Hypomethylating Agent (HMA) Naive Myelodysplastic Syndromes (MDS), Myelodysplastic Syndromes (MDS)
Conditions
Brief 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.
Interventions
DRUGIvosidenib
Two 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.
DRUGAzacitidine
Azacitidine 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.
Sponsors
Institut de Recherches Internationales Servier
Servier Bio-Innovation LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of HMA naive IDH1 R132 mutated MDS defined according to WHO criteria (5th edition): * 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%. * Low and moderate low-risk MDS per IPSS-M score must: * 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) * Locally or centrally confirmed IDH1 R132 C/G/H/L/S mutation
Exclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants achieving CR and PR by 4 months | Through 4 months after starting treatment | Complete remission (CR) or Partial remission (PR) as per International Working Group (IWG) 2006 criteria |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of CR and PR | Through the end of the study (approximately 4 years) | Among participants who achieved CR+PR per IWG 2006 criteria |
| Time to CR and PR | Through the end of the study (approximately 4 years) | 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 |
| Acute myeloid leukemia (AML) transformation rate | Through the end of the study (approximately 4 years) | — |
| Time to transfusion independence (TTTI) | Through the end of the study (approximately 4 years) | 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. |
| Duration of transfusion independence (DOTI) | Through the end of the study (approximately 4 years) | 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. |
| 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 | Through the Event Free Survival Follow up (approximately 4 years) | Quality of Life in Myelodysplasia Scale (QUALMS) scores range from 0 to 100, with a higher score representing a better QOL. |
| Overall Response (OR) rate per IWG 2023 criteria | Through the end of the study (approximately 4 years) | Defined as CR (or CR equivalent) + PR + CRL + CRh + hematological improvement (HI) |
| Event-free survival (EFS) | Through the end of the study (approximately 4 years) | Defined as the date of randomization to the date of first documented confirmed relapse /progression /death, whichever occurs first |
| Change from baseline in health economic outcomes measures based on EQ-5D-5L score | Through the Event Free Survival Follow up (approximately 4 years) | 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. |
| Number of participants who proceed to hematopoietic stem cell transplantation (HSCT) | Through the end of the study (approximately 4 years) | — |
| Ivosidenib plasma concentrations | Through Cycle 22 (each cycle is 28 days) | For participants receiving ivosidenib monotherapy |
| 2-HG plasma concentrations | Through Cycle 22 (each cycle is 28 days) | For participants receiving ivosidenib monotherapy |
| Number of participants achieving CR and PR by 6 months as per IWG 2006 criteria | Through 6 months after starting treatment | — |
| Number of participants achieving CR and PR by 6 months as per IWG 2023 criteria | Through 6 months after starting treatment | — |
| Number of participants achieving CR and PR by 4 months as per IWG 2023 criteria | Through 4 months after starting treatment | — |
| Overall Survival (OS) | Through the end of the study (approximately 4 years) | 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. |
| Number of adverse events (AEs) and serious adverse events (SAEs) | Through the Safety Follow-up Visit (30-35 days after discontinuation of treatment) | — |
Countries
Australia, Brazil, France, Germany, Italy, Japan, Netherlands, Spain, United Kingdom, United States
Contacts
CONTACTInstitut de Recherches Internationales Servier (I.R.I.S.), Clinical Studies Department
Outcome results
None listed