Belumosudil for Chronic Graft-Versus-Host Disease
Recruiting in Palo Alto (17 mi)
+12 other locations
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Kadmon, a Sanofi Company
Must be taking: Glucocorticoids
Must not be taking: Ibrutinib, Ruxolitinib
Disqualifiers: Cancer relapse, Severe illness, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?
The purpose of this study is to measure safety and efficacy of oral belumosudil in Black or African American, American Indian or Alaska Native, and Native Hawaiian or Other Pacific Islander male and female participants with cGVHD who have previously been treated with at least 2 prior lines of systemic therapy aged 12 years and above. The duration of participants participation will be up to 4 weeks for screening, treatment until clinically significant progression of disease, and 4 weeks of safety follow-up, and then long-term follow-up every 12 weeks.1 Cycle = 28 days.
Will I have to stop taking my current medications?
The trial does not specify if you must stop all current medications, but you need to be on a stable dose of your current cGVHD treatments for at least 2 weeks before screening. If you are taking ibrutinib or ruxolitinib, you must stop them at least 28 days before joining the trial.
What data supports the effectiveness of the drug Belumosudil for chronic graft-versus-host disease?
Belumosudil has shown effectiveness in treating chronic graft-versus-host disease (cGVHD) with a high overall response rate of 74-77% in patients who had tried at least two other treatments. It was well tolerated and led to symptom reduction in over half of the patients, with many maintaining their response for a year or more.12345
Is Belumosudil safe for human use?
Belumosudil has been approved for use in patients with chronic graft-versus-host disease (cGVHD) and has been generally well tolerated in clinical trials. Common side effects include infections, fatigue, nausea, diarrhea, and high blood pressure, and some patients discontinued due to possible drug-related adverse effects.14567
What makes the drug Belumosudil unique for treating chronic graft-versus-host disease?
Eligibility Criteria
This trial is for Black, African American, American Indian or Alaska Native, and Native Hawaiian or Other Pacific Islander individuals aged 12+ with chronic Graft Versus Host Disease (cGVHD) who have tried at least two systemic therapies. Participants must be in stable condition with a certain performance score and not on specific treatments like ibrutinib or ruxolitinib recently.Inclusion Criteria
I have been on a stable dose of glucocorticoid therapy for the last 2 weeks.
I am using two forms of birth control and am not pregnant or breastfeeding.
I have ongoing symptoms from a chronic graft-versus-host disease needing systemic treatment.
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Exclusion Criteria
History or other evidence of severe illness or any other conditions that would make the participant, in the opinion of the Investigator, unsuitable for the study (such as malabsorption syndromes, poorly controlled psychiatric disease, or coronary artery disease)
I haven't changed my chronic GVHD treatment in the last 2 weeks.
I am currently on ibrutinib or ruxolitinib, or stopped it at least 28 days ago.
See 3 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
Up to 4 weeks
Treatment
Participants receive oral belumosudil once daily or twice daily until clinically significant progression of disease
Safety Follow-up
Participants are monitored for safety after treatment
4 weeks
Long-term Follow-up
Participants are monitored every 12 weeks for long-term outcomes
Treatment Details
Interventions
- Belumosudil (Kinase Inhibitor)
Trial OverviewThe study tests the safety and effectiveness of an oral drug called Belumosudil in patients with cGVHD. The treatment period includes up to four weeks of screening, ongoing treatment until disease progression, followed by a safety check-up after four weeks and long-term follow-ups every three months.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: BelumosudilExperimental Treatment1 Intervention
Participants will receive belumosudil orally, once daily (QD) or twice daily (BID) if they are taking strong CYP3A4 inducers or proton pump inhibitors.
