Chronic Graft-versus-host-disease
Conditions
Brief summary
This is a Phase 2, randomized, multicenter study to evaluate the efficacy and safety of KD025 in subjects with Chronic Graft Versus Host Disease (cGVHD) after at least 2 prior lines of systemic therapy
Detailed description
Phase 2, open label, randomized, multicenter study in subjects with cGVHD who have previously been treated with at least 2 prior lines of systemic therapy. Approximately 166 subjects with active cGVHD will be randomized (1:1) to receive treatment with one of two belumosudil (formerly known as KD025) regimens: * Arm A: belumosudil 200 mg QD * Arm B: belumosudil 200 mg BID With Amendment 2, the sample size was increased from approximately 126 subjects, with additional subjects to be enrolled as follows: * 20 adolescents * 20 adults into a site-specific Companion Study to collect biospecimens These additional subjects will also be randomized (1:1) to Arm A or Arm B. Any adolescent taking a proton pump inhibitor (PPI) or a strong CYP3A4 inducer will begin Cycle 1 Day 1 at the escalated dose of belumosudil 200 mg BID. Randomization will be stratified according to prior cGVHD treatment with ibrutinib (Yes / No) and severe cGVHD at baseline (Yes / No). Subjects may receive treatment in 28-day treatment cycles until clinically significant progression of cGVHD. Subjects who have not achieved a response after 12 cycles of belumosudil should be withdrawn if in the Investigator's judgment there is no evidence of clinical benefit. Subjects will undergo evaluations as outlined in the Study Assessments table (Appendix A). The primary endpoint is the overall response rate (ORR) with responses as defined by the 2014 National Institute of Health (NIH) Consensus Development Project on clinical trials in cGVHD.
Interventions
Belumosudil is an orally available Rho-associated protein kinase-2 (ROCK2) selective inhibitor.
Sponsors
Kadmon, a Sanofi Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 2, open label, randomized, multicenter study in subjects with cGVHD who have previously been treated with at least 2 prior lines of systemic therapy
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Male and female subjects at least 12 years of age who have had allogenic hematopoietic cell transplant (HCT). 2. Previously received at least 2 and not more than 5 lines of systemic therapy for cGVHD 3. Receiving glucocorticoid therapy with a stable dose over the 2 weeks prior to screening 4. Have persistent cGVHD manifestations and systemic therapy is indicated 5. Karnofsky Performance Score of ≥ 60 (if aged 16 years or older); Lansky Performance Score of ≥ 60 (if aged \< 16 years) 6. Weight ≥ 40kg
Exclusion criteria
1. Subjects has not been on a stable dose / regimen of systemic cGVHD treatments for at least 2 weeks prior to screening. (Note: Concomitant corticosteroids, calcineurin inhibitors, sirolimus, MMF, methotrexate, rituximab, and extracorporeal photophoresis (ECP) are acceptable. Systemic investigational GVHD treatments are not permitted). 2. Histological relapse of the underlying cancer or post-transplant lymphoproliferative disease at the time of screening. 3. Current treatment with ibrutinib. Prior treatment with ibrutinib is allowed with a washout of at least 28 days prior to randomization.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | 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 40.5 months for adult arms and 27.6 months for adolescent arms) | The ORR was defined as the percentage of participants with a best response meeting the overall response criteria assessment of complete response (CR) or partial response (PR) at any post-baseline response assessment. CR was defined as resolution of all manifestations of cGVHD in each organ or site. PR was defined as the improvement in at least one organ or site without progression in any other organ or site. Responses were assessed by the 2014 National Institutes of Health (NIH) Consensus Development Project on Clinical Trials in cGVHD. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Improvement (>=7-Point Reduction [7-PtR] From Baseline) as Assessed by Lee Symptom Scale (LSS) Score | Baseline (Day 1) up to 40.5 months for adult arms; Baseline (Day 1) up to 27.6 months for adolescent arms | The questionnaire asked participants to indicate the degree of bother that they experienced due to symptoms in 7 domains potentially affected by chronic GVHD. 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 is scored 0, 1, 2, 3 or 4. 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 summary score was calculated as average of all non-missing domain scores if more than 50% of them were non-missing. A higher score indicated more bothersome symptoms. A 7-point difference on the summary score of cGVHD symptom scale was found to be clinically meaningful. |
| Number of Participants With Best Response by Organ System | From date of randomization until disease progression or data cut-off, whichever occurred first (maximum duration: up to 40.5 months for adult arms and 27.6 months for adolescent arms) | The best response (CR, PR) for individual organs (skin, eyes, mouth, esophagus, upper gastrointestinal \[GI\], lower GI, liver, lungs, joints and fascia) were summarized. CR was defined as resolution of all manifestations of cGVHD in each organ or site. PR was defined as the improvement in at least one organ or site without progression in any other organ or site. |
| Percentage of Participants With Best Response of PR and CR | 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 40.5 months for adult arms and 27.6 months for adolescent arms) | PR was defined as the improvement in at least one organ or site without progression in any other organ or site. CR was defined as resolution of all manifestations of cGVHD in each organ or site. Responses were assessed by the 2014 NIH Consensus Development Project on Clinical Trials in cGVHD. |
| Percent Change From Baseline in Corticosteroid Dose to Greatest Reduction | Baseline (Day 1) and 40.5 months for adult arms; Baseline (Day 1) and 27.6 months for adolescent arms | 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. |
