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

Phase 2TerminatedNCT03640481

Kadmon, a Sanofi Company159 enrolled

Overview

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

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 Subjects who have not achieved a response after 12 cycles of belumosudil should be withdrawn if in the Investigator's judgment there is no evidence of clinical benefit.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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

159

Conditions

Chronic Graft-versus-host-disease

Interventions

Belumosudil (KD025)DRUG

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

Eligibility

Sex: ALLMin age: 12 YearsHealthy volunteers:

Medical Language ↔ Plain English

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.

Locations (35)

Outcomes

Primary Outcomes

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.

Time frame: 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

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.

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.

Data from ClinicalTrials.gov

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Phoenix Childrens Hospital Site Number : 154

Phoenix, Arizona, United States

University of Arizona - Cancer Center Site Number : 122

Tucson, Arizona, United States

City of Hope Medical Center Site Number : 050

Duarte, California, United States

University of California, Los Angeles (UCLA) - Medical Center Site Number : 104

Los Angeles, California, United States

University of California, San Francisco (UCSF) - Helen Diller Family Comprehensive Cancer Center Site Number : 058

San Francisco, California, United States

Stanford Cancer Center Site Number : 108

Stanford, California, United States

Colorado Blood Cancer Institute Site Number : 098

Denver, Colorado, United States

University of Miami - Sylvester Cancer Center Site Number : 097

Miami, Florida, United States

Moffitt Site Number : 102

Tampa, Florida, United States

Emory University School of Medicine Site Number : 100

Atlanta, Georgia, United States

...and 25 more locations

Time frame: 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.

Time frame: 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.

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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)