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)

Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal myeloid disorders that occur predominantly in older patients (median age at diagnosis is ~70 years) and are characterized by ineffective hematopoiesis and cytopenias with variable risk of progression to acute myeloid leukemia (AML). According to International Prognostic Scoring Systems (IPSS, IPSS-R and more recently IPSS-M), patients with lower-risk MDS (LR-MDS) and cytopenias can be treated with different drugs (erythropoietin stimulating agents, lenalidomide, luspatercept, imetelstat) and in some cases hypomethylating agents (HMAs). However, in higher-risk MDS (HR-MDS), HMAs are the only available standard of care therapy. The complete response (CR) + partial response (PR) rate of azacitidine in treatment-naive MDS ranges between 16% and 22%. These low response rates, combined with the short duration of responses observed with these approaches highlight an unmet medical need for this population.

Somatic mutations in isocitrate dehydrogenase 1 gene (mIDH1) are detected in approximately 3% of MDS patients and portend a poor prognosis regardless of MDS risk category, as evidenced by high rates of transformation to AML (50%–67%), worse event-free survival (EFS), and reduced overall survival (OS) compared with patients with wild-type IDH1. Ivosidenib (IVO) is an oral, targeted small molecule inhibitor of mutant IDH1. Ivosidenib (IVO) monotherapy is currently FDA approved in relapsed/refractory (R/R) MDS with a complete remission (CR) + partial remission (PR) rate of 38.9% (95% CI: 17.3%, 64.3%) with all responses being CR. In the phase 2 IDIOME study, 72% of patients with previously untreated mIDH1 HR-MDS obtained CR+PR with IVO monotherapy; median OS and DOR were not reached after median follow-up of 25.2 months. The current phase 3 PyramIDH study was designed to confirm the safety and clinical activity of IVO monotherapy in HMA–naive mIDH1 MDS in a larger cohort of patients.

Methods: The PyramIDH study (NCT06465953) is a phase 3, multicenter, open-label, randomized, non-comparative two-arm study of IVO or azacitidine (AZA) monotherapy in patients with mIDH1 MDS who are hypomethylating agent (HMA) naive. Key eligibility criteria include diagnosis of HMA-naive IDH1 R132 C/G/H/L/S mutated MDS. HR-MDS, defined as moderate high-, high- and very-high-risk MDS per Molecular International Scoring System (IPSS-M) score, will be eligible if the bone marrow blast count is <20% regardless of blood cell counts. LR-MDS, defined as low- and moderate-low-risk MDS per IPSS-M score, must have cytopenias related to MDS, defined as: <100 platelets/μL, or absolute neutrophil count (ANC) <1000/mm³, or hemoglobin <10g/dL, have a blast count between 5% and19%, and be eligible for HMA therapy. Very-low-risk MDS per IPSS-M will not be eligible for enrollment as these patients are likely not candidates for HMAs.

Enrolled patients (n=~48) will be randomized (2:1) to IVO monotherapy or AZA monotherapy and they will be stratified by IPSS-M risk status (HR versus LR) after randomization. The primary endpoint is CR+PR at 4 months as per IWG 2006 criteria. Key secondary endpoints include duration of CR+PR as per IWG 2006 criteria, time to CR+PR as per IWG 2006 criteria, transfusion independence rate, AML transformation rate, and number of participants going to transplant. Other secondary endpoints are CR+PR at 6 months as per IWG 2006 criteria; CR+PR at 4 and 6 months as per IWG 2023 criteria; overall response rate (ORR) per IWG 2023 criteria, duration of response, EFS, OS, duration of transfusion independence, time to transfusion independence, AML transformation, quality of life, PK/PD, and safety.

The global trial will begin enrollment by December 2024.