| Percentage of Participants With Reduction and Discontinuation of Calcineurin Inhibitor Dose | Baseline (Day 1) up to 40.5 months for adult arms; Baseline (Day 1) up to 27.6 months for adolescent arms | Calcineurin inhibitors include systemic tacrolimus and cyclosporine. Percentage of participants with reduction and discontinuation of calcineurin inhibitor dose is presented. |
| Failure-Free Survival (FFS) | From first dose of study drug to the time of first documentation of response or data cut-off, whichever occurred first (maximum duration: up to 40.5 months for adult arms and 27.6 months for adolescent arms) | 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. |
| Overall Survival (OS) | From first dose of study drug to date of death from any cause or data cut-off, whichever occurred first (maximum duration: up to 40.5 months for adult arms and 27.6 months for adolescent arms) | OS was defined as time from first dose of belumosudil to the date of death due to any cause. |
| Duration of Response (DOR) | 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 40.5 months for adult arms and 27.6 months for adolescent arms) | DOR is defined as the time from first documentation of response to the time of first documentation of deterioration from best response (e.g., CR to PR, or PR to Lack of response \[LR\]). CR was defined as resolution of all manifestations of cGVHD in each organ or site. PR was defined as the improvement in at least one organ or site without progression in any other organ or site. LR included the response status of mixed, unchanged, or progression. Mixed LR was defined as complete or partial response in at least one organ accompanied by progression in another organ. Unchanged LR was defined as outcomes that did not meet the criteria for complete response, partial response, progression or mixed response. Progression LR-P was defined as progression in at least one organ or site without a response in any other organ or site. Confidence interval (CI) is calculated using Kaplan-Meier method. |
| Change From Baseline in Patient Self-Reported Symptom Activity Based on cGVHD Activity Assessment | Baseline (Day 1) and 40.5 months for adult arms; Baseline (Day 1) and 27.6 months for adolescent arms | The symptom activity item is a 0-10-point numeric rating scale with a score of 0 indicating cGVHD symptoms not at all severe and a score of 10 being most severe cGVHD symptoms possible. The status reported by participants were categorized as none, mild, moderate, and severe. Higher scores indicated worse symptoms. Baseline was defined as the valid and last non-missing value obtained within 14 days prior to participants receiving the first study drug. |
| Maximum Concentration Observed (Cmax) of Belumosudil | Cycles 1 and 2: Pre-dose and 1, 2, 3, 4, 5, 6, 7, 8, and 12 hours post dose on Day 1 for adult arms; Cycles 2 and 4: Pre-dose and 3 and 5 hours post dose on Day 1 for adolescent arms | Blood samples were collected at the specified timepoints to evaluate Cmax of belumosudil. As pre-specified in protocol, pharmacokinetic (PK) parameters were only calculated for participants with full PK samples. Thus, PK parameters were not calculated for adolescent participants who only had sparse PK samples. |
| Observed Time to Reach Peak Plasma Concentration (Tmax) of Belumosudil | Cycles 1 and 2: Pre-dose and 1, 2, 3, 4, 5, 6, 7, 8, and 12 hours post dose on Day 1 for adult arms; Cycles 2 and 4: Pre-dose and 3 and 5 hours post dose on Day 1 for adolescent arms | Blood samples were collected at the specified timepoints to evaluate Tmax of belumosudil. As pre-specified in protocol, PK parameters were only calculated for participants with full PK samples. Thus, PK parameters were not calculated for adolescent participants who only had sparse PK samples. |
| Area Under the Curve Over Time Interval From 0 to 6 Hours (AUC0-6) of Belumosudil | Cycles 1 and 2: Pre-dose and 1, 2, 3, 4, 5, 6, 7, 8, and 12 hours post dose on Day 1 for adult arms; Cycles 2 and 4: Pre-dose and 3 and 5 hours post dose on Day 1 for adolescent arms | Blood samples were collected at the specified timepoints to evaluate AUC0-6 of belumosudil. As pre-specified in protocol, PK parameters were only calculated for participants with full PK samples. Thus, PK parameters were not calculated for adolescent participants who only had sparse PK samples. |
| Time to Response (TTR) | From first dose of study drug to the time of first documentation of response or data cut-off, whichever occurred first(maximum duration: up to 40.5 months for adult arms and 27.6 months for adolescent arms) | TTR was measured as the time from first treatment to the time of first documentation of response. |
| Time to Next Treatment (TTNT) | From first dose of study drug to the time of new treatment or censoring date, whichever occurred first (maximum duration: up to 40.5 months for adult arms and 27.6 months for adolescent arms) | 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. |
| Number of Participants With Best Response of Global Severity Rating Score as Based on the Clinician-Reported Global cGVHD Activity Assessment | Baseline (Day 1) up to 40.5 months for adult arms; Baseline (Day 1) up to 27.6 months for adolescent arms | The Clinician-reported global cGVHD Activity Assessment is a 0-10 point numeric rating scale with a score of 0 indicating cGVHD symptoms not at all severe and a score of 10 being most severe cGVHD symptoms possible. Higher scores indicated worse symptoms. Best response was defined as PR+CR. PR was defined as the improvement in at least one organ or site without progression in any other organ or site. CR was defined as resolution of all manifestations of cGVHD in each organ or site. Participants were categorized in 3 categories at baseline based on the global severity scores of \<6, =6-7 and \>7 and number of participants with best response for them is reported. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 33 centers in the United States. A total of 251 participants were screened between 11 October 2018 to 08 August 2023, of which 92 participants were screen failures in adult cohort due to not meeting eligibility criteria, there were no screen failures in adolescent cohort.
