@article{60636a410f20432681c06e7723ee7796,
title = "Safety and efficacy of BAY1436032 in IDH1-mutant AML: phase I study results",
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.",
author = "Michael Heuser and Neil Palmisiano and Ioannis Mantzaris and Alice Mims and Courtney DiNardo and Silverman, {Lewis R.} and Wang, {Eunice S.} and Walter Fiedler and Claudia Baldus and Sebastian Schwind and Timothy Pardee and Perl, {Alexander E.} and Charles Cai and Stefan Kaulfuss and Eleni Lagkadinou and Christine Rentzsch and Markus Wagner and Gary Wilkinson and Bingyan Wu and Michael Jeffers and Isabelle Genvresse and Alwin Kr{\"a}mer",
note = "Funding Information: Acknowledgements We would like to acknowledge the following individuals for their contributions: David Bauer for PK and biomarker sample management, Rong Liu for statistical analyses and trial design, Claudia Merz for biomarker analyses, Martin Michels and Dirk Laurent for trial design and clinical site selection, Olaf Panknin and Dejan Djuric for chemistry and formulation, Carol Pe{\~n}a for scientific input, Susanne Reschke for PK analyses, and Thomas Wagener for study management. Aurexel Life Sciences Ltd. (www.aurexel.com) is acknowledged for editorial support funded by Bayer U.S. LLC. Open access funding provided by Projekt DEAL. Funding Information: Conflict of interest MH reports honoraria from Novartis, Pfizer, PriME Oncology, consulting or advisory role for Abbvie, Bayer Pharma AG, Daiichi Sankyo, Jazz Pharmaceuticals, Novartis and Pfizer, research funding from Astellas, Bayer Pharma AG, BergenBio, Daiichi Sankyo, Karyopharm, Novartis, Pfizer and Roche. NP receives research funding from AbbVie and Genentech. AM reports consulting or advisory role for Abbvie, Jazz Pharmaceuticals, Syndax, and Kura Oncology. CD reports personal fees from Abbvie, Agios, Novartis, ImmuneOnc, Daiichi Sankyo, Celgene, Jazz, and Notable Labs. ESW served on advisory boards and/or provided consulting for Abbvie, Arog, Astellas, Daiichi Sankyo, Genentech, Jazz, Kite Pharmaceuticals, Kura Oncology, Macrogenics, Pfizer, PTC Therapeutics, and Stemline. ESW served on independent data review committees for clinical trials for Abbvie and Rafael Pharmaceuticals. She serves as a speaker for Stemline, Pfizer, and Dava Oncology. WF has participated in advisory boards for Amgen, Pfizer, Novartis, Jazz Pharmaceuticals, Celgene, and Ariad/Incyte; received research funding from Amgen; received support for meeting attendance from Amgen, Jazz Pharmaceuticals, Daiichi Sankyo Oncology and Servier and has received support in medical writing from Amgen, Pfizer and AbbVie. SS reports consulting or advisory role for Daiichi Sankyo, Pfizer, Novartis and research funding from Novartis. TP reports the role of the CoChief Medical Officer of Rafael Pharmaceuticals; a speaker for Cel-gene/BMS, Amgen, and Pharmacyclics/Janssen; consulting or advisory role for CBM Biopharma, AbbVie/Genentech, and BMS; and research support from Karyopharm, Rafael Pharmaceuticals, and Spherix Intellectual Property. AEP reports consulting or advisory role for Abbvie, Actinium, Agios, Astellas, Daiichi Sankyo, Forma, Jazz, Loxo, NewLink Genetics, Syndax, and Takeda; research funding from Abbvie, Actinium, Astellas, Bayer Pharma AG, BioMed Valley Discoveries, FujiFilm, and Novartis. CC and GW are employees and hold shares of Bayer U.S. LLC. SK, EL, and IG are employees of Bayer AG. CR is an employee and holds shares of Bayer AG. MW is an employee of MSD RBSC GmbH, a subsidiary of Merck & Co., Inc., Kenilworth, N.J., USA, and was a former employee of Bayer AG, Berlin, Germany. BW and MJ are employees of Bayer U.S. LLC. AK has received self-honoraria from F. Hoffmann-La Roche Ltd, Daiichi Sankyo, and AbbVie, has received institutional honoraria from F. Hoffmann-La Roche Ltd and Bayer, has received institutional research funding from Bayer and Merck, travel/accommodation/expenses from F. Hoffmann-La Roche Ltd, Celgene, and Daiichi Sankyo, and has been an advisory consultant for F. Hoffmann-La Roche Ltd, Daiichi Sankyo, BMS, and AbbVie. The authors declare that they have no conflict of interest. Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2020",
month = nov,
day = "1",
doi = "10.1038/s41375-020-0996-5",
language = "English (US)",
volume = "34",
pages = "2903--2913",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Nature Publishing Group",
number = "11",
}
