This phase II MyeloMATCH treatment trial compares the usual treatment of cedazuridine-decitabine (ASTX727) to the combination treatment of ASTX727 and enasidenib in treating patients with higher-risk, IDH2-mutated myelodysplastic syndrome (MDS). ASTX727 is a combination of two drugs, decitabine and cedazuridine. 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. Enasidenib is an enzyme inhibitor that may stop the growth of cells by blocking some of the enzymes needed for cell growth. Giving ASTX727 in combination with enasidenib may be effective in treating patients with higher-risk IDH2-mutated MDS.

PRIMARY OBJECTIVE:

I. To compare the complete remission (CR) rate of enasidenib + decitabine and cedazuridine (ASTX727) and ASTX727 monotherapy in patients with higher-risk IDH2-mutated MDS using International Working Group 2023 (IWG2023) response criteria.

SECONDARY OBJECTIVES:

I. To estimate the median event-free survival (EFS) at designated time point(s) for each treatment arm.

II. To estimate the median overall survival (OS) at designated time point(s) for each treatment arm.

III. To estimate the frequency and severity of toxicities with each regimen in this patient population.

IV. To estimate the median time to response for each treatment arm. V. To estimate the median duration of response for each treatment arm. VI. To estimate the IDH2 variant allele frequency (VAF) reduction for each treatment arm.

VII. To estimate the rate of allogeneic hematopoietic cell transplantation for each treatment arm.

VIII. To compare rates of partial response (PR), CR with limited count recovery (CRL), CR with partial count recovery (CRh), and hematologic improvement (HI) using IWG 2023 response criteria between treatment arms.

IX. To compare the measurable residual disease (MRD) kinetics by flow cytometry and next generation sequencing (NGS) at designated time point(s) at the end of cycle 4 & 6 and to assess any correlation with clinical outcomes (e.g. CR, EFS, OS).

X. To estimate the median time to transformation of MDS to acute myeloid leukemia (AML).

EXPLORATORY OBJECTIVES:

I. To estimate CR rate, median EFS, and median OS in patients treated with ASTX727 monotherapy that crossover to the treatment arm with ASTX727 + enasidenib after 6 cycles if CR is not achieved.

II. To estimate CR rate, median EFS, and median OS for patients based on Molecular International Prognostic Scoring System (IPSS-M) prognostic risk score at diagnosis, stratified for score level.

III. To estimate concordance between centrally-performed molecular studies and cytogenetics to those done locally.

OUTLINE: Patients are randomized to 1 of 2 regimens.

REGIMEN 1: Patients receive ASTX727 orally (PO) once daily (QD) on days 1-5 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who do not achieve a CR, CRL, or CRh at the end of cycle 6 may cross-over to Regimen 2. Patients who experience CR, PR, or stable disease (SD) any time after 4 cycles of treatment may be reassessed in order to go to a higher myeloMATCH tier assignment or to Tier Advancement Pathway (TAP). Patients also undergo bone marrow biopsy and aspiration throughout the study. Patients may also undergo optional buccal swab on study, and/or optional additional bone marrow aspiration and blood sample collection on study and at disease progression.

REGIMEN 2: Patients receive ASTX727 PO QD on days 1-5 and enasidenib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience CR, PR, or SD any time after 4 cycles of treatment may be reassessed in order to go to a higher myeloMATCH tier assignment or to TAP. Patients also undergo bone marrow biopsy and aspiration throughout the study. Patients may also undergo optional buccal swab on study, and/or optional additional bone marrow aspiration and blood sample collection on study and at disease progression.

After completion of study treatment, patients are followed up every 6 months for up to 5 years after registration.

Inclusion Criteria:

• GENERAL MYLEOMATCH REGISTRATION CRITERIA:

  • Patients must be registered to the Master Screening and Reassessment Protocol (MSRP) and assigned to this protocol by the MATCHBox Treatment Verification Team.

  • Participants must not have received prior anti-cancer therapy for AML or MDS.

