A Study to Evaluate the Safety, Tolerability, and Activity of KD025 in Subjects With Chronic Graft Versus Host Disease

Study Overview
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Brief Summary
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This study was been conducted to evaluate the safety, tolerability, and activity of belumosudil (formerly known as KD025) in adult participants with chronic graft versus host disease (cGVHD).

Detailed Description
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Fifty four (54) participants were enrolled to receive orally administered belumosudil 200 milligrams (mg) once daily (QD), belumosudil 200 mg twice daily (BID), or belumosudil 400 mg QD. Study drug was administered in 28-day cycles until disease progression or occurrence of unacceptable toxicity. Participants received study drug in the inpatient or outpatient setting.

Official Title
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A Phase 2a, Dose-Escalation, Open-Label Study to Evaluate the Safety, Tolerability, and Activity of KD025 in Subjects With Chronic Graft Versus Host Disease

Conditions
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Graft vs Host Disease

Intervention / Treatment
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* Drug: Belumosudil (KD025)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult male and female participants at least 18 years of age who had allogenic bone marrow transplant (BMT) or hematopoietic stem cell transplantation (HSCT). Received glucocorticoid therapy and calcineurin therapy or glucocorticoid therapy alone for cGVHD at study entry. Participants on calcineurin therapy only, without glucocorticoid therapy, were not eligible. Participants also received other therapies thought not to be immunosuppressive (such as extracorporeal photopheresis; ECP), were considered for enrollment in this study on a case-by-case basis. Had persistent active cGVHD manifestations, as defined by 2014 NIH Consensus Development Project on Criteria for Clinical trials in cGVHD, after at least 2 months of steroid therapy. No more than 3 prior lines of treatment for cGVHD. Karnofsky Performance Scale of greater than (>) 40. Adequate organ and bone marrow functions evaluated during the 14 days prior to enrollment as follows: Absolute neutrophil count greater than or equal to (>=) 1.5*10^9/L (without myeloid growth factors within 1 week of study entry) Platelet count >=50*10^9/L (without transfusion or thrombopoietin or thrombopoietin analogues within 2 weeks of study entry) Adequate safety laboratory values: Total bilirubin less than or equal to (<=) 1.5*upper limit of normal (ULN) Alanine aminotransferase and aspartate aminotransferase <=3*ULN Glomerular filtration rate (GFR) >= 30 milliliter per minute per 1.73 square meter (mL/min/1.73 m^2) using the 4-Variable Modification of Diet in Renal Disease variable formula Female participants of childbearing potential have a negative pregnancy test at screening. Females of childbearing potential were defined as sexually mature women without prior hysterectomy or who had any evidence of menses in the past 12 months. However, women who had been amenorrheic for 12 or more months were still considered to be of childbearing potential if the amenorrhea was possibly due to prior chemotherapy, anti estrogens, or ovarian suppression. Women of childbearing potential (i.e., menstruating women) must had a negative urine pregnancy test (positive urine tests were to be confirmed by serum test) documented within the 24-hour period prior to the first dose of study drug. Sexually active women of childbearing potential enrolled in the study must agree to use two forms of accepted methods of contraception during the course of the study and for 3 months after their last dose of study drug. Effective birth control includes: Intrauterine device plus one barrier method; Stable doses of hormonal contraception for at least 3 months (e.g., oral, injectable, implant, transdermal) plus one barrier method; 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm); or A vasectomized partner For male participants who were sexually active and who were partners of premenopausal women: agreement to use two forms of contraception as in criterion 10 above during the treatment period and for at least 3 months after the last dose of study drug. Able to provide written informed consent prior to the performance of any study-specific procedures. Exclusion Criteria: Female participant who was pregnant or breastfeeding. Received an investigational GVHD treatment within 28 days of study entry. Had acute GVHD. Taken any medication known to be a moderate or strong inhibitor of the cytochrome (CY) CYP3A4 isozyme or any drugs that are moderate or strong CYP3A4 inducers. 