Phase I Assessment of Safety and Therapeutic Activity of BAY1436032 in Patients with IDH1-Mutant Solid Tumors

Clin Cancer Res. 2021 May 15;27(10):2723-2733. doi: 10.1158/1078-0432.CCR-20-4256. Epub 2021 Feb 23.


Purpose: BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics of BAY1436032, and to evaluate its potential pharmacodynamics and antitumor effects.

Patients and methods: The study comprised of dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily on a continuous basis in subjects with mIDH1 solid tumors.

Results: In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across five doses (150-1,500 mg twice daily). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2-hydroxyglutarate levels of 76%. BAY1436032 was well tolerated and an MTD was not identified. A dose of 1,500 mg twice daily was selected for dose expansion, where 52 subjects were treated in cohorts representing four different tumor types [lower grade glioma (LGG), glioblastoma, intrahepatic cholangiocarcinoma, and a basket cohort of other tumor types]. The best clinical outcomes were in subjects with LGG (n = 35), with an objective response rate of 11% (one complete response and three partial responses) and stable disease in 43%. As of August 2020, four of these subjects were in treatment for >2 years and still ongoing. Objective responses were observed only in LGG.

Conclusions: BAY1436032 was well tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • 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*
  • Biomarkers, Tumor
  • DNA Mutational Analysis
  • Disease Management
  • Disease Susceptibility
  • Female
  • Humans
  • Isocitrate Dehydrogenase / antagonists & inhibitors*
  • Isocitrate Dehydrogenase / genetics*
  • Male
  • Middle Aged
  • Mutation*
  • Neoplasm Grading
  • Neoplasm Staging
  • Neoplasms / diagnosis
  • Neoplasms / drug therapy*
  • Neoplasms / genetics*
  • Neoplasms / mortality


  • Aniline Compounds
  • Antineoplastic Agents
  • BAY 1436032
  • Benzimidazoles
  • Biomarkers, Tumor
  • Isocitrate Dehydrogenase
  • IDH1 protein, human