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

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ClinicalTrials.gov Identifier: NCT03640481
Recruitment Status : Recruiting
First Posted : August 21, 2018
Last Update Posted : March 17, 2023
Sponsor:
Information provided by (Responsible Party):
Sanofi ( Kadmon, a Sanofi Company )

Study Description
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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

Condition or disease Intervention/treatment Phase
Chronic Graft-versus-host-disease Drug: Belumosudil (KD025) Phase 2

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 Subjects who have not achieved a response after 12 cycles of belumosudil should be withdrawn if in the Investigator's judgment there is no evidence of clinical benefit.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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 175 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : October 11, 2018
Actual Primary Completion Date : February 19, 2020
Estimated Study Completion Date : January 1, 2026

Resource links provided by the National Library of Medicine

Drug Information available for: Belumosudil

Arms and Interventions
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Arm Intervention/treatment
Experimental: 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 Name: REZUROCK
Experimental: 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 Name: REZUROCK


Outcome Measures
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Primary Outcome Measures :
  1. Overall Response Rate (ORR) [ Time Frame: 6 months ]
    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.


Secondary Outcome Measures :
  1. Duration of Response (DOR) [ Time Frame: 6 months ]
    The time from initial response of PR or CR until documented progression of cGVHD

  2. Change in Lee Symptom Scale Score [ Time Frame: 6 months ]
    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.

  3. Response rate by organ system [ Time Frame: 6 months ]
    The response assessment for the nine individual organs (Skin, Eyes, Mouth, Esophagus, Upper GI, Lower GI, Liver, Lungs, and Joints and fascia).

  4. Percentage of subjects who have a best response of PR or CR [ Time Frame: 6 months ]
  5. Change in corticosteroid dose [ Time Frame: 6 months ]
  6. Change in calcineurin inhibitor dose [ Time Frame: 6 months ]
  7. Failure-free survival (FFS) [ Time Frame: 6 months ]
    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.

  8. Overall Survival (OS) [ Time Frame: 6 months ]
    Time from first dose of belumosudil to the date of death due to any cause.

  9. Change in cGVHD severity as based on the Physician-reported global cGVHD Activity Assessment [ Time Frame: 6 months ]
    Physician-reported outcome

  10. Change in symptom activity as based on cGVHD Activity Assessment Patient Self-Report [ Time Frame: 6 months ]
    Patient-reported outcome

  11. Determine the Peak Plasma Concentration (Cmax) of belumosudil [ Time Frame: Pre-dose and post-dose sampling within 12 hours. ]
    Determine the maximum plasma concentration (Cmax) of belumosudil

  12. Determine the observed time to reach peak plasma concentration (Tmax) of belumosudil [ Time Frame: Pre-dose and post-dose sampling within 12 hours. ]
    The time that belumosudil reach the maximum plasma concentration (Tmax).

  13. Determine the half-life (T1/2) of belumosudil [ Time Frame: Pre-dose and post-dose sampling within 12 hours. ]
    The time it takes for half of belumosudil to be removed from plasma by biological processes (T1/2)

  14. Determine the area under the plasma concentration versus time curve (AUC) of belumosudil [ Time Frame: Pre-dose and post-dose sampling within 12 hours. ]
    Area under the plasma concentration versus time curve (AUC)

  15. Time to Response [ Time Frame: 6 months ]
    The time it takes to obtain a cGVHD response to belumosudil.

  16. Time to next treatment [ Time Frame: 6 months ]
    The time it takes to initiate a new systemic cGVHD treatment after starting belumosudil.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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. Subject 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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03640481


Contacts
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Contact: Trial Transparency email recommended (Toll free number for US & Canada) 800-633-1610 ext option 6 Contact-US@sanofi.com

Locations
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Sponsors and Collaborators
Kadmon, a Sanofi Company
More Information
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Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Kadmon, a Sanofi Company
ClinicalTrials.gov Identifier: NCT03640481    
Other Study ID Numbers: DRI17633
KD025-213 ( Other Identifier: Kadmon )
First Posted: August 21, 2018    Key Record Dates
Last Update Posted: March 17, 2023
Last Verified: March 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Bronchiolitis Obliterans Syndrome
Graft vs Host Disease
Immune System Diseases
Organizing Pneumonia
Bronchiolitis Obliterans
Bronchiolitis
Bronchitis
Bronchial Diseases
 Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Belumosudil
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action