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

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)

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

Study Overview

• Status: Terminated
• Conditions: Chronic Graft-versus-host-disease
• Intervention / Treatment: Drug: Belumosudil (KD025)

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 Subjects who have not achieved a response after 12 cycles of belumosudil should be withdrawn if in the Investigator's judgment there is no evidence of clinical benefit.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

• Study Type: Interventional
• Enrollment (Actual): 159
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Childrens Hospital Site Number : 154
    • Tucson, Arizona, United States, 85724
      • University of Arizona - Cancer Center Site Number : 122
  • California
    • Duarte, California, United States, 91010
      • City of Hope Medical Center Site Number : 050
    • Los Angeles, California, United States, 90059
      • University of California, Los Angeles (UCLA) - Medical Center Site Number : 104
    • San Francisco, California, United States, 94143
      • University of California, San Francisco (UCSF) - Helen Diller Family Comprehensive Cancer Center Site Number : 058
    • Stanford, California, United States, 94305
      • Stanford Cancer Center Site Number : 108
  • Colorado
    • Denver, Colorado, United States, 80218
      • Colorado Blood Cancer Institute Site Number : 098
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami - Sylvester Cancer Center Site Number : 097
    • Tampa, Florida, United States, 33612
      • Moffitt Site Number : 102
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School of Medicine Site Number : 100
    • Augusta, Georgia, United States, 30912
      • Augusta University Medical Center Site Number : 093
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago Site Number : 139
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Site Number : 126
  • Kansas
    • Fairway, Kansas, United States, 66205
      • University of Kansas Cancer Center Site Number : 105
  • Maryland
    • Bethesda, Maryland, United States, 20892-1203
      • Center for Cancer Research National Cancer Institute Site Number : 107
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Site Number : 002
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute Site Number : 004
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-5718
      • CS Mott Children's Hospital Site Number : 157
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmanos Cancer Institute-4100 John R St Site Number : 094
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Site Number : 051
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine Site Number : 125
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester Site Number : 106
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Site Number : 123
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • The Cleveland Clinic Foundation Site Number : 041
    • Columbus, Ohio, United States, 43210
      • James Cancer Hospital & Wexner Medical Center at the Ohio State University Comprehensive Cancer Center Site Number : 103
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • Oregon Health & Science University (OHSU) Site Number : 095
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Medical Center (UPMC) - Hillman Cancer Center Site Number : 132
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon and HCA Research Institute Site Number : 007
    • Nashville, Tennessee, United States, 37232-6868
      • Vanderbilt University Medical Center Site Number : 063
  • Texas
    • Austin, Texas, United States, 78704
      • South Austin Medical Center Site Number : 091
    • Houston, Texas, United States, 77030-4009
      • MD Anderson Cancer Center Site Number : 057
    • San Antonio, Texas, United States, 78229
      • Texas Transplant Institute Site Number : 079
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center Site Number : 052
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin - Carbone Cancer Center Site Number : 135
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert Hospital and the Medical College of Wisconsin Site Number : 101

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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)
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.	Baseline (Day 1) up to 40.5 months for adult arms; Baseline (Day 1) up to 27.6 months for adolescent arms
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.	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)
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.	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)
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.	Baseline (Day 1) and 40.5 months for adult arms; Baseline (Day 1) and 27.6 months for adolescent arms
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.	Baseline (Day 1) up to 40.5 months for adult arms; Baseline (Day 1) up to 27.6 months for adolescent arms
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.	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)
Overall Survival (OS)	OS was defined as time from first dose of belumosudil to the date of death due to any cause.	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)
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.	Baseline (Day 1) up to 40.5 months for adult arms; Baseline (Day 1) up to 27.6 months for adolescent arms
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.	Baseline (Day 1) and 40.5 months for adult arms; Baseline (Day 1) and 27.6 months for adolescent arms
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.	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
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.	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
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.	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
Time to Response (TTR)	TTR was measured as the time from first treatment to the time of first documentation of response.	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)
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.	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)

Collaborators and Investigators

• Sponsor: Kadmon, a Sanofi Company

Publications and helpful links

General Publications

• Przepiorka D, Le RQ, Ionan A, Li RJ, Wang YH, Gudi R, Mitra S, Vallejo J, Okusanya OO, Ma L, Yang Y, Patel P, Mezaache D, Shah R, Banerjee A, McLamore S, Maung AN, Goldberg KB, Pazdur R, Theoret MR, De Claro RA. FDA Approval Summary: Belumosudil for Adult and Pediatric Patients 12 Years and Older with Chronic GvHD after Two or More Prior Lines of Systemic Therapy. Clin Cancer Res. 2022 Jun 13;28(12):2488-2492. doi: 10.1158/1078-0432.CCR-21-4176.
• Lee SJ, Cutler C, Blazar BR, Tu A, Yang Z, Pavletic SZ. Correlation of Patient-Reported Outcomes with Clinical Organ Responses: Data from the Belumosudil Chronic Graft-versus-Host Disease Studies. Transplant Cell Ther. 2022 Oct;28(10):700.e1-700.e6. doi: 10.1016/j.jtct.2022.06.020. Epub 2022 Jul 1.
• Cutler C, Lee SJ, Arai S, Rotta M, Zoghi B, Lazaryan A, Ramakrishnan A, DeFilipp Z, Salhotra A, Chai-Ho W, Mehta R, Wang T, Arora M, Pusic I, Saad A, Shah NN, Abhyankar S, Bachier C, Galvin J, Im A, Langston A, Liesveld J, Juckett M, Logan A, Schachter L, Alavi A, Howard D, Waksal HW, Ryan J, Eiznhamer D, Aggarwal SK, Ieyoub J, Schueller O, Green L, Yang Z, Krenz H, Jagasia M, Blazar BR, Pavletic S. Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study. Blood. 2021 Dec 2;138(22):2278-2289. doi: 10.1182/blood.2021012021. Erratum In: Blood. 2022 Mar 17;139(11):1772. doi: 10.1182/blood.2022015598.

Study record dates

Study Major Dates

• Study Start (Actual): October 11, 2018
• Primary Completion (Actual): December 11, 2023
• Study Completion (Actual): December 11, 2023

Study Registration Dates

• First Submitted: August 13, 2018
• First Submitted That Met QC Criteria: August 17, 2018
• First Posted (Actual): August 21, 2018

Study Record Updates

• Last Update Posted (Actual): December 12, 2024
• Last Update Submitted That Met QC Criteria: November 14, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Organizing Pneumonia; Immune System Diseases; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchiolitis Obliterans Syndrome; Graft vs Host Disease; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Belumosudil
• Other Study ID Numbers: DRI17633 (Other Identifier: Sanofi Identifier); KD025-213 (Other Identifier: Kadmon); U1111-1279-2518 (Registry Identifier: ICTRP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No