Evaluation of Venetoclax and Azacitidine Combination Therapy Versus Placebo and Azacitidine in Treatment-Naïve Patients with Higher-Risk Myelodysplastic Syndrome

The primary objective of this study is to assess the **efficacy** of **venetoclax** in combination with **azacitidine** compared to placebo with azacitidine in a treatment-naïve, higher-risk **Myelodysplastic Syndrome** (MDS) population. The clinical relevance of this objective lies in the potential improvement of overall survival (OS) when venetoclax is added to the standard of care azacitidine treatment for patients newly diagnosed with higher-risk MDS.

Secondary objectives include:

• Evaluating various efficacy measures of venetoclax in combination with azacitidine compared to placebo with azacitidine in the same patient population.
• Assessing the safety profile of venetoclax in combination with azacitidine versus placebo with azacitidine.
• Evaluating patient-reported outcomes (PROs) for subjects on venetoclax in combination with azacitidine compared to placebo with azacitidine.

The clinical trial involves a total of **340 participants** diagnosed with **Higher-Risk Myelodysplastic Syndrome**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific criteria, including a diagnosis of Myelodysplastic Syndrome according to the 2016 World Health Organization classification, with less than 20% bone marrow blasts per marrow biopsy or aspirate at screening. The trial population comprises individuals who have not received prior therapy for Myelodysplastic Syndrome with any hypomethylating agent, chemotherapy, or allogeneic stem cell transplantation. Participants must have an Eastern Cooperative Oncology Group performance status of 2 or less and meet the disease activity criteria with an Overall Revised International Prognostic Scoring System score greater than 3. The study includes both hematopoietic stem cell transplant-eligible and ineligible individuals, with no pre-arranged transplant plans at the time of study initiation. The trial considers vulnerable populations, ensuring a comprehensive assessment of the treatment's efficacy across diverse demographic groups.

The clinical trial is a **randomized, double-blind, controlled** study designed to evaluate the safety and efficacy of **venetoclax** in combination with **azacitidine** in patients newly diagnosed with higher-risk **myelodysplastic syndrome** (MDS). The trial aims to assess whether the addition of venetoclax to standard azacitidine treatment improves overall survival compared to a placebo. The study is structured as a Phase 3 trial, with an estimated duration from January 15, 2021, to October 31, 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis according to the 2016 World Health Organization classification, and absence of prior therapy for MDS. The trial will include follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The primary endpoint is overall survival, with secondary endpoints including modified overall response, hematological improvement, and time to deterioration in physical functioning.

The expected length of participant involvement is up to 53 weeks, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial will ensure that all participants receive either the investigational treatment or a placebo in a blinded manner, maintaining the integrity of the study design.

**Venetoclax** is an experimental medication used in this clinical trial. It is a **film-coated tablet** designed for **oral use**. Venetoclax functions as a small molecule Bcl-2 family protein inhibitor. The specific dosage and frequency of administration are not detailed in the provided data, but the maximum treatment period is specified as 53 weeks. The medication is produced by AbbVie Deutschland GmbH & Co. KG, and it is not a paediatric formulation. Participant compliance with the dosing schedule will be monitored throughout the trial.

The trial also includes a **placebo** group, which receives a placebo version of Venetoclax, also in the form of a film-coated tablet for oral use. The placebo is used to compare the effects of Venetoclax in combination with azacitidine against the standard treatment. The placebo does not contain any active substance and is intended to mimic the administration of Venetoclax without providing therapeutic effects.

**Azacitidine**, marketed as Vidaza, is used as a **comparator treatment** in this study. It is provided as a **powder for suspension for injection** and is administered via **intravenous use**. Azacitidine acts as a nucleoside metabolic inhibitor. The maximum daily dose is 75 mg/m², with a total maximum dose of 525 mg/m² over the treatment period. The treatment duration is also set at 53 weeks. Azacitidine is produced by Bristol-Myers Squibb Pharma EEIG and is not a paediatric formulation. Compliance with the dosing schedule will be monitored to ensure accurate assessment of treatment efficacy.

The efficacy of the clinical trial will be assessed by evaluating the primary endpoint of **Overall Survival (OS)** in patients with higher-risk Myelodysplastic Syndrome (MDS) who are newly diagnosed and treatment-naïve. The trial aims to compare the efficacy of **Venetoclax** in combination with **Azacitidine** against a placebo with Azacitidine. The hypothesis is that Venetoclax will improve OS when added to the standard of care Azacitidine treatment.

Secondary endpoints include several measures of response and improvement: modified overall response (mOR) defined as complete remission (CR) + partial remission (PR) + marrow CR (mCR), overall hematological improvement (HI) in platelet, neutrophil, or erythroid counts, complete remission, and red blood cell (RBC) and platelet transfusion independence for subjects who are transfusion-dependent at baseline. Additionally, the time to deterioration in physical functioning will be measured using the physical functioning domain of the EORTC QLQ-C30, and changes from baseline in fatigue will be assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue SF 7a. Overall response (OR) defined as CR + PR will also be evaluated.