Pre-assignment details
156 participants were randomized in the adult cohort, 4 of which did not receive treatment. 3 participants were randomized in the adolescent cohort. The sponsor decided to prematurely terminate the study due to the challenges encountered in recruiting adolescent participants. This decision was made without any safety concerns.
Participants by arm
| Arm | Count |
|---|---|
| Adult Arm A: Belumosudil 200 mg QD Participants received belumosudil 200 mg tablet orally QD in 28-day cycles until clinically significant progression of cGVHD, histologic recurrence of underlying malignancy, unacceptable toxicity, Investigator decision, participant preference/withdrawal of consent, loss of follow-up, sponsor decision, or death (whichever occurred first). | 77 |
| Adult Arm B: Belumosudil 200 mg BID Participants belumosudil 200 mg tablet orally BID in 28-day cycles until clinically significant progression of cGVHD, histologic recurrence of underlying malignancy, unacceptable toxicity, Investigator decision, participant preference/withdrawal of consent, loss of follow-up, sponsor decision, or death (whichever occurred first). | 75 |
| Adolescent Arm A: Belumosudil 200 mg QD Participants received belumosudil 200 mg tablet orally QD in 28-day cycles until clinically significant progression of cGVHD, histologic recurrence of underlying malignancy, unacceptable toxicity, Investigator decision, participant preference/withdrawal of consent, loss of follow-up, sponsor decision, or death (whichever occurred first). | 2 |
| Adolescent Arm B: Belumosudil 200 mg BID Participants received belumosudil 200 mg tablet orally BID in 28-day cycles until clinically significant progression of cGVHD, histologic recurrence of underlying malignancy, unacceptable toxicity, Investigator decision, participant preference/withdrawal of consent, loss of follow-up, sponsor decision, or death (whichever occurred first). | 1 |
| Total | 155 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 14 | 14 | 0 | 0 |
| Overall Study | Lost to Follow-up | 2 | 0 | 0 | 0 |
| Overall Study | Other | 26 | 12 | 1 | 0 |
| Overall Study | Randomized, but not treated | 1 | 3 | 0 | 0 |
| Overall Study | Site terminated by sponsor | 1 | 3 | 0 | 0 |
| Overall Study | Study terminated by sponsor | 29 | 42 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 4 | 0 | 1 |
Baseline characteristics
| Characteristic | Adult Arm A: Belumosudil 200 mg QD | Adult Arm B: Belumosudil 200 mg BID | Adolescent Arm A: Belumosudil 200 mg QD | Adolescent Arm B: Belumosudil 200 mg BID | Total |
|---|---|---|---|---|---|
| Age, Customized 12-17 Years | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Age, Customized 18-77 Years | 77 Participants | 75 Participants | 0 Participants | 0 Participants | 152 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 1 Participants | 1 Participants | 0 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 0 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) White | 65 Participants | 67 Participants | 1 Participants | 1 Participants | 134 Participants |
| Sex: Female, Male Female | 28 Participants | 38 Participants | 0 Participants | 1 Participants | 67 Participants |
| Sex: Female, Male Male | 49 Participants | 37 Participants | 2 Participants | 0 Participants | 88 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 14 / 77 | 14 / 75 | 0 / 2 | 0 / 1 |
| other Total, other adverse events | 73 / 77 | 73 / 75 | 2 / 2 | 1 / 1 |
| serious Total, serious adverse events | 36 / 77 | 30 / 75 | 1 / 2 | 0 / 1 |
Outcome results
Primary
Overall Response Rate (ORR)
The ORR was defined as the percentage of participants with a best response meeting the overall response criteria assessment of complete response (CR) or partial response (PR) at any post-baseline response assessment. CR was defined as resolution of all manifestations of cGVHD in each organ or site. PR was defined as the improvement in at least one organ or site without progression in any other organ or site. Responses were assessed by the 2014 National Institutes of Health (NIH) Consensus Development Project on Clinical Trials in cGVHD.
Time frame: 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 40.5 months for adult arms and 27.6 months for adolescent arms)
Population: mITT population included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adult Arm A: Belumosudil 200 mg QD | Overall Response Rate (ORR) | 74.0 Percentage of participants |
| Adult Arm B: Belumosudil 200 mg BID | Overall Response Rate (ORR) | 76.0 Percentage of participants |
| Adolescent Arm A: Belumosudil 200 mg QD | Overall Response Rate (ORR) | 50.0 Percentage of participants |
| Adolescent Arm B: Belumosudil 200 mg BID | Overall Response Rate (ORR) | 100.0 Percentage of participants |
Secondary
Area Under the Curve Over Time Interval From 0 to 6 Hours (AUC0-6) of Belumosudil
Blood samples were collected at the specified timepoints to evaluate AUC0-6 of belumosudil. As pre-specified in protocol, PK parameters were only calculated for participants with full PK samples. Thus, PK parameters were not calculated for adolescent participants who only had sparse PK samples.
