A phase 1 study of IDH305 in patients with IDH1^R132-mutant acute myeloid leukemia or myelodysplastic syndrome

Purpose: Isocitrate dehydrogenase enzyme 1 (IDH1) mutations at 132nd amino acid residue (R132*) result in the cellular accumulation of the oncometabolite, 2-hydroxyglutarate (2-HG). IDH305 is an orally bioavailable, brain-penetrant, mutant-selective allosteric IDH1 inhibitor demonstrating target engagement in preclinical models. This first-in human study was designed to identify the recommended dose for expansion/maximum tolerated dose of IDH305 in patients with IDH1^R132-mutant acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Methods: IDH305 was given at doses 75–750 mg twice daily in 41 patients with IDH1^R132-mutant AML/MDS. Dose escalation was designed using Bayesian hierarchical model with overdose control principle and relationship with dose-limiting toxicity. Results: IDH305 exhibited rapid absorption with mean T_1/2 approximately 4–10 h across doses. Interpatient variability was moderate and exposure increased with dose in a less than dose proportional manner. Most patients (35/41) demonstrated target engagement with reduction in 2-HG concentration at all doses. Complete remission (CR) or CR with incomplete count recovery occurred in 10/37 (27%) patients with AML and 1/ 4 patients with MDS. Adverse events (AEs) suspected to be related to study drug were reported in 53.7% of patients: increased blood bilirubin (14.6%), nausea (14.6%), increased alanine aminotransferase and aspartate aminotransferase (12.2%, each); most frequent grade 3 or 4 AEs were differentiation syndrome and tumor lysis syndrome (n = 3; 7.3%, each). Hepatotoxicity was manageable with dose modification. Conclusion: Due to potentially narrow therapeutic window, the study was prematurely halted and recommended phase 2 dose could not be declared. Trial registration: Clinicaltrials.gov identifier: NCT02381886.