Targeted Therapy of Bronchiolitis Obliterans Syndrome

Study Overview
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Brief Summary
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This phase II trial studies how well giving fluticasone propionate, azithromycin, and montelukast sodium (FAM) together works in treating patients with bronchiolitis obliterans who previously underwent stem cell transplant. FAM may be an effective treatment for bronchiolitis obliterans

Detailed Description
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PRIMARY OBJECTIVES: I. To determine if the combination treatment of FAM administered in post hematopoietic cell transplantation (HCT) recipients after the diagnosis of new onset bronchiolitis obliterans syndrome (BOS) can decrease the rate of treatment failure relative to an estimated historical rate of 40% using current therapies. SECONDARY OBJECTIVES: I. To confirm the safety profile of FAM. II. To describe the effect on other standard pulmonary function test parameters: forced expiratory flow at 25%-75% of forced vital capacity (FVC) (FEF25-75), residual volume (RV), diffusion capacity of carbon monoxide (DLCO), forced expiratory volume in 1 second (FEV1)/FVC ratio and FEV1/slow vital capacity (SVC) ratio with FAM treatment. III. To determine the change in molecular markers of inflammation and fibrosis in the blood with FAM treatment. IV. To assess the impact of FAM on other chronic graft-versus-host disease (GVHD) manifestations. V. To assess the impact of FAM on functional status, and health-related quality of life (HRQOL). VI. To describe changes in steroid dosing. OUTLINE: Patients receive fluticasone propionate inhaled orally (PO) twice daily (BID), azithromycin PO 3 days a week, and montelukast sodium PO once daily (QD). Treatment continues for 6 months in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 6 months.

Official Title
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Fluticasone Propionate, Azithromycin, and Montelukast Sodium in Treating Patients With Bronchiolitis Obliterans Who Previously Underwent Stem Cell Transplant

Conditions
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Bronchiolitis Obliterans

Intervention / Treatment
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* Drug: fluticasone propionate
* Drug: montelukast sodium
* Drug: azithromycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of BOS after HCT within the 6 months before study enrollment; for this study, BOS is defined as: Forced expiratory volume in 1 second (FEV1) < 75% of the predicted normal and FEV1 to slow or inspiratory vital capacity ratio (FEV1/SVC or FEV1/IVC) =< 0.7, both measured before and after administration of bronchodilator OR Pathologic diagnosis of BOS demonstrated by lung biopsy The baseline absolute FEV1 must be >= 10% lower than the pre-transplant absolute FEV1 as defined by the pre-transplant FEV1 minus the baseline FEV1, both measured before administration of a bronchodilator Participant (or parent/guardian) has the ability to understand and willingness to sign a written consent document Exclusion Criteria: Recurrent or progressive malignancy requiring anticancer treatment Known history of allergy to or intolerance of montelukast, zafirlukast, azithromycin, erythromycin, or clarithromycin Pregnancy or nursing; all females of childbearing potential must have a negative serum or urine pregnancy test < 7 days before study drug administration Transaminases > 5 X upper limit of normal (ULN) Total bilirubin > 3 X ULN Chronic treatment with any inhaled steroid for > 1 month in the past three months Treatment with montelukast or zafirlukast for > 1 month during the past three months Treatment with prednisone at > 1.2 mg/kg/day (or equivalent steroid) Treatment with rifampin or phenobarbital, aspirin at doses > 325 mg/day, or ibuprofen at doses > 1200 mg/day Treatment with any Food and Drug Administration (FDA) non approved study medication within the past 4 weeks; off-label treatment with an FDA-approved medication is allowed Chronic oxygen therapy Evidence of any viral, bacterial or fungal infection involving the lung and not responding to appropriate treatment Clinical asthma (variable and recurring symptoms of airflow obstruction and bronchial hyper-responsiveness) Any condition that, in the opinion of the enrolling investigator, would interfere with the subject's ability to comply with the study requirements Uncontrolled substance abuse or psychiatric disorder Inability to perform pulmonary function tests (PFT) reliably, as determined by the enrolling investigator or PFT lab Life expectancy < 6 months at the time of enrollment as judged by the enrolling investigator Baseline post-bronchodilator FEV1 < 20% of predicted normal before or after albuterol

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 99 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: Treatment (BOS therapy)<br>Patients receive fluticasone propionate inhaled PO BID, azithromycin PO 3 days a week, and montelukast sodium PO QD. Treatment continues for 6 months in the absence of disease progression or unacceptable toxicity. | Drug: fluticasone propionate<br>* Given inhaled PO<br>* Other names: Flovent;Drug: montelukast sodium<br>* Given PO<br>* Other names: Singulair;Drug: azithromycin<br>* Given PO<br>* Other names: XZ-450;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Who Failed Treatment | Treatment failure is defined as sustained, absolute decrease (worsening) of the FEV1 by >= 10% predicted in comparison to the baseline FEV1. Must be confirmed by a second PFT 2 weeks after the first measurement. | Within 3 months after initiation of study medications | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Who Experienced Grade 3-5 SAEs Attributable to FAM and Number of Subjects Who Stopped FAM as a Result | National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) (v4.0) | From baseline to 6 months | 
| Number of Subjects Who Experienced Statistically Significant Changes in FVC, TLC, RV, DLCO |  | Baseline and 6 months | 
| Changes in Blood Molecular Markers: IL8 (Azithromycin), Cysteinyl and LTB4 (Monteleukast), and IL1B, TNF, and IL6, as Well as Neutrophil Count (Fluticasone) |  | Baseline to 6 months | 
| Number of Subjects With Improvements in Other Chronic GVHD Characteristics | Only includes subjects who had complete or partial response according to the National Institute of Health (NIH) consensus criteria. | Baseline and 3 months | 
| Number of Subjects Were Able to Reduce Their Systemic Steroid Exposure by >=50% |  | Baseline to 6 months | 
| Changes in Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | SF-36 subscales have min=0 and max=100; results are given as change in 6mo score compared to baseline score, not actual score, and a positive change is correlated with improvement in clinical outcome. | Baseline and 6 months | 
| Changes in Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT) | FACT-BMT subscales have various min/max, see below; results are given as change in 6mo score compared to baseline score, not actual score, and a positive change is correlated with improvement in clinical outcome. FACT physical well-being (0-28) FACT social/family well-being (0-28) FACT emotional well-being (0-24) FACT functional well-being (0-28) FACT Bone Marrow Transplant (BMT) subscale (0-40) FACT trial outcome index (0-96) FACT-General (G) (0-108) FACT-BMT total (0-148) | Baseline and 6 months | 
| Changes in Symptoms as Measured by Patient Self-report--Human Activities Profile (HAP) | HAP subscales have min=0 and max=94; results are given as change in 6mo score compared to baseline score, not actual score, and a positive change is correlated with improvement in clinical outcome. Maximum Activity Score (MAS) is highest item number answered still doing. Represents highest oxygen demanding activity that respondent still performs. Adjusted Activity Score (AAS) is MAS minus total number of stopped doing responses below MAS. A measure of usual daily activities. Modified AAS is MAS minus total number of stopped doing responses below MAS but not penalized for not doing activities not permitted post transplant. The following items are not counted against the score:11,15,19,20,22,25,34,41,42,47,49,50,52,53,54,57,72,73,77,78. | Baseline and 6 months | 
| Changes in Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale | Lee symptom scale (LSS) has subscales with min=0, max=100; results are given as change in 6mo score compared to baseline score, not actual score, and a negative change is correlated with improvement in clinical outcome. | Baseline and 6 months |