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 poorly controlled psychiatric disease or coronary artery disease). Regular and excessive use of alcohol within the 6 months prior to study entry defined as alcohol intake >14 drinks per week in a man or >7 drinks per week in a woman. Approximately 10 grams of alcohol equals one drink unit. One unit equals 1 ounce of distilled spirits, one 12-ounce beer, or one 4-ounce glass of wine. Known history of human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or hepatitis B virus (HBV). Diagnosed with another malignancy (other than malignancy for which transplant was performed) within 3 years of enrollment, with the exception of completely resected basal cell or squamous cell carcinoma of the skin, resected in situ cervical malignancy, resected breast ductal carcinoma in situ, or low-risk prostate cancer after curative resection. Relapse of the underlying cancer or post-transplant lymphoproliferative disease at the time of screening. Had previous exposure to belumosudil or known allergy/sensitivity to belumosudil or any other Rho-associated protein kinase-2 inhibitor. Taken other immunosuppressant drugs for GVHD, including mammalian target of rapamycin inhibitors (Note: Only steroids, calcineurin inhibitors, and ECP are acceptable). Corrected QT interval using Fridericia's formula >450 milliseconds. Female participant who was pregnant or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Belumosudil 200 mg QD<br>Participants received belumosudil 200 mg orally QD in each 28-day treatment cycle until disease progression, unacceptable toxicity, or death whichever occurred first (maximum duration: 64.2 months). | Drug: Belumosudil (KD025)<br>* Pharmaceutical form: Capsules or Tablets Route of administration: Oral<br>* Other names: REZUROCK;|
| Experimental: Cohort 2: Belumosudil 200 mg BID<br>Participants received belumosudil 200 mg orally BID in each 28-day treatment cycle until disease progression, unacceptable toxicity, or death whichever occurred first (maximum duration: 45.9 months). | Drug: Belumosudil (KD025)<br>* Pharmaceutical form: Capsules or Tablets Route of administration: Oral<br>* Other names: REZUROCK;|
| Experimental: Cohort 3: Belumosudil 400 mg QD<br>Participants received belumosudil 400 mg orally QD in each 28-day treatment cycle until disease progression, unacceptable toxicity, or death whichever occurred first (maximum duration: 49.2 months). | Drug: Belumosudil (KD025)<br>* Pharmaceutical form: Capsules or Tablets Route of administration: Oral<br>* Other names: REZUROCK;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Overall Response (OR) | OR was defined as the percentage of participants with complete response (CR) or partial response (PR). The OR determination of chronic graft versus host disease (cGVHD) was based on cGVHD response assessment performed by clinicians as per the 2014 National Institutes of Health (NIH) Consensus Development Project for Clinical Trials in cGVHD criteria. CR was defined as the resolution of all manifestations 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; and cGVHD progression was defined as the clinically meaningful worsening in 1 or more organs regardless of improvement in other organs. | From the date of randomization to the date of first documentation of progression or death due to any cause or data cut-off, whichever occurred first (maximum duration: up to 64.2 months) | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs), and Treatment-emergent Serious Adverse Events (TESAEs) | An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. Serious adverse events (SAEs) 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 disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as AEs that developed, worsened or became serious during the TEAE period (defined as the time from the first dose of study drug up to 28 days after the last dose of study drug). TEAEs included both SAEs and non-SAEs. | From first dose of study drug up to 28 days after the last dose of study drug (maximum duration: up to 64.2 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Best Overall Response (BOR) | BOR was defined as the participants with either a CR or PR or lack of response (LOR), where LOR included the response status of unchanged (LOR-U), mixed (LOR-M), or progression (LOR-P). BOR was assessed per the 2014 NIH Consensus Development Project for Clinical Trials in cGVHD criteria. CR was defined as the resolution of all manifestations 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; LOR-M was defined as CR or PR in at least one organ accompanied by progression in another organ, LOR-U was defined as outcomes that did not meet the criteria for CR, PR, progression or mixed response, LOR-P was defined as progression in at least one organ or site without a response in any other organ or site. | From the date of randomization to the date of first documentation of progression or death due to any cause or data cut-off, whichever occurred first (maximum duration: up to 64.2 months) | 