Time frame: Cycles 1 and 2: Pre-dose and 1, 2, 3, 4, 5, 6, 7, 8, and 12 hours post dose on Day 1 for adult arms; Cycles 2 and 4: Pre-dose and 3 and 5 hours post dose on Day 1 for adolescent arms
Population: PK population included all study participants who provided samples for dense PK sampling. Only those participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Adult Arm A: Belumosudil 200 mg QD | Area Under the Curve Over Time Interval From 0 to 6 Hours (AUC0-6) of Belumosudil | Cycle 1 | 4430 Hours*ng/mL | Geometric Coefficient of Variation 153 |
| Adult Arm A: Belumosudil 200 mg QD | Area Under the Curve Over Time Interval From 0 to 6 Hours (AUC0-6) of Belumosudil | Cycle 2 | 6860 Hours*ng/mL | Geometric Coefficient of Variation 123 |
| Adult Arm B: Belumosudil 200 mg BID | Area Under the Curve Over Time Interval From 0 to 6 Hours (AUC0-6) of Belumosudil | Cycle 1 | 2380 Hours*ng/mL | Geometric Coefficient of Variation 204 |
| Adult Arm B: Belumosudil 200 mg BID | Area Under the Curve Over Time Interval From 0 to 6 Hours (AUC0-6) of Belumosudil | Cycle 2 | 6520 Hours*ng/mL | Geometric Coefficient of Variation 108 |
| Adolescent Arm A: Belumosudil 200 mg QD | Area Under the Curve Over Time Interval From 0 to 6 Hours (AUC0-6) of Belumosudil | Cycle 2 | NA Hours*ng/mL | — |
| Adolescent Arm A: Belumosudil 200 mg QD | Area Under the Curve Over Time Interval From 0 to 6 Hours (AUC0-6) of Belumosudil | Cycle 4 | NA Hours*ng/mL | — |
| Adolescent Arm B: Belumosudil 200 mg BID | Area Under the Curve Over Time Interval From 0 to 6 Hours (AUC0-6) of Belumosudil | Cycle 4 | NA Hours*ng/mL | — |
| Adolescent Arm B: Belumosudil 200 mg BID | Area Under the Curve Over Time Interval From 0 to 6 Hours (AUC0-6) of Belumosudil | Cycle 2 | NA Hours*ng/mL | — |
Secondary
Change From Baseline in Patient Self-Reported Symptom Activity Based on cGVHD Activity Assessment
The symptom activity item is a 0-10-point numeric rating scale with a score of 0 indicating cGVHD symptoms not at all severe and a score of 10 being most severe cGVHD symptoms possible. The status reported by participants were categorized as none, mild, moderate, and severe. Higher scores indicated worse symptoms. Baseline was defined as the valid and last non-missing value obtained within 14 days prior to participants receiving the first study drug.
Time frame: Baseline (Day 1) and 40.5 months for adult arms; Baseline (Day 1) and 27.6 months for adolescent arms
Population: mITT population included all randomized participants who received at least one dose of study drug. Only those participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Adult Arm A: Belumosudil 200 mg QD | Change From Baseline in Patient Self-Reported Symptom Activity Based on cGVHD Activity Assessment | -0.9 Score on a scale | Standard Deviation 2.4 |
| Adult Arm B: Belumosudil 200 mg BID | Change From Baseline in Patient Self-Reported Symptom Activity Based on cGVHD Activity Assessment | -1.5 Score on a scale | Standard Deviation 2.4 |
| Adolescent Arm A: Belumosudil 200 mg QD | Change From Baseline in Patient Self-Reported Symptom Activity Based on cGVHD Activity Assessment | 0.0 Score on a scale | Standard Deviation 0 |
| Adolescent Arm B: Belumosudil 200 mg BID | Change From Baseline in Patient Self-Reported Symptom Activity Based on cGVHD Activity Assessment | -1.0 Score on a scale | — |
Secondary
Duration of Response (DOR)
DOR is defined as the time from first documentation of response to the time of first documentation of deterioration from best response (e.g., CR to PR, or PR to Lack of response \[LR\]). CR was defined as resolution of all manifestations of cGVHD in each organ or site. PR was defined as the improvement in at least one organ or site without progression in any other organ or site. LR included the response status of mixed, unchanged, or progression. Mixed LR was defined as complete or partial response in at least one organ accompanied by progression in another organ. Unchanged LR was defined as outcomes that did not meet the criteria for complete response, partial response, progression or mixed response. Progression LR-P was defined as progression in at least one organ or site without a response in any other organ or site. Confidence interval (CI) is calculated using Kaplan-Meier method.
Time frame: 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 40.5 months for adult arms and 27.6 months for adolescent arms)
Population: Responder population included participants in the mITT population that achieved a partial or complete response at any post-baseline response assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Adult Arm A: Belumosudil 200 mg QD | Duration of Response (DOR) | 23.9 Weeks |
| Adult Arm B: Belumosudil 200 mg BID | Duration of Response (DOR) | 32.0 Weeks |
| Adolescent Arm A: Belumosudil 200 mg QD | Duration of Response (DOR) | 16.1 Weeks |
| Adolescent Arm B: Belumosudil 200 mg BID | Duration of Response (DOR) | 4.1 Weeks |
Secondary
Failure-Free Survival (FFS)
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.
