Belumosudil for Bronchiolitis Obliterans Syndrome

Recruiting at 5 trial locations

Overseen By Corey Cutler, MD, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Investigational immunosuppressants

Disqualifiers: Prior BOS therapy, HIV, Hepatitis B/C, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 13

Duration: 48 weeks

45 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this research study is to test the efficacy of a novel immunosuppressive agent, belumosudil, in allogeneic hematopoietic stem cell transplant (HSCT) recipients who have been newly diagnosed or have developing (early stage) bronchiolitis obliterans syndrome (BOS). The name of the study drugs involved in this study are: * Belumosudil (an immunotherapy) * Fluticasone (an intranasal corticosteroid) * Azithromycin (an antibiotic) * Montelukast (a leukotriene receptor antagonist) * Prednisone (a corticosteroid)

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it does mention that participants should not have received prior therapy specifically for bronchiolitis obliterans syndrome (BOS) or be on other investigational immunosuppressive agents for chronic graft-versus-host disease (cGVHD). It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Belumosudil for treating bronchiolitis obliterans syndrome?

Belumosudil has shown lung-specific clinical responses in patients with bronchiolitis obliterans syndrome (BOS), especially in those with less advanced disease, with a 32% overall response rate in a study involving 59 subjects. Additionally, a combination of fluticasone, azithromycin, and montelukast (FAM) has been effective in preventing the progression of new-onset BOS, with only 6% treatment failure compared to 40% in historical controls. ^{1 2 3 4 5}

Is Belumosudil safe for humans?

Belumosudil has been studied in clinical trials for chronic graft-versus-host disease and was generally well tolerated, with adverse events similar to those expected in patients receiving other treatments for this condition. No notable adverse events were reported in a study assessing drug interactions, indicating it is generally safe when administered with other medications. ^{3 4 5 6 7}

How is the drug Belumosudil unique for treating Bronchiolitis Obliterans Syndrome?

Belumosudil is unique because it targets a specific pathway involved in inflammation and fibrosis (scarring), which may offer a novel approach compared to traditional treatments that often focus on suppressing the immune system more broadly. This could potentially provide a more targeted and effective treatment option for Bronchiolitis Obliterans Syndrome, a condition with limited standard therapies. ^{8 9 10 11 12}

Research Team

Corey Cutler, MD, MPH

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

This trial is for adults over 18 with early stage bronchiolitis obliterans syndrome (BOS) after a stem cell transplant. They must have specific lung function test results, no active infections or recent cancers, and not be on other investigational drugs for chronic graft-versus-host disease.

Inclusion Criteria

My lung function has significantly declined in the last 2 years or since my transplant.

I can take care of myself but might not be able to do heavy physical work.

Your white blood cell count is at least 3,000 per microliter.

Exclusion Criteria

You are taking any other experimental drugs to suppress the immune system for chronic graft-versus-host disease.

I have an active hepatitis B or C infection needing treatment.

I have previously been treated with belumosudil.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive Belumosudil with or without standard of care medications for 48 weeks

48 weeks

12 cycles of 28 days each, with regular in-person visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Regular follow-up visits

Treatment Details

Interventions

• Azithromycin
• Belumosudil
• Fluticasone
• Montelukast
• Prednisone

Trial Overview The BEBOP study tests the effectiveness of belumosudil, an immunotherapy drug, in combination with fluticasone (a steroid), azithromycin (an antibiotic), montelukast (for asthma), and prednisone (another steroid) to treat BOS in stem cell transplant recipients.

Participant Groups

Group I: Cohort B: Belumosudil Experimental Treatment 1 Intervention

15 participants with signs concerning developing BOS will complete study procedure as follows: * Drug diary * CT scans at Cycles 3 and 7 and at End of Treatment. * Cycle 1 - 12 - Day 1 - 28 of 28-day cycle: Predetermined dose of Belumosudil 1x daily.

Group II: Cohort A: Belumosudil + Standard of Care Medications Experimental Treatment 5 Interventions

30 participants with bronchiolitis obliterans syndrome (BOS) will complete study procedures as follows: * Drug diary * CT scans at Cycles 3 and 7 and at End of Treatment. * Cycle 1 * Day 1 - 28 of 28-day cycle: Predetermined dose of Belumosudil 1x daily. * Predetermined doses of Fluticasone, Montelukast, and Prednisone 1x daily. * Predetermined dose of azithromycin 3 days per treatment week. * Cycle 2 - 3 * Day 1 - 28 of 28-day cycle: Predetermined dose of Belumosudil 1x daily. * Predetermined doses of Fluticasone Montelukast 1x daily. Predetermined doses of Prednisone 1x daily at treating physician's discretion. * Predetermined dose of azithromycin 3 days per treatment week. * Cycle 4 - 12 * Day 1 - 28 of 28-day cycle: Predetermined dose of Belumosudil 1x daily. * Predetermined doses of Fluticasone and Montelukast 1x daily. * Predetermined dose of azithromycin 3 days per treatment week.