| Number of Participants With Maximal Improvement From Baseline in Global Severity Rating (GSR) by Clinician-reported cGVHD Assessment | 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 gastrointestinal (GI) track, lower GI tract, liver, lungs, and joints and fascia plus GSR. End of treatment (EOT) visit was performed within 3 days after participant's last dose of study drug. Baseline value was defined as valid and last non-missing value obtained within 28 days prior to participant receiving first study medication. 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. Only those categories in which at least 1 participant had data were reported. | From Baseline up to end of treatment (i.e., up to 64.2 months) | 
| Number of Participants With Maximal Improvement From Baseline in Symptom Activity by cGVHD Activity Assessment Participant Self-Report | cGVHD symptom severity was self-reported by participants. Participants were asked to rate their disease symptom severity over the last week on the following questions: skin itching at its worst, moth dryness at its worst, mouth pain at its worst, mouth sensitivity at its worst, main compliant on eyes, symptom severity on eyes. Severity rating was done on a 0 to 10-point numeric rating scare, where score 0 indicated 'not at all severe cGVHD symptoms' and score 10 indicated 'most severe cGVHD symptoms possible'. EOT visit was performed within 3 days after participant's last dose of study drug. Baseline value was defined as valid and last non-missing value obtained within 28 days prior to participant receiving first study medication. Maximal improvement from Baseline was calculated as the lowest symptom severity score on scheduled visits minus the symptom severity score at Baseline with possible ranges from -10 to 10. The lower the number means the better improvement in cGVHD symptoms. | From Baseline up to end of treatment (i.e., up to 64.2 months) | 
| Failure-free Survival (FFS) | Failure-free survival was defined as the time (in months) from first dose of study drug to either the start of another new systemic treatment for cGVHD, relapse of the underlying disease or death. If no such events happened, FFS was censored by last response assessment or long term follow up assessment, whichever was the latest and available. Kaplan-Meier survival method was used for the analysis. | From first dose of study drug to either start of another new systemic treatment for cGVHD, relapse of the underlying disease or death or data cut-off, whichever occurred first (maximum duration: up to 64.2 months) | 
| Change From Baseline in Corticosteroids Dose | Baseline value was defined as valid and last non-missing value obtained within 28 days prior to participant receiving first study medication. EOT visit was performed within 3 days after the participant's last dose of study drug. | Baseline up to end of treatment (i.e., anytime up to 64.2 months) | 
| Number of Participants With Change From Baseline in Calcineurin Inhibitor (CNI) Usage | Calcineurin inhibitors included systemic tacrolimus and cyclosporine. Number of participants who took CNI at Baseline and had reduction and discontinuation in CNI use as compared to Baseline during the study are reported in this outcome measure. EOT visit was performed within 3 days after the participant's last dose of study drug. Baseline value was defined as valid and last non-missing value obtained within 28 days prior to participant receiving first study medication. | Baseline up to end of treatment (i.e., anytime up to 64.2 months) | 
