Randomized Clinical Trial Comparing Post-Transplant Cyclophosphamide Versus Anti-T Lymphocyte Immunoglobulin for Graft Versus Host Disease Prophylaxis in Unrelated Donor Hematopoietic Cell Transplantation

The primary objective of this randomized clinical trial is to evaluate the impact of post-transplant cyclophosphamide (**PTCY**) versus anti-thymocyte globulin (**ATG**) as part of a conditioning regimen for allogeneic hematopoietic cell transplantation (**alloHCT**) on overall survival (**OS**) and graft-versus-host disease-free and relapse-free survival (**GRFS**). This assessment is clinically relevant as it aims to optimize conditioning treatments to improve engraftment, prevent graft-versus-host disease (**GVHD**), and induce tolerance of donor immune cells, thereby potentially enhancing patient outcomes in unrelated donor transplantation.

Secondary objectives include:

• Assessing the risk of acute and chronic GVHD, relapse, and non-relapse mortality (**NRM**) per treatment arm.
• Evaluating risk factors for acute and chronic GVHD, relapse, and NRM.
• Testing for interactions between the presence or absence of specific human leukocyte antigen (**HLA**) mismatches and major alloHCT outcomes.
• Testing for interactions between sex mismatches and major alloHCT outcomes.
• Describing organ-specific clinical patterns of GVHD depending on the study arm.

The clinical trial involves participants diagnosed with **Graft Versus Host Disease**, Peripheral Blood Stem Cell Transplantation, Acute Myeloid Leukemia (AML), Myelodysplastic Syndromes (MDS), Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN), and Chronic Myelomonocytic Leukemia (CMML). The study population includes both male and female subjects aged 18 years and older. Participants are required to have a left ventricular ejection fraction of 40% or higher and must be scheduled for transplantation with Peripheral Blood Stem Cells. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria include the absence of pregnancy for women of childbearing potential, confirmed by a highly sensitive pregnancy test. The trial population was selected based on specific medical conditions and planned transplantation procedures, with no more than one allele or antigen mismatch at HLA-A, -B, -C, or -DRB1 with an unrelated donor. Lifestyle considerations such as diet, physical activity, or habits are not specified in the provided data.

The clinical trial is designed to evaluate the efficacy of different immunosuppressive regimens in the context of **Graft vs Host Disease** (GVHD) prophylaxis during unrelated donor transplantation. This is a randomized, double-blind, controlled trial comparing post-transplant cyclophosphamide (PTCY) versus anti-thymocyte globulin (ATG) as part of the conditioning treatment for allogeneic hematopoietic cell transplantation (alloHCT). The trial aims to assess the impact of these regimens on overall survival (OS) and graft-versus-host disease-free and relapse-free survival (GRFS). The study is expected to run from February 2022 to March 2027, with participants involved for a maximum of 12 months, depending on the treatment arm.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and planned transplantation with peripheral blood stem cells. The inclusion visit will also ensure the absence of pregnancy in women of childbearing potential. Following randomization, participants will receive either PTCY or ATG as part of their conditioning regimen. The trial includes multiple follow-up visits to monitor the participants' health status, treatment adherence, and any adverse events. The end-of-study visit will occur after the completion of the treatment period, where final assessments will be conducted to evaluate the primary and secondary endpoints.

Participants may be withdrawn from the study early if they experience significant adverse effects, fail to comply with the study protocol, or withdraw consent. The trial's primary endpoints include overall survival from randomization and GRFS from the time of transplantation. Secondary endpoints encompass overall survival from HCT, relapse- and immunosuppression-free survival, event-free survival, and cumulative incidences of relapse and non-relapse mortality. The trial is categorized as a Phase III clinical trial, with the use of authorized investigational medicinal products in accordance with their marketing authorization, ensuring a low-intervention approach.

The clinical trial involves the administration of several treatments, including **mycophenolate mofetil**, **cyclophosphamide**, **tacrolimus**, and **anti-T lymphocyte immunoglobulin for human use, rabbit**. **Mycophenolate mofetil** is administered orally in a pharmaceutical form identified as PHF00170MIG. The maximum daily dose is 15 mg/kg, with a total maximum dose of 1000 mg over a treatment period of 1 month. This chemical substance is used as an auxiliary treatment in the trial.

**Cyclophosphamide** is provided as a powder for solution for injection or infusion. It is administered via infusion with a maximum daily dose of 50 mg/kg and a total maximum dose of 100 mg over a treatment period of 2 days. This chemical substance serves as a comparator in the study.

**Tacrolimus** is administered orally, also in the pharmaceutical form PHF00170MIG. The maximum daily dose is 0.01 mg/l, with a total maximum dose of 3.65 mg/l over a treatment period of 12 months. This chemical substance is used as an auxiliary treatment in the trial.

**Anti-T lymphocyte immunoglobulin for human use, rabbit**, marketed as Grafalon, is administered as a solution for infusion. The maximum daily dose is 10 mg/kg, with a total maximum dose of 30 mg/kg over a treatment period of 3 days. This structurally diverse substance, derived from blood, is used as a test treatment in the trial.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy and safety of these treatments in the context of graft versus host disease prophylaxis in unrelated donor transplantation.

Efficacy in this clinical trial will be assessed using the primary endpoints of overall survival (OS) from randomization and **graft-versus-host disease-free and relapse-free survival (GRFS)** from the time of transplantation. These endpoints are critical for evaluating the impact of the conditioning treatment involving PTCY versus ATG Grafalon® on the outcomes of allogeneic hematopoietic cell transplantation (alloHCT). Secondary endpoints include overall survival from HCT, relapse- and immunosuppression-free survival (RIFS) from HCT, event-free survival (EFS) from HCT, and cumulative incidences of relapse and non-relapse mortality (NRM) from HCT.

The collection and analysis of these efficacy parameters will be conducted at specified timepoints throughout the trial, ensuring a comprehensive assessment of the investigational drugs' impact on the trial's objectives. The data gathered will provide valuable insights into the effectiveness of the two approaches for alloHCT, contributing to the scientific community's understanding of optimized conditioning treatments in unrelated donor transplantation.