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

Chronic Graft-versus-host-disease Clinical Trial

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03640481
• Other study ID #: DRI17633
• Secondary ID: KD025-213U1111-1
• Status: Terminated
• Phase: Phase 2
• Start date: October 11, 2018
• Est. completion date: December 11, 2023

Study information

• Verified date: December 2023
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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 Subjects who have not achieved a response after 12 cycles of belumosudil should be withdrawn if in the Investigator's judgment there is no evidence of clinical benefit.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

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 159
• Est. completion date: December 11, 2023
• Est. primary completion date: December 11, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Bronchiolitis Obliterans Syndrome
• Chronic Graft-versus-host-disease
• Graft vs Host Disease

Intervention

Drug:
• Belumosudil (KD025)
Belumosudil is an orally available Rho-associated protein kinase-2 (ROCK2) selective inhibitor.

Locations

Country	Name	City	State
United States	CS Mott Children's Hospital Site Number : 157	Ann Arbor	Michigan
United States	Emory University School of Medicine Site Number : 100	Atlanta	Georgia
United States	Augusta University Medical Center Site Number : 093	Augusta	Georgia
United States	South Austin Medical Center Site Number : 091	Austin	Texas
United States	Center for Cancer Research National Cancer Institute Site Number : 107	Bethesda	Maryland
United States	University of Alabama at Birmingham (UAB) - Children's of Alabama Site Number : 156	Birmingham	Alabama
United States	Dana-Farber Cancer Institute Site Number : 004	Boston	Massachusetts
United States	Massachusetts General Hospital Site Number : 002	Boston	Massachusetts
United States	University of Illinois at Chicago Site Number : 139	Chicago	Illinois
United States	The Cleveland Clinic Foundation Site Number : 041	Cleveland	Ohio
United States	James Cancer Hospital & Wexner Medical Center at the Ohio State University Comprehensive Cancer Center Site Number : 103	Columbus	Ohio
United States	University of Texas Southwestern Site Number : 155	Dallas	Texas
United States	Colorado Blood Cancer Institute Site Number : 098	Denver	Colorado
United States	Barbara Ann Karmanos Cancer Institute-4100 John R St Site Number : 094	Detroit	Michigan
United States	Childrens Hospital of Michigan Site Number : 161	Detroit	Michigan
United States	City of Hope Medical Center Site Number : 050	Duarte	California
United States	University of Kansas Cancer Center Site Number : 105	Fairway	Kansas
United States	MD Anderson Cancer Center Site Number : 057	Houston	Texas
United States	University of Iowa Site Number : 126	Iowa City	Iowa
United States	University of California, Los Angeles (UCLA) - Medical Center Site Number : 104	Los Angeles	California
United States	University of Wisconsin - Carbone Cancer Center Site Number : 135	Madison	Wisconsin
United States	University of Miami - Sylvester Cancer Center Site Number : 097	Miami	Florida
United States	Froedtert Hospital and the Medical College of Wisconsin Site Number : 101	Milwaukee	Wisconsin
United States	University of Minnesota Site Number : 051	Minneapolis	Minnesota
United States	Sarah Cannon and HCA Research Institute Site Number : 007	Nashville	Tennessee
United States	Vanderbilt University Medical Center Site Number : 063	Nashville	Tennessee
United States	Childrens Hospital of Orange County Site Number : 165	Orange	California
United States	Phoenix Childrens Hospital Site Number : 154	Phoenix	Arizona
United States	University of Pittsburgh Medical Center (UPMC) - Hillman Cancer Center Site Number : 132	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University (OHSU) Site Number : 095	Portland	Oregon
United States	University of Rochester Site Number : 106	Rochester	New York
United States	Washington University School of Medicine Site Number : 125	Saint Louis	Missouri
United States	Texas Transplant Institute Site Number : 079	San Antonio	Texas
United States	University of California, San Francisco (UCSF) - Helen Diller Family Comprehensive Cancer Center Site Number : 058	San Francisco	California
United States	Fred Hutchinson Cancer Research Center Site Number : 052	Seattle	Washington
United States	Stanford Cancer Center Site Number : 108	Stanford	California
United States	Moffitt Site Number : 102	Tampa	Florida
United States	University of Arizona - Cancer Center Site Number : 122	Tucson	Arizona
United States	Wake Forest Site Number : 123	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Kadmon, a Sanofi Company

Country where clinical trial is conducted

United States, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Duration of Response (DOR)	The time from initial response of PR or CR until documented progression of cGVHD	up to approximately 40 months
Secondary	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
Secondary	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
Secondary	Percentage of subjects who have a best response of PR or CR		up to approximately 40 months
Secondary	Change in corticosteroid dose		up to approximately 40 months
Secondary	Change in calcineurin inhibitor dose		up to approximately 40 months
Secondary	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
Secondary	Overall Survival (OS)	Time from first dose of belumosudil to the date of death due to any cause.	up to approximately 7 years
Secondary	Change in cGVHD severity as based on the Physician-reported global cGVHD Activity Assessment	Physician-reported outcome	up to approximately 40 months
Secondary	Change in symptom activity as based on cGVHD Activity Assessment Patient Self-Report	Patient-reported outcome	up to approximately 40 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Time to Response	The time it takes to obtain a cGVHD response to belumosudil.	up to approximately 40 months
Secondary	Time to next treatment	The time it takes to initiate a new systemic cGVHD treatment after starting belumosudil.	up to approximately 40 months
Secondary	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