Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Leukemia			2020 Jul 30	2903-2913	Leukemia

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
BAY1436032	BAY1436032	8	2

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