Clinical trial NCT03640481: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Chronic Graft-versus-host-disease
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2018-08-21
Enrollment: 159
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
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
Primary purpose: TREATMENT

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 Subjects who have not achieved a response after 12 cycles of belumosudil should be withdrawn if in the Investigator's judgment there is no evidence of clinical benefit.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

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.

Primary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: 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 outcomes:
measure: Duration of Response (DOR)
timeFrame: 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)
measure: Number of Participants With Improvement (>=7-Point Reduction [7-PtR] From Baseline) as Assessed by Lee Symptom Scale (LSS) Score
timeFrame: Baseline (Day 1) up to 40.5 months for adult arms; Baseline (Day 1) up to 27.6 months for adolescent arms
measure: Number of Participants With Best Response by Organ System
timeFrame: 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)
measure: Percentage of Participants With Best Response of PR and CR
timeFrame: 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)
measure: Percent Change From Baseline in Corticosteroid Dose to Greatest Reduction
timeFrame: Baseline (Day 1) and 40.5 months for adult arms; Baseline (Day 1) and 27.6 months for adolescent arms
measure: Percentage of Participants With Reduction and Discontinuation of Calcineurin Inhibitor Dose
timeFrame: Baseline (Day 1) up to 40.5 months for adult arms; Baseline (Day 1) up to 27.6 months for adolescent arms
measure: Failure-Free Survival (FFS)
timeFrame: 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)
measure: Overall Survival (OS)
timeFrame: 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)
measure: Number of Participants With Best Response of Global Severity Rating Score as Based on the Clinician-Reported Global cGVHD Activity Assessment
timeFrame: Baseline (Day 1) up to 40.5 months for adult arms; Baseline (Day 1) up to 27.6 months for adolescent arms
measure: Change From Baseline in Patient Self-Reported Symptom Activity Based on cGVHD Activity Assessment
timeFrame: Baseline (Day 1) and 40.5 months for adult arms; Baseline (Day 1) and 27.6 months for adolescent arms
measure: Maximum Concentration Observed (Cmax) of Belumosudil
timeFrame: 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
measure: Observed Time to Reach Peak Plasma Concentration (Tmax) of Belumosudil
timeFrame: 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
measure: Area Under the Curve Over Time Interval From 0 to 6 Hours (AUC0-6) of Belumosudil
timeFrame: 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
measure: Time to Response (TTR)
timeFrame: 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)
measure: Time to Next Treatment (TTNT)
timeFrame: 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)
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Childrens Hospital Site Number : 154
state: Arizona
city: Tucson
country: United States
facility: University of Arizona - Cancer Center Site Number : 122
state: Arizona
city: Duarte
country: United States
facility: City of Hope Medical Center Site Number : 050
state: California
city: Los Angeles
country: United States
facility: University of California, Los Angeles (UCLA) - Medical Center Site Number : 104
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco (UCSF) - Helen Diller Family Comprehensive Cancer Center Site Number : 058
state: California
city: Stanford
country: United States
facility: Stanford Cancer Center Site Number : 108
state: California
city: Denver
country: United States
facility: Colorado Blood Cancer Institute Site Number : 098
state: Colorado
city: Miami
country: United States
facility: University of Miami - Sylvester Cancer Center Site Number : 097
state: Florida
city: Tampa
country: United States
facility: Moffitt Site Number : 102
state: Florida
city: Atlanta
country: United States
facility: Emory University School of Medicine Site Number : 100
state: Georgia
city: Augusta
country: United States
facility: Augusta University Medical Center Site Number : 093
state: Georgia
city: Chicago
country: United States
facility: University of Illinois at Chicago Site Number : 139
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Site Number : 126
state: Iowa
city: Fairway
country: United States
facility: University of Kansas Cancer Center Site Number : 105
state: Kansas
city: Bethesda
country: United States
facility: Center for Cancer Research National Cancer Institute Site Number : 107
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Site Number : 002
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute Site Number : 004
state: Massachusetts
city: Ann Arbor
country: United States
facility: CS Mott Children's Hospital Site Number : 157
state: Michigan
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute-4100 John R St Site Number : 094
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota Site Number : 051
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine Site Number : 125
state: Missouri
city: Rochester
country: United States
facility: University of Rochester Site Number : 106
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest Site Number : 123
state: North Carolina
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation Site Number : 041
state: Ohio
city: Columbus
country: United States
facility: James Cancer Hospital & Wexner Medical Center at the Ohio State University Comprehensive Cancer Center Site Number : 103
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University (OHSU) Site Number : 095
state: Oregon
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center (UPMC) - Hillman Cancer Center Site Number : 132
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon and HCA Research Institute Site Number : 007
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center Site Number : 063
state: Tennessee
city: Austin
country: United States
facility: South Austin Medical Center Site Number : 091
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center Site Number : 057
state: Texas
city: San Antonio
country: United States
facility: Texas Transplant Institute Site Number : 079
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center Site Number : 052
state: Washington
city: Madison
country: United States
facility: University of Wisconsin - Carbone Cancer Center Site Number : 135
state: Wisconsin
city: Milwaukee
country: United States
facility: Froedtert Hospital and the Medical College of Wisconsin Site Number : 101
state: Wisconsin
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.