A randomized Phase II trial of ASTX727 and venetoclax with or without enasidenib for newly diagnosed older adults with IDH2 mutant Acute Myeloid Leukemia: A myelomatch substudy (MM1OA-S03)

Abstract

Abstract Background: Acute myeloid leukemia (AML) with an IDH2 mutation represents a distinct molecular subtype with sensitivity to venetoclax-based regimens. In the VIALE A trial, 56% of IDH2 mutant patients treated with azacitidine and venetoclax achieved a complete remission (CR) and 50% of patients achieving CR/CRi were negative for measurable residual disease (MRD) as assessed by flow cytometry to <10–3. However, molecular MRD persisted in 6 out of 7 patients, presenting an opportunity for targeted therapy to improve outcomes. Preclinical data suggest that adding IDH inhibition to venetoclax results in high response rates in IDH mutant AML without evidence of additive toxicity. In IDH1 mutant AML, a phase 1b trial of the combination of the IDH1 inhibitor ivosidenib with venetoclax and azacitidine resulted in an overall response rate of 94% with MRD negativity achieved in 77%, without any patients discontinuing therapy due to intolerance. ASTX727, an oral fixed-dose combination of decitabine and cedazuridine, enables oral administration of decitabine with pharmacokinetically equivalent exposure to IV decitabine. Enasidenib, an IDH2 inhibitor, has shown efficacy as monotherapy and in combination with HMAs in IDH2 mutant AML. This study evaluates whether the triplet combination of ASTX727, venetoclax, and enasidenib improves MRD negative complete remission rates in older/unfit adults with newly diagnosed IDH2 mutant AML. Study Design and Methods This tier 1 MyeloMATCH substudy is an open-label, randomized phase 2 trial enrolling newly diagnosed adults ≥60 years (or ≥18 years and unfit for intensive chemotherapy as determined by their treating physician) with IDH2 mutant AML. Subjects will be enrolled through the central MyeloMATCH Master Screening and Reassessment Protocol (MSRP, NCT05564390) and are assigned to the MM1OA-S03 substudy (NCT06672146) based on the presence of an IDH2 mutation by NGS. The first 6 patients will receive the triplet regimen of ASTX727, venetoclax, and enasidenib as a safety run in to evaluate for toxicities of interest, which include severe cytopenias persisting beyond day 42 and clinically relevant grade 3 or greater nonhematologic AEs that do not resolve within 7 days. After the 6 patient safety run in for the triplet regimen, patients will be randomized 1:1 to receive ASTX727 and venetoclax or ASTX727, venetoclax, and enasidenib, stratified by age (<70 vs older) and performance status (0-1 vs 2-3). Both study arms consist of ASTX727 given days 1-5 and venetoclax days 1-28 after an initial ramp up, with arm 2 adding enasidenib 100 mg daily. A marrow biopsy is performed during the first cycle (between days 15-21) and venetoclax can be held (no earlier than day 21) if marrow blasts are <5%. To minimize myelosuppression, dose reductions of venetoclax and ASTX727 and delays are recommended for subsequent cycles to target continuing 28 to 42 day cycles of therapy. Responses will be assessed following cycles 2, 4, 6, and 12, and prior to allogeneic transplant (if applicable). The primary outcomes of this trial are to evaluate the safety of the ASTX727, venetoclax, and enasidenib triplet regimen during the safety run in, and to compare the rate of MRD negative complete remission (CR) based on flow cytometry after 2 cycles between treatment arms. Key secondary objectives including estimating rates of CR with incomplete and partial hematologic recovery, RFS, EFS, DOR, and OS between treatment arms, as well as IDH2 variant allele frequency, flow cytometry MRD, and molecular MRD between arms and how this correlates with RFS and OS. The study is powered to detect a 25% improvement in rate of MRD negative CR rate with a target accrual of 102 patients. The study was activated on April 1, 2025 and is expected to continue until October 2027. Funding Funding: NIH/NCI grants U10CA180888, U10CA180819