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

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Sanofi

Industry Sponsor

Trials

2,246

Recruited

4,085,000+

Paul Hudson

Sanofi

Chief Executive Officer since 2019

Degree in Economics from Manchester Metropolitan University

Christopher Corsico

Sanofi

Chief Medical Officer

MD from Cornell University, MPH in Chronic Disease Epidemiology from Yale University

Findings from Research

In a phase II study involving 36 patients with new-onset bronchiolitis obliterans syndrome (BOS), treatment with inhaled fluticasone, azithromycin, and montelukast (FAM) significantly reduced the rate of treatment failure to 6% at 3 months, compared to 40% in historical controls, indicating its efficacy in halting pulmonary decline.

FAM was well tolerated, allowing for a 50% or greater reduction in steroid dosage for nearly half of the evaluable patients, and led to significant improvements in patient-reported quality of life measures at 3 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fluticasone, Azithromycin, and Montelukast Treatment for New-Onset Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation. Williams, KM., Cheng, GS., Pusic, I., et al.[2023]

In a pilot study involving 22 lung transplant patients with bronchiolitis obliterans syndrome (BOS), the addition of montelukast significantly reduced the decline in lung function (FEV1) from 112 ml/month to 13 ml/month after 6 months of treatment (P = 0.001).

In contrast, the control group showed no significant change in FEV1 decline, indicating that montelukast may be an effective treatment option for patients with low neutrophilic BOS who are also receiving azithromycin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Montelukast for bronchiolitis obliterans syndrome after lung transplantation: a pilot study. Verleden, GM., Verleden, SE., Vos, R., et al.[2021]

Belumosudil, a new oral medication, showed a 32% overall response rate in treating lung cGVHD (bronchiolitis obliterans syndrome) in 59 patients, with better outcomes in those with less severe disease.

Response rates were significantly higher in patients with lower NIH lung scores at enrollment, indicating that earlier intervention may lead to better treatment results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical response to belumosudil in bronchiolitis obliterans syndrome: a combined analysis from 2 prospective trials. DeFilipp, Z., Kim, HT., Yang, Z., et al.[2023]

Belumosudil, an oral medication targeting ROCK2, showed a high overall response rate of 74% for the 200 mg daily dose and 77% for the 200 mg twice daily dose in patients with chronic graft-versus-host disease (cGVHD) after multiple prior treatments, indicating its efficacy in this challenging condition.

The treatment was well tolerated, with a median duration of response of 54 weeks and significant symptom reduction in 59% to 62% of subjects, while adverse events were consistent with those expected in cGVHD patients, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study. Cutler, C., Lee, SJ., Arai, S., et al.[2022]

Belumosudil (REZUROCK™) is a newly approved ROCK inhibitor specifically designed for treating chronic graft-versus-host disease (cGVHD) in patients aged 12 and older who have not responded to at least two prior treatments.

The drug has received regulatory approval in the USA and is currently under review in several other countries, with ongoing clinical development for systemic sclerosis, highlighting its potential as a significant therapeutic option for these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belumosudil: First Approval. Blair, HA.[2022]

Belumosudil (BLM) is a ROCK inhibitor approved by the FDA for treating chronic graft-versus-host disease (cGVHD) in patients aged 12 and older who have not responded to at least two prior therapies, highlighting its efficacy in a challenging patient population.

BLM received breakthrough therapy designation and orphan drug status, indicating its potential significance in treating rare diseases like cGVHD and systemic sclerosis, and it is currently undergoing further regulatory assessments and clinical trials for additional indications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belumosudil with ROCK-2 inhibition: chemical and therapeutic development to FDA approval for the treatment of chronic graft-versus-host disease. Ali, F., Ilyas, A.[2022]

Belumosudil, a selective Rho-associated protein kinase 2 inhibitor, shows promise in treating chronic graft-versus-host disease by restoring immune balance and reducing fibrosis, with no significant adverse events reported during the study.

