Targeted Therapy of Bronchiolitis Obliterans Syndrome

Bronchiolitis Obliterans Clinical Trial

— FAM for BOS  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01307462
• Other study ID #: 2367.00
• Secondary ID: NCI-2011-00203U5
• Status: Completed
• Phase: Phase 2
• First received: March 1, 2011
• Last updated: September 6, 2017
• Start date: June 2011
• Est. completion date: December 2015

Study information

• Verified date: September 2017
• Source: Fred Hutchinson Cancer Research Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. completion date: December 2015
• Est. primary completion date: September 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years to 99 Years

Eligibility

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

Related Conditions & MeSH terms

• Bronchiolitis
• Bronchiolitis Obliterans

Intervention

Drug:
• fluticasone propionate
Given inhaled PO
• montelukast sodium
Given PO
• azithromycin
Given PO

Locations

Country	Name	City	State
United States	National Cancer Institute Experimental Transplantation & Immunology Branch	Bethesda	Maryland
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Masonic Cancer Center, University of Minnesota	Minneapolis	Minnesota
United States	Vanderbilt University	Nashville	Tennessee
United States	Weill Cornell Medical College	New York	New York
United States	Siteman Cancer Center at Washington University	Saint Louis	Missouri
United States	Mayo Clinic - Scottsdale	Scottsdale	Arizona
United States	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington
United States	Stanford University	Stanford	California
United States	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Stephanie Lee	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

Williams KM, Cheng GS, Pusic I, Jagasia M, Burns L, Ho VT, Pidala J, Palmer J, Johnston L, Mayer S, Chien JW, Jacobsohn DA, Pavletic SZ, Martin PJ, Storer BE, Inamoto Y, Chai X, Flowers MED, Lee SJ. Fluticasone, Azithromycin, and Montelukast Treatment for — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Number of Subjects Who Experienced Statistically Significant Changes in FVC, TLC, RV, DLCO		Baseline and 6 months
Secondary	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
Secondary	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
Secondary	Number of Subjects Were Able to Reduce Their Systemic Steroid Exposure by >=50%		Baseline to 6 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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