Testing the Use of an IDH1 Inhibitor, Olutasidenib, in Acute Myeloid Leukemia Added to ASTX727 and Venetoclax; in High-Risk MDS Added to ASTX727; and Alone in Low Risk MDS (A MyeloMATCH Treatment Substudy)

A Randomized Phase 2 Trial of Olutasidenib-Based Therapies in Patients With Newly Diagnosed IDH1-Mutant Myeloid Malignancies: A MyeloMATCH Substudy

This phase II MyeloMATCH treatment substudy tests the addition of olutasidenib to usual treatment in patients with higher-risk myelodysplastic syndrome (MDS) or patients with acute myeloid leukemia (AML) with a mutation in the IDH1 gene. Olutasidenib blocks the protein made by the mutated IDH1 gene. Blocking this protein may help keep cancer cells from growing. For patients with MDS, olutasidenib will be added to decitabine-cedazuridine (also called ASTX727). Decitabine is in a class of medications called hypomethylating agents and is the standard treatment for MDS. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. The cedazuridine makes it possible to take the decitabine by mouth. Adding olutasidenib to the usual treatment for MDS (ASTX727) may increase the likelihood of going into remission. For patients with AML, olutasidenib and ASTX727 will be combined with venetoclax, a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. Venetoclax may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Adding olutasidenib to the usual treatment for AML (ASTX727 and venetoclax) may increase the likelihood of going into remission. For low risk MDS, the substudy tests whether giving olutasidenib alone helps improve blood counts.

PRIMARY OBJECTIVES:

I. To assess the rate of minimal residual disease (MRD)-negative composite complete response (CRc) (CR + CR with partial hematological recovery [CRh] + CR with incomplete bone marrow recovery [CRi]), based on multiparametric flow cytometry (MFC), in older adults with IDH1-mutant acute myeloid leukemia (AML) treated with decitabine and cedazuridine (ASTX727), venetoclax (VEN), and olutasidenib compared to ASTX727 plus VEN, within 4 cycles of treatment. (Cohort A: IDH1-mutant AML) II. To assess the CR rate (including CR equivalent), using the modified International Working Group (IWG) 2023 response criteria, for patients with IDH1-mutant high-risk (HR)-MDS treated with ASTX727 plus olutasidenib compared to ASTX727 alone. (Cohort B: IDH1-mutant HR-MDS) III. To assess the rate of hematologic improvement (HI), using the IWG 2018 response criteria, for patients with IDH1-mutant low risk (LR)-MDS treated with olutasidenib. (Cohort C: IDH1-mutant LR-MDS)

SECONDARY OBJECTIVES:

I. To compare the rate of CR and composite CR (CR, CRh, CRi) by treatment arm. (Cohort A: IDH1-mutant AML) II. To compare the rate and duration of transfusion independence by treatment arm. (Cohort A: IDH1-mutant AML) III. To compare the event-free survival (EFS), cumulative incidence of relapse (CIR), early mortality, and overall survival (OS) by treatment arm. (Cohort A: IDH1-mutant AML) IV. To estimate the frequency and severity of toxicities by treatment arm. (Cohort A: IDH1-mutant AML) V. To compare the clearance of IDH1 mutation in bone marrow by treatment arm. (Cohort A: IDH1-mutant AML) VI. To compare the correlation between MRD clearance (including MFC and molecular MRD) and survival (including OS and EFS) by treatment arm. (Cohort A: IDH1-mutant AML) VII. To compare the rate of composite CR (CR [or CR equivalent] + CR with lesser hematological recovery [CRL] [CR with unilineage recovery (CRuni), CR with bilineage recovery (CRbi)] + CRh) using the modified IWG 2023 response criteria for patients with IDH1-mutant HR-MDS treated with ASTX727 plus olutasidenib compared to ASTX727 alone. (Cohort B: IDH1-mutant HR-MDS) VIII. To compare the overall response rate (ORR; defined as CR [or CR equivalent] + partial response [PR] + CRL [CRuni, CRbi] + CRh + HI) using the modified IWG 2023 response criteria for each treatment arm. (Cohort B: IDH1-mutant HR-MDS) IX. To compare the rate and duration of transfusion independence by treatment arm. (Cohort B: IDH1-mutant HR-MDS) X. To compare the time to response and duration of response (DoR) by treatment arm. (Cohort B: IDH1-mutant HR-MDS) XI. To compare the EFS and OS of patients by treatment arm. (Cohort B: IDH1-mutant HR-MDS) XII. To estimate the frequency and severity of toxicities by treatment arm. (Cohort B: IDH1-mutant HR-MDS) XIII. To compare the rate of patients bridged to allogeneic stem cell transplantation (allo-SCT) by treatment arm. (Cohort B: IDH1-mutant HR-MDS) XIV. To compare the clearance of IDH1 mutation, in bone marrow by treatment arm and correlation with survival (including OS and EFS) (Cohort B: IDH1-mutant HR-MDS) XV. To compare ORR, EFS, and OS by treatment arm stratified by the Molecular International Prognostic Scoring System for Myelodysplastic Syndromes (IPSS-M) prognostic scoring system. (Cohort B: IDH1-mutant HR-MDS) XVI. To estimate the rate of CR, median EFS, and median OS in patients who do not achieve CR with ASTX727 monotherapy, who are treated with the combination of ASTX727 plus olutasidenib. (Cohort B: IDH1-mutant HR-MDS) XVII. In patients with red blood cell transfusion-dependent (RBC-TD) anemia: To assess the rate of 8-week and 24-week red blood cell (RBC) transfusion independence (RBC-TI) with olutasidenib, time to RBC-TI, rate of transformation to AML and rate of 1-year RBC-TI. (Cohort C: IDH1-mutant LR-MDS) XVIII. To estimate the frequency and severity of toxicities with olutasidenib. (Cohort C: IDH1-mutant LR-MDS) XIX. To estimate rate of cytogenetic response (in patients with baseline cytogenetic abnormalities) and IDH1 mutational clearance with olutasidenib and correlation with rate of HI. (Cohort C: IDH1-mutant LR-MDS)

OUTLINE: Patients are assigned to 1 of 3 cohorts.

