Safety and efficacy of BAY1436032 in IDH1-mutant AML: phase I study results

Author:

Heuser MichaelORCID,Palmisiano NeilORCID,Mantzaris Ioannis,Mims AliceORCID,DiNardo CourtneyORCID,Silverman Lewis R.,Wang Eunice S.ORCID,Fiedler Walter,Baldus Claudia,Schwind SebastianORCID,Pardee TimothyORCID,Perl Alexander E.,Cai Charles,Kaulfuss Stefan,Lagkadinou Eleni,Rentzsch Christine,Wagner Markus,Wilkinson Gary,Wu Bingyan,Jeffers Michael,Genvresse Isabelle,Krämer Alwin

Abstract

AbstractThe 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.

Publisher

Springer Science and Business Media LLC

Subject

Oncology,Cancer Research,Hematology

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