Montelukast to Treat Bronchiolitis Obliterans

Study Overview
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Brief Summary
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Background: Bronchiolitis obliterans is a form of chronic graft-versus-host disease (GVHD) that sometimes develops after stem cell transplantation (SCT) or bone marrow transplantation (BMT). In bronchiolitis obliterans, immune cells that normally fight infections attack the lungs of the transplant recipient, causing destruction of lung tissue and fibrosis (scarring). When fibrosis develops, the lungs cannot work properly. Montelukast (Singulair) is a drug that has been used for many years to treat asthma. Its use as a treatment for bronchiolitis obliterans is experimental. Objectives: To see if montelukast improves or stabilizes lung function in patients who develop bronchiolitis obliterans after BMT or SCT. To assess the safety of montelukast in patients with bronchiolitis obliterans after BMT or SCT To see if montelukast affects the cells that damage the lungs. To see if montelukast improves other forms of chronic GVHD, quality of life, and overall survival in patients with bronchiolitis obliterans after BMT or SCT. Eligibility: Patients 6 years of age and older with bronchiolitis obliterans following stem cell transplantation. Design: Patients take one montelukast tablet daily for 6 months and undergo the following procedures during this period: Lung function tests. The patient breathes into a machine that measures the amount of air that goes into and out of the lungs. This test is done once a month for 3 months, then at 6 months, 12 months and 24 months. Medical history and physical examination at the study site about every 3 months for the first year of the study and then at 12 months and 24 months. Patients also have physical examinations monthly for the first 6 months at their primary doctors office. Tests may include blood and urine tests, chest computed tomography (CT) scans, echocardiogram (heart ultrasound), 2- and 6-minute walk tests, and quality-of-life questionnaires. Bronchoalveolar lavage in patients 18 years of age and older. The subject s mouth, nose and airways are numbed with lidocaine. Some patients may need sedation or anesthesia for the procedure. A tube (bronchoscope) is then passed through the nose into the airway, and a small amount of fluid is put into the lung. The fluid is then removed and tested for infections or other lung problems. Apheresis to collect white blood cells. Whole blood is collected through a tube inserted into a vein in the arm. The white cells are extracted in a cell separator machine, and the rest of the blood is returned to the body through a tube placed in a vein in the other arm. The cells are used to study GVHD and bronchiolitis obliterans. Patients who wish to continue montelukast therapy after 6 months may do so under the care of their primary doctor, if both agree to the continuation....

Detailed Description
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Background: Bronchiolitis obliterans (BO) is an insidious disease with high mortality following allogeneic blood or marrow transplantation (BMT). There are no consistently effective treatments for BO following BMT and the pathogenesis is largely unknown. The mechanisms underlying similar immune-mediated lung destructive processes are better elucidated. Rejection following allogeneic lung transplantation and scleroderma lung disease result from analogous immunologically mediated destruction of lung tissue leading to similar pathologic and clinical presentations to post-BMT BO. Increased leukotriene production has recently been implicated in the development of both post-lung transplant BO and scleroderma lung disease in animal models and patient studies. Montelukast (singulair) is an approved, well-tolerated, oral agent that inhibits leukotriene action in lung inflammation. This agent has been extensively used in children and adults to treat asthma with an excellent safety profile. Objectives: To evaluate if montelukast stabilizes or improves pulmonary function in patients with BO after BMT using forced expiratory volume 1 (FEV-1) changes as primary endpoints, and oxygen saturation, pulmonary function test (PFT) parameters (forced expiratory flow (FEF) 25-75, residual volume (RV) and RV/forced vital capacity (FVC), carbon monoxide diffusing capacity (DLC02), FEV-1/FVC, FEV-1/slow vital capacity (SVC) ratio), and timed walk tests as secondary endpoints. To evaluate the safety of montelukast in the population of patients with BO after BMT. To investigate if leukotriene elevation contributes to the pathogenesis of BO after BMT by measuring leukotriene levels of the blood, urine, and bronchoalveolar lavage (BAL), and leukotriene surface receptor expression on immune cells before and after montelukast administration. To determine if montelukast improves other chronic graft versus host disease (cGVHD) manifestations, quality of life, and overall survival. Eligibility: Patients greater than or equal to 6 years old with bronchiolitis obliterans following stem cell transplantation for any disease indication may be enrolled. Design: This is a prospective phase II study, the primary aim of which is to assess whether montelukast improves or stabilizes the pulmonary function of patients with BO after BMT. Primary outcome data will be analyzed in 2 ways. 1) The proportion of patients with stable or improved percent predicted of FEV-1 will be compared against benchmark data obtained from a literature review. 2) The slope of FEV-1 before and after the introduction of montelukast will be compared. Pediatric and adult patients with BO following BMT will receive approved doses of montelukast continuously. The planned length of the study would be 2 years per patient with primary endpoint at 6 months, permitting sufficient time to determine safety and meet other endpoints. This phase II trial will be conducted at 2 institutions: National Institutes of Health (NIH) and Fred Hutchinson Cancer Research Center. Forty-five patients will be enrolled on this trial.

