Targeted Therapy of Bronchiolitis Obliterans Syndrome (FAM for BOS)

Study Description

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Brief 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

Condition or disease	Intervention/treatment	Phase
Bronchiolitis Obliterans	Drug: fluticasone propionate; Drug: montelukast sodium; Drug: azithromycin	Phase 2

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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	36 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Fluticasone Propionate, Azithromycin, and Montelukast Sodium in Treating Patients With Bronchiolitis Obliterans Who Previously Underwent Stem Cell Transplant
Study Start Date :	June 2011
Actual Primary Completion Date :	September 2014
Actual Study Completion Date :	December 2015

Arms and Interventions

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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: Flonase; Flovent; Drug: montelukast sodium; Given PO; Other Name: Singulair; Drug: azithromycin; Given PO; Other Names: AzaSite; CP 62993; XZ-450

Outcome Measures

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Primary Outcome Measures :

1. Number of Subjects Who Failed Treatment [ Time Frame: Within 3 months after initiation of study medications ]
   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.

Secondary Outcome Measures :

1. Number of Subjects Who Experienced Grade 3-5 SAEs Attributable to FAM and Number of Subjects Who Stopped FAM as a Result [ Time Frame: From baseline to 6 months ]
   National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) (v4.0)
2. Number of Subjects Who Experienced Statistically Significant Changes in FVC, TLC, RV, DLCO [ Time Frame: Baseline and 6 months ]
3. Changes in Blood Molecular Markers: IL8 (Azithromycin), Cysteinyl and LTB4 (Monteleukast), and IL1B, TNF, and IL6, as Well as Neutrophil Count (Fluticasone) [ Time Frame: Baseline to 6 months ]
4. Number of Subjects With Improvements in Other Chronic GVHD Characteristics [ Time Frame: Baseline and 3 months ]
   Only includes subjects who had complete or partial response according to the National Institute of Health (NIH) consensus criteria.
5. Number of Subjects Were Able to Reduce Their Systemic Steroid Exposure by >=50% [ Time Frame: Baseline to 6 months ]
6. Changes in Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) [ Time Frame: Baseline and 6 months ]
   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.
7. Changes in Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT) [ Time Frame: Baseline and 6 months ]

   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)

8. Changes in Symptoms as Measured by Patient Self-report--Human Activities Profile (HAP) [ Time Frame: Baseline and 6 months ]

   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.

9. Changes in Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale [ Time Frame: Baseline and 6 months ]
   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.

Eligibility Criteria

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Ages Eligible for Study:	6 Years to 99 Years (Child, Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Locations

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

Sponsors and Collaborators

Stephanie Lee

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)

More Information

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Publications of Results:

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.

Responsible Party:	Stephanie Lee, Principal Investigator, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
ClinicalTrials.gov Identifier:	NCT01307462 History of Changes
Other Study ID Numbers:	2367.00; NCI-2011-00203 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); U54CA163438 ( U.S. NIH Grant/Contract ); RDCRN 6503 ( Other Identifier: DMCC )
First Posted:	March 3, 2011
Results First Posted:	October 4, 2017
Last Update Posted:	October 4, 2017
Last Verified:	September 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No
Plan Description:	De-identified data are reported in aggregate.

Additional relevant MeSH terms:

Bronchiolitis; Bronchiolitis Obliterans; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Infections; Fluticasone; Montelukast; Anti-Inflammatory Agents; Bronchodilator Agents; Autonomic Agents	Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Asthmatic Agents; Respiratory System Agents; Dermatologic Agents; Anti-Allergic Agents; Leukotriene Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP1A2 Inducers; Cytochrome P-450 Enzyme Inducers; Molecular Mechanisms of Pharmacological Action