Study Of Venetoclax Tablet With Intravenous or Subcutaneous Azacitidine to Assess Change in Disease Activity In Adult Participants With Newly Diagnosed Higher-Risk Myelodysplastic Syndrome

Study Overview
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Brief Summary
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Myelodysplastic Syndrome (MDS) is a group of disorders that gradually affect the ability of a person's bone marrow (semi-liquid tissue present in many bones like backbones) to produce normal blood cells. Some people with MDS have a risk of the disease progressing to acute myeloid leukemia (AML), and a risk of death from the disease itself. Symptoms of MDS include fatigue, shortness of breath, unusual paleness due to anemia (low red blood cell count), easy or unusual bruising, and red spots just beneath the skin caused by bleeding. The purpose of this study is to see how safe and effective venetoclax and azacitidine (AZA) combination are when compared to AZA and a placebo (contains no medicine), in participants with newly diagnosed higher-risk MDS. Venetoclax is an investigational drug being developed for the treatment of MDS. The study consists of two treatment arms - In one arm, participants will receive venetoclax and AZA. In another arm, participants will receive AZA and placebo. Adult participants with newly diagnosed higher-risk MDS will be enrolled. Around 500 participants will be enrolled in approximately 220 sites worldwide. Participants in one arm will receive oral doses of venetoclax tablet and intravenous (infusion in the vein) or subcutaneous (given under the skin) AZA solution. Participants in another arm will receive oral doses of placebo tablet and intravenous or subcutaneous AZA solution. There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the course of the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood and bone marrow tests, checking for side effects, and completing questionnaires.

Official Title
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A Randomized, Double-Blind, Phase 3 Study Evaluating the Safety and Efficacy of Venetoclax in Combination With Azacitidine in Patients Newly Diagnosed With Higher-Risk Myelodysplastic Syndrome (Higher-Risk MDS)

Conditions
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Myelodysplastic Syndrome (MDS)

Intervention / Treatment
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* Drug: Venetoclax
* Drug: Azacitidine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with a diagnosis of Myelodysplastic Syndrome (MDS) according to the 2016 World Health Organization (WHO) classification wtih presence of < 20% bone marrow blasts per marrow biopsy/aspirate at screening. Participants must meet the following disease activity criteria: Overall Revised International Prognostic Scoring System (IPSS-R) score > 3 (intermediate, high or very high). Eastern Cooperative Oncology Group (ECOG) performance status of <= 2. Hematopoietic stem cell transplant (HSCT) eligible with no pre-arranged HSCT at the time of Study Day 1, or HSCT ineligible without plan for HSCT at the time of Study Day 1. Exclusion Criteria: Prior therapy for MDS with any hypomethylating agent, chemotherapy, or allogenic stem cell transplantation. Prior diagnosis of therapy-related MDS (t-MDS), MDS evolving from a pre-existing myeloproliferative neoplasm (MPN), MDS/MPN including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML) and unclassifiable MDS/MPN.

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: Arm 1: Venetoclax + Azacitidine (AZA)<br>Participants will receive venetoclax once daily (QD) (Days 1-14) in combination with AZA QD (7 days of the first 9 days) of each 28 day cycle. | Drug: Venetoclax<br>* Tablet: Oral<br>* Other names: Venclexta;Drug: Azacitidine<br>* Subcutaneous (SC) or Intravenous (IV) injection<br>* Other names: AZA;|
| Active Comparator: Arm 2: Placebo + Azacitidine<br>Participants will receive placebo once daily (QD) (Days 1-14) in combination with AZA QD (7 days of the first 9 days) of each 28 day cycle. | Drug: Azacitidine<br>* Subcutaneous (SC) or Intravenous (IV) injection<br>* Other names: AZA;Drug: Placebo<br>* Tablet; Oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | OS is defined as the number of days from the date of randomization to the date of death of any cause, or last known date to be alive. | Up To 5 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Overall Response (mOR) | mOR [complete remission (CR) + marrow complete remission (mCR) + partial response (PR)] is defined as achieving a CR, mCR, or PR at any time point during the study per the modified International Working Group (IWG) 2006 criteria for myelodysplastic syndrome (MDS). | Up To 5 Years | 
| Percentage of Participants Achieving Overall Hematological Improvement (HI) | Overall HI is defined as achieving the response of HI-platelet or HI-neutrophil, or HI-erythroid at any time point during the study prior to post-treatment therapy per the modified IWG 2006 criteria for MDS. | Up to 5 Years | 
| Complete Remission (CR) | CR is defined as achieving a complete remission at any time point during the study per the modified International Working Group (IWG) 2006 criteria for myelodysplastic syndrome (MDS). | Up To 36 Months | 
| Percentage of Participants Achieving Transfusion Independence (TI) Who are Transfusion Dependent at Baseline | TI is when the participants who were transfusion dependent on red blood cell (RBC) and/or Platelet at baseline achieve transfusion independence post baseline. TI is a period of at least 56 days with no transfusion after the date of the first dose of study drug to the last dose of study drug + 30 days, or 1 day before the date of progressive disease/ relapse from CR or PR per the modified IWG 2006 criteria for MDS, or 1 day before the initiation of post-treatment therapy or 1 day before death, whichever is earliest. | Up To 5 Years | 
| Time to Deterioration in Physical Functioning as Measured by Physical Functioning Domain of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Scale | Time to deterioration in physical functioning, as measured by the EORTC QLQ-C30 physical functioning score is defined as the time from the date of randomization to the date of death of any cause, or the first time worsening of score from baseline >= a pre-specified threshold. Participants rate items on a 4-point scale, with 1 as not at all and 4 as very much. | Up To 5 Years | 
| Change in Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue Short Form (SF) 7a Scale Score | Fatigue will be assessed using the PROMIS Fatigue SF 7a Global Fatigue Score. PROMIS Fatigue SF 7a is a 7-item questionnaire that assesses the impact and experience of fatigue over the past 7 days. Participants rate items on a 5-point scale, with 1 as never an 5 as always. | Up To 5 Years | 
| Overall Response (OR) | OR [complete remission (CR) + partial response (PR)] is defined as achieving a CR or PR at any time point during the study per the modified IWG 2006 criteria for MDS. | Up To 5 Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDS, Myelodysplastic Syndrome, Venetoclax, Azacitidine, AZA, Venclexta