    • Note: Hydroxyurea to control the white blood cell count (WBC) is allowed.
    • Note: Prior erythroid stimulating agent (ESA) is not considered prior therapy for the purposes of eligibility.

  • Participants must not be currently receiving any cytarabine-containing therapy other than up to 1 g/m^2 of cytarabine, which is allowed for urgent cytoreduction. The use of prior hydroxyurea, all-trans retinoic acid (ATRA), BCR-ABL directed tyrosine kinase inhibitor, erythropoiesis-stimulating agent, thrombopoietin receptor agonist and lenalidomide is allowed

• REGISTRATION ELIGIBILITY CRITERIA (STEP 1): Patients must have a morphologically-confirmed diagnosis of MDS with a Revised International Prognostic Scoring System (IPSS-R) score ≥ 4.

• REGISTRATION ELIGIBILITY CRITERIA (STEP 1): Patients must have a detectable pathogenic IDH2 mutation based on the National Cancer Institute (NCI) Myeloid Panel.

• REGISTRATION ELIGIBILITY CRITERIA (STEP 1): No prior treatment with deoxyribonucleic acid (DNA) methyltransferase inhibitors (ASTX727, azacitidine, or decitabine).

• REGISTRATION ELIGIBILITY CRITERIA (STEP 1): Prior treatment with growth factors (ESA, granulocyte colony-stimulating factor [g-CSF], thrombopoietin [TPO] agonist), lenalidomide or luspatercept is allowed with a maximum limit of 1 month of exposure.

• REGISTRATION ELIGIBILITY CRITERIA (STEP 1): Patients with therapy-related MDS are allowed.

• REGISTRATION ELIGIBILITY CRITERIA (STEP 1): Age ≥ 18 years.

• REGISTRATION ELIGIBILITY CRITERIA (STEP 1): Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

• REGISTRATION ELIGIBILITY CRITERIA (STEP 1): Total bilirubin ≤ 1.5 x upper limit of normal (ULN)

  • Unless elevated due to Gilbert's syndrome. In patients with Gilbert's syndrome, if the total bilirubin is ≤ 3.0 x ULN, then they are eligible for enrollment.

• REGISTRATION ELIGIBILITY CRITERIA (STEP 1): Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) ≤ 3.0 x upper limit of normal (ULN).

• REGISTRATION ELIGIBILITY CRITERIA (STEP 1): Creatinine clearance ≥ 30 mL/min

  • To be calculated using Cockroft Gault formula.

• REGISTRATION ELIGIBILITY CRITERIA (STEP 1): Not pregnant and not nursing, because this study involves: an agent that has known genotoxic, mutagenic and teratogenic effects.

  • Therefore, for women of childbearing potential only, a negative pregnancy test done as part of screening lab work prior to registration is required.

• REGISTRATION ELIGIBILITY CRITERIA (STEP 1): Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

• REGISTRATION ELIGIBILITY CRITERIA (STEP 1): HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial.

• REGISTRATION ELIGIBILITY CRITERIA (STEP 1): For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

• REGISTRATION ELIGIBILITY CRITERIA (STEP 1): Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

• RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Patients on the ASTX727 monotherapy arm (Regimen 1) that do not achieve a CR (complete response), CRL (CR with limited count recovery), or CRh (CR with partial count recovery) after completing 6 cycles of study treatment.

• RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): ECOG performance status ≤ 2.

• RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Total bilirubin ≤ 1.5 x upper limit of normal (ULN).

  • Unless elevated due to Gilbert's syndrome. In patients with Gilbert's syndrome if the total bilirubin is ≤ 3.0 x ULN, then they are eligible for enrollment.

• RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): AST (SGOT)/ALT (SGPT) ≤ 3.0 x upper limit of normal (ULN)

• RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Creatinine clearance ≥ 30 mL/min

  • To be calculated using Cockroft Gault formula.

• RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Not pregnant and not nursing, because this study involves: an agent that has known genotoxic, mutagenic and teratogenic effects.

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