Time frame: From first dose of study drug to the time of first documentation of response or data cut-off, whichever occurred first (maximum duration: up to 40.5 months for adult arms and 27.6 months for adolescent arms)
Population: mITT population included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Adult Arm A: Belumosudil 200 mg QD | Failure-Free Survival (FFS) | 16.3 Months |
| Adult Arm B: Belumosudil 200 mg BID | Failure-Free Survival (FFS) | 17.2 Months |
| Adolescent Arm A: Belumosudil 200 mg QD | Failure-Free Survival (FFS) | NA Months |
| Adolescent Arm B: Belumosudil 200 mg BID | Failure-Free Survival (FFS) | 6.8 Months |
Secondary
Maximum Concentration Observed (Cmax) of Belumosudil
Blood samples were collected at the specified timepoints to evaluate Cmax of belumosudil. As pre-specified in protocol, pharmacokinetic (PK) parameters were only calculated for participants with full PK samples. Thus, PK parameters were not calculated for adolescent participants who only had sparse PK samples.
Time frame: Cycles 1 and 2: Pre-dose and 1, 2, 3, 4, 5, 6, 7, 8, and 12 hours post dose on Day 1 for adult arms; Cycles 2 and 4: Pre-dose and 3 and 5 hours post dose on Day 1 for adolescent arms
Population: PK population included all study participants who provided samples for dense PK sampling. Only those participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Adult Arm A: Belumosudil 200 mg QD | Maximum Concentration Observed (Cmax) of Belumosudil | Cycle 1 | 1350 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 127 |
| Adult Arm A: Belumosudil 200 mg QD | Maximum Concentration Observed (Cmax) of Belumosudil | Cycle 2 | 1780 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 154 |
| Adult Arm B: Belumosudil 200 mg BID | Maximum Concentration Observed (Cmax) of Belumosudil | Cycle 1 | 870 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 177 |
| Adult Arm B: Belumosudil 200 mg BID | Maximum Concentration Observed (Cmax) of Belumosudil | Cycle 2 | 2050 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 99.9 |
| Adolescent Arm A: Belumosudil 200 mg QD | Maximum Concentration Observed (Cmax) of Belumosudil | Cycle 2 | NA Nanograms per milliliter (ng/mL) | — |
| Adolescent Arm A: Belumosudil 200 mg QD | Maximum Concentration Observed (Cmax) of Belumosudil | Cycle 4 | NA Nanograms per milliliter (ng/mL) | — |
| Adolescent Arm B: Belumosudil 200 mg BID | Maximum Concentration Observed (Cmax) of Belumosudil | Cycle 4 | NA Nanograms per milliliter (ng/mL) | — |
| Adolescent Arm B: Belumosudil 200 mg BID | Maximum Concentration Observed (Cmax) of Belumosudil | Cycle 2 | NA Nanograms per milliliter (ng/mL) | — |
Secondary
Number of Participants With Best Response by Organ System
The best response (CR, PR) for individual organs (skin, eyes, mouth, esophagus, upper gastrointestinal \[GI\], lower GI, liver, lungs, joints and fascia) were summarized. CR was defined as resolution of all manifestations of cGVHD in each organ or site. PR was defined as the improvement in at least one organ or site without progression in any other organ or site.
Time frame: From date of randomization until disease progression or data cut-off, whichever occurred first (maximum duration: up to 40.5 months for adult arms and 27.6 months for adolescent arms)
Population: mITT population included all randomized participants who received at least one dose of study drug. Only those participants with data collected for each specified category are reported.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Adult Arm A: Belumosudil 200 mg QD | Number of Participants With Best Response by Organ System | Joints and Fascia | 42 Participants |
| Adult Arm A: Belumosudil 200 mg QD | Number of Participants With Best Response by Organ System | Skin | 20 Participants |
| Adult Arm A: Belumosudil 200 mg QD | Number of Participants With Best Response by Organ System | Eyes | 24 Participants |
| Adult Arm A: Belumosudil 200 mg QD | Number of Participants With Best Response by Organ System | Mouth | 23 Participants |
| Adult Arm A: Belumosudil 200 mg QD | Number of Participants With Best Response by Organ System | Esophagus | 13 Participants |
| Adult Arm A: Belumosudil 200 mg QD | Number of Participants With Best Response by Organ System | Upper GI | 9 Participants |
| Adult Arm A: Belumosudil 200 mg QD | Number of Participants With Best Response by Organ System | Lower GI | 5 Participants |
| Adult Arm A: Belumosudil 200 mg QD | Number of Participants With Best Response by Organ System | Liver | 2 Participants |
| Adult Arm A: Belumosudil 200 mg QD | Number of Participants With Best Response by Organ System | Lungs | 9 Participants |
| Adult Arm B: Belumosudil 200 mg BID | Number of Participants With Best Response by Organ System | Mouth | 31 Participants |
| Adult Arm B: Belumosudil 200 mg BID | Number of Participants With Best Response by Organ System | Upper GI | 4 Participants |
| Adult Arm B: Belumosudil 200 mg BID | Number of Participants With Best Response by Organ System | Lungs | 6 Participants |
| Adult Arm B: Belumosudil 200 mg BID | Number of Participants With Best Response by Organ System | Skin | 28 Participants |
| Adult Arm B: Belumosudil 200 mg BID | Number of Participants With Best Response by Organ System | Lower GI | 6 Participants |
| Adult Arm B: Belumosudil 200 mg BID | Number of Participants With Best Response by Organ System | Eyes | 26 Participants |
