This phase II MyeloMATCH treatment trial studies how well ASTX727 and venetoclax plus enasidenib works compared to ASTX727 and venetoclax alone for the treatment of older patients with newly diagnosed acute myeloid leukemia (AML) or younger patients who are considered unfit for standard treatment, and who have an abnormal change (mutation) in the IDH2 gene. This gene mutation can cause AML to grow and spread. This trial is being done to see if adding enasidenib to the usual treatment can help more patients with the IDH2 gene get rid of AML.
ASTX727 is a fixed-dose formulation of two drugs, cedazuridine and decitabine. Cedazuridine is in a class of medications called cytidine deaminase inhibitors. It prevents the breakdown of decitabine, making it more available in the body so that decitabine will have a greater effect. Decitabine is in a class of medications called hypomethylation agents. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Enasidenib works by stopping the growth and spread of tumor cells that have the IDH2 mutation. Giving ASTX727 and venetoclax plus enasidenib may work better in treating AML patients with the IDH2 mutation.
Participants must have been registered to the MYELOMATCH Master Screening and Reassessment Protocol prior to consenting to this study. Participants must have disease with a detectable IDH2 mutation based on central testing through the MYELOMATCH and be assigned to this clinical trial via MATCHBox prior to registration to this study
Note: Pre-enrollment/diagnosis labs must have already been performed under MYELOMATCH
Participants must have newly diagnosed, untreated acute myeloid leukemia (AML) defined by having ≥ 20% blasts in the bone marrow and/or peripheral blood, or with an AML defining genetic abnormality as described by the World Health Organization (WHO) classification of AML, excluding acute promyelocytic leukemia (APL) with PML-RARA
Participants must not be receiving or planning to receive any other investigational agents while on protocol therapy
None
Parallel
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Bone Marrow Aspiration
Procedure/SurgeryUndergo bone marrow aspiration
Bone Marrow Biopsy
Procedure/SurgeryUndergo bone marrow biopsy
Decitabine and Cedazuridine
DrugGiven PO
Enasidenib
DrugGiven PO
Venetoclax
DrugGiven PO
Minimal residual disease negative (MRDneg) complete remission (CR) rate
A randomized design will be used to compare binary endpoints in two arms with a single interim futility analysis. For the final analysis, a 2-sample proportion z-test will be used to compare the MRDneg-CR+complete remission with partial hematologic recovery (CRh) rates between arms with a two-sided alpha of 20%.
Relapse-free survival (RFS)
Survival endpoints will be estimated using the Kaplan-Meier method and compared between arms using the log-rank test. Landmark survival endpoints after 2- and 4-cycles of therapy will be estimated using the Kaplan-Meier method. Time-dependent Cox regression models with response as a time-dependent covariate will be fit. Landmark Kaplan-Meier plots will be used describe marker associations with overall survival (OS) and RFS. Landmark and time-dependent Cox regression models will be fit with marker values as covariates. If endpoints subject to competing risks are analyzed, non-parametric cumulative incidence rates will be calculated, and associations will be evaluated using cause-specific hazard models
Event-free survival
Survival endpoints will be estimated using the Kaplan-Meier method and compared between arms using the log-rank test. Landmark survival endpoints after 2- and 4-cycles of therapy will be estimated using the Kaplan-Meier method. Time-dependent Cox regression models with response as a time-dependent covariate will be fit. Molecular and flow MRD rates in the peripheral blood will be tabulated and summarized by arm. Landmark and time-dependent Cox regression models will be fit with marker values as covariates. If endpoints subject to competing risks are analyzed, non-parametric cumulative incidence rates will be calculated, and associations will be evaluated using cause-specific hazard models
Duration of response
Response and toxicity rates will be tabulated. Survival endpoints will be estimated using the Kaplan-Meier method and compared between arms using the log-rank test. Landmark survival endpoints after 2- and 4-cycles of therapy will be estimated using the Kaplan-Meier method. Time-dependent Cox regression models with response as a time-dependent covariate will be fit. Landmark and time-dependent Cox regression models will be fit with marker values as covariates. If endpoints subject to competing risks are analyzed, non-parametric cumulative incidence rates will be calculated, and associations will be evaluated using cause-specific hazard models
OS
Survival endpoints will be estimated using the Kaplan-Meier method and compared between arms using the log-rank test. Landmark survival endpoints after 2- and 4-cycles of therapy will be estimated using the Kaplan-Meier method. Time-dependent Cox regression models with response as a time-dependent covariate will be fit. Molecular and flow MRD rates in the peripheral blood will be tabulated and summarized by arm. Landmark Kaplan-Meier plots will be used describe marker associations with OS and RFS. Landmark and time-dependent Cox regression models will be fit with marker values as covariates. If endpoints subject to competing risks are analyzed, non-parametric cumulative incidence rates will be calculated, and associations will be evaluated using cause-specific hazard models
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