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.
Highlights
Somatic hotspot mutations in isocitrate dehydrogenase 1 (IDH1) have been identified in a variety of cancers, with a frequency of ~7% in acute myeloid leukemia (AML) [1,2,3,4,5,6]
The prevalence of individual IDH1R132X mutations across the 27 treated subjects based on investigator-reported information was as follows: R132C (n = 15), R132H (n = 5), R132G (n = 3), R132L and
The mutant IDH1 (mIDH1) inhibitor BAY1436032 was evaluated at 4 different dose levels in a total of 27 AML subjects who harbored a mutation which altered the residue at position R132 of IDH1 to any one of 5 different amino acids, each of which is known to generate the R-2HG oncometabolite and to be inhibited by BAY1436032 [16, 17]
Summary
Somatic hotspot mutations in isocitrate dehydrogenase 1 (IDH1) have been identified in a variety of cancers, with a frequency of ~7% in acute myeloid leukemia (AML) [1,2,3,4,5,6]. Preclinical experiments focusing on mIDH1 AML found that BAY1436032 inhibits R-2HG production and colony growth in vitro, while promoting leukemic blast clearance, myeloid differentiation, and survival in animal models [16]. Supported by these encouraging preclinical findings, BAY1436032 was evaluated in a phase I clinical study in subjects with mIDH1 AML (NCT03127735), the results of which are presented . Objectives of the study include determination of the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D), and evaluation of the safety, tolerability, pharmacokinetics (PK), pharmacodynamics and clinical activity of BAY1436032
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
