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)

The primary objective of this study is to evaluate the **safety** and **efficacy** of two dose regimens of oral azacitidine (Oral-Aza) in participants with International Prognostic Scoring System-Revised (IPSS-R) low- or intermediate-risk **myelodysplastic syndrome** (MDS). For Part I (Phase 2), the focus is on assessing the complete response (CR) within six cycles and recommending the optimal dose for the Phase 3 study based on comprehensive safety, efficacy, pharmacokinetic (PK), and pharmacodynamic (PD) data. For Part II (Phase 3), the primary objective is to evaluate the CR within six cycles for both study arms. The clinical relevance of these objectives lies in optimizing treatment regimens for MDS, potentially improving patient outcomes by identifying the most effective and safe dosing strategy.

Secondary objectives include:

• Evaluating and assessing overall response (OR) to Oral-Aza, including overall response rate (ORR) within six cycles, OR duration, and best OR.
• Assessing CR duration.
• Evaluating and assessing transfusion independence after treatment with Oral-Aza, including rates and durations for both packed red blood cells (pRBC) and platelets.
• Evaluating and assessing overall survival (OS), event-free survival (EFS), time to transformation to acute myeloid leukemia (AML), and time to subsequent therapy.
• Monitoring iron overload.
• Evaluating safety assessments.
• Evaluating and assessing health-related quality of life and health care resource utilization.

The clinical trial involves a total of **140 participants** diagnosed with **Myelodysplastic Syndrome (MDS)**, specifically those classified under the **International Prognostic Scoring System-Revised (IPSS-R)** as low- or intermediate-risk. The study population includes both male and female participants who are **18 years of age or older**. Participants were selected based on a documented diagnosis of MDS according to the WHO 2016 classification, with specific IPSS-R score criteria. The trial includes individuals with at least one cytopenia, such as anemia, thrombocytopenia, or neutropenia, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. The trial population is diverse, encompassing various MDS subtypes, and includes a vulnerable population. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase 2/3**, multicenter, randomized, dose optimization (Part I), double-blind (Part II) study designed 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). The trial is structured to evaluate two oral azacitidine dose regimens in Part I (Phase 2) to recommend the optimal dose for Part II (Phase 3) based on safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) data. The primary objective for Part II is to evaluate the complete response (CR) within six cycles for both study arms. The trial is expected to conclude by August 4, 2031, with recruitment having commenced on March 30, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), documented diagnosis of MDS according to WHO 2016 classification, and IPSS-R classification of low- or intermediate-risk disease. Participants must also have at least one cytopenia and an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. Follow-up visits will occur throughout the study to monitor safety and efficacy, with assessments including adverse events (AEs) evaluated using NCI CTCAE criteria, laboratory assessments, and vital signs. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 60 days, corresponding to the maximum treatment period.

Participants may be subject to early termination from the study if they experience significant adverse events, fail to comply with study procedures, or withdraw consent. The trial's endpoints include the achievement of CR within six cycles, overall response (OR) rates, and duration of response, among others. Secondary endpoints will assess parameters such as transfusion independence, overall survival (OS), and event-free survival (EFS). The study will also evaluate healthcare resource use associated with the condition during the trial. The trial is not classified as low intervention, and the investigational product is a small molecule administered orally in tablet form.

The clinical trial involves the administration of **azacitidine** in tablet form, with two different dosages being evaluated. The first experimental medication is the **azacitidine 200 mg tablet**, which is administered orally. The maximum daily dose for this formulation is 200 mg, with a total maximum dose of 168,000 mg over a treatment period of 60 days. The active substance, **azacitidine**, is of chemical origin and is manufactured by Bristol-Myers Squibb International Corporation. This formulation is not a pediatric formulation and is classified as a small molecule.

The second experimental medication is the **azacitidine 300 mg tablet**, also administered orally. The maximum daily dose for this formulation is 300 mg, with a total maximum dose of 252,000 mg over the same 60-day treatment period. Like the 200 mg tablet, the active substance is **azacitidine**, and it is also produced by Bristol-Myers Squibb International Corporation. This formulation is similarly classified as a small molecule and is not intended for pediatric use.

In addition to the experimental medications, the study includes a placebo group. Participants in this group will receive a placebo tablet, which is designed to mimic the appearance and administration route of the azacitidine tablets. The placebo is administered orally, in conjunction with best supportive care (BSC), to provide a comparator for evaluating the efficacy and safety of the azacitidine treatments. Compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. For Part I (Phase 2), the primary endpoint is the achievement of **Complete Remission (CR)** within 6 cycles, evaluated according to the International Working Group (IWG) 2006 criteria. In Part II (Phase 3), the primary endpoint remains the achievement of CR within 6 cycles. Secondary endpoints for Part I include the achievement of Overall Response (OR) within 6 cycles, CR duration, and the achievement of 84-day platelet and red blood cell transfusion independence (PLT-TI and pRBC-TI) within 6 cycles. For Part II, secondary endpoints include OR achievement, CR duration, overall survival (OS), event-free survival (EFS), and changes in iron parameters. Additionally, patient-reported outcomes will be measured using validated instruments such as the FACT-An, QUALMS, and EQ-5D-5L scales.

The efficacy parameters will be collected and analyzed at specified timepoints, including within 6 cycles of treatment. The trial will utilize laboratory assessments and patient-reported outcomes to gather data. Adverse events will be evaluated using the NCI CTCAE criteria, version 5.0, which includes treatment-emergent adverse events (TEAEs), laboratory assessments, and vital signs. The trial aims to recommend the optimal dose for the Phase 3 study based on the totality of safety, efficacy, pharmacokinetic (PK), and pharmacodynamic (PD) data.