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

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

Tracking Information

• First Submitted Date: August 13, 2018
• First Posted Date: August 21, 2018
• Last Update Posted Date: December 21, 2023
• Actual Study Start Date: October 11, 2018
• Actual Primary Completion Date: December 11, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 1, 2023)

Overall Response Rate (ORR) [ Time Frame: up to approximately 40 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.

Original Primary Outcome Measures (submitted: August 17, 2018)

Overall Response Rate (ORR) [ Time Frame: 12 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.

Current Secondary Outcome Measures (submitted: August 1, 2023)

• Duration of Response (DOR) [ Time Frame: up to approximately 40 months ]
  The time from initial response of PR or CR until documented progression of cGVHD
• Change in Lee Symptom Scale Score [ Time Frame: up to approximately 40 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.
• Response rate by organ system [ Time Frame: up to approximately 40 months ]
  The response assessment for the nine individual organs (Skin, Eyes, Mouth, Esophagus, Upper GI, Lower GI, Liver, Lungs, and Joints and fascia).
• Percentage of subjects who have a best response of PR or CR [ Time Frame: up to approximately 40 months ]
• Change in corticosteroid dose [ Time Frame: up to approximately 40 months ]
• Change in calcineurin inhibitor dose [ Time Frame: up to approximately 40 months ]
• Failure-free survival (FFS) [ Time Frame: up to approximately 7 years ]
  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.
• Overall Survival (OS) [ Time Frame: up to approximately 7 years ]
  Time from first dose of belumosudil to the date of death due to any cause.
• Change in cGVHD severity as based on the Physician-reported global cGVHD Activity Assessment [ Time Frame: up to approximately 40 months ]
  Physician-reported outcome
• Change in symptom activity as based on cGVHD Activity Assessment Patient Self-Report [ Time Frame: up to approximately 40 months ]
  Patient-reported outcome
• 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
• 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).
• 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)
• 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)
• Time to Response [ Time Frame: up to approximately 40 months ]
  The time it takes to obtain a cGVHD response to belumosudil.
• Time to next treatment [ Time Frame: up to approximately 40 months ]
  The time it takes to initiate a new systemic cGVHD treatment after starting belumosudil.
• Number pf participants with adverse event and serious adverse events [ Time Frame: Up to 28 days after the last dose of study treatment i.e., up to approximately 7 years ]
  Safety will be assessed by monitoring adverse events, clinical laboratory evaluations, vital sign measurements, and ECG parameters.

Original Secondary Outcome Measures (submitted: August 17, 2018)

• Duration of Response (DOR) [ Time Frame: 12 months ]
  The time from initial response of PR or CR until documented progression of cGVHD
• Change in Lee Symptom Scale Score [ Time Frame: 12 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.
• Response rate by organ system [ Time Frame: 12 months ]
  The response assessment for the nine individual organs (Skin, Eyes, Mouth, Esophagus, Upper GI, Lower GI, Liver, Lungs, and Joints and fascia).
• Percentage of subjects who have a best response of PR or CR [ Time Frame: 12 months ]
• Change in corticosteroid dose [ Time Frame: 12 months ]
• Change in calcineurin inhibitor dose [ Time Frame: 12 months ]
• Failure-free survival (FFS) [ Time Frame: 12 months ]
  FFS is defined as the absence of cGVHD treatment change, non-relapse mortality and recurrent malignancy. Median FFS (from first dose of KD025) and landmark FFS at 1 year will be analyzed.
• Overall Survival (OS) [ Time Frame: 12 months ]
  Time from first dose of KD025 to the date of death due to any cause.
• Change in cGVHD severity as based on the Physician-reported global cGVHD Activity Assessment [ Time Frame: 12 months ]
  Physician-reported outcome
• Change in symptom activity as based on cGVHD Activity Assessment Patient Self-Report [ Time Frame: 12 months ]
  Patient-reported outcome
• Determine the Peak Plasma Concentration (Cmax) of KD025 [ Time Frame: Pre-dose and post-dose sampling within 12 hours. ]
  Determine the maximum plasma concentration (Cmax) of KD025
• Determine the observed time to reach peak plasma concentration (Tmax) of KD025 [ Time Frame: Pre-dose and post-dose sampling within 12 hours. ]
  The time that KD025 reach the maximum plasma concentration (Tmax).
• Determine the half-life (T1/2) of KD025 [ Time Frame: Pre-dose and post-dose sampling within 12 hours. ]
  The time it takes for half of KD025 to be removed from plasma by biological processes (T1/2)
• Determine the area under the plasma concentration versus time curve (AUC) of KD025 [ Time Frame: Pre-dose and post-dose sampling within 12 hours. ]
  Area under the plasma concentration versus time curve (AUC)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy and Safety of KD025 in Subjects With cGVHD After At Least 2 Prior Lines of Systemic Therapy
• 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)
• 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.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

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

• Condition: Chronic Graft-versus-host-disease

Intervention

Drug: Belumosudil (KD025)

Belumosudil is an orally available Rho-associated protein kinase-2 (ROCK2) selective inhibitor.

Other Name: REZUROCK

Study Arms

• Experimental: Arm A: belumosudil 200 mg QD
  Eligible subjects randomized to arm A will take belumosudil 200 mg once daily
  Intervention: Drug: Belumosudil (KD025)
• Experimental: Arm B: belumosudil 200 mg BID
  Eligible subjects randomized to arm B will take belumosudil 200 mg twice daily
  Intervention: Drug: Belumosudil (KD025)

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.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: November 23, 2023): 159
• Original Estimated Enrollment (submitted: August 17, 2018): 126
• Actual Study Completion Date: December 11, 2023
• Actual Primary Completion Date: December 11, 2023 (Final data collection date for primary outcome measure)

Eligibility 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. 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03640481
• Other Study ID Numbers: DRI17633; KD025-213 ( Other Identifier: Kadmon ); U1111-1279-2518 ( Registry Identifier: ICTRP )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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.

• Current Responsible Party: Sanofi ( Kadmon, a Sanofi Company )
• Original Responsible Party: Kadmon Corporation, LLC
• Current Study Sponsor: Kadmon, a Sanofi Company
• Original Study Sponsor: Kadmon Corporation, LLC
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Sanofi
• Verification Date: December 2023