A Study to Test an Oral Medicine, Belumosudil, in Combination With Corticosteroids in Participants at Least 12 Years of Age With Newly Diagnosed Chronic Graft Versus Host Disease.

Study Overview
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Brief Summary
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This is a parallel, Phase 3, two-arm study for the treatment of newly diagnosed moderate or severe chronic GVHD. The study duration for a participant includes up to 4 weeks for screening; a treatment period until clinically meaningful cGVHD progression (defined as progression requiring addition of new systemic treatment for cGVHD), relapse/recurrence of the underlying disease, participant starts new systemic treatment for cGVHD or experiences an unacceptable toxicity, at the request of the participants or the investigators, or until the end of study is reached, whichever comes first; at least 30 days follow-up of adverse events (AEs) after the last dose until resolution or stabilization, if applicable; and long-term follow-up until death or study close-out, whichever comes first.

Detailed Description
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Up to 5 years

Official Title
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A Randomized, Double-blind, Multicenter, Phase 3 Study to Evaluate Efficacy and Safety of Belumosudil in Combination With Corticosteroids Versus Placebo in Combination With Corticosteroids in Participants at Least 12 Years of Age With Newly Diagnosed Chronic Graft Versus Host Disease (cGVHD)

Conditions
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Chronic Graft Versus Host Disease

Intervention / Treatment
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* Drug: Belumosudil
* Drug: Placebo
* Drug: Prednisone
* Drug: Prednisolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be at least 12 years of age inclusive, at the time of signing the informed consent Participants who have undergone allogenic HCT with newly diagnosed moderate to severe cGVHD according to NIH consensus diagnosis and staging criteria (2014) Participants who require systemic treatment with corticosteroids for cGVHD Participants who have not received any prior systemic treatment for cGVHD (including ECP) If participants are receiving other immunosuppressive agents for the prophylaxis or treatment of acute GVHD, the dose should be under the threshold pre-defined in protocol Body weight ≥ 40kg Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Participants or their legally authorized representative must be capable of giving signed informed consent Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: Medical conditions Histological relapse of the underlying disease after most recent allogeneic HCT Post-transplant lymphoproliferative disease within 4 weeks prior to randomization Female participants who are pregnant or breastfeeding Unable to tolerate a prednisone equivalent dose of corticosteroids ≥ 1 mg/kg/day Prior/concomitant therapy Participant has had previous exposure to belumosudil. Received any previous systemic treatment for cGVHD with the following exception: Corticosteroids for cGVHD received within 7 days prior to the planned administration of IMP only if in the interest of participant. Prior/concurrent clinical study experience Received any investigational agents, or any investigational device or procedure, or prohibited therapy for this study within 28 days or 5 elimination half-lives prior to randomization, whichever is longer Diagnostic assessments Karnofsky (if aged ≥16 years)/Lansky (if aged <16 years) Performance Score of < 60 Platelets <50 x 109/L. Platelet transfusion is not allowed within 3 days before the screening hematological test Absolute neutrophil count (ANC) <1.0 x 109/L. The use of granulocyte-colony stimulating factor (G-CSF) is not allowed to reach this level during screening Estimated Glomerular Filtration Rate (eGFR) <30 mL/min/1.73 m2 using the MDRD-4 variable formula (if aged ≥18 years) or using the Bedside Schwartz formula (if aged <18 years) Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3 x ULN without liver cGVHD (or >5 × ULN if due to cGVHD with liver cGVHD) Total bilirubin >1.5 × (ULN) (>3 × ULN if Gilbert syndrome) Participant has forced expiratory volume in 1 second (FEV1) of predicted ≤39% or has lung score of 3 according to NIH consensus diagnostic and staging criteria (2014) History or other evidence of severe illness or any other conditions that would make the participant, in the opinion of the Investigator, unsuitable for the study (such as malabsorption syndromes, poorly controlled psychiatric disease or coronary artery disease) Known history of human immunodeficiency virus (HIV) Active viral disease including hepatitis B virus (HBV) or hepatitis C virus (HCV) Active uncontrolled cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of infection worsening are present according to Investigator's judgement Diagnosed or treated for another malignancy other than the underlying disease allogeneic HCT was indicated for, within 3 years prior to randomization with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in-situ malignancy, or low risk prostate cancer after curative therapy Unable to swallow tablets Participant not suitable for participation, whatever the reason, as judged by the Investigator, including medical or clinical conditions, or participants potentially at risk of noncompliance to study procedures

