Belumosudil + Rituximab for Graft-versus-Host Disease
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Northside Hospital, Inc.
Disqualifiers: HIV, Active HBV, Active HCV, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This is an open-label, Phase 2 study designed to evaluate the safety and efficacy of belumosudil and rituximab as primary treatment of cGVHD.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications. However, it mentions that participants should not have received more than 10 days of corticosteroids or other systemic immunosuppressive agents for cGVHD before joining the study.
What data supports the effectiveness of the drugs Belumosudil and Rituximab for treating graft-versus-host disease?
Belumosudil has shown promising results in treating chronic graft-versus-host disease (cGVHD) with a high response rate of 74-77% in patients who had previously tried other treatments. Rituximab, when used prior to transplantation, has been associated with less severe acute graft-versus-host disease and better survival outcomes in patients.
12345Is the combination of Belumosudil and Rituximab safe for treating graft-versus-host disease?
Rituximab has been studied in various settings and is generally well tolerated, with no severe toxicity observed in patients with graft-versus-host disease. It has been used safely in combination with other treatments for different conditions, showing no significant increase in adverse effects.
678910How is the drug combination of Belumosudil and Rituximab unique for treating graft-versus-host disease?
The combination of Belumosudil and Rituximab is unique because Belumosudil is a novel oral drug that targets specific proteins (ROCK2) to help regulate immune cells, while Rituximab is an antibody that targets B cells, both working together to address chronic graft-versus-host disease in patients who have not responded to other treatments.
1241112Eligibility Criteria
This trial is for individuals with a new diagnosis of chronic Graft-Versus-Host Disease (cGVHD) who haven't been treated yet, or have had less than 10 days of corticosteroids. Participants must be in good physical condition (KPS >/= 70%) and have adequate blood cell counts without recent transfusions. People with HIV, active hepatitis B or C, severe liver issues, poor kidney function, uncontrolled infections or heart problems cannot join.Inclusion Criteria
My blood counts are within the required range without transfusions for a week.
I have started treatment for cGVHD less than 10 days ago.
I am mostly able to care for myself and carry out daily activities.
+1 more
Exclusion Criteria
I do not have an active hepatitis B or C infection.
My kidney function is low, with a filtration rate under 30 mL/min.
I have ongoing or returning graft-versus-host disease.
+5 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive Belumosudil and Rituximab as primary treatment for chronic graft-versus-host disease
12 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
12 weeks
Participant Groups
The study is testing the combination of two drugs—Belumosudil and Rituximab—as a primary treatment for cGVHD. It's an open-label Phase 2 trial which means everyone knows what treatment they're getting and it's fairly early in the testing process to see if it works well and is safe.
1Treatment groups
Experimental Treatment
Group I: Belumosudil Plus RituximabExperimental Treatment2 Interventions
Belumosudil plus Rituximab
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:
Northside HospitalAtlanta, GA
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Who Is Running the Clinical Trial?
Northside Hospital, Inc.Lead Sponsor
SanofiIndustry Sponsor
References
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.
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.
Risk of graft-versus-host disease with rituximab-containing conditioning regimens in allogeneic hematopoietic stem cell transplant. [2018]Graft-versus-host disease represents a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant patients. There is growing evidence that B lymphocytes may play a role in the pathogenesis of acute graft-versus-host disease. The purpose of this retrospective cohort study was to evaluate the efficacy of rituximab-containing conditioning regimens in decreasing graft-versus-host disease in allogeneic hematopoietic stem cell transplant patients who received standardized tacrolimus-based graft-versus-host disease prophylaxis regimens. Patients were divided into two cohorts, based on the presence (RTX, n = 54) or absence (No-RTX, n = 105) of rituximab in the conditioning regimen and were matched 1:2 for major graft-versus-host disease risk factors. The incidence of grade II-IV acute graft-versus-host disease was not different between the two groups (37% vs. 26%, p = 0.147). When restricting the analysis to recipients of peripheral blood hematopoietic stem cell transplants, the RTX group had a higher incidence of grade II-IV acute graft-versus-host disease, relapse, or death prior to day 100 (55% vs. 36%, p = 0.037). The median time to the onset of acute graft-versus-host disease was no different between the RTX and No-RTX groups (67 vs. 74 days, respectively, p = 0.141). Inhibition of antigen presentation by B cells with rituximab-based conditioning regimens does not appear to reduce the incidence of acute graft-versus-host disease in allogeneic hematopoietic stem cell transplant recipients.
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.