Belumosudil is already approved in United States, Canada for the following indications:
🇺🇸 Approved in United States as Rezurock for:
- Chronic graft-versus-host disease (cGVHD) in patients aged 12 years and older after failure of at least two prior lines of systemic therapy
🇨🇦 Approved in Canada as Rholistiq for:
- Chronic graft-versus-host disease (cGVHD) in adult and pediatric patients 12 years or older
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Washington University School of Medicine Site Number : 125Saint Louis, MO
Texas Oncology - Baylor Charles A. Sammons Cancer Center Site Number : 126Dallas, TX
Massachusetts General Hospital Site Number : 002Boston, MA
Dana-Farber Cancer Institute Site Number : 004Boston, MA
More Trial Locations
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Who Is Running the Clinical Trial?
Kadmon, a Sanofi CompanyLead Sponsor
References
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. [2022]On July 16, 2021, the FDA approved belumosudil, a kinase inhibitor, for adult and pediatric patients 12 years and older with chronic GvHD (cGvHD) after failure of at least two prior lines of systemic therapy. Approval was based on the results of Study KD025-213, which included 65 patients with cGvHD treated with belumosudil 200 mg daily in an open-label, single-arm cohort. Efficacy was determined by the overall response rate (ORR) through Cycle 7 Day 1, which included complete response (CR) or partial response (PR) according to the 2014 NIH consensus criteria, and durability of response. The ORR through Cycle 7 Day 1 was 75% [95% confidence interval (CI), 63-85]; 6% of patients achieved a CR, and 69% achieved a PR. The median duration of response was 1.9 months (95% CI, 1.2-2.9), and 62% (95% CI, 46-74) of responding patients remained alive without new systemic therapy for at least 12 months from response. The common adverse reactions were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, phosphate decreased, gamma-glutamyl transferase increased, lymphocytes decreased, and hypertension. Additional study is warranted to confirm safety with long-term use.
Belumosudil for chronic graft-versus-host disease. [2022]Chronic graft-versus-host disease (cGvHD) is a multisystem disease that is diagnosed in up to 70% of patients following allogeneic hematopoietic cell transplantation. In cGvHD, the donor immune cells attack the patient's cells, resulting in inflammation and fibrosis in multiple tissues. cGvHD can affect almost any organ and is the major cause of morbidity and mortality in transplant survivors. Rho-associated coiled-coil-containing protein kinase (ROCK) is a signaling pathway that modulates inflammatory response and fibrotic processes and is dysregulated in autoimmune disorders. Many inhibitors targeting the ROCK pathway have been studied, but most lack isoform selectivity resulting in dose-limiting effects. Belumosudil mesylate is a selective oral ROCK2 inhibitor that has demonstrated safety and efficacy for cGvHD. It has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult and pediatric patients 12 years and older with cGvHD after failure of at least two prior lines of systemic therapy, becoming the first and only approved therapy targeting ROCK2. This review examines the preclinical and clinical studies leading to the first approval of the novel drug belumosudil for cGvHD.
Belumosudil Impacts Immunosuppression Pharmacokinetics in Patients with Chronic Graft-versus-Host Disease. [2023]Belumosudil (BEL) is a novel Rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor approved for the treatment of chronic graft-versus-host disease (cGVHD) in patients who have failed 2 or more prior lines of systemic therapy. Although the pharmacokinetic effects of BEL on other immunosuppressive (IS) agents have not been clinically evaluated, in vitro data indicate that BEL may have possible interactions with drugs with a narrow therapeutic index used to treat cGVHD, such as tacrolimus, sirolimus, and cyclosporine, through cytochrome P450 (CYP3A) and p-glycoprotein interactions. Further evaluation of these potential interactions is warranted to optimize the safety and effectiveness of these medications when combined with BEL. In this study, we investigated the potential effects of BEL on sirolimus and tacrolimus levels when used concurrently by assessing changes in IS levels after the addition of BEL. This retrospective single-center study of patients who started BEL while on tacrolimus and/or sirolimus between February 1, 2019, to February 1, 2023, included patients who had IS levels measured at baseline prior to starting BEL and at least 1 subsequent IS measurement to assess changes over time. The primary endpoint was the concentration-dose (C/D) ratio analyzed before and after the addition of BEL. Secondary endpoints included the incidence of IS levels outside of the therapeutic range (subtherapeutic or supratherapeutic) and mean dosage changes over time. Thirty-seven patients met our eligibility criteria and were included in this analysis. Patients taking sirolimus (n = 30) or tacrolimus (n = 16) concurrently with BEL had a statistically significant increase in the C/D ratio (sirolimus recipients, 160% [P 15 ng/mL during the study period, indicating a potential risk for toxicity if this interaction is unmonitored. We recommend empiric dose reductions of 25% for tacrolimus and 25% to 50% for sirolimus when adding BEL, as well as close monitoring of IS levels during the initial weeks of BEL therapy. Future studies are warranted to better describe the impact of BEL on patients taking CYP3A inhibitors.
Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study. [2022]Belumosudil, an investigational oral selective inhibitor of Rho-associated coiled-coil-containing protein kinase 2 (ROCK2), reduces type 17 and follicular T helper cells via downregulation of STAT3 and enhances regulatory T cells via upregulation of STAT5. Belumosudil may effectively treat patients with chronic graft-versus-host disease (cGVHD), a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2 randomized multicenter registration study evaluated belumosudil 200 mg daily (n = 66) and 200 mg twice daily (n = 66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions, and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR for belumosudil 200 mg daily and 200 mg twice daily was 74% (95% confidence interval [CI], 62-84) and 77% (95% CI, 65-87), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg daily and 200 mg twice daily was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil because of possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. This trial was registered at www.clinicaltrials.gov as #NCT03640481.
Belumosudil: First Approval. [2022]Belumosudil (REZUROCK™) is a Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor that has been developed by Kadmon Pharmaceuticals for the treatment of chronic graft-versus-host disease (cGVHD) and systemic sclerosis. In July 2021, belumosudil received its first approval in the USA for the treatment of adult and paediatric patients aged ≥ 12 years with cGVHD after failure of at least two prior lines of systemic therapy. Belumosudil is under regulatory review in Australia, Canada, the UK and Switzerland for cGVHD. Clinical development for systemic sclerosis is ongoing in the USA. This article summarizes the milestones in the development of belumosudil leading to this first approval for the treatment of cGVHD.
The Addition of Sirolimus to GVHD Prophylaxis After Allogeneic Hematopoietic Stem Cell Transplantation: A Meta-Analysis of Efficacy and Safety. [2022]Label="OBJECTIVE" NlmCategory="OBJECTIVE">The objective of this study was to evaluate the safety and efficacy of sirolimus (SRL) in the prevention of graft-versus-host disease (GVHD) in recipients following allogeneic hematopoietic stem cell transplantation (allo-HSCT).
Clinical response to belumosudil in bronchiolitis obliterans syndrome: a combined analysis from 2 prospective trials. [2023]Chronic graft-versus-host disease (cGVHD) of the lung, or bronchiolitis obliterans syndrome (BOS), is a high-risk disease manifestation associated with poor outcomes. Currently available treatments have demonstrated limited clinical efficacy in this setting. Belumosudil is a novel oral selective rho-associated coiled-coil-containing protein kinase-2 inhibitor that was recently approved by the US Food and Drug Administration in the treatment of cGVHD. We identified 59 subjects with BOS who were enrolled and treated in 2 prospective clinical trials of belumosudil. Patients with BOS had a percentage predicted forced expiratory volume in 1 second (FEV1) of ≤79% at enrollment and clinician attribution of lung disease owing to cGVHD. The National Institutes of Health (NIH) cGVHD lung scores at enrollment were 1 (n = 30, 59%), 2 (n = 23, 39%), or 3 (n = 6, 10%). According to NIH response criteria, the best overall response rate (ORR) for lung cGVHD was 32% (partial response: 17%; complete response: 15%). Response rates were inversely proportional to baseline NIH GVHD lung score at enrollment (lung score 1: ORR 50%; lung score 2: ORR 17%, lung score 3: ORR 0%) (P = .006). In multivariable analysis, male sex, lower baseline NIH cGVHD lung score, and partial response to previous line of cGVHD therapy before enrollment were associated with higher rates of lung-specific response. No significant correlation was identified between pulmonary function evaluations and measures of patient symptoms (NIH lung symptom score or Lee Symptom Scale score for lung). In conclusion, belumosudil treatment was associated with lung-specific clinical responses for subjects with BOS, which were more commonly observed in less advanced disease. Optimization of treatment response evaluations remains a challenge in patients with BOS.
