Phase 3 Randomized Open-Label Study of Mesenchymal Stromal Cells MC0518 Versus Best Available Therapy in Steroid-Refractory Acute Graft-Versus-Host Disease

The primary objective of this study is to demonstrate the superiority of **MC0518** compared to the first used Best Available Therapy (BAT) in terms of Overall Response Rate (ORR) in adult and adolescent subjects with **steroid refractory Acute Graft versus Host Disease (SR aGvHD)** at Visit Day 28. Additionally, the study aims to demonstrate the superiority of MC0518 over BAT with respect to overall survival (OS) in the same patient population until Visit Month 24. These objectives are clinically relevant as they address the efficacy of MC0518 in improving response rates and survival outcomes in a challenging patient group with limited treatment options.

Secondary objectives include:

• Demonstrating the superiority of MC0518 compared with the first used BAT with respect to freedom from treatment failure (FFTF), defined by the absence of death, malignancy relapse or progression, or addition or change to any further systemic aGvHD immunosuppressive therapy within 6 months from the date of randomization and before the diagnosis of chronic graft-versus-host disease (cGvHD).
• Comparing the efficacy of MC0518 and BAT in further secondary long-term efficacy endpoints and response to treatment.
• Investigating the safety of MC0518.
• Comparing health-related quality of life (HRQoL) when treated with MC0518 compared with BAT.

The clinical trial involves participants diagnosed with **steroid refractory Acute Graft versus host Disease** (SR aGvHD). The study population includes both male and female subjects aged 12 years and older, with a minimum weight of 15 kg. Participants are required to have undergone a previous allogeneic hematopoietic stem cell transplantation (HSCT) for either non-malignant or hematological malignant diseases. The trial targets individuals who have experienced failure of first-line aGvHD treatment. The sponsor has not provided information regarding the total number of participants. The trial population was selected based on specific inclusion criteria, including a clinical diagnosis of Grade II to IV aGvHD and an estimated life expectancy of more than 28 days at the screening visit. Participants are expected to adhere to certain lifestyle considerations, such as the use of highly effective contraceptive measures for females of childbearing potential and sexual abstinence or condom use for fertile males. The trial includes a vulnerable population, and informed consent is required from all participants or their legal guardians.

The clinical trial is designed as a **randomized**, open-label, multicenter, Phase 3 study aimed at evaluating the efficacy of **mesenchymal stromal cells, ex vivo cultured** (MC0518) compared to the best available therapy in adult and adolescent subjects with **steroid refractory acute graft versus host disease** (SR aGvHD) following allogeneic hematopoietic stem cell transplantation. The trial's primary objective is to demonstrate the superiority of MC0518 in terms of overall response rate (ORR) at Day 28 and overall survival (OS) until Month 24. The trial is expected to conclude by September 2030, with recruitment having commenced in July 2021.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as previous allogeneic HSCT, clinical diagnosis of Grade II to IV aGvHD, and failure of first-line aGvHD treatment. The trial includes multiple follow-up visits at specified intervals: Day 8, Day 15, Day 22, Day 28, Day 60, Day 100, and Day 180, with assessments continuing until Month 24. These visits are designed to monitor the participants' response to treatment, assess changes in aGvHD grade, and evaluate the incidence of adverse events and other clinical outcomes.

The expected duration of participant involvement is approximately 24 months, with conditions for early termination including significant adverse events, disease progression, or withdrawal of consent. The trial will utilize a combination of oral and intravenous administration routes for the investigational products, with MC0518 being administered as a dispersion for infusion. The study will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Everolimus** is utilized as an auxiliary treatment in the study. It is administered in an oral pharmaceutical form, with a maximum daily dose of 10 mg and a total maximum dose of 990 mg over a treatment period of up to 99 days. The route of administration is oral, and the medication is classified as a biological product. Participant compliance with the dosing schedule is monitored throughout the trial.

**Mycophenolate mofetil** is another auxiliary treatment used in the trial. It is also administered orally, with a maximum daily dose of 3 g and a total maximum dose of 298 g over a 99-day treatment period. This chemical substance is provided in a specific pharmaceutical form, and adherence to the dosing regimen is closely observed to ensure participant compliance.

**Mycophenolic acid**, synonymous with mycophenolate, is administered intravenously as a biological product. The maximum daily dose is 5 mg/kg, with a total maximum dose of 70 mg/kg over a 14-day treatment period. The intravenous route of administration requires careful monitoring to ensure proper dosing and participant adherence.

The experimental treatment in the trial is **MC0518**, which consists of **mesenchymal stromal cells, ex vivo cultured**. This advanced therapy investigational medicinal product (ATMP) is administered as a dispersion for infusion via the intravenous route. 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 somatic cell therapy medicinal product is provided by MEDAC GMBH and is designated as an orphan drug. Compliance with the infusion schedule is rigorously monitored to ensure the integrity of the trial data.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints include the **Overall Response Rate (ORR)**, defined as complete response (CR) or partial response (PR) at Visit Day 28 relative to acute Graft versus Host Disease (aGvHD) status at baseline, and overall survival (OS) until Visit Month 24, which is defined as the time from the date of randomization to the date of death due to any cause.

Secondary endpoints will further evaluate efficacy through various measures, including Failure-Free Survival (FFTF) until 6 months, aGvHD response at multiple time points (Visit Day 28, Visit Day 60, Visit Day 100, and Visit Day 180), and changes in aGvHD grade at specified intervals. Additional secondary endpoints include time to response, duration of response until Visit Month 24, best OR until Visit Day 28, cumulative dose of steroids, incidence of chronic Graft versus Host Disease (cGvHD), graft failure, and relapse or progression of underlying malignant disease. Event-free survival and the incidence and severity of adverse events will also be documented. Performance scores using the Karnofsky/Lansky scale and health-related quality of life measures (EuroQol 5D 5L and FACT-BMT) will be assessed at various time points in comparison to baseline.