, The University of Texas MD Anderson Cancer Center, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Roswell Park Comprehensive Cancer Center, University Medical Center Hamburg-Eppendorf, Charité - Universitätsmedizin Berlin, University Hospital Leipzig, Atrium Health Wake Forest Baptist, Wake Forest Baptist Comprehensive Cancer Center, Abramson Cancer Center, University of Pennsylvania, Bayer (United States), Bayer (Germany), German Cancer Research Center, Heidelberg University
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,480
OpenAlex ID: W3046061007