| Adult Arm B: Belumosudil 200 mg BID | Number of Participants With Best Response by Organ System | Liver | 1 Participants |
| Adult Arm B: Belumosudil 200 mg BID | Number of Participants With Best Response by Organ System | Esophagus | 7 Participants |
| Adult Arm B: Belumosudil 200 mg BID | Number of Participants With Best Response by Organ System | Joints and Fascia | 39 Participants |
| Adolescent Arm A: Belumosudil 200 mg QD | Number of Participants With Best Response by Organ System | Mouth | 1 Participants |
| Adolescent Arm A: Belumosudil 200 mg QD | Number of Participants With Best Response by Organ System | Skin | 1 Participants |
| Adolescent Arm A: Belumosudil 200 mg QD | Number of Participants With Best Response by Organ System | Lungs | 0 Participants |
| Adolescent Arm B: Belumosudil 200 mg BID | Number of Participants With Best Response by Organ System | Mouth | 1 Participants |
| Adolescent Arm B: Belumosudil 200 mg BID | Number of Participants With Best Response by Organ System | Eyes | 1 Participants |
Secondary
Number of Participants With Best Response of Global Severity Rating Score as Based on the Clinician-Reported Global cGVHD Activity Assessment
The Clinician-reported global cGVHD Activity Assessment is a 0-10 point numeric rating scale with a score of 0 indicating cGVHD symptoms not at all severe and a score of 10 being most severe cGVHD symptoms possible. Higher scores indicated worse symptoms. Best response was defined as PR+CR. PR was defined as the improvement in at least one organ or site without progression in any other organ or site. CR was defined as resolution of all manifestations of cGVHD in each organ or site. Participants were categorized in 3 categories at baseline based on the global severity scores of \<6, =6-7 and \>7 and number of participants with best response for them is reported.
Time frame: Baseline (Day 1) up to 40.5 months for adult arms; Baseline (Day 1) up to 27.6 months for adolescent arms
Population: mITT population included all randomized participants who received at least one dose of study drug. Only participants with respective global severity rating score categories of \<6, =6-7 and \>7 assessed at baseline are reported.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Adult Arm A: Belumosudil 200 mg QD | Number of Participants With Best Response of Global Severity Rating Score as Based on the Clinician-Reported Global cGVHD Activity Assessment | Baseline global severity rating score < 6: Best response | 9 Participants |
| Adult Arm A: Belumosudil 200 mg QD | Number of Participants With Best Response of Global Severity Rating Score as Based on the Clinician-Reported Global cGVHD Activity Assessment | Baseline global severity rating score= 6-7: Best response | 15 Participants |
| Adult Arm A: Belumosudil 200 mg QD | Number of Participants With Best Response of Global Severity Rating Score as Based on the Clinician-Reported Global cGVHD Activity Assessment | Baseline global severity rating score >7: Best response | 11 Participants |
| Adult Arm B: Belumosudil 200 mg BID | Number of Participants With Best Response of Global Severity Rating Score as Based on the Clinician-Reported Global cGVHD Activity Assessment | Baseline global severity rating score >7: Best response | 9 Participants |
| Adult Arm B: Belumosudil 200 mg BID | Number of Participants With Best Response of Global Severity Rating Score as Based on the Clinician-Reported Global cGVHD Activity Assessment | Baseline global severity rating score= 6-7: Best response | 28 Participants |
| Adult Arm B: Belumosudil 200 mg BID | Number of Participants With Best Response of Global Severity Rating Score as Based on the Clinician-Reported Global cGVHD Activity Assessment | Baseline global severity rating score < 6: Best response | 8 Participants |
| Adolescent Arm A: Belumosudil 200 mg QD | Number of Participants With Best Response of Global Severity Rating Score as Based on the Clinician-Reported Global cGVHD Activity Assessment | Baseline global severity rating score= 6-7: Best response | 1 Participants |
| Adolescent Arm A: Belumosudil 200 mg QD | Number of Participants With Best Response of Global Severity Rating Score as Based on the Clinician-Reported Global cGVHD Activity Assessment | Baseline global severity rating score < 6: Best response | 0 Participants |
| Adolescent Arm B: Belumosudil 200 mg BID | Number of Participants With Best Response of Global Severity Rating Score as Based on the Clinician-Reported Global cGVHD Activity Assessment | Baseline global severity rating score < 6: Best response | 0 Participants |
Secondary
Number of Participants With Improvement (>=7-Point Reduction [7-PtR] From Baseline) as Assessed by Lee Symptom Scale (LSS) Score
The questionnaire asked participants to indicate the degree of bother that they experienced due to symptoms in 7 domains potentially affected by chronic GVHD. 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 is scored 0, 1, 2, 3 or 4. 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 summary score was calculated as average of all non-missing domain scores if more than 50% of them were non-missing. A higher score indicated more bothersome symptoms. A 7-point difference on the summary score of cGVHD symptom scale was found to be clinically meaningful.
