Phase 3 Trial to Explore Ivosidenib for IDH1-Mutated MDS

A new clinical trial aims to expand treatment options for patients with isocitrate dehydrogenase 1 (IDH1) mutant myelodysplastic syndromes (MDS), a challenging subset of patients characterized by poor prognosis and limited therapeutic options.

MDS are a group of clonal hematopoietic disorders affecting predominantly older adults, with symptoms ranging from anemia to severe cytopenias. Current treatments, particularly for high-risk MDS (HR-MDS), are limited to hypomethylating agents (HMAs) such as azacitidine. For patients with MDS and IDH1 mutations—detected in approximately 3% of cases—the prognosis is especially dire, with transformation to acute myeloid leukemia (AML) occurring in more than half of these patients.

Marie Sebert, MD, PhD,  Hôpital Saint-Louis, Paris, France, presented the design of the upcoming phase 3 PyramIDH study to investigate the efficacy of ivosidenib, a targeted oral inhibitor of mutant IDH1, compared with azacitidine monotherapy.¹ Building on encouraging results from earlier trials, including a phase 2 study showing a 72% overall response rate for ivosidenib monotherapy in untreated IDH1-mutant HR-MDS,^2,3 the PyramIDH trial aims to validate these findings in a larger cohort. The global multicenter trial will enroll approximately 48 patients with HMA-naive MDS, stratified by molecular risk (high-risk vs low-risk) and randomized 2:1 to receive either ivosidenib or azacitidine.

The primary endpoint is the combined complete and partial response (CR+PR) rate at 4 months per International Working Group (IWG) 2006 criteria. Secondary endpoints include response durability, transfusion independence rates, progression to AML, and overall survival. The study will also evaluate outcomes using updated IWG 2023 criteria, reflecting updated response assessment standards. Enrollment is set to begin in December 2024 in nine countries across 52 sites in Australia, France, Germany, Italy, Japan, Spain, the Netherlands, the UK, and the US.

Ivosidenib is a promising oral therapy for patients with IDH1-mutated MDS. The upcoming phase 3 PyramIDH study is designed to confirm the efficacy and tolerability of ivosidenib in a larger cohort of patients with IDH1-mutated MDS.

REFERENCE:

1. Sebert M, Platzbecker U, Valcárcel-Ferreiras D, et al. Phase 3 study of either ivosidenib (IVO) monotherapy or azacitidine (AZA) monotherapy in patients with IDH1 mutant myelodysplastic syndromes (MDS) who are hypomethylating agent (HMA) naive (PyramIDH). Abstract #1845.1. Presented at the American Society of Hematology Annual Meeting; December 7-10, 2024; San Diego, California.
2. DiNardo CD, Roboz GJ, Watts JM, et al. Final phase 1 substudy results of ivosidenib for patients with mutant IDH1 relapsed/refractory myelodysplastic syndrome. Blood Adv. 2024;8(15):4209-4220. doi: 10.1182/bloodadvances.2023012302
3. Sébert M, Clappier E, Cluzeau T, et al. Ivosidenib monotherapy in IDH1 mutated myelodysplastic syndrome, final results of the IDIOME trial, a GFM study. Abstract #S182. Presented at the European Hematology Association 2024 Congress; June 13-16; Madrid, Spain.