Phase 3 Study of ivosidenib (IVO) and azacitidine (AZA) with or without venetoclax in adult patients with newly diagnosed IDH1-mutated AML or MDS/AML ineligible for intensive chemotherapy (EVOLVE-1)

Abstract Background: Acute myeloid leukemia (AML) is a clonal hematopoietic stem cell disorder characterized by the infiltration of the bone marrow, peripheral blood, and other tissues by proliferative, immature progenitor cells. Somatic mutations in isocitrate dehydrogenase 1 (IDH1) are present in approximately 6-8% of AML cases and are associated with a poor prognosis. Ivosidenib (IVO) is an oral, targeted small molecule inhibitor of mutant IDH1, and in combination with azacitidine (AZA), has resulted in a 29.3 month overall survival benefit for patients with IDH1-mutated (mIDH1) AML. Venetoclax (VEN) is a BCL-2 inhibitor that has demonstrated activity in AML, particularly when combined with hypomethylating agents. It remains unclear whether the addition of VEN to IVO/AZA can improve outcomes for patients with newly-diagnosed mIDH1 AML or MDS/AML who are ineligible for intensive chemotherapy. The phase 3 EVOLVE-1 study aims to addresse the unmet medical need for more effective treatment options in this patient population by evaluating the efficacy and safety of IVO and AZA with or without VEN in patients with newly diagnosed IDH1-mutated AML or MDS/AML who are ineligible for intensive chemotherapy. Methods: The EVOLVE-1 study (NCT06465953) is a prospective, multicenter, randomized, double-blind, placebo-controlled, phase 3 clinical trial. Eligible patients (n=~227) will be randomized (1:1) to receive either IVO/AZA with VEN or IVO/AZA with placebo. Key eligibility criteria include a diagnosis of newly-diagnosed mIDH AML or myelodysplastic syndrome (MDS)/AML according to the 2022 International Consensus Classification, age ≥18 years, and ineligibility for intensive chemotherapy. Treatment will be administered in 28-day cycles, with IVO given continuously at a dose of 500 mg/day, AZA administered subcutaneously at 75 mg/m2/day for 7 days, and VEN or placebo given orally at 400 mg/day for 7 days following a 2-day ramp-up phase in cycle 1. The primary endpoint is event-free survival (EFS), defined as the time from randomization to treatment failure, hematologic relapse, or death from any cause. Secondary endpoints include overall survival (OS), rates of complete remission (CR) and CR with partial hematologic recovery (CRh), duration of response, transfusion independence rate, and quality of life. Exploratory endpoints include quality of life, cumulative incidence of relapse (CIR), cumulative incidence of death (CID). The global trial is expected to begin enrollment by Aug 2025.