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

• Published in: Leukemia Vol. 34; no. 11; pp. 2903 - 2913
• Main Authors: Heuser, Michael, Palmisiano, Neil, Mantzaris, Ioannis, Mims, Alice, DiNardo, Courtney, Silverman, Lewis R., Wang, Eunice S., Fiedler, Walter, Baldus, Claudia, Schwind, Sebastian, Pardee, Timothy, Perl, Alexander E., Cai, Charles, Kaulfuss, Stefan, Lagkadinou, Eleni, Rentzsch, Christine, Wagner, Markus, Wilkinson, Gary, Wu, Bingyan, Jeffers, Michael, Genvresse, Isabelle, Krämer, Alwin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2020; Nature Publishing Group
• Subjects: 38; 38/23; 692/308/153; 692/308/2779/109/1940; 692/699/67/1990/283/1897; 82/58; Adult; Aged; Aniline Compounds - administration & dosage; Aniline Compounds - adverse effects; Aniline Compounds - pharmacokinetics; Aniline Compounds - therapeutic use; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Benzimidazoles - administration & dosage; Benzimidazoles - adverse effects; Benzimidazoles - pharmacokinetics; Benzimidazoles - therapeutic use; Bone Marrow - pathology; Cancer; Cancer Research; Chemotherapy; Critical Care Medicine; DNA Mutational Analysis; Dosage; Dose-response relationship (Biochemistry); Drug dosages; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - therapeutic use; Enzymes; Female; Health aspects; Hematology; Humans; Intensive; Internal Medicine; Isocitrate Dehydrogenase - antagonists & inhibitors; Isocitrate Dehydrogenase - genetics; Isocitrate Dehydrogenase - metabolism; Leukemia; Leukemia, Myeloid, Acute - diagnosis; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - mortality; Male; Medical research; Medicine; Medicine & Public Health; Methods; Middle Aged; Molecular Targeted Therapy; Mutants; Mutation; Oncology; Oral administration; Oxidoreductases; Patient outcomes; Pharmaceuticals; Pharmacokinetics; Prognosis; Response rates; Robustness; Survival Analysis; Treatment Outcome; Germany
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/s41375-020-0996-5

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.