Phase II Multicenter Study on Azacitidine for Minimal Residual Disease Management Post-Allogeneic Stem Cell Transplantation in Myelodysplastic Syndrome

The primary objective of this phase II multicenter study is to prevent clinical events, specifically **relapse** or non-relapse death, in subjects with minimal residual disease (MRD) positive **myelodysplastic syndrome** (MDS) following allogeneic stem cell transplantation. This objective is clinically relevant as it aims to improve post-transplant outcomes and survival rates in this patient population, addressing a critical need for effective management strategies in MRD positive MDS.

Secondary objectives include:

• For the MRD positive cohort: To induce molecular remission, evaluate the incidence and severity of **graft-versus-host disease** (GVHD), and assess safety during pre-emptive treatment.
• For the whole study cohort: To prevent relapse or non-relapse death, evaluate the incidence and severity of GVHD, and prolong overall survival.

The clinical trial involves participants diagnosed with **myelodysplastic syndrome** (MDS), mixed myelodysplastic/myeloproliferative syndrome, or acute myeloid leukemia (AML) with myelodysplasia-related dysplasia and 20-29% marrow blasts. The study population includes both male and female subjects aged 18 years and older, who are eligible for stem cell transplantation. All female participants of childbearing potential are required to have a negative pregnancy test within two weeks prior to inclusion in the study. The trial population was selected based on specific inclusion criteria, including the ability to provide signed informed consent. The sponsor has not provided information regarding the total number of participants. The study aims to prevent clinical events such as relapse or non-relapse death in minimal residual disease (MRD) positive subjects. Participants may include vulnerable populations, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **phase II** multicenter, single-armed study designed to evaluate the efficacy of subject-specific minimal residual disease (MRD) markers in adapting treatment post-allogeneic stem cell transplantation for individuals diagnosed with **myelodysplastic syndrome** (MDS). The primary objective is to prevent clinical events, such as relapse or non-relapse death, in MRD-positive subjects. The trial will utilize **azacitidine**, administered as a **subcutaneous** injection, with a maximum daily dose of 75 mg/m². The estimated duration of the trial is from October 2021 to October 2025, with a maximum treatment period of 630 days for each participant.

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), diagnosis of MDS, and eligibility for stem cell transplantation. Female participants of childbearing potential must have a negative pregnancy test within two weeks prior to inclusion. Follow-up visits will be scheduled to monitor the participants' response to treatment and assess MRD status. The primary endpoint is the percentage of clinical events at 12 months from verified MRD positivity. Secondary endpoints include relapse-free survival, incidence and severity of graft-versus-host disease (GVHD), and overall survival.

The expected length of participant involvement is up to 630 days, with conditions for early termination including withdrawal of consent, adverse events, or any situation where continued participation is deemed not in the participant's best interest. The study aims to provide valuable insights into the management of MRD-positive MDS patients, potentially improving outcomes through tailored therapeutic interventions.

The clinical trial involves the administration of **Azacitidine**, a chemical compound used as the experimental medication. Azacitidine is provided in the form of a **powder for suspension for injection**. The route of administration is **subcutaneous**, and the dosage is calculated based on body surface area, with a maximum daily dose of 75 mg/m². The total maximum dose is also 75 mg/m². The treatment period for Azacitidine is set to a maximum of 630 days. This medication is not formulated specifically for pediatric use and is not classified as an orphan drug. The active substance in Azacitidine is chemically derived, and the product is identified by the scientific product evaluation code SUB05624MIG.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of Azacitidine to assess its efficacy in preventing clinical events such as relapse or non-relapse death in subjects with minimal residual disease (MRD) positive **myelodysplastic syndrome (MDS)** following allogeneic stem cell transplantation. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment protocol.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the percentage of clinical events, specifically **relapse** or non-relapse death, at 12 months from verified minimal residual disease (MRD) positivity. This will be compared between NMDSG14B Part 2 and Part 1. Secondary endpoints include several measures for both the MRD positive cohort and the whole study cohort. For the MRD positive cohort, these include relapse-free survival, GVHD (graft-versus-host disease) and relapse-free survival, the proportion of MRD positive subjects achieving MRD-negativity, incidence and severity of GVHD, and safety in MRD positive subjects subjected to MRD-guided clinical intervention. For the whole study cohort, secondary endpoints include relapse-free survival, GVHD and relapse-free survival, incidence and severity of GVHD, and overall survival.