Prior rituximab correlates with less acute graft-versus-host disease and better survival in B-cell lymphoma patients who received allogeneic peripheral blood stem cell transplantation. [2021]Prior therapy with rituximab might attenuate disparate histocompatibility antigen presentation by B cells, thus decreased the risk of acute graft-versus-host disease (GVHD) and improved survival. We tested this hypothesis by comparing the outcomes of 435 B-cell lymphoma patients who received allogeneic transplantation from 1999 to 2004 in the Center for International Blood and Marrow Transplant Research database: 179 subjects who received rituximab within 6 months prior to transplantation (RTX cohort) and 256 subjects who did not receive RTX within 6 months prior to transplantation (No-RTX cohort). The RTX cohort had a significantly lower incidence of treatment-related mortality (TRM) [relative risk (RR) = 0.68; 95% confidence interval (CI), 0.47-1.0; P = 0.05], lower acute grade II-IV (RR = 0.72; 95% CI, 0.53-0.97; P = 0.03) and III-IV GVHD (RR = 0.55; 95% CI, 0.34-0.91; P = 0.02). There was no difference in the risk of chronic GVHD, disease progression or relapse. Progression-free survival (PFS) (RR = 0.68; 95% CI 0.50-0.92; P = 0.01) and overall survival (OS) (RR = 0.63; 95% CI, 0.46-0.86; P = 0.004) were significantly better in the RTX cohort. Prior RTX therapy correlated with less acute GVHD, similar chronic GVHD, less TRM, better PFS and OS.
Protective Effect of Rituximab in Chronic Graft-Versus-Host Disease Occurrence in Allogeneic Transplant patients with Epstein Barr Virus Viremia. [2020]B cells are involved in chronic graft-versus-host disease (cGVHD) pathogenesis, and Rituximab may have a therapeutic effect on cGVHD in allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients. Herein, we retrospectively evaluated the prophylactic effect of Rituximab on cGVHD in a group of Chinese allo-HSCT patients. A total of 102 patients, who suffered Epstein Barr virus (EBV) viremia within 100 days after allo-HSCT, were included in this study. Fifty patients received Rituximab (375 mg/m2 weekly) for EBV viremia, while fifty-two patients did not receive Rituximab. A competing risk model was adopted to compare cumulative incidence of cGVHD, cumulative incidence of relapse (CIR) and transplantation-related mortality (TRM) between two groups. Cumulative incidence of cGVHD in the Rituximab group was lower than in controls (P = 0.0579). Multivariate analyses confirmed that Rituximab was an independent factor for the reduction of cumulative cGVHD incidence (P = 0.0069). No significant difference was observed in CIR (P = 0.39) or TRM (P = 0.48) between two groups and 2-year OS and DFS were comparable (OS, P = 0.667; DFS, P = 0.571). Administration of Rituximab in the early post-transplantation phase may protect against cGVHD in allo-HSCT patients without increasing CIR or TRM.
Rituximab for the treatment of corticosteroid-refractory chronic graft-versus-host disease. [2021]We prospectively evaluated the safety and efficacy of the anti-CD20 chimeric monoclonal antibody rituximab for the treatment of corticosteroid-refractory chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. Seven patients were treated with 375 mg/m(2) rituximab weekly for 4 consecutive weeks. Rituximab was well tolerated with no severe toxicity observed during treatment. At 1 year, 3 patients showed a partial response to rituximab therapy, 3 had stable disease, and 1 had progressive disease. Rituximab allowed a reduction in the dose of steroids in 4 patients. Responsive manifestations included mild to moderate skin and oral lesions, and immune hemolytic anemia, and thrombocytopenia. Severe manifestations involving the skin, fascia, and eye did not respond to treatment. These observations suggest that rituximab therapy may be effective for select patients with corticosteroid-refractory chronic GVHD that is not advanced.
Addition of Rituximab in Reduced Intensity Conditioning Regimens for B-Cell Malignancies Does Not Influence Transplant Outcomes: EBMT Registry Analyses Following Allogeneic Stem Cell Transplantation for B-Cell Malignancies. [2021]Rituximab (R) is increasingly incorporated in reduced intensity conditioning (RIC) regimens for allogeneic hematopoietic cell transplantation (alloHCT) in patients with B-cell malignancies, not only to improve disease control, but also to prevent graft-versus-host disease (GVHD). There are no randomized prospective data to validate this practice, although single center data and the CIBMTR analysis have shown promising results. We aimed at validation of these findings in a large registry study. We conducted a retrospective analysis using the EBMT registry of 3,803 adult patients with B-cell malignancies undergoing alloHCT (2001-2013) with either rituximab (R-RIC-9%) or non-rituximab (RIC-91%) reduced intensity regimens respectively. Median age and median follow up were 55 years (range 19.1-77.3) and 43.2 months (range 0.3-179.8), respectively. There was no difference in transplant outcomes (R-RIC vs RIC), including 1-year overall survival (69.9% vs 70.7%), 1-year disease-free survival (64.4% vs 62.2%), 1-year non-relapse mortality (21% vs 22%), and day-100 incidence of acute GVHD 2-4° (12% vs 12%). In summary, we found that addition of rituximab in RIC regimens for B-cell malignancies had no significant impact on major transplant outcome variables. Of note, data on chronic GVHD was not available, limiting the conclusions that can be drawn from the present study.