Belumosudil with ROCK-2 inhibition: chemical and therapeutic development to FDA approval for the treatment of chronic graft-versus-host disease. [2022]Belumosudil (BLM) is a ROCK inhibitor that has been firstly developed by Surface Logix, later acquired by Kadmon Pharmaceuticals for the treatment of chronic graft-versus-host disease (cGVHD), Psoriasis Vulgaris (PV), idiopathic pulmonary fibrosis (IPF), hepatic impairment (HI), diffuse cutaneous systemic sclerosis (dcSSc). BLM received a breakthrough therapy designation and priority review from the FDA, which reviewed the NDA under the real-time oncology review (RTOR) pilot programme and approved it six weeks ahead of the PDUFA deadline of August 30, 2021. On July 16th, 2021, The USFDA authorized BLM under the brand name REZUROCKTM for the treatment of cGVHD in adults and pediatric patients aged ≥ 12 years after the failure of at least two prior lines of systemic therapy. It has been granted orphan drug status by the FDA on August 9, 2020, for the treatment of systemic sclerosis. The European Union (EU) granted Quality Regulatory Clinical Ireland Limited, Ireland, orphan drug status for BLM (KD025) for the treatment of cGVHD on October 17, 2019. BLM is under regulatory assessment by Therapeutic Good Administration (TGA) Australia, Health Canada, MHRA (UK), and The Swiss Agency for Therapeutic Products (Swissmedic), Switzerland for cGVHD. A clinical trial is ongoing in the United States for cutaneous systemic sclerosis. This review article summarizes the milestones in the development of BLM chemistry, Chemical synthesis and development, mechanism of action, pharmacokinetics (PK), pharmacodynamics (PD), adverse effects, regulatory status, and ongoing clinical trials (CT) of BLM.
A Phase 1 Pharmacokinetic Drug Interaction Study of Belumosudil Coadministered With CYP3A4 Inhibitors and Inducers and Proton Pump Inhibitors. [2022]Belumosudil is a selective Rho-associated protein kinase 2 inhibitor. Inhibition of Rho-associated protein kinase 2 has emerged as a promising treatment for chronic graft-versus-host disease by restoring immune homeostasis and reducing fibrosis. In vitro assessments have suggested that metabolism of belumosudil is primarily dependent on cytochrome P450 (CYP) 3A4 activity and that the solubility of belumosudil is pH dependent. As such, this 2-part clinical drug-drug interaction study was conducted to assess the effect of itraconazole (a strong CYP3A4 inhibitor), rifampicin (a strong CYP3A4 inducer), rabeprazole, and omeprazole (both proton pump inhibitors) on the pharmacokinetics of belumosudil. No clinically relevant change in belumosudil exposure was observed following a 200-mg single oral dose of belumosudil with itraconazole; however, exposure of main metabolite, KD025m2, was decreased. Consistent with the proposed metabolic pathway of belumosudil, the strong CYP3A4 inducer rifampicin significantly decreased exposure of belumosudil and KD025m2 and increased KD025m1 exposure. When a 200-mg single oral dose of belumosudil was coadministered with both rabeprazole and omeprazole, parent and metabolite exposures were largely reduced, suggesting that belumosudil dosage should be increased when given with PPIs. Administration of belumosudil with and without perpetrator drugs was safe, and no notable adverse events were reported.