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Targeted Therapy of Bronchiolitis Obliterans Syndrome (FAM for BOS)

Primary Purpose

Bronchiolitis Obliterans

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
fluticasone propionate
montelukast sodium
azithromycin
Sponsored by
Stephanie Lee
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Bronchiolitis Obliterans

Eligibility Criteria

6 Years - 99 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Mayo Clinic - Scottsdale
  • Stanford University
  • H. Lee Moffitt Cancer Center and Research Institute
  • National Cancer Institute Experimental Transplantation & Immunology Branch
  • Dana-Farber Cancer Institute
  • Masonic Cancer Center, University of Minnesota
  • Siteman Cancer Center at Washington University
  • Weill Cornell Medical College
  • Vanderbilt University
  • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  • Medical College of Wisconsin

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (BOS therapy)

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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)
Number of Subjects Who Experienced Statistically Significant Changes in FVC, TLC, RV, DLCO
Changes in Blood Molecular Markers: IL8 (Azithromycin), Cysteinyl and LTB4 (Monteleukast), and IL1B, TNF, and IL6, as Well as Neutrophil Count (Fluticasone)
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.
Number of Subjects Were Able to Reduce Their Systemic Steroid Exposure by >=50%
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.
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)
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.
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.

Full Information

First Posted
March 1, 2011
Last Updated
September 6, 2017
Sponsor
Stephanie Lee
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01307462
Brief Title
Targeted Therapy of Bronchiolitis Obliterans Syndrome
Acronym
FAM for BOS
Official Title
Fluticasone Propionate, Azithromycin, and Montelukast Sodium in Treating Patients With Bronchiolitis Obliterans Who Previously Underwent Stem Cell Transplant
Study Type
Interventional

2. Study Status

Record Verification Date
September 2017
Overall Recruitment Status
Completed
Study Start Date
June 2011 (undefined)
Primary Completion Date
September 2014 (Actual)
Study Completion Date
December 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Stephanie Lee
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bronchiolitis Obliterans

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
36 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (BOS therapy)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
fluticasone propionate
Other Intervention Name(s)
Flonase, Flovent
Intervention Description
Given inhaled PO
Intervention Type
Drug
Intervention Name(s)
montelukast sodium
Other Intervention Name(s)
Singulair
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
azithromycin
Other Intervention Name(s)
AzaSite, CP 62993, XZ-450
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Number of Subjects Who Failed Treatment
Description
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.
Time Frame
Within 3 months after initiation of study medications
Secondary Outcome Measure Information:
Title
Number of Subjects Who Experienced Grade 3-5 SAEs Attributable to FAM and Number of Subjects Who Stopped FAM as a Result
Description
National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) (v4.0)
Time Frame
From baseline to 6 months
Title
Number of Subjects Who Experienced Statistically Significant Changes in FVC, TLC, RV, DLCO
Time Frame
Baseline and 6 months
Title
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
Title
Number of Subjects With Improvements in Other Chronic GVHD Characteristics
Description
Only includes subjects who had complete or partial response according to the National Institute of Health (NIH) consensus criteria.
Time Frame
Baseline and 3 months
Title
Number of Subjects Were Able to Reduce Their Systemic Steroid Exposure by >=50%
Time Frame
Baseline to 6 months
Title
Changes in Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36)
Description
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.
Time Frame
Baseline and 6 months
Title
Changes in Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT)
Description
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)
Time Frame
Baseline and 6 months
Title
Changes in Symptoms as Measured by Patient Self-report--Human Activities Profile (HAP)
Description
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.
Time Frame
Baseline and 6 months
Title
Changes in Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale
Description
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.
Time Frame
Baseline and 6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stephanie Lee
Organizational Affiliation
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Kirsten Williams
Organizational Affiliation
National Cancer Institute (NCI)
Official's Role
Study Chair
Facility Information:
Facility Name
Mayo Clinic - Scottsdale
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85054
Country
United States
Facility Name
Stanford University
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
H. Lee Moffitt Cancer Center and Research Institute
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
National Cancer Institute Experimental Transplantation & Immunology Branch
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Masonic Cancer Center, University of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Siteman Cancer Center at Washington University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Weill Cornell Medical College
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Vanderbilt University
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Facility Name
Medical College of Wisconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
De-identified data are reported in aggregate.
Citations:
PubMed Identifier
26475726
Citation
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.
Results Reference
result
PubMed Identifier
34126278
Citation
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.
Results Reference
derived

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Targeted Therapy of Bronchiolitis Obliterans Syndrome

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