Evaluation of Belumosudil and Prednisone Versus Placebo and Prednisone in Patients Aged 12 and Older with Newly Diagnosed Chronic Graft-Versus-Host Disease

The primary objective of this Phase 3 study is to demonstrate the superiority of **belumosudil** in combination with prednisone versus placebo in combination with prednisone in improving **Event-Free Survival (EFS)** in participants with newly diagnosed chronic graft versus host disease (cGVHD). This objective is clinically relevant as it aims to establish a more effective treatment regimen that could potentially improve patient outcomes by reducing the occurrence of adverse events or disease progression.

Secondary objectives include:

• Demonstrating the superiority of belumosudil in combination with prednisone versus prednisone alone in improving the modified Lee Symptom Scale (mLSS).
• Assessing the superiority of belumosudil in combination with prednisone versus prednisone alone in achieving a durable overall response rate (ORR).
• Evaluating the rate of corticosteroid withdrawal when using belumosudil in combination with prednisone versus prednisone alone.
• Measuring the overall response rate (ORR) and ORR by 24 weeks.
• Determining the duration of response (DOR) and the time to response (TTR).
• Assessing dose reduction in corticosteroids and failure-free survival (FFS).
• Evaluating changes in patient-reported outcomes (PRO) and safety.
• Assessing overall survival and response by organ.

The clinical trial involves a total of **193 participants** diagnosed with **chronic graft versus host disease** (cGVHD). The study population includes both male and female subjects, aged 12 years and older, who have undergone allogenic hematopoietic cell transplantation (HCT) and have newly diagnosed moderate to severe cGVHD. Participants are required to have a body weight of at least 40 kg and must necessitate systemic treatment with corticosteroids for cGVHD. The trial population was selected based on specific inclusion criteria, ensuring that participants have not received any prior systemic treatment for cGVHD. The study also considers lifestyle factors such as the use of contraceptives, which must align with local regulations. The trial includes a vulnerable population, indicating that additional ethical considerations are in place to protect the participants. The selection process ensures that participants or their legally authorized representatives are capable of providing informed consent, highlighting the importance of ethical standards in clinical research.

The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the efficacy and safety of **belumosudil** in combination with corticosteroids compared to a placebo in combination with corticosteroids in participants aged 12 years and older with newly diagnosed **chronic graft versus host disease** (cGVHD). The trial aims to demonstrate the superiority of belumosudil in combination with prednisone over placebo in terms of Event-Free Survival (EFS). The trial is expected to commence recruitment on February 22, 2024, and is estimated to conclude by September 29, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on predefined criteria, including age, diagnosis, and treatment history. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. These visits will include assessments of primary and secondary endpoints, such as the proportion of participants achieving a clinically relevant reduction in symptoms and overall response rates. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

The expected duration of participant involvement is up to 36 months, with conditions for early termination including the occurrence of predefined events such as disease progression, unacceptable toxicity, or withdrawal of consent. Participants will be monitored for treatment-emergent adverse events and other safety parameters throughout the study. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.

The clinical trial involves the administration of **belumosudil mesilate**, marketed under the product name SAR445761, as the experimental medication. This compound is provided in the form of a film-coated tablet and is administered orally. The maximum daily dose is 400 mg, with a total maximum dose of 432,000 mg over a treatment period of 36 months. The medication is classified as a chemical substance and is not a pediatric formulation. Participant compliance with the dosing schedule will be monitored throughout the trial.

In addition to the experimental treatment, the trial includes the use of **prednisolone** as a standard-of-care therapy. Prednisolone is administered orally, with a maximum daily dose of 1 mg/kg and a total maximum dose of 1080 mg/kg over the same 36-month period. This medication is also a chemical substance and is not formulated for pediatric use. The administration of prednisolone will be closely monitored to ensure adherence to the prescribed dosing regimen.

The trial also involves a comparator treatment, which is a placebo administered in combination with corticosteroids. The placebo is designed to match the experimental treatment in appearance and administration route, ensuring the double-blind nature of the study. The placebo will be administered orally, and participant compliance will be monitored to maintain the integrity of the trial results.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Event-Free Survival (EFS)**, which is measured from the date of randomization to the occurrence of any predefined event. Secondary endpoints include the proportion of participants achieving a clinically relevant reduction in the modified Lee Symptom Scale (mLSS) of at least 6 points from baseline, the proportion of participants achieving an overall response (partial response [PR] or complete response [CR]) as per the 2014 NIH consensus response criteria by 48 weeks, and the proportion of participants who successfully discontinue all systemic corticosteroids for chronic graft versus host disease (cGVHD) for at least 30 days before the occurrence of cGVHD progression or the start of a new systemic treatment.

Additional secondary endpoints include the time from the first response to cGVHD progression, the proportion of participants with a reduction in daily corticosteroid dose, and Failure Free Survival (FFS), defined as the time from randomization to the start of a new systemic treatment for cGVHD, relapse, or death. Patient-reported outcomes will be measured using the Patient-Reported Outcomes Measurement Information System Global Health (PROMIS-GH) and the European Quality of Life Group Questionnaire with 5 Dimensions and 5 Levels (EQ5D5L). The trial will also monitor the number of participants with treatment-emergent adverse events (TEAEs), serious TEAEs, and adverse events of special interest (AESIs). The time to response, defined as the time from randomization to the first response (CR or PR), will also be evaluated.