Evaluation of ASTX727 and Donor Lymphocyte Infusions Post-Allogeneic Stem Cell Transplantation in High-Risk Myelodysplastic Syndromes or Acute Myeloid Leukemia

The primary objective of this study is to achieve a **disease-free survival** of 35% at 12 months post-transplant in patients with very high-risk **myelodysplastic syndrome** (MDS) or **acute myeloid leukemia** (AML). This objective is clinically significant as it aims to improve the long-term outcomes and survival rates in a population with limited treatment options and poor prognosis.

Secondary objectives include evaluating the following:

• Proportion of patients receiving allogeneic stem cell transplantation (allo SCT).
• Proportion of patients eligible for post-transplant oral decitabine.
• Proportion of patients eligible for post-transplant donor lymphocyte infusions (DLI).
• Incidence of Grade III/IV toxicities.
• Non-relapse mortality rates.
• Proportion of patients completing the treatment schedule.
• Overall survival at 12 and 24 months, and disease-free survival at 24 months after transplant.

These secondary objectives are crucial for understanding the broader impact of the treatment regimen on patient outcomes, including safety, tolerability, and long-term survival benefits.

The clinical trial involves **patients with high-risk myelodysplastic syndrome** or acute myeloid leukemia, focusing on achieving a disease-free survival rate of 35% at 12 months post-transplant. The study population comprises both male and female participants aged between 18 and 70 years. The trial includes individuals with specific genetic and clinical criteria, such as those with unfavorable genetics or a history of chemotherapy for acute myeloid leukemia. Participants are required to have a donor available, either HLA matched or mismatched, and must adhere to effective contraception guidelines if applicable. The trial population was selected based on these criteria, and the sponsor has not provided the total number of participants. The study includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **ASTX727**, a combination of **decitabine** and **cedazuridine**, in conjunction with donor lymphocyte infusions (DLI) following allogeneic stem cell transplantation in patients with very high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). This is a Phase 4, randomized, double-blind, controlled trial with an estimated duration from June 2021 to March 2025. The primary objective is to achieve a disease-free survival (DFS) rate of 35% at 12 months post-transplant, with secondary endpoints including overall survival (OS) and risk factors for DFS and OS at one and two years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (18-70 years), specific disease characteristics, and availability of a suitable donor. The trial will include follow-up visits to monitor the participants' response to treatment and any adverse effects. The end-of-study visit will evaluate the primary and secondary endpoints. The expected length of participant involvement is up to 10 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent.

Key elements of the research methodology include the administration of the investigational product, **ASTX727**, in tablet form via oral use, with a maximum daily dose of one tablet. The trial will ensure that participants adhere to effective contraception throughout the study and for three months after the last dose. The trial's design and procedures are structured to maintain scientific rigor and ensure the safety and well-being of participants while providing valuable data on the therapeutic potential of **ASTX727** in this high-risk patient population.

The clinical trial involves the administration of **ASTX727**, an experimental medication formulated as a **tablet**. This pharmaceutical product is composed of two active chemical substances: **decitabine** and **cedazuridine**. The medication is manufactured by Taiho Oncology, Inc. and is intended for **oral use**. The dosing regimen for ASTX727 is set at a maximum of one tablet per day, with a total treatment period not exceeding 10 days. The trial aims to evaluate the efficacy of ASTX727 in achieving a disease-free survival rate in patients with very high-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) following allogeneic stem cell transplantation.

**Decitabine**, also known by its chemical name 5-aza-2'-deoxycytidine, is a nucleoside analog that functions as a DNA methyltransferase inhibitor. It is included in the formulation to exert its therapeutic effects by incorporating into DNA and inhibiting DNA methylation, which can lead to the reactivation of silenced genes and induction of cellular differentiation and apoptosis in malignant cells.

**Cedazuridine**, chemically identified as (4R)-2'-deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine, is a cytidine deaminase inhibitor. Its role in the formulation is to enhance the bioavailability of decitabine by inhibiting its degradation in the gastrointestinal tract, thereby allowing for effective oral administration of the combination therapy.

In addition to the experimental treatment, the study protocol may include standard-of-care therapies as deemed necessary by the clinical investigators. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment regimen. The trial does not involve the use of a placebo or comparator treatment, focusing solely on the effects of ASTX727 in the specified patient population.

Efficacy in the clinical trial titled "GFM-DACORAL-DLI: ASTX727 and donor lymphocyte infusions (DLI) after allogeneic stem cell transplantation (ALLO SCT) in very high-risk MDS or AML patients" will be assessed using specific primary and secondary endpoints. The primary endpoint is **disease-free survival (DFS)** at one year post-transplant. Secondary endpoints include overall survival from the date of transplantation and from the date of inclusion at one year and two years, as well as risk factors for DFS, overall survival (OS), and non-relapse mortality (NRM) at one year and two years.