Clinical trial NCT01307462: Targeted Therapy of Bronchiolitis Obliterans Syndrome
Official title: Fluticasone Propionate, Azithromycin, and Montelukast Sodium in Treating Patients With Bronchiolitis Obliterans Who Previously Underwent Stem Cell Transplant
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Bronchiolitis Obliterans
Lead sponsor: Fred Hutchinson Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2011-03-03
Enrollment: 36
Sex: ALL
Minimum age (years): 6
Maximum age (years): 99
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number of Subjects Who Failed Treatment
timeFrame: Within 3 months after initiation of study medications
Secondary outcomes:
measure: Number of Subjects Who Experienced Grade 3-5 SAEs Attributable to FAM and Number of Subjects Who Stopped FAM as a Result
timeFrame: From baseline to 6 months
measure: Number of Subjects Who Experienced Statistically Significant Changes in FVC, TLC, RV, DLCO
timeFrame: Baseline and 6 months
measure: Changes in Blood Molecular Markers: IL8 (Azithromycin), Cysteinyl and LTB4 (Monteleukast), and IL1B, TNF, and IL6, as Well as Neutrophil Count (Fluticasone)
timeFrame: Baseline to 6 months
measure: Number of Subjects With Improvements in Other Chronic GVHD Characteristics
timeFrame: Baseline and 3 months
measure: Number of Subjects Were Able to Reduce Their Systemic Steroid Exposure by >=50%
timeFrame: Baseline to 6 months
measure: Changes in Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36)
timeFrame: Baseline and 6 months
measure: Changes in Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT)
timeFrame: Baseline and 6 months
measure: Changes in Symptoms as Measured by Patient Self-report--Human Activities Profile (HAP)
timeFrame: Baseline and 6 months
measure: Changes in Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale
timeFrame: Baseline and 6 months
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic - Scottsdale
state: Arizona
city: Stanford
country: United States
facility: Stanford University
state: California
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Bethesda
country: United States
facility: National Cancer Institute Experimental Transplantation & Immunology Branch
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Minneapolis
country: United States
facility: Masonic Cancer Center, University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Siteman Cancer Center at Washington University
state: Missouri
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
name: Stephanie Lee
role: PRINCIPAL_INVESTIGATOR
affiliation: National Cancer Institute (NCI)
name: Kirsten Williams
role: STUDY_CHAIR
References:
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.
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.