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
3 other identifiers
interventional
132
0 countries
N/A
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_2
Started May 2026
Typical duration for phase_2
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
September 3, 2025
CompletedFirst Posted
Study publicly available on registry
September 4, 2025
CompletedStudy Start
First participant enrolled
May 27, 2026
CompletedPrimary Completion
Last participant's last visit for primary outcome
April 26, 2030
ExpectedStudy Completion
Last participant's last visit for all outcomes
April 26, 2030
May 13, 2026
December 1, 2025
3.9 years
September 3, 2025
May 12, 2026
Conditions
Outcome Measures
Primary Outcomes (3)
Minimal residual disease (MRD)-negative complete response (CR) + CR with partial hematological recovery (CRh) + CR with incomplete bone marrow recovery (CRi) (Cohort A)
Will compare the MRD-negative composite complete response (CRc) rate between the two treatment arms to determine if older adults with IDH1-mutant acute myeloid leukemia (AML) treated with the triplet ASTX727, venetoclax (VEN), and olutasidenib have a statistically significantly higher MRD-negative CRc rate than patients treated with the doublet ASTX727 and VEN. CRc will be determined based on multiparametric flow cytometry.
Up to 4 cycles post randomization (Cycles = 28 days)
Rate of CR (Cohort B)
Will include CR equivalent. Will compare the CR rate between the two treatment arms to determine if patients with IDH1-mutant higher-risk-myelodysplastic syndrome (MDS) treated with ASTX727 plus olutasidenib have a statistically significantly higher CR rate than those treated with ASTX727 alone. Complete response will be determined using the modified International Working Group (IWG) 2023 response criteria.
Up to 6 cycles post randomization (Cycles = 28 days)
Rate of hematologic improvement (HI) (Cohort C)
Will be determined using the IWG 2018 response criteria for patients with IDH1-mutant low risk-MDS treated with olutasidenib.
Up to 6 cycles post randomization (Cycles = 28 days)
Secondary Outcomes (17)
CR and CRc (Cohort A)
Up to 5 years
Transfusion independence (Cohorts A)
Up to 5 years
Event-free survival (EFS) (Cohort A)
From randomization until either a failure to achieve a CRc after four cycles of treatment, relapse, or death due to any cause, assessed up to 5 years
Cumulative incidence of relapse (Cohort A)
From which a patient achieves a CR to the time of relapse, assessed up to 5 years
Early mortality (Cohort A)
Up to 30 and 60 days
- +12 more secondary outcomes
Study Arms (5)
Cohort A, Arm 1 (ASTX727, venetoclax)
ACTIVE COMPARATORPatients receive ASTX727 PO 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.
Cohort A, Arm 2 (ASTX727, venetoclax, olutasidenib)
EXPERIMENTALPatients receive ASTX727 PO QD on days 1-5 of each cycle, venetoclax PO QD on days 1-28 of each cycle, and olutasidenib PO 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, Arm 3 (ASTX727, olutasidenib)
EXPERIMENTALPatients 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.
Cohort B, Arm 4 (ASTX727)
ACTIVE COMPARATORPatients 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 (olutasidenib)
EXPERIMENTALPatients 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.
Interventions
Given PO
Undergo collection of blood samples
Undergo bone marrow aspiration
Undergo bone marrow biopsy
Given PO
Given PO
Eligibility Criteria
You may qualify if:
- 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)
- +16 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
John L Reagan
Alliance for Clinical Trials in Oncology
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
September 3, 2025
First Posted
September 4, 2025
Study Start
May 27, 2026
Primary Completion (Estimated)
April 26, 2030
Study Completion (Estimated)
April 26, 2030
Last Updated
May 13, 2026
Record last verified: 2025-12
Data Sharing
- IPD Sharing
- Will share
NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.