A Study to Compare the Efficacy and Safety of Oral Azacitidine Plus Best Supportive Care (BSC) Versus Placebo Plus BSC in Participants With International Prognostic Scoring System Revised (IPSS-R) Low- or Intermediate-risk Myelodysplastic Syndrome (MDS)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of oral azacitidine in participants with low to intermediate International Prognostic Scoring System Revised (IPSS-R) myelodysplastic syndrome (MDS).

Official Title
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A Phase 2/3, Multicenter, Randomized, Dose Optimization (Part I), Double-blind (Part II) Study to Compare the Efficacy and Safety of Oral Azacitidine (Oral-Aza, ONUREG®) Plus Best Supportive Care (BSC) Versus Placebo Plus BSC in Participants With IPSS-R Low- or Intermediate-risk Myelodysplastic Syndrome (MDS)

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: Oral Azacitidine
* Drug: Placebo for Oral Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • Participant has a documented diagnosis of MDS according to WHO 2016 classification that meets International Prognostic Scoring System Revised (IPSS-R) classification of low- or intermediate-risk disease (IPSS-R score between 1.5 and 4.5). MDS diagnosis, WHO classification, and IPSS-R risk classification will be prospectively determined by independent central pathology and cytogenetics review, and applicable central laboratory results. • Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. Exclusion Criteria: Participants with prior malignancies must have an expected median life expectancy of at least 12 months at the time of inclusion and no active treatment of any sort for at least 24 weeks prior to randomization (including but not limited to immunotherapy or targeted therapy) Hypoplastic Myelodysplastic Syndrome (MDS) with a marrow cellularity of ≤ 10% Participants diagnosed with MDS with excess blasts-2 (MDS-EB2) Prior treatment with azacitidine (any formulation), decitabine, or other hypomethylating agent Other protocol-defined inclusion/exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part I - Oral-Aza (Dose 1)<br> | Drug: Oral Azacitidine<br>* Specified dose on specified days<br>* Other names: ONUREG®;|
| Experimental: Part I - Oral-Aza (Dose 2)<br> | Drug: Oral Azacitidine<br>* Specified dose on specified days<br>* Other names: ONUREG®;|
| Experimental: Part II - Oral-Aza (RP3D)<br>RP3D: Recommended Phase 3 Dose | Drug: Oral Azacitidine<br>* Specified dose on specified days<br>* Other names: ONUREG®;|
| Experimental: Part II - Placebo<br> | Drug: Placebo for Oral Azacitidine<br>* Specified dose on specified days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Adverse Events (AEs) evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) criteria v.5.0 | Phase 2 | 6 cycles plus 28 days (up to 24 weeks) | 
| Number of participants who achieved complete remission (CR) per International Working Group (IWG) 2006 criteria within 6 cycles | Phase 2 and 3 | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants who achieved Overall Response (OR) per IWG 2006 criteria within 6 cycles | Phase 2 and Phase 3 Overall Response is defined as complete response (CR), partial remission (PR), marrow complete response (mCR), hematologic improvement-erythroid response (HI-E), hematologic improvement-platelet response (HI-P), or hematologic improvement-neutrophil response (HI-N) as per IWG 2006 criteria | Up to 24 weeks | 
| Number of participants who achieved 84-day packed red blood cells transfusion independence (pRBC-TI) | Phase 2 and Phase 3 | Up to 32 weeks | 
| pRBC-TI duration | Phase 2 and Phase 3 | Over the course of the study, an average of 1 year | 
| Number of participants who achieve 84 day platelet transfusion independence (PLT-TI) within 6 cycles | Phase 2 and Phase 3 | Over the course of the study, an average of 1 year | 
| PLT-TI duration | Phase 2 and Phase 3 | Over the course of the study, an average of 1 year | 
| Number of participants who achieved pRBC transfusion reduction | Phase 3 | Over the course of the study, an average of 1 year | 
| pRBC transfusion reduction duration | Phase 3 | Over the course of the study, an average of 1 year | 
| CR duration | Phase 2 and Phase 3 | Over the course of the study, an average of 1 year | 
| Best OR | Phase 2 and Phase 3 | Over the course of the study, an average of 1 year | 
| OR duration | Phase 2 and Phase 3 | Over the course of the study, an average of 1 year | 
| Overall Survival (OS) | Phase 3 | Up to 5 years after discontinuation of Investigational Product, approximately 6 years | 
| Event-free Survival (EFS) | Phase 3 | Up to 5 years after discontinuation of Investigational Product, approximately 6 years | 
| Time to acute myeloid leukemia (AML) | Phase 3 | Up to 5 years after discontinuation of Investigational Product, approximately 6 years | 
| Time to subsequent therapy | Phase 3 | Up to 5 years after discontinuation of Investigational Product, approximately 6 years | 
| Iron parameters measured from blood | Phase 3 | Over the course of the study, an average of 1 year | 
| Number of participants with Adverse Events (AEs) evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) criteria v.5.0 | Phase 3 | Up to end of treatment/early termination, an average of 1 year | 
| Summary statistics for Functional Assessment of Cancer Therapy-Anemia (FACT-An) scales and subscales at each assessment point for each treatment arm | Phase 3 | Up to end of treatment/early termination, an average of 1 year | 
| Summary statistics for Quality of Life in Myelodysplasia Scale (QUALMS) scales and subscales at each assessment point for each treatment arm | Phase 3 | Up to end of treatment/early termination, an average of 1 year | 
| Summary statistics for the EuroQol 5 Dimension 5 Level (EQ-5D-5L) scales and subscales at each assessment point for each treatment arm | Phase 3 | Up to end of treatment/early termination, an average of 1 year | 
| Number of participants with healthcare resource use associated with the investigational product (IP) | Phase 3 | Over the course of the study, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anemia, Thrombocytopenia