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Ref Type Journal Article
PMID (32733012)
Authors Heuser M, Palmisiano N, Mantzaris I, Mims A, DiNardo C, Silverman LR, Wang ES, Fiedler W, Baldus C, Schwind S, Pardee T, Perl AE, Cai C, Kaulfuss S, Lagkadinou E, Rentzsch C, Wagner M, Wilkinson G, Wu B, Jeffers M, Genvresse I, Krämer A
Title Safety and efficacy of BAY1436032 in IDH1-mutant AML: phase I study results.
Journal Leukemia
Vol
Issue
Date 2020 Jul 30
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
BAY1436032 BAY-1436032|BAY 1436032 IDH1 Inhibitor 8 BAY1436032 inhibits mutant IDH1, resulting in decreased levels of (R)-2-hydroxyglutarate (R-2HG) and leading to reduced proliferation and increased differentiation of IDH1-mutant tumor cells (PMID: 28232670, PMID: 32733012).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
IDH1 R132X acute myeloid leukemia no benefit BAY1436032 Phase I Actionable In a Phase I trial, treatment with BAY1436032 in acute myeloid leukemia patients harboring an IDH1 R132X mutation demonstrated safety and resulted in an overall response rate of 15% (4/27), including one complete remission, one partial remission, and morphologic leukemia-free state in two patients, stable disease in 67% (18/27), and a median overall survival of 6.6 months, however, due to low response rates for all doses, further clinical development was not supported (PMID: 32733012; NCT03127735). 32733012