Phase 2 Multicenter Trial of Mesenchymal Stromal Cells MC0518 vs. Best Available Therapy in Pediatric Steroid-Refractory Acute Graft-Versus-Host Disease

The primary objective of this study is the **comparative evaluation** of the overall response rate in pediatric participants with **steroid-refractory acute graft-versus-host disease** (SR aGvHD) at Visit Day 28 after treatment with MC0518 or the first used best available therapy (BAT). This objective is clinically relevant as it aims to determine the efficacy of MC0518 in improving response rates in a population with limited treatment options, potentially offering a new therapeutic avenue for managing SR aGvHD.

Secondary objectives include:

• Comparative evaluation of freedom from treatment failure, defined by the absence of death, malignancy relapse or progression, or addition of or change to any further systemic acute graft-versus-host disease (aGvHD) therapy within 6 months after randomization and prior to diagnosis of chronic graft-versus-host disease (cGvHD).
• Comparative evaluation of further secondary efficacy endpoints with respect to overall survival (OS) and response to treatment.
• Comparative evaluation of the safety.
• Comparative evaluation of health-related quality of life (HRQoL).

The clinical trial involves a **pediatric** population diagnosed with **steroid-refractory acute graft-versus-host disease** (SR aGvHD). Participants include both male and female subjects, aged between 28 days and less than 18 years, with a minimum body weight of 3.2 kg. The study population is characterized by individuals who have previously undergone allogeneic hematopoietic stem cell transplantation (HSCT) for non-malignant conditions, hematological malignancies, or neuroblastoma. Participants must have a clinically diagnosed Grade II to IV aGvHD and have experienced failure of first-line aGvHD treatment. The trial includes a vulnerable population, and all participants are required to have an estimated life expectancy of more than 28 days. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as the use of effective contraceptive measures are mandated for participants of childbearing potential and their partners. The selection process ensures that informed consent is obtained from the participant's parent(s) or legal guardian(s), with the participant's assent when applicable, in accordance with national regulations.

The clinical trial is designed as a **randomized**, open-label, controlled, multicenter, Phase 2 study. It aims to evaluate the efficacy and safety of **mesenchymal stromal cells, ex vivo cultured** (MC0518) compared to the best available therapy in pediatric participants with steroid-refractory acute graft versus host disease (SR-aGvHD) following allogeneic stem cell transplantation. The trial is expected to commence on November 30, 2023, and conclude by May 31, 2031. Participants will be involved in the study for a maximum of 36 months, with the primary endpoint being the overall response rate at Visit Day 28.

The study will include several key visits: an initial screening visit to confirm eligibility, followed by treatment visits on Day 1, and subsequent follow-up visits on Days 8, 15, 22, 28, 60, 100, and 180. The end-of-study visit will occur at Month 24. The primary purpose of these visits is to monitor the participants' response to treatment, assess any adverse events, and evaluate the overall health status using various clinical measures. Participants will be randomly assigned to receive either MC0518 or the best available therapy, with the treatment administered according to the protocol's specifications.

Inclusion criteria require participants to have previously undergone allogeneic hematopoietic stem cell transplantation (HSCT) for specific non-malignant or malignant conditions and to have a clinical diagnosis of Grade II to IV aGvHD. Participants must have experienced failure of first-line aGvHD treatment and meet age and weight requirements. Exclusion criteria are not specified in the provided data. Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it necessary for their safety.

The trial will assess both primary and secondary endpoints, including overall response, freedom from treatment failure, overall survival, and incidence of chronic graft versus host disease (cGvHD). The study will also evaluate the incidence and severity of adverse events, quality of life measures, and performance scores. The trial's design ensures a comprehensive evaluation of the therapeutic potential of MC0518 in this patient population, with rigorous monitoring and data collection throughout the study duration.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Ruxolitinib** is an experimental medication used in this trial. It is a chemical substance administered orally in the form of a pharmaceutical formulation identified as PHF00245MIG. The maximum daily dose is 20 mg, with a total maximum dose of 1200 mg over a treatment period of up to 60 days. Participant compliance with the dosing schedule is monitored throughout the trial.

**Infliximab** is another treatment used in the study, classified as a biological product. It is administered via intravenous use, with a pharmaceutical form identified as PHF00230MIG. The dosing regimen allows for a maximum daily dose of 5 mg/kg and a total maximum dose of 15 mg/kg over a 6-week treatment period. This medication is part of the standard-of-care therapy in the trial.

**Methoxsalen** is included as an auxiliary treatment in the trial. It is a chemical substance used for extracorporeal application, specifically in the form of a solution for blood fraction modification. The maximum daily dose is 17 units, with a total maximum dose of 102 units over a 60-day period. This treatment is designated as an orphan drug.

**Etanercept** is also utilized in the trial as a biological product. It is administered via subcutaneous injection, with a pharmaceutical form identified as PHF00231MIG. The maximum daily dose is 50 mg, with a total maximum dose of 1200 mg over a 24-week treatment period. This medication serves as a comparator treatment in the study.

The experimental treatment **MC0518**, containing **mesenchymal stromal cells, ex vivo cultured**, is administered intravenously in the form of a dispersion for infusion. This advanced therapy investigational medicinal product (ATIMP) is used as the primary experimental treatment in the trial. The maximum daily dose is 2,000,000 cells, with a total maximum dose of 12,000,000 cells over a 36-day treatment period. This product is designated as an orphan drug and is monitored for participant compliance.

Lastly, **Antithymocyte Immunoglobulin (Rabbit)** is used as a biological product in the trial. It is administered intravenously, with a pharmaceutical form identified as PHF00230MIG. The dosing regimen allows for a maximum daily dose of 5 mg/kg and a total maximum dose of 70 mg/kg over a 14-day treatment period. This medication is part of the standard-of-care therapy in the trial.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the overall response (OR) at Visit Day 28, defined as a complete response (CR) or partial response (PR) relative to the acute graft-versus-host disease (aGvHD) status at baseline (Visit Day 1 prior to the first treatment). Secondary endpoints include freedom from treatment failure until 6 months (Visit Day 180), overall survival (OS) until Visit Month 24, and aGvHD response at various timepoints including Visit Day 28, Visit Day 60, Visit Day 100, and Visit Day 180. Additional secondary endpoints involve the change of aGvHD grade at multiple visits, time to response, duration of response until Visit Month 24, and best OR until Visit Day 28.

Further assessments will include the cumulative dose of steroids given for steroid-refractory aGvHD per kilogram of body weight from the date of the first treatment administration until Visit Day 28, Visit Day 60, and until Visit Month 24. The incidence of and time to chronic graft-versus-host disease (cGvHD) from Visit Day 60 until Visit Month 24, incidence of graft failure (GF) from baseline until Visit Month 24, and incidence of and time to relapse or progression of the underlying disease in participants with underlying malignant disease from randomisation until Visit Month 24 will also be evaluated. Event-free survival until Visit Month 24 and non-relapse mortality until Visit Month 24 are additional secondary endpoints.

The trial will also monitor the incidence and severity of all adverse events (AEs), including viral, bacterial, and fungal infections until Visit Day 60, and adverse reactions (ARs) until Visit Month 24. Performance scores using the Karnofsky/Lansky scale will be assessed at several timepoints compared to baseline. Health-related quality of life (HRQoL) measures will be evaluated using the Paediatric Quality of Life Inventory™ (PedsQL™) 4.0 Generic Core Scales with the PedsQL™ Stem Cell Transplant Module at specified visits compared to baseline.