COHORT A: Patients are randomized to 1 of 2 arms.

ARM 1: Patients receive ASTX727 orally (PO) once daily (QD) on days 1-5 of each cycle and venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with CR, CRh, or CRi after cycle 4 continue treatment cycles every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow biopsy/aspiration and collection of blood samples throughout the trial.

ARM 2: Patients receive ASTX727 PO QD on days 1-5 of each cycle, venetoclax PO QD on days 1-28 of each cycle, and olutasidenib PO twice daily (BID) on days 1-28 of each cycle. Cycles repeat every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with CR, CRh, or CRi after cycle 4 continue treatment cycles every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow biopsy/aspiration and collection of blood samples throughout the trial.

COHORT B: Patients are randomized to 1 of 2 arms.

ARM 3: Patients receive ASTX727 PO QD on days 1-5 of each cycle and olutasidenib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with CR continue treatment cycles every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow biopsy/aspiration and collection of blood samples throughout the trial.

ARM 4: Patients receive ASTX727 PO QD on days 1-5 of each cycle. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients without CR after cycle 6 may then cross-over to Arm 3. Patients with CR, as well as patients without CR but deriving clinical benefit after cycle 6 continue treatment cycles every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow biopsy/aspiration and collection of blood samples throughout the trial.

COHORT C: Patients receive olutasidenib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit after cycle 6 continue treatment cycles every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow biopsy/aspiration and collection of blood samples throughout the trial.

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

Inclusion Criteria:

• Patient must be enrolled on the MYELOMATCH Master Screening and Reassessment Protocol (MSRP), determined to have an IDH1-R132 mutation and assigned to this trial via MATCHBox

• REGISTRATION ELIGIBILITY CRITERIA (STEP 1):

• Documentation of IDH1 mutated MDS or AML

• COHORT A: Age ≥ 60 years or adults ˂ 60 and ≥ 18 who in the opinion of the treating physician are not candidates for intensive, cytarabine-based induction based on clinical status (i.e., performance status), organ dysfunction, or disease biology with a morphologically confirmed diagnosis of AML with ≥ 20% myeloblasts in the bone marrow or peripheral blood

• COHORT B: Age ≥ 18 years with treatment-naïve HR-MDS with an IPSS-R score ≥ 4.0 at time of enrollment

• COHORT C: Age ≥ 18 years with LR-MDS with an IPSS-R score ≤ 3.5 at time of enrollment and either:

  • RBC-TD anemia (≥ 2 units/8 weeks in the 16 weeks prior to registration) who have failed or are ineligible to erythropoiesis-stimulating agents (ESA) therapy
  • Presence of either neutropenia (< 1 x 10^9/L) or thrombocytopenia (< 100 x 10^9/L) for use as frontline therapy or after failure of prior therapies, including growth factors. Patient must be hypomethylating agent (HMA)-naïve

• No prior therapy excluding:

  • Cohort A: hydroxyurea and all-trans retinoic acid (ATRA) for AML
  • Cohort B: ESAs (erythropoiesis-stimulating agents) and/or TGF-β inhibitors for HR-MDS
  • Cohort C: ESAs (erythropoiesis-stimulating agents, TGF-β inhibitors, telomerase inhibitors, and/or G-CSF for LR-MDS)

• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 3

• Creatinine clearance ≥ 30 mL/min (using the Cockcroft-Gault equation)

• Total bilirubin ≤ 3 x upper limit of normal (ULN)

  • Unless the increase is due to Gilbert's disease as determined per physician discretion/institutional practice

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 3 x upper limit of normal (ULN)

• Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effect on the developing fetus and newborn are unknown

  • Therefore, for women of childbearing potential only, a negative pregnancy test must be done ≤ 7 days prior to registration. (Cohorts B and C only)

• 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

• Patients with known HIV infection on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated

• 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

• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. A corrected QT interval < 480 msec (calculated using the Fridericia's formula [QTcF]) excluding patients with a right bundle branch block (RBBB) after approval of the principal investigator (PI)

• No known medical condition causing an inability to swallow, tolerate oral medications and must have no known malabsorption syndrome or any other uncontrolled gastrointestinal condition (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or small bowel resection) that may significantly alter the absorption of the study drugs

• RE-REGISTRATION ELIGIBILITY CRITERIA FOR COHORT B, ARM 3 (STEP 2): Patients on the ASTX727 monotherapy arm (Cohort B-Arm 3) 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 FOR COHORT B, ARM 3 (STEP 2): ECOG Performance Status ≤ 3

• RE-REGISTRATION ELIGIBILITY CRITERIA FOR COHORT B, ARM 3 (STEP 2): Creatinine clearance ≥ 30 mL/min (using the Cockcroft-Gault equation)

• RE-REGISTRATION ELIGIBILITY CRITERIA FOR COHORT B, ARM 3 (STEP 2): Total bilirubin ≤ 3 x upper limit of normal (ULN)

  • Unless the increase is due to Gilbert's disease as determined per physician discretion/institutional practice

• RE-REGISTRATION ELIGIBILITY CRITERIA FOR COHORT B, ARM 3 (STEP 2): AST (SGOT)/ALT (SGPT) ≤ 3 x upper limit of normal (ULN)