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.
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
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
None
Parallel
Biospecimen Collection
Procedure/SurgeryUndergo collection of blood samples
Bone Marrow Aspiration
Procedure/SurgeryUndergo bone marrow aspiration
Bone Marrow Biopsy
Procedure/SurgeryUndergo bone marrow biopsy
Decitabine and Cedazuridine
DrugGiven PO
Olutasidenib
DrugGiven PO
Venetoclax
DrugGiven PO
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.
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.
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.
CR and CRc (Cohort A)
CRc will be defined as CR, CRh, or CRi. Both the CR rate and the composite CR rate will be determined for each treatment arm. The difference in rate between the two arms will be provided along with a 95% confidence interval.
Transfusion independence (Cohorts A)
Will report the difference in rate of transfusion independence between the two treatment arms along with a 95% confidence interval. Additionally, will report the duration of transfusion independence, defined as the time from randomization to transfusion dependence, with the corresponding hazard ratio and Kaplan Meier curve.
Event-free survival (EFS) (Cohort A)
Sensitivity analyses will be conducted to evaluate different definitions in EFS, e.g., patients who failed to achieve a CR, CRh, or Cri after four cycles of treatment will be censored at the time of randomization. Will utilize the methods of Kaplan-Meier as well as Cox regression models to evaluate these time-to-event outcomes.
Cumulative incidence of relapse (Cohort A)
A cumulative incidence function will be created and a cause-specific hazard approach will be utilized with the event of interest being relapse and the competing risk being death.
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