Time frame: Baseline (Day 1) up to 40.5 months for adult arms; Baseline (Day 1) up to 27.6 months for adolescent arms
Population: mITT population included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Adult Arm A: Belumosudil 200 mg QD | Number of Participants With Improvement (>=7-Point Reduction [7-PtR] From Baseline) as Assessed by Lee Symptom Scale (LSS) Score | 45 Participants |
| Adult Arm B: Belumosudil 200 mg BID | Number of Participants With Improvement (>=7-Point Reduction [7-PtR] From Baseline) as Assessed by Lee Symptom Scale (LSS) Score | 48 Participants |
| Adolescent Arm A: Belumosudil 200 mg QD | Number of Participants With Improvement (>=7-Point Reduction [7-PtR] From Baseline) as Assessed by Lee Symptom Scale (LSS) Score | 0 Participants |
| Adolescent Arm B: Belumosudil 200 mg BID | Number of Participants With Improvement (>=7-Point Reduction [7-PtR] From Baseline) as Assessed by Lee Symptom Scale (LSS) Score | 0 Participants |
Secondary
Observed Time to Reach Peak Plasma Concentration (Tmax) of Belumosudil
Blood samples were collected at the specified timepoints to evaluate Tmax of belumosudil. As pre-specified in protocol, PK parameters were only calculated for participants with full PK samples. Thus, PK parameters were not calculated for adolescent participants who only had sparse PK samples.
Time frame: Cycles 1 and 2: Pre-dose and 1, 2, 3, 4, 5, 6, 7, 8, and 12 hours post dose on Day 1 for adult arms; Cycles 2 and 4: Pre-dose and 3 and 5 hours post dose on Day 1 for adolescent arms
Population: PK population included all study participants who provided samples for dense PK sampling. Only those participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Adult Arm A: Belumosudil 200 mg QD | Observed Time to Reach Peak Plasma Concentration (Tmax) of Belumosudil | Cycle 1 | 2.90 Hours |
| Adult Arm A: Belumosudil 200 mg QD | Observed Time to Reach Peak Plasma Concentration (Tmax) of Belumosudil | Cycle 2 | 1.98 Hours |
| Adult Arm B: Belumosudil 200 mg BID | Observed Time to Reach Peak Plasma Concentration (Tmax) of Belumosudil | Cycle 1 | 4.00 Hours |
| Adult Arm B: Belumosudil 200 mg BID | Observed Time to Reach Peak Plasma Concentration (Tmax) of Belumosudil | Cycle 2 | 1.26 Hours |
| Adolescent Arm A: Belumosudil 200 mg QD | Observed Time to Reach Peak Plasma Concentration (Tmax) of Belumosudil | Cycle 2 | NA Hours |
| Adolescent Arm A: Belumosudil 200 mg QD | Observed Time to Reach Peak Plasma Concentration (Tmax) of Belumosudil | Cycle 4 | NA Hours |
| Adolescent Arm B: Belumosudil 200 mg BID | Observed Time to Reach Peak Plasma Concentration (Tmax) of Belumosudil | Cycle 4 | NA Hours |
| Adolescent Arm B: Belumosudil 200 mg BID | Observed Time to Reach Peak Plasma Concentration (Tmax) of Belumosudil | Cycle 2 | NA Hours |
Secondary
Overall Survival (OS)
OS was defined as time from first dose of belumosudil to the date of death due to any cause.
Time frame: From first dose of study drug to date of death from any cause or data cut-off, whichever occurred first (maximum duration: up to 40.5 months for adult arms and 27.6 months for adolescent arms)
Population: mITT population included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Adult Arm A: Belumosudil 200 mg QD | Overall Survival (OS) | NA Months |
| Adult Arm B: Belumosudil 200 mg BID | Overall Survival (OS) | NA Months |
| Adolescent Arm A: Belumosudil 200 mg QD | Overall Survival (OS) | NA Months |
| Adolescent Arm B: Belumosudil 200 mg BID | Overall Survival (OS) | NA Months |
Secondary
Percentage of Participants With Best Response of PR and CR
PR was defined as the improvement in at least one organ or site without progression in any other organ or site. CR was defined as resolution of all manifestations of cGVHD in each organ or site. Responses were assessed by the 2014 NIH Consensus Development Project on Clinical Trials in cGVHD.
