Extended Treatment and Follow-up of Subjects Treated With Belumosudil in Study KD025-208 or Study KD025-213

Primary outcomes

1. Duration of Response (DOR)

   Time frame: At Baseline (Day 1), Month 3 and every 3 months thereafter (+/-14 days), up to 23 months

   DOR is defined as time from first documentation of response to time of first documentation of deterioration from best response (e.g., complete response [CR] to partial response [PR], or PR to Lack of response [LR]). As per the 2014 National Institutes of Health (NIH) Consensus Development Project for clinical trials in cGVHD criteria: CR was defined as resolution of all manifestations of cGVHD in each organ or site.PR was defined as the improvement in at least 1 organ or site without progression in any other organ or site.LR included response status of mixed, unchanged, or progression.Mixed LR was defined as complete or partial response in at least 1 organ accompanied by progression in another organ. Unchanged LR was defined as outcomes that did not meet criteria for CR, PR, progression or mixed response. Progression LR was defined as progression in at least 1 organ or site without a response in any other organ or site. Confidence interval (CI) is calculated using Kaplan-Meier method.

2. Number of Participants With a >=7 Point Reduction (7PtR) From Baseline and >=7 Point Reduction From Baseline on 2 Consecutive Post-Baseline Assessments as Assessed by Lee Symptom Scale (LSS)

   Time frame: Baseline (Day 1) up to 23 months

   The questionnaire asked participants to indicate the degree of bother that they experienced due to symptoms in 7 domains potentially affected by cGVHD. It consists of 30 items of 7 domains: skin, eyes and mouth, breathing, eating and digestion, muscles and joints, energy, and mental and emotional. Each question was rated/scored as 0-not at all, 1-slightly, 2-moderately, 3-quite a bit, 4-extremely with lower values representing better outcome. A domain score was calculated for each domain by taking the mean of all items completed if more than 50% were answered and normalizing to a 0 to 100 scale. A total score was calculated as average of all non-missing domain scores if more than 50% of them were non-missing, ranged from 0-100. A higher score indicated more bothersome symptoms. A 7-point difference on the total score of cGVHD symptom scale was found to be clinically meaningful.

3. Duration of >=7 Point Reduction as Assessed by Lee Symptom Scale

   Time frame: Baseline (Day 1) up to 23 months

   The questionnaire asked participants to indicate the degree of bother that they experienced due to symptoms in 7 domains potentially affected by cGVHD. It consisted of 30 items of 7 domains: skin, eyes and mouth, breathing, eating and digestion, muscles and joints, energy, and mental and emotional. Each question was rated/scored as 0-not at all, 1-slightly, 2-moderately, 3-quite a bit, 4-extremely with lower values representing better outcome. A domain score was calculated for each domain by taking the mean of all items completed if more than 50% were answered and normalizing to a 0 to 100 scale. A total score was calculated as average of all non-missing domain scores if more than 50% of them were non-missing, ranged from 0-100. A higher score indicated more bothersome symptoms. A 7-point difference on the total score of cGVHD symptom scale was found to be clinically meaningful. Mean of duration of >=7PtR is presented.

4. Time to Next Treatment (TTNT)

   Time frame: At Baseline (Day 1), Month 3 and every 3 months thereafter (+/-14 days), up to 23 months

   The TTNT was measured as the time from first treatment to the time of new systemic cGVHD treatment, censored by last response assessment or long term follow up assessment, whichever was the latest and available. TTNT was analyzed by the Kaplan-Meier survival method.

5. Failure-Free Survival (FFS)

   Time frame: At Baseline (Day 1), Month 3 and every 3 months thereafter (+/-14 days), up to 23 months

   FFS was defined as the absence of new cGVHD systemic therapy, non-relapse mortality and recurrent malignancy (i.e. underlying disease) and was censored by last response assessment or long term follow up assessment, whichever was the latest and available. Kaplan-Meier method was used for the analysis.

6. Overall Survival (OS)

   Time frame: From first dose of study drug (Day 1) to the date of death due to any cause, up to approximately 24 months

   OS was defined as time from first dose of belumosudil to the date of death due to any cause. CI was calculated using Kaplan-Meier method.

7. Percentage of Participants With Complete Response (CR) and Partial Response (PR)

   Time frame: At Baseline (Day 1), Month 3 and every 3 months thereafter (+/-14 days), up to 23 months

   As per the 2014 NIH Consensus Development Project for clinical trials in cGVHD criteria: CR was defined as resolution of all manifestations of cGVHD in each organ or site. PR was defined as the improvement in at least 1 organ or site without progression in any other organ or site.

8. Number of Participants With Best Response by Organ System

   Time frame: At Baseline (Day 1), Month 3 and every 3 months thereafter (+/-14 days), up to 23 months

   The best response (CR, PR) for individual organs (skin, eyes, mouth, esophagus, upper gastrointestinal [GI], lower GI, liver, lungs, joints and fascia) was summarized. As per the 2014 NIH Consensus Development Project for clinical trials in cGVHD criteria, CR was defined as resolution of all manifestations of cGVHD in each organ or site. PR was defined as the improvement in at least 1 organ or site without progression in any other organ or site.

9. Percent Change From Baseline in Corticosteroid Dose to Greatest Reduction

   Time frame: Baseline (Day 1) and Month 23

   Change in corticosteroid doses was analyzed by using prednisone dose equivalents. If participants were not using prednisone as the systemic corticosteroid, then the prednisone dose equivalent would be determined according to following conversion ratios: 1 mg prednisone is equivalent to: 4.0 mg Hydrocortisone; 0.8 mg Methylprednisolone; 0.15 mg Dexamethasone; 1.0 mg Prednisolone and 0.8 mg Triamcinolone. Baseline was defined as the valid and last non-missing value obtained within 28 days prior to participant receiving the first study drug in parent study (KD025-208 [NCT02841995] or KD025-213 [NCT03640481]).

10. Number of Participants With Maximal Improvement From Baseline in Global Severity Rating (GSR) Based on Clinician-Reported Chronic Graft-Versus-Host-Disease Assessment

    Time frame: From Baseline (Day 1) up to 23 months

    The GSR assessment was performed by asking the participants to rate their disease severity of cGVHD symptoms on a 0 to 10-point numeric rating scale, where score 0 indicated 'not at all severe cGVHD symptoms' and score 10 indicated 'most severe cGVHD symptoms possible'. The response was defined using scores from 9 organs: skin, eyes, mouth, esophagus, upper GI track, lower GI tract, liver, lungs, and joints and fascia plus GSR. Baseline was defined as the valid and last non-missing value obtained within 28 days prior to participant receiving the first study drug in parent study (KD025-208 [NCT02841995] or KD025-213 [NCT03640481]). Maximal improvement from Baseline was calculated as lowest GSR score on scheduled visits minus GSR score at Baseline with possible ranges from -10 to 10. The lower the number means the better improvement in cGVHD symptoms.

11. Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs), Grade >=3 Treatment-Emergent Adverse Events and Deaths

    Time frame: From the first dose of study drug (Day 1) up to 28 days after the last dose of study drug, approximately 24 months

    An adverse event (AE) was defined as any untoward medical occurrence in a clinical trial participant associated with the use of a study drug, whether or not considered drug-related. Serious adverse event (SAE) was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, was a congenital anomaly/birth defect or was an important medical event. The severity of each AE was graded using the Common Terminology Criteria for Adverse Events version 4.03 scale. TEAEs were defined as AEs that developed, worsened or became serious during the TE period.