Official Title
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Multi-Institutional Prospective Phase II Study of Montelukast for the Treatment of Bronchiolitis Obliterans Following Allogeneic or Autologous Stem Cell Transplantation in Children and Adults

Conditions
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Bronchiolitis Obliterans, Chronic Graft Versus Host Disease, Leukotriene, Montelukast, Stem Cell Transplant

Intervention / Treatment
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* Drug: Singulair (Montelukast Sodium)


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Age greater than 6 years old. Diagnosis of bronchiolitis obliterans after allogeneic or autologous stem cell transplant. The criteria will be based on the definitions created by the National Institutes of Health (NIH) consortium on chronic graft versus host disease (cGVHD). As part of these criterion, for patients without pathologic evidence of BO, one other sign of chronic GVHD must be present. For diagnosis of cGVHD, a minimum of the following must be present: 1) a process distinct from that diagnosed as acute GVHD, 2) the presence of a diagnostic sign or a distinctive sign supported by another clinical or laboratory test, and 3) the exclusion of other pathologies (i.e. recurrent cancer, drug reaction or infection (see Appendix 5a for a list of diagnostic signs.). To meet criteria for a diagnosis of bronchiolitis obliterans, patients must fulfill all 3 criteria. Prior lung tissue biopsy will be analyzed and confirmed to show evidence of bronchiolitis obliterans by the National Cancer Institute (NCI) Laboratory of Pathology if available. If tissue is not available for confirmation, a new biopsy will not be performed. For bronchiolitis obliterans: Forced expiratory volume 1 (FEV1) less than or equal to 75 percent of predicted by pulmonary function evaluation for height and weight. Evidence of air-trapping or small airway thickening or bronchiectasis on high resolution chest computed tomography (CT) and residual volume (RV) or RV/forced vital capacity (FVC) greater than 120 percent and evidence of chronic GVHD of another organ, OR FEV1/ vital capacity (slow or forced VC whichever is larger) ratio less than 5 percent of predicted for age or less than 0.7, OR pathologic evidence of bronchiolar inflammation and obstruction of the lumen consistent with a diagnosis of BO. Pulmonary function tests will utilize body plethysmography not helium studies for pertinent values when there is a discrepancy if available. Absence of active infection with appropriate investigation of any clinical symptoms to include radiographic, microbiologic, and pathologic studies as determined by the PI or LAI. Patients must also have 2 PFT measurements with documented FEV1 values greater than 3 months apart to calculate the entry FEV1 slope. All available prior PFTs will be utilized for baseline slope calculation. For adult patients, the absolute FEV1 will be utilized for slope calculation; for pediatric patients, the percent predicted will be used. For patients enrolled after an acute decline following BMT without 2 post-BMT values greater than 3 months apart, the pre-BMT value may be utilized as the first value and the entry PFT value may be the second for the slope calculation. The baseline and 6th-cycle PFT should be done at the accruing site. Prior therapy: For patients with a chronic diagnosis of BO who have been on treatments, any prior therapy that has been administered chronically for > 3 months will be acceptable for enrollment as long as the patient has not demonstrated consistent improvement attributed to these agents in a one month (or more) period of observation preceding enrollment. For patients on steroids, a steroid burst exceeding and increase of one half mg/kg/day will be considered for the start of the 3 month monitoring period. Notably, documented intercurrent infections that are treated with antimicrobials that result in improvements to, but not above previous baselines will not be considered an improvement attributable to immunosuppressive therapy. Patients who have had consistent improvements in the months preceding trial entry will not be eligible since there will be no way to discern improvement due to montelukast versus another therapy. Alternatively, a patient with a new diagnosis of bronchiolitis obliterans characterized by a new decrease in FEV1 is also eligible for this study. Notably, patients who have received bronchodilators or other pulmonary therapies may be included in this study as long as montelukast is not part of this regimen. Performance status: Karnofsky or Lansky performance status greater than or equal to 40 percent (Appendix 1). Ability to give informed consent. For patients less than 18 years of age, their legal guardian must give informed consent. Pediatric patients will be included in an age