Efficacy and Safety of KD025 in Subjects With cGVHD After At Least 2 Prior Lines of Systemic Therapy

Study Overview
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Brief Summary
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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
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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 Subjects who have not achieved a response after 12 cycles of belumosudil should be withdrawn if in the Investigator's judgment there is no evidence of clinical benefit.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.

Official Title
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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 (The ROCKstar Study)

Conditions
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Chronic Graft-versus-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: Male and female subjects at least 12 years of age who have had allogenic hematopoietic cell transplant (HCT). Previously received at least 2 and not more than 5 lines of systemic therapy for cGVHD Receiving glucocorticoid therapy with a stable dose over the 2 weeks prior to screening Have persistent cGVHD manifestations and systemic therapy is indicated Karnofsky Performance Score of ≥ 60 (if aged 16 years or older); Lansky Performance Score of ≥ 60 (if aged < 16 years) Weight ≥ 40kg Exclusion Criteria: 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). Histological relapse of the underlying cancer or post-transplant lymphoproliferative disease at the time of screening. Current treatment with ibrutinib. Prior treatment with ibrutinib is allowed with a washout of at least 28 days prior to randomization.

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
Interventional 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: belumosudil 200 mg QD<br>Eligible subjects randomized to arm A will take belumosudil 200 mg once daily | Drug: Belumosudil (KD025)<br>* Belumosudil is an orally available Rho-associated protein kinase-2 (ROCK2) selective inhibitor.<br>* Other names: REZUROCK;|
| Experimental: Arm B: belumosudil 200 mg BID<br>Eligible subjects randomized to arm B will take belumosudil 200 mg twice daily | Drug: Belumosudil (KD025)<br>* Belumosudil is an orally available Rho-associated protein kinase-2 (ROCK2) selective inhibitor.<br>* Other names: REZUROCK;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | The primary endpoint is the ORR with responses as defined by the 2014 National Institute of Health (NIH) Consensus Development Project on clinical trials in cGVHD. | up to approximately 40 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) | The time from initial response of PR or CR until documented progression of cGVHD | up to approximately 40 months | 
| Change in Lee Symptom Scale Score | Analyses will include: Number of subjects with a ≥7 point reduction, Number of subjects with a ≥7 point reduction on 2 consecutive assessments and Duration of a ≥7 point reduction. Symptom burden will be assessed on Day 1 of each cycle starting on Cycle 1 Day 1, as well as at the EOT visit. The questionnaire asks subjects to indicate the degree of bother that they experienced due to symptoms in seven domains potentially affected by chronic GVHD (skin, eyes, mouth, breathing, eating and digestion, energy, and emotional distress). The response will be determined based on clinician assessment specifically for each of affected organ as a Complete Response, Partial Response or Progression. | up to approximately 40 months | 
| Response rate by organ system | The response assessment for the nine individual organs (Skin, Eyes, Mouth, Esophagus, Upper GI, Lower GI, Liver, Lungs, and Joints and fascia). | up to approximately 40 months | 
| Percentage of subjects who have a best response of PR or CR |  | up to approximately 40 months | 
| Change in corticosteroid dose |  | up to approximately 40 months | 
| Change in calcineurin inhibitor dose |  | up to approximately 40 months | 
| Failure-free survival (FFS) | FFS is defined as the absence of cGVHD treatment change, non-relapse mortality and recurrent malignancy. Median FFS (from first dose of belumosudil) and landmark FFS at 1 year will be analyzed. | up to approximately 7 years | 
| Overall Survival (OS) | Time from first dose of belumosudil to the date of death due to any cause. | up to approximately 7 years | 
| Change in cGVHD severity as based on the Physician-reported global cGVHD Activity Assessment | Physician-reported outcome | up to approximately 40 months | 
| Change in symptom activity as based on cGVHD Activity Assessment Patient Self-Report | Patient-reported outcome | up to approximately 40 months | 
| Determine the Peak Plasma Concentration (Cmax) of belumosudil | Determine the maximum plasma concentration (Cmax) of belumosudil | Pre-dose and post-dose sampling within 12 hours | 
| Determine the observed time to reach peak plasma concentration (Tmax) of belumosudil | The time that belumosudil reach the maximum plasma concentration (Tmax). | Pre-dose and post-dose sampling within 12 hours | 
| Determine the half-life (T1/2) of belumosudil | The time it takes for half of belumosudil to be removed from plasma by biological processes (T1/2) | Pre-dose and post-dose sampling within 12 hours | 
| Determine the area under the plasma concentration versus time curve (AUC) of belumosudil | Area under the plasma concentration versus time curve (AUC) | Pre-dose and post-dose sampling within 12 hours | 
| Time to Response | The time it takes to obtain a cGVHD response to belumosudil. | up to approximately 40 months | 
| Time to next treatment | The time it takes to initiate a new systemic cGVHD treatment after starting belumosudil. | up to approximately 40 months | 
| Number pf participants with adverse event and serious adverse events | Safety will be assessed by monitoring adverse events, clinical laboratory evaluations, vital sign measurements, and ECG parameters. | Up to 28 days after the last dose of study treatment i.e., up to approximately 7 years |