Ivosidenib (IVO) Monotherapy and Azacitidine (AZA) Monotherapy in Patients With Hypomethylating Agent (HMA) Naive Myelodysplastic Syndromes (MDS) With an IDH1 Mutation
NCT Number: NCT06465953
Acronym: PyramIDH
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE3
Conditions: Hypomethylating Agent (HMA) Naive Myelodysplastic Syndromes (MDS)|Myelodysplastic Syndromes (MDS)
Interventions: DRUG: Ivosidenib|DRUG: Azacitidine
Sponsor: Institut de Recherches Internationales Servier
Collaborators: Servier Bio-Innovation LLC
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 48
Study Design: Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: NONE|Primary Purpose: TREATMENT
Start Date: 2024-12-30
Completion Date: 2028-12-01

Summary:
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.

Primary Outcome Measures: Number of participants achieving CR and PR at 4 months, Complete remission (CR) or Partial remission (PR) as per International Working Group (IWG) 2006 criteria, Through 4 months after starting treatment
Secondary Outcome Measures: Overall Response (OR) rate per IWG 2023 criteria, Defined as CR (or CR equivalent) + PR + CRL + CRh + hematological improvement (HI), Through the end of the study (approximately 4 years)|Event-free survival (EFS), Defined as the date of randomization to the date of first documented confirmed relapse /progression /death, whichever occurs first, Through the end of the study (approximately 4 years)|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., Through the end of the study (approximately 4 years)|Duration of CR and PR, Among participants who achieved CR+PR per IWG 2006 criteria, Through the end of the study (approximately 4 years)|Time to CR and PR, Defined as time from the date of the randomization to the date of CR+PR, among participants who achieve CR+PR based on IWG 2006 Response Criteria, Through the end of the study (approximately 4 years)|Acute myeloid leukemia (AML) transformation rate, Through the end of the study (approximately 4 years)|Time to transfusion independence (TTTI), Defined as time from date of randomization to date transfusion independence (TI) is first observed (Day 1 of a ≥ 56 days period without a transfusion), among participants who are baseline transfusion dependent and have achieved post-baseline TI. In the event a participant had more than one ≥ 56-day period, which met TI criteria, the earliest period will be used in analysis., Through the end of the study (approximately 4 years)|Duration of transfusion independence (DOTI), Among participants who have achieved post-baseline TI, DOTI will be calculated as the time from the date TI is first observed (Day 1 of a ≥ 56-day period without a transfusion) until the day before the participants had a subsequent transfusion., Through the end of the study (approximately 4 years)|Transfusion independence rate, Through the end of the study (approximately 4 years)|Change from baseline in Quality of life (QOL) based on the QUALMS score, Quality of Life in Myelodysplasia Scale (QUALMS) scores range from 0 to 100, with a higher score representing a better QOL., Through the Event Free Survival Follow up (approximately 4 years)|Change from baseline in health economic outcomes measures based on EQ-5D-5L score, Health economic outcomes measures as assessed by the 5-level EuroQol five dimensions questionnaire (EQ-5D-5L) scores range from 5 to 25 with a higher number representing a worse health status., Through the Event Free Survival Follow up (approximately 4 years)|Number of participants who proceed to hematopoietic stem cell transplantation (HSCT), Through the end of the study (approximately 4 years)|Ivosidenib plasma concentrations, For participants receiving ivosidenib monotherapy, Through Cycle 22 (each cycle is 28 days)|2-HG plasma concentrations, For participants receiving ivosidenib monotherapy, Through Cycle 22 (each cycle is 28 days)|Number of participants achieving CR and PR at 6 months as per IWG 2006 criteria, Through 6 months after starting treatment|Number of participants achieving CR and PR at 6 months as per IWG 2023 criteria, Through 6 months after starting treatment|Number of participants achieving CR and PR at 4 months as per IWG 2023 criteria, Through 4 months after starting treatment|Number of adverse events (AEs) and serious adverse events (SAEs), Through the Safety Follow-up Visit (30-35 days after discontinuation of treatment)