A phase II study of a nonmyeloablative allogeneic stem cell transplant with peritransplant rituximab in patients with B cell lymphoid malignancies: favorably durable event-free survival in chemosensitive patients. [2021]The aim of this prospective phase II trial was to determine the safety and efficacy of a nonmyeloablative conditioning program incorporating peritransplant rituximab in patients with CD20+ B cell non-Hodgkin lymphoma (B-NHL) receiving an allogeneic stem cell transplant (allo-SCT). Fifty-one adult B-NHL patients, with a median age of 54 years, were treated with cyclophosphamide, fludarabine, and 200 cGy of total body irradiation. Rituximab 375 mg/m(2) was given on day -8 and in 4 weekly doses beginning day +21. Equine antithymocyte globulin was given to recipients of volunteer unrelated donor grafts. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate mofetil and tacrolimus, sirolimus, and methotrexate in 8 and 43 patients, respectively. Thirty-three patients received grafts from unrelated donors, and 18 received grafts from matched related donors. All patients engrafted. Full donor chimerism in bone marrow and peripheral T cells was seen in 92% and 89% of patients, respectively, at 3 months after allo-SCT. The cumulative incidence of grades II to IV acute GVHD at 6 months was 25% (95% confidence interval [CI], 13% to 38%) and grades III to IV was 11% (95% CI, 2% to 20%). The 2-year cumulative incidence of chronic GVHD was 29% (95% CI, 15% to 44%). The 2-year event-free and overall survival for all patients was 72% (95% CI, 59% to 85%) and 78% (95% CI, 66% to 90%), respectively. The 2-year event-free survival for chemosensitive patients was 84% (95% CI, 72% to 96%) compared with 30% (95% CI, 2% to 58%) for chemorefractory patients before allo-SCT (P
Allogeneic Transplantation after Myeloablative Rituximab/BEAM ± Bortezomib for Patients with Relapsed/Refractory Lymphoid Malignancies: 5-Year Follow-Up Results. [2020]Although bortezomib and rituximab have synergistic activity in patients with lymphoma and both can attenuate graft-versus-host disease (GVHD), the drugs have not been used together in patients undergoing allogeneic stem cell transplantation (alloSCT). In this phase I/II trial, we assessed the safety and activity of bortezomib added to the rituximab (R) plus BEAM (carmustine, etoposide, cytarabine, melphalan) regimen in patients with relapsed lymphoma undergoing alloSCT. Primary GVHD prophylaxis consisted of tacrolimus and methotrexate. Bortezomib (1 to 1.3 mg/m2 per dose) was administered i.v. on days -13, -6, -1, and +2. We performed inverse probability weighting analysis to compare GVHD and survival results with an historical control group that received R-BEAM without bortezomib. Thirty-nine patients were assessable for toxic effects and response. The median age was 54 years. The most common diagnosis was diffuse large B cell lymphoma (41%). Twenty-two patients (56%) and 17 patients (44%) received their transplants from matched related and matched unrelated donors, respectively. The maximum tolerated bortezomib dose was 1 mg/m2. The weighted cumulative incidences of grades II to IV and III or IV acute GVHD were 50% and 34%, respectively; these incidences and survival rates were not significantly different from those of the control group. Median survival was not reached in patients age ≤ 50 years and with a long follow-up time of 60.7 months. The R-BEAM regimen has a survival benefit in lymphoma patients age ≤ 50 years undergoing alloSCT. The addition of bortezomib has no impact on survival or incidence of GVHD.
Rituximab for prevention and treatment of graft-versus-host disease. [2021]Growing understanding of the important role of B lymphocytes in alloreactivity has paved the way for evaluating anti-B cell therapy with rituximab in patients undergoing allogeneic hematopoietic cell transplantation. Data suggesting a beneficial reduction in incidence and severity of acute graft-versus-host disease (GVHD) are limited to non-randomized studies from single institutions using higher than conventional doses of rituximab. Additionally, rituximab is used as an effective treatment of corticosteroid-refractory chronic GVHD with good responses, particularly in cases of dermatologic and mucosal involvement. Post-transplant administration of rituximab appears to reduce the rate of chronic GVHD in preliminary studies.
Rituximab in critically ill patients. [2019]Rituximab is a monoclonal chimeric antibody used in the treatment of CD20-positive B-cell malignancies and rheumatoid arthritis. However, it is used in several other off-label indications including acute graft-versus-host disease. We sought to critically examine the role of rituximab in the treatment of acute graft versus host disease (aGVHD) in critically ill patients and the potential associations with infectious complications in transplant recipients.