Journal Article

A phase 1 study of IDH305 in patients with IDH1R132-mutant acute myeloid leukemia or myelodysplastic syndrome

Choi, Joanne, DiNardo, Courtney D., Yee, Karen, Wei, Andrew H., Hochhaus, Andreas, Chen, Xueying, Ji, Yan, Frattini, Mark G., Parikh, Nehal S., Krämer, Alwin, Zander, Thomas

2023

Overview

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.

• Publisher: Springer Berlin Heidelberg,Springer Nature B.V
• Subject: absorption / Acute myeloid leukemia / Alanine transaminase / Allosteric properties / Amino acids / Aspartate aminotransferase / aspartate transaminase / Bayesian analysis / Bayesian theory / Bilirubin / bioavailability / blood / Cancer Research / drugs / Hematology / Hepatotoxicity / humans / Internal Medicine / Isocitrate dehydrogenase / Leukemia / Lysis / Mathematical models / Medicine / Medicine & Public Health / Mutants / Myelodysplastic syndrome / Myelodysplastic syndromes / myeloid leukemia / nausea / NCT / NCT02381886 / Oncology / Original Article – Clinical Oncology / Original – Clinical Oncology / Overdose / Remission