Time frame: 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 40.5 months for adult arms and 27.6 months for adolescent arms)
Population: mITT population included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Adult Arm A: Belumosudil 200 mg QD | Percentage of Participants With Best Response of PR and CR | PR | 68.8 Percentage of participants |
| Adult Arm A: Belumosudil 200 mg QD | Percentage of Participants With Best Response of PR and CR | CR | 5.2 Percentage of participants |
| Adult Arm B: Belumosudil 200 mg BID | Percentage of Participants With Best Response of PR and CR | CR | 2.7 Percentage of participants |
| Adult Arm B: Belumosudil 200 mg BID | Percentage of Participants With Best Response of PR and CR | PR | 73.3 Percentage of participants |
| Adolescent Arm A: Belumosudil 200 mg QD | Percentage of Participants With Best Response of PR and CR | PR | 50.0 Percentage of participants |
| Adolescent Arm A: Belumosudil 200 mg QD | Percentage of Participants With Best Response of PR and CR | CR | 0 Percentage of participants |
| Adolescent Arm B: Belumosudil 200 mg BID | Percentage of Participants With Best Response of PR and CR | PR | 100.0 Percentage of participants |
| Adolescent Arm B: Belumosudil 200 mg BID | Percentage of Participants With Best Response of PR and CR | CR | 0 Percentage of participants |
Secondary
Percentage of Participants With Reduction and Discontinuation of Calcineurin Inhibitor Dose
Calcineurin inhibitors include systemic tacrolimus and cyclosporine. Percentage of participants with reduction and discontinuation of calcineurin inhibitor dose is presented.
Time frame: Baseline (Day 1) up to 40.5 months for adult arms; Baseline (Day 1) up to 27.6 months for adolescent arms
Population: mITT population included all randomized participants who received at least one dose of study drug. Only those participants who received CNI at baseline were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Adult Arm A: Belumosudil 200 mg QD | Percentage of Participants With Reduction and Discontinuation of Calcineurin Inhibitor Dose | Reduction of Calcineurin Inhibitor Dose | 46.9 Percentage of participants |
| Adult Arm A: Belumosudil 200 mg QD | Percentage of Participants With Reduction and Discontinuation of Calcineurin Inhibitor Dose | Discontinuation of Calcineurin Inhibitor Dose | 21.9 Percentage of participants |
| Adult Arm B: Belumosudil 200 mg BID | Percentage of Participants With Reduction and Discontinuation of Calcineurin Inhibitor Dose | Reduction of Calcineurin Inhibitor Dose | 57.7 Percentage of participants |
| Adult Arm B: Belumosudil 200 mg BID | Percentage of Participants With Reduction and Discontinuation of Calcineurin Inhibitor Dose | Discontinuation of Calcineurin Inhibitor Dose | 34.6 Percentage of participants |
| Adolescent Arm A: Belumosudil 200 mg QD | Percentage of Participants With Reduction and Discontinuation of Calcineurin Inhibitor Dose | Reduction of Calcineurin Inhibitor Dose | 100.0 Percentage of participants |
| Adolescent Arm A: Belumosudil 200 mg QD | Percentage of Participants With Reduction and Discontinuation of Calcineurin Inhibitor Dose | Discontinuation of Calcineurin Inhibitor Dose | 0 Percentage of participants |
Secondary
Percent Change From Baseline in Corticosteroid Dose to Greatest Reduction
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.
Time frame: Baseline (Day 1) and 40.5 months for adult arms; Baseline (Day 1) and 27.6 months for adolescent arms
Population: mITT population included all randomized participants who received at least one dose of study drug. Only those participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Adult Arm A: Belumosudil 200 mg QD | Percent Change From Baseline in Corticosteroid Dose to Greatest Reduction | -50.00 Percent change |
| Adult Arm B: Belumosudil 200 mg BID | Percent Change From Baseline in Corticosteroid Dose to Greatest Reduction | -66.67 Percent change |
| Adolescent Arm A: Belumosudil 200 mg QD | Percent Change From Baseline in Corticosteroid Dose to Greatest Reduction | -50.00 Percent change |
| Adolescent Arm B: Belumosudil 200 mg BID | Percent Change From Baseline in Corticosteroid Dose to Greatest Reduction | -60.00 Percent change |
Secondary
Time to Next Treatment (TTNT)
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.
Time frame: From first dose of study drug to the time of new treatment or censoring date, whichever occurred first (maximum duration: up to 40.5 months for adult arms and 27.6 months for adolescent arms)
Population: mITT population included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Adult Arm A: Belumosudil 200 mg QD | Time to Next Treatment (TTNT) | 24.2 Months |
| Adult Arm B: Belumosudil 200 mg BID | Time to Next Treatment (TTNT) | NA Months |
| Adolescent Arm A: Belumosudil 200 mg QD | Time to Next Treatment (TTNT) | NA Months |
| Adolescent Arm B: Belumosudil 200 mg BID | Time to Next Treatment (TTNT) | 6.8 Months |
Secondary
Time to Response (TTR)
TTR was measured as the time from first treatment to the time of first documentation of response.
Time frame: From first dose of study drug to the time of first documentation of response or data cut-off, whichever occurred first(maximum duration: up to 40.5 months for adult arms and 27.6 months for adolescent arms)
Population: Responder population included participants in the mITT population that achieved a partial or complete response at any post-baseline response assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Adult Arm A: Belumosudil 200 mg QD | Time to Response (TTR) | 4.43 Weeks |
| Adult Arm B: Belumosudil 200 mg BID | Time to Response (TTR) | 4.43 Weeks |
| Adolescent Arm A: Belumosudil 200 mg QD | Time to Response (TTR) | 7.57 Weeks |
| Adolescent Arm B: Belumosudil 200 mg BID | Time to Response (TTR) | 4.14 Weeks |