This study will enroll participants with myelodysplastic syndromes (MDS) with an Isocitrate dehydrogenase protein, 1 (IDH1) mutation, who have not received treatment with a hypomethylating agent previously. Participants will be randomized to receive either ivosidenib (IVO) alone or azacitidine (AZA) alone. IVO will be administered daily throughout the 28-day treatment cycle and AZA will be administered for the first 7 days of each 28-day cycle. Study visits will be conducted every week during Cycle 1 (Days 1, 8, 15, and 22), and Day 1 of each cycle thereafter. After the last dose of treatment, participants will attend an safety follow-up visit and participants will be followed to assess overall survival. Study visits may include a bone marrow aspirate, physical exam, echocardiogram (ECHO), electrocardiogram (ECG), blood and urine analysis, and questionnaires.
Moderate high, high and very high-risk MDS per IPSS-M score will be eligible regardless of blood counts and with blast counts 0-19%.
Have cytopenias related to MDS, defined as: <100 platelets/microliter, or absolute neutrophil count (ANC) <1000/mm3, or hemoglobin <10g/dL AND
Have a blast count between 5-19% AND
Be eligible for HMA therapy (very low risk participants are to be excluded)
Received prior anticancer/disease modifying treatment for MDS (including HMA's, cytotoxic chemotherapy, investigational agents, bcl-2 inhibitor based-regimens, hematopoietic stem cell transplant (HSCT), IDH1 inhibitors). For LR-MDS patients, prior treatment with growth factors, luspatercept, lenalidomide, and imetelstat are allowed.
>20% blasts by morphology or immunohistochemistry on screening bone marrow aspirate/biopsy
Parallel
Ivosidenib
DrugTwo 250 mg tablets, totaling 500 mg, administered orally once daily until disease relapse or progression, unacceptable toxicity, confirmed pregnancy, undergoing HSCT, death, withdrawal of consent, lost to follow-up, or Sponsor ending the study, whichever occurs first.
Azacitidine
DrugAzacitidine 75mg/m\^2/day administered by subcutaneous (SC) or intravenous (IV) injection for 1 week (7 days) of each 4-week (28 day) treatment cycle until disease relapse or progression, unacceptable toxicity, confirmed pregnancy, undergoing HSCT, death, withdrawal of consent, lost to follow-up, or Sponsor ending the study, whichever occurs first.
Number of participants achieving CR and PR by 4 months
Complete remission (CR) or Partial remission (PR) as per International Working Group (IWG) 2006 criteria
Overall Response (OR) rate per IWG 2023 criteria
Defined as CR (or CR equivalent) + PR + CRL + CRh + hematological improvement (HI)
Event-free survival (EFS)
Defined as the date of randomization to the date of first documented confirmed relapse /progression /death, whichever occurs first
Overall Survival (OS)
Defined as the time from randomization to the date of death due to any cause. Participants who are alive at the analysis cutoff date will be censored at the date they were last known to be alive.
Duration of CR and PR
Among participants who achieved CR+PR per IWG 2006 criteria
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Institut de Recherches Internationales Servier
Lead sponsor
Servier Bio-Innovation LLC
Collaborator
