Targeted Therapy of Bronchiolitis Obliterans Syndrome (FAM for BOS)

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

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

Study Overview

• Status: Completed
• Conditions: Bronchiolitis Obliterans
• Intervention / Treatment: Drug: fluticasone propionate; Drug: montelukast sodium; Drug: azithromycin

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85054
      • Mayo Clinic - Scottsdale
  • California
    • Stanford, California, United States, 94305
      • Stanford University
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center and Research Institute
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Cancer Institute Experimental Transplantation & Immunology Branch
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Masonic Cancer Center, University of Minnesota
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Siteman Cancer Center at Washington University
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Medical College
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 97 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (BOS therapy); 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; Given inhaled PO; Other Names: Flovent; Flonase; Drug: montelukast sodium; Given PO; Other Names: Singulair; Drug: azithromycin; Given PO; Other Names: AzaSite; CP 62993; XZ-450

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Stephanie Lee
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Stephanie Lee, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium; Study Chair: Kirsten Williams, National Cancer Institute (NCI)

Publications and helpful links

General Publications

• 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 New-Onset Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2016 Apr;22(4):710-716. doi: 10.1016/j.bbmt.2015.10.009. Epub 2015 Oct 22.
• Inamoto Y, Martin PJ, Onstad LE, Cheng GS, Williams KM, Pusic I, Ho VT, Arora M, Pidala J, Flowers MED, Gooley TA, Lawler RL, Hansen JA, Lee SJ. Relevance of Plasma Matrix Metalloproteinase-9 for Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Cell Transplantation. Transplant Cell Ther. 2021 Sep;27(9):759.e1-759.e8. doi: 10.1016/j.jtct.2021.06.006. Epub 2021 Jun 12.

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: March 1, 2011
• First Submitted That Met QC Criteria: March 1, 2011
• First Posted (Estimate): March 3, 2011

Study Record Updates

• Last Update Posted (Actual): October 4, 2017
• Last Update Submitted That Met QC Criteria: September 6, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Bronchitis; Bronchiolitis; Bronchiolitis Obliterans; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Dermatologic Agents; Anti-Bacterial Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Leukotriene Antagonists; Hormone Antagonists; Cytochrome P-450 CYP1A2 Inducers; Cytochrome P-450 Enzyme Inducers; Anti-Allergic Agents; Montelukast; Fluticasone; Xhance; Azithromycin
• Other Study ID Numbers: 2367.00; U54CA163438 (U.S. NIH Grant/Contract); NCI-2011-00203 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); RDCRN 6503 (Other Identifier: DMCC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: De-identified data are reported in aggregate.