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Belumosudil<br>Participants will receive belumosudil 200 mg tablets Per os(PO) once daily (QD) per 28-day cycles starting on Day 1 until discontinuation criteria are met or until end of study note: 200mg two times a day (BID) is used in some cases, when the subject is taking a proton pump inhibitor or a strong CYP3A4 inducer) | Drug: Belumosudil<br>* Pharmaceutical form:Tablet-Route of administration:oral<br>* Other names: REZUROCK;Drug: Prednisone<br>* Pharmaceutical form:Tablet-Route of administration:oral<br>Drug: Prednisolone<br>* Pharmaceutical form:Tablet-Route of administration:oral<br>|
| Placebo Comparator: Placebo<br>Participants will receive matching placebo tablets PO QD per 28-day cycles starting on Day 1 until discontinuation criteria are met or until end of study | Drug: Placebo<br>* Pharmaceutical form:Table-Route of administration:oral<br>Drug: Prednisone<br>* Pharmaceutical form:Tablet-Route of administration:oral<br>Drug: Prednisolone<br>* Pharmaceutical form:Tablet-Route of administration:oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-Free Survival (EFS) | from the date of randomization to the date of any predefined event, whichever occurs first | Until the end of the study (up to 5 years since first patient in). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| modified Lee Symptom Scale (mLSS) | Proportion of participants who achieve a clinically relevant reduction in mLSS of at least 6 points from baseline (Only in participants at least 18 years of age) | Until the end of the study (up to 5 years since first patient in). | 
| overall response rate (ORR) | Proportion of participants who achieve an overall response (PR or CR) as per 2014 NIH consensus response criteria by 48 weeks and maintained the response for a duration of at least 6 months | Until the end of the study (up to 5 years since first patient in). | 
| rate of corticosteroid withdrawal | Proportion of participants who successfully discontinue all systemic corticosteroids for cGVHD for at least 30 days before the occurrence of cGVHD progression, or start of a new systemic treatment for cGVHD, relapse or recurrence of the underlying disease, or unacceptable toxicity | Until the end of the study (up to 5 years since first patient in). | 
| Overall response rate (ORR) | Proportion of participants who achieve an overall response (CR or PR) as per 2014 NIH consensus response criteria at any time before the start of new systemic treatment for cGVHD | Until the end of the study (up to 5 years since first patient in). | 
| ORR by 24 weeks | Proportion of participants who achieve an overall response (CR or PR) as per 2014 NIH consensus response criteria by 24 weeks (Cycle 7 Day 1) before the start of new systemic treatment for cGVHD | Until the end of the study (up to 5 years since first patient in). | 
| Duration of response (DOR) | Time from the date of the first response to the date of cGVHD progression as defined by 2014 NIH consensus response criteria, start of new systemic treatment for cGVHD, or death, whichever occurs first. DOR is determined only for participants who achieved overall response (PR or CR) as per 2014 NIH consensus response criteria | Until the end of the study (up to 5 years since first patient in). | 
| Dose reduction in corticosteroid | Proportion of participants with a reduction in daily corticosteroid dose | Until the end of the study (up to 5 years since first patient in). | 
| Failure Free Survival (FFS) | Failure Free Survival (FFS) is defined as the time from the date of randomization to the date of start of a new systemic treatment for cGVHD, relapse or recurrence of the underlying disease, or death, whichever occurs first. | Until the end of the study (up to 5 years since first patient in). | 
| Change in patient reported outcome (PRO) | Change from baseline in Patient-Reported Outcomes Measurement Information System Global Health (PROMIS-GH) (Only in participants at least 18 years of age) and the European Quality of Life Group Questionnaire with 5 Dimensions and 5 Levels (EQ5D5L) | Until the end of the study (up to 5 years since first patient in). | 
| Number of participants with treatment-emergent adverse events [TEAEs], serious TEAEs, and adverse events of special interest (AESIs) |  | Until the end of the study (up to 5 years since first patient in). | 
| Overall survival | The time from the date of randomization to the date of death due to any cause | Until the end of the study (up to 5 years since first patient in). |