Evaluation of Treosulfan Versus Melphalan Conditioning with Fludarabine and PTCy in Allogeneic Transplantation for AML and MDS Patients

The primary objective of this study is to evaluate the **efficacy** of fludarabine combined with either treosulfan or melphalan in allogeneic hematopoietic cell transplantation (HCT) with post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GvHD) prophylaxis in patients with acute myeloid leukemia (AML) in first or second complete remission (CR) or patients with myelodysplastic syndromes (MDS). This evaluation is clinically relevant as it aims to determine the most effective conditioning regimen to improve patient outcomes in allogeneic transplantation, a critical treatment for these hematological malignancies.

Secondary objectives include:

• Evaluating the rate of remission in both treatment arms.
• Assessing engraftment and graft failure in both treatment arms.
• Evaluating both acute and chronic GvHD in both treatment arms.
• Assessing survival and non-relapse mortality in both treatment arms.
• Evaluating the tolerability in both treatment arms.

The clinical trial involves participants diagnosed with **acute myeloid leukemia (AML)** or myelodysplastic syndromes (MDS) who are undergoing allogeneic transplantation. The study population includes both male and female subjects aged 18 years and older. Participants are required to be in either the first or second complete remission of AML or have MDS as per the World Health Organization (WHO) criteria, with an indication for allogeneic hematopoietic cell transplantation (HCT). The trial population was selected based on specific inclusion criteria, including the availability of a suitable donor and planned graft-versus-host disease (GvHD) prophylaxis with post-transplant cyclophosphamide (PTCy). Participants must not have a history of cardiac disease that precludes allogeneic HCT and should not require supplementary oxygen on the day of randomization. The sponsor has not provided information regarding the total number of participants. The trial includes a vulnerable population, and lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **fludarabine** in combination with either **treosulfan** or **melphalan** as conditioning therapies for patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT). This is a randomized, controlled, double-blind trial, categorized as a phase II study, with the primary objective of assessing overall survival as a time-to-event endpoint. Secondary endpoints include non-relapse mortality, graft-versus-host-free and relapse-free survival, cumulative incidences of acute and chronic graft-versus-host disease (GvHD), and rates of adverse events. The trial is expected to commence recruitment on April 1, 2025, and conclude by September 30, 2028.

Participants will be involved in the study for a period that includes a screening visit, multiple follow-up visits, and an end-of-study visit. The inclusion visit will involve screening for eligibility criteria, such as age, diagnosis of AML or MDS, and the availability of a suitable donor. Follow-up visits will be scheduled to monitor the participants' response to treatment, assess any adverse events, and ensure compliance with the study protocol. The end-of-study visit will evaluate the overall outcomes and collect final data on the primary and secondary endpoints.

The expected length of participant involvement will vary depending on individual treatment responses and the occurrence of any adverse events. Participants may be withdrawn from the study early if they experience significant adverse reactions, fail to comply with the study protocol, or if the investigator deems it in the best interest of the participant's health. The trial will adhere to strict ethical guidelines, ensuring that all participants provide informed consent and that their safety and well-being are prioritized throughout the study duration.

The clinical trial involves the administration of **FLUDARABINE**, an antineoplastic agent classified under purin-analoga. The pharmaceutical form of FLUDARABINE is a solution for infusion, administered via **intravenous infusion**. The dosing regimen for FLUDARABINE is set at a maximum daily dose of 30 mg/m², with a total maximum dose of 150 mg/m² over a treatment period of up to 5 days. This medication is not a paediatric formulation and is used as an auxiliary treatment in the trial.

**MELPHALAN** is another investigational product used in this study, categorized as an antineoplastic and immunomodulating agent, specifically an alkylating agent. MELPHALAN is provided as a powder and solvent for solution for infusion, also administered via intravenous infusion. The dosing schedule for MELPHALAN allows for a maximum daily and total dose of 140 mg/m², administered over a single day. This product is not formulated for paediatric use and serves as a comparator in the trial.

The trial also includes **TREOSULFAN**, an antineoplastic agent within the alkylating agents category. TREOSULFAN is available as a solution for infusion and is administered through intravenous infusion. The dosing protocol for TREOSULFAN specifies a maximum daily dose of 10,000 mg/m², with a total maximum dose of 30,000 mg/m² over a treatment period of up to 3 days. TREOSULFAN is not a paediatric formulation and is the test product in this clinical trial.

All medications are administered under strict compliance monitoring to ensure adherence to the dosing schedules and to evaluate the efficacy of the treatment regimens in patients with acute myeloid leukemia (AML) in first or second complete remission (CR) or patients with myelodysplastic syndromes (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT) with post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GvHD) prophylaxis.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is **Overall Survival (OS)**, which will be evaluated as a time-to-event endpoint. This involves tracking the duration of survival from the start of the trial until the occurrence of death from any cause. Secondary endpoints include non-relapse mortality (NRM), graft-versus-host-free and relapse-free survival (GRFS), cumulative incidences of acute and chronic graft-versus-host disease (GvHD) as per NIH criteria, rates of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESI), cumulative incidence of relapse (CIR), relapse-free survival (RFS), rate of morphologic and molecular complete remission (CR), complete remission with incomplete hematologic recovery (CRi), complete remission with partial hematologic recovery (CRh), and morphologic leukemia-free state (MLFS). Additionally, the rate of engraftment on day +28 and the rate of complete donor-type chimerism on day +28 and day +56 will be measured.

The trial will involve the administration of fludarabine in combination with either treosulfan or melphalan, followed by post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GvHD) prophylaxis in patients with acute myeloid leukemia (AML) in first or second complete remission (CR) or patients with myelodysplastic syndromes (MDS). The efficacy parameters will be collected and analyzed at specified timepoints throughout the trial duration, which is estimated to conclude by September 30, 2028. The trial is designed to evaluate the efficacy and tolerability of these conditioning therapies prior to allogeneic stem cell transplantation.