appropriate discussion in accordance with NIH guidelines or participating institutional guidelines. Hepatic function: Patients must have evidence of adequate liver function prior to enrollment defined by total bilirubin less than 3 times the upper limit of normal and transaminases less than 5 times the upper limit of normal for age appropriate indices. Cardiac function: Patients must have evidence of adequate cardiac function prior to enrollment defined by ejection fraction greater than 25 percent performed within the last 6 months at NIH and absence of symptoms of cardiac disease at FHCRC, JHH, or Hackensack. Pulmonary function: Patients must have an FEV1 greater than or equal to 20 percent predicted for inclusion in this study. EXCLUSION CRITERIA: Underlying disease status: Patients with tumor burden greater than minimal residual disease (i.e. tumor burden that can only be detected by molecular methods) would be excluded from this study. Prior post-transplant treatment with montelukast or zakirlukast within the past 2 months and total duration of therapy does not exceed 3 months. Clinically significant systemic illness with manifestations of significant organ dysfunction which in the judgment of Principal or Associate Investigator would render the patient unlikely to tolerate the protocol therapy or complete the study. Patients must have been on their current cGVHD therapeutic regimen for at least 3 months with stable or decreasing FEV1 to be eligible for this trial. Any patient who has been on a therapy for less than 3 months for cGVHD will need to be monitored for 3 months without improvement in FEV1 prior to enrollment. Ventilated patients are excluded. Patients taking rifampin or phenobarbital as these medications alter the metabolism of montelukast. Patients taking greater than one age-appropriate dose of ibuprofen or aspirin containing products per day that inhibit cyclooxygenase will be excluded from this trial. The acceptable upper limit for adult daily doses of aspirin is 650mg/day and 800mg/day of ibuprophen. For children, the acceptable upper limit of ibuprophen is pediatric dose per day (less than 10 mg per kg to a maximum of 800 mg). Children should not take aspirin due to risk of Reye's syndrome unless specifically prescribed by their physician. Patients with a history of allergy to montelukast. Pregnant females and nursing mothers will be excluded from this trial due to unknown risks to the developing fetus. While on study, patients of child-bearing potential must be able to consent to utilize effective birth control measures.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Montelukast to Treat Bronchiolitis Obliterans<br>Montelukast for the treatment of BO following allogeneic or autologous stem cell transplant. | Drug: Singulair (Montelukast Sodium)<br>* Singulair (Montelukast Sodium):5-10 mg (weight based dosing) by mouth (PO) hour of sleep (HS)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Stable or Improved Predicted Forced Expiratory Volume 1 (FEV-1) With Published Literature | Responsive disease (RD) will be defined as ≥15% absolute improvement in the percentage predicted FEV-1. Progressive disease (PD) will be defined as >15% decrease in FEV-1 documented on 2 pulmonary function test (PFT) evaluations greater than 2 weeks apart. Stable disease (SD) will be defined as <15% change in the absolute FEV-1. | 180 days | 
| Number of Participants With Improved, Stable or Declined Forced Expiratory Volume 1 (FEV-1) Slope at 6 Months | FEV-1 slope of decline was generated using regression line of FEV-1 value vs. days post hematopoietic stem cell transplant. Responsive disease (RD) for the slope of FEV-1 change will be an increase in the slope of absolute FEV-1. Progressive disease (PD) for the slope of FEV-1 change will be a decrease in the slope of absolute FEV-1. Stable disease (SD) for the slope of FEV-1 change will be a 0 change in FEV-1 slope. | 180 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module. | Date treatment consent signed to date off study, approximately 71 months and 17 days | 
| Forced Expiratory Volume 1 (FEV-1)/Vital Capacity (VC) | Pulmonary function test performed for eligibility and baseline. | Baseline | 
| Percentage Overall 2-Year Survival | Percentage of participants alive at 2 years. | 2 years | 
| Number of Non-Infected Participants at Baseline With Cysteinyl Leukotriene Receptor Expression on Cluster of Differentiation (CD4) and CD8 T Cells, Granulocytes, and Eosinophils in Bronchoalveolar Lavage (BAL) Fluid | Fluid from the bronchoalveolar lavage in adult participants (pediatric optional) will be collected and sent to the lab to be evaluated for infectious diseases by flow cytometry | Day 1 of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukotriene, Chronic Graft-Versus-Host Disease, Montelukast, Stem Cell Transplant, Bronchiolitis Obliterans