The pharmacokinetics of belumosudil are significantly affected by other medications, such as itraconazole and rifampicin, indicating that dosage adjustments may be necessary when coadministered with proton pump inhibitors like rabeprazole and omeprazole.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 1 Pharmacokinetic Drug Interaction Study of Belumosudil Coadministered With CYP3A4 Inhibitors and Inducers and Proton Pump Inhibitors. Schueller, O., Willson, A., Singh, N., et al.[2022]

In a study of 50 patients with severe, progressive interstitial lung disease (ILD) treated with rituximab, there was a significant median improvement in forced vital capacity (FVC) of 6.7% after treatment, indicating potential efficacy as a rescue therapy.

Despite the benefits, there were safety concerns, as two patients experienced serious infections and ten patients died from disease progression within a median of 5.1 months post-treatment, highlighting the need for further research on safety outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab in severe, treatment-refractory interstitial lung disease. Keir, GJ., Maher, TM., Ming, D., et al.[2022]

Zafirlukast, a leukotriene inhibitor approved for asthma prevention, is generally well-tolerated with convenient dosing and few side effects.

However, there have been reports of serious side effects, including Churg-Strauss syndrome, as demonstrated in a case of a 54-year-old man who developed leukocytoclastic vasculitis, hepatitis, and eosinophilia while on zafirlukast therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vasculitis induced by zafirlukast therapy. Soy, M., Ozer, H., Canataroglu, A., et al.[2021]

Rituximab, an anti-B lymphocyte monoclonal antibody, was effective in treating a case of refractory polymyositis with interstitial pulmonary disease, suggesting its potential as a treatment option for this condition.

The treatment was well tolerated, indicating a favorable safety profile, which supports further evaluation of rituximab's efficacy in inflammatory myositis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of rituximab in refractory polymyositis. Lambotte, O., Kotb, R., Maigne, G., et al.[2015]

In a study of 15 patients with anti-aaRS-associated interstitial lung disease (ILD) treated with tacrolimus for an average of 51.2 months, significant improvements were observed in pulmonary function and muscle strength, indicating its efficacy in managing these conditions.

Tacrolimus was found to be well-tolerated, leading to a significant reduction in corticosteroid dosage, which suggests it may be a safer alternative for patients with refractory ILD and myositis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of antisynthetase-associated interstitial lung disease with tacrolimus. Wilkes, MR., Sereika, SM., Fertig, N., et al.[2022]

In a study of 253 patients with unclassifiable interstitial lung disease (uILD), pirfenidone showed a significant treatment effect on lung function in patients not receiving concomitant mycophenolate mofetil (MMF), with a mean improvement in forced vital capacity (FVC) of 115.5 mL compared to placebo.

The analysis indicated that pirfenidone may be less effective in patients receiving MMF, as shown by a negligible change in FVC in that subgroup, but overall, pirfenidone was well tolerated across all groups, regardless of MMF or corticosteroid use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pirfenidone in Unclassifiable Interstitial Lung Disease: A Subgroup Analysis by Concomitant Mycophenolate Mofetil and/or Previous Corticosteroid Use. Kreuter, M., Maher, TM., Corte, TJ., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Fluticasone, Azithromycin, and Montelukast Treatment for New-Onset Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Montelukast for bronchiolitis obliterans syndrome after lung transplantation: a pilot study. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Clinical response to belumosudil in bronchiolitis obliterans syndrome: a combined analysis from 2 prospective trials. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study. [2022]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Belumosudil: First Approval. [2022]

6. France pubmed.ncbi.nlm.nih.gov

Belumosudil with ROCK-2 inhibition: chemical and therapeutic development to FDA approval for the treatment of chronic graft-versus-host disease. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

A Phase 1 Pharmacokinetic Drug Interaction Study of Belumosudil Coadministered With CYP3A4 Inhibitors and Inducers and Proton Pump Inhibitors. [2022]

8. Australia pubmed.ncbi.nlm.nih.gov

Rituximab in severe, treatment-refractory interstitial lung disease. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

Vasculitis induced by zafirlukast therapy. [2021]

10. Canada pubmed.ncbi.nlm.nih.gov

Efficacy of rituximab in refractory polymyositis. [2015]

11. United States pubmed.ncbi.nlm.nih.gov

Treatment of antisynthetase-associated interstitial lung disease with tacrolimus. [2022]

12. United States pubmed.ncbi.nlm.nih.gov

Pirfenidone in Unclassifiable Interstitial Lung Disease: A Subgroup Analysis by Concomitant Mycophenolate Mofetil and/or Previous Corticosteroid Use. [2023]