| Duration of Response (DOR) | The DOR was defined as the time (in weeks) from first documentation of response to the time of first documentation of deterioration from best response (e.g., CR to PR, or PR to LR). LOR included the response status of unchanged (LOR-U), mixed (LOR-M), or progression (LOR-P). Per the 2014 NIH Consensus Development Project for Clinical Trials in cGVHD criteria; CR was defined as the resolution of all manifestations 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; LOR-M was defined as CR or PR in at least one organ accompanied by progression in another organ, LOR-U was defined as outcomes that did not meet the criteria for CR, PR, progression or mixed response, LOR-P was defined as progression in at least one organ or site without a response in any other organ or site. Kaplan-Meier was used for the analysis. | From the date of first response until documented disease progression or death due to any cause or data cut-off, whichever occurred first (maximum duration: up to 64.2 months) | 
| Time-to-Response (TTR) | Time-to-response was measured as the time (in weeks) from first dose of study drug to the time of first documentation of response. Response was defined as the participants achieving a PR or CR at any post-baseline response assessment. Per the 2014 NIH Consensus Development Project for Clinical Trials in cGVHD criteria; CR was defined as the resolution of all manifestations in each organ or site and PR was defined as the improvement in at least 1 organ or site without progression in any other organ or site. | From first dose of study drug treatment to the time of first documentation of response or data cut-off, whichever occurred first (maximum duration: up to 64.2 months) | 
| Percentage of Participants With Best Response in Each Individual Organ | Best response was defined as the percentage of participants with CR or PR. Response was assessed per the 2014 NIH Consensus Development Project for Clinical Trials in cGVHD criteria; CR was defined as the resolution of all manifestations 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. Organ response assessment was performed on 9 individual organs: skin, eyes, mouth, esophagus, upper gastrointestinal (GI), lower GI, liver, lungs, and joints and fascia and is reported in this outcome measure. | From date of randomization until disease progression or data cut-off, whichever occurred first (maximum duration: up to 64.2 months) | 
| Overall Survival (OS) | Overall survival was defined as the time (in months) from first dose of study drug to the death due to any reason. If there was no death, OS was censored by last visit, last long-term follow-up, or study cut-off date, whichever occurred first. Kaplan-Meier survival method was used for the analysis. | From first dose of study drug to date of death from any cause or data cut-off, whichever occurred first (maximum duration: up to 64.2 months) | 
| Time to Next Therapy (TTNT) | The TTNT was defined as the time (in months) from first treatment to the time of new systemic cGVHD treatment. TTNT was censored by last response assessment or long term follow up assessment, whichever was earlier. Kaplan-Meier survival method was used for the analysis. | From time of first treatment to the time of new systemic cGVHD treatment or long term follow-up assessment, whichever occurred first (maximum duration: up to 64.2 months) | 
| Change From Baseline in Overall Score on Lee cGvHD Symptom Scale at Specified Time Points | Lee cGVHD symptom scale, a patient-reported symptom scale used to measure symptom burden and has 7 subscales (Skin, Eyes and Mouth, Breathing, Eating and Digestion, Muscles and Joints, Energy, and Mental and Emotional) with ratings as follows: 0-Not at all, 1-Slightly, 2-Moderately, 3-Quite a bit, 4-Extremely, with lower values representing better outcome. Score for each subscale was normalized to a score ranged from 0 to 100, where higher score=worse symptoms. An overall Lee cGvHD score was calculated as average of these 7 subscales and it ranged from 0 to 100, where a higher score = worse symptoms. EOT visit was performed within 3 days after the participant's last dose of study drug. Baseline value was defined as valid and last non-missing value obtained within 28 days prior to participant receiving first study medication. | Baseline, Day 1 of Cycles 2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26, 27,28,29,30,31,32,33,34,35,36,37, 38,39,40,41,42,43,44,45,46,47,48, 49, 50,51,52,53, 54,55, 56, 57,58,59,60,61,62,63,67 and EOT (i.e., anytime up to 64.2 months) | 
| Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Each Specified Time Points | FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. Baseline value was defined as valid and last non-missing value obtained within 28 days prior to participant receiving first study medication. EOT visit was performed within 3 days after the participant's last dose of study drug. | Baseline, Day 1 of Cycles 2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27, 29,30,31,32,33,34,35,36,37,38, 39,40,41,43, 47,48,49,51,52,53, 54, 55,56, 57,58,60,61,62,63,67, EOT (i.e., anytime up to 64.2 months) | 
| Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) at Each Specified Time Points | FVC was the total amount of air (in liters) exhaled from the lungs during the lung function test measured by spirometer which assessed the change in lung function related to the disease status. Baseline value was defined as valid and last non-missing value obtained within 28 days prior to participant receiving first study medication. EOT visit was performed within 3 days after the participant's last dose of study drug. | Baseline, Day 1 of Cycles 2, 3,4, 5,6,7,8,9,10,11,12,13, 14,15,16,17,18,19,20,21,22,23,24,25,26, 27,29,30,31,32,33,34,35,36,37,38,39,40,41,43,47, 48,49, 51,52,53,54, 55, 56,57,58,60,61, 62, 63,67, EOT (i.e., anytime up to 64.2 months) | 
| Change From Baseline in Percent Predicted Hemoglobin (HGB) Corrected Diffusing Capacity of Lung for Carbon Monoxide (DLco) at Each Specified Time Points | DLco is a measurement of the ability of the lungs to transfer gases from the air to the blood. Change from baseline in diffusing capacity of the lung for carbon monoxide (percent predicted hemoglobin level corrected) was reported for this measure. Baseline value was defined as valid and last non-missing value obtained within 28 days prior to participant receiving first study medication. EOT visit was performed within 3 days after the participant's last dose of study drug. | Baseline, Day 1 of Cycles 2,3,4,5,6,7,8,9,10,11,12,13, 14,15,16,17,18,19,20,21,22,23,24,25,26,27, 29,31,32,33,34,35,36,37,39,40,41,43,47,49,51,53,55, 61, 62, 63, 67, EOT (i.e., anytime up to 64.2 Months) | 
| Change From Baseline in Percent Predicted Total Lung Capacity (TLC) at Each Specified Time Points | TLC is the volume of air in the lungs upon the maximum effort of inspiration. Baseline value was defined as valid and last non-missing value obtained within 28 days prior to participant receiving first study medication. EOT visit was performed within 3 days after the participant's last dose of study drug. | Baseline, Day 1 of Cycles 2,3, 4, 5,6,7, 8, 9, 10,11,12,13, 14, 15, 16, 17, 18, 19, 20,21, 22,23,24, 25, 26, 27,29, 30, 31,32, 33, 34, 35,36, 37, 38,39, 40,41,43,47, 48, 49,51,52,53, 54,55,56,57,58, 60,61,62, 63, 67, EOT (i.e., anytime up to 64.2 Months) | 
| Change From Baseline in Percent Predicted Residual Volume (RV) at Each Specified Time Points | RV is the volume of air remaining in the lungs after maximum forceful expiration. Baseline value was defined as valid and last non-missing value obtained within 28 days prior to participant receiving first study medication. EOT visit was performed within 3 days after the participant's last dose of study drug. | Baseline, Day 1 of Cycles 2, 3, 4,5, 6,7, 8, 9, 10, 11,12, 13, 14,15, 16,17, 18, 19,20, 21,22,23, 24, 25, 26,27, 29, 30, 31, 32, 33,34, 35,36, 37,38, 39, 40,41, 43,47, 48, 49,51,52,53, 54, 55,56,57, 58,60,61,62,63,67, EOT (i.e., anytime up to 64.2 Months) | 
| Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of Belumosudil and Its Metabolites (KD025m1 and KD025m2) | Cmax was the maximum observed plasma concentration, obtained by a non-compartmental analysis. Cmax data for Belumosudil and its metabolites KD025m1 and KD025m2 are reported in this outcome measure. | Cycles 1 and 2: pre-dose (0 hour), 1, 2, 3, 4, 5, and 6 hours post-dose on Day 1 | 
| Pharmacokinetics: Time of the Maximum Observed Plasma Concentration (Tmax) of Belumosudil and Its Metabolites (KD025m1 and KD025m2) | Tmax was defined as time to reach maximum observed plasma concentration, obtained by a non-compartmental analysis. Tmax data for Belumosudil and its metabolites KD025m1 and KD025m2 are reported in this outcome measure. | Cycles 1 and 2: pre-dose (0 hour), 1, 2, 3, 4, 5, and 6 hours post-dose on Day 1 | 
| Pharmacokinetics: The Area Under the Plasma Concentration Versus Time Curve From Time 0 to 6 Hours Post-dose (AUC0-6hr) of Belumosudil and Its Metabolites (KD025m1 and KD025m2) | AUC0-6hr was defined as area under the plasma concentration versus time curve from time 0 to 6 hours post-dose, obtained by a non-compartmental analysis from the concentration-time data. AUC0-6hr data for Belumosudil and its metabolites KD025m1 and KD025m2 are reported in this outcome measure. | Cycles 1 and 2: pre-dose (0 hour), 1, 2, 3, 4, 5, and 6 hours post-dose on Day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bone Marrow Transplantation, cGVHD, Allogeneic hematopoietic stem cell transplantation, Immune System Diseases, Steroid refractory chronic graft vs host disease (cGVHD), Anti-Inflammatory Agents, Glucocorticoids, Corticosteroids