Bronchiolitis Obliterans
Conditions
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.
Interventions
DRUGfluticasone propionate
Given inhaled PO
DRUGmontelukast sodium
Given PO
DRUGazithromycin
Given PO
Sponsors
National Cancer Institute (NCI)
Stephanie Lee
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 99 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Who Failed Treatment | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Who Experienced Grade 3-5 SAEs Attributable to FAM and Number of Subjects Who Stopped FAM as a Result | From baseline to 6 months | National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) (v4.0) |
| 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 | Baseline and 3 months | 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% | Baseline to 6 months | — |
| Number of Subjects Who Experienced Statistically Significant Changes in FVC, TLC, RV, DLCO | Baseline and 6 months | — |
| Changes in Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT) | 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) |
| Changes in Symptoms as Measured by Patient Self-report--Human Activities Profile (HAP) | 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. |
| Changes in Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale | 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. |
| Changes in Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 36 |
| Total | 36 |
Baseline characteristics
| Characteristic | Treatment (BOS Therapy) |
|---|---|
| Age, Continuous | 57 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 34 Participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 36 |
| other Total, other adverse events | 9 / 36 |
| serious Total, serious adverse events | 24 / 36 |
Outcome results
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.
Time frame: Within 3 months after initiation of study medications
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (BOS Therapy) | Number of Subjects Who Failed Treatment | 2 Participants |
Secondary
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
Population: Data were not collected
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)
Time frame: Baseline and 6 months
Population: 24 of 36 subjects were evaluable at 6mo due to missing patient survey data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT) | FACT physical well-being | 0.5 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT) | FACT social/family well-being | -1 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT) | FACT emotional well-being | 0 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT) | FACT functional well-being | 1 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT) | FACT BMT subscale | -0.78 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT) | FACT trial outcome index | 2 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT) | FACT-G | 2.5 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT) | FACT-BMT total | 2.17 units on a scale |
Comparison: FACT physical well-beingp-value: 0.28Wilcoxon (Mann-Whitney)
Comparison: FACT social/family well-beingp-value: 0.1Wilcoxon (Mann-Whitney)
Comparison: FACT emotional well-beingp-value: 0.63Wilcoxon (Mann-Whitney)
Comparison: FACT functional well-beingp-value: 0.78Wilcoxon (Mann-Whitney)
Comparison: FACT BMT subscalep-value: 0.84Wilcoxon (Mann-Whitney)
Comparison: FACT trial outcome indexp-value: 0.37Wilcoxon (Mann-Whitney)
Comparison: FACT-Gp-value: 0.71Wilcoxon (Mann-Whitney)
Comparison: FACT-BMT totalp-value: 0.54Wilcoxon (Mann-Whitney)
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.
Time frame: Baseline and 6 months
Population: 24 of 36 subjects were evaluable at 6mo due to missing patient survey data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Human Activities Profile (HAP) | HAP MAS | 0.5 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Human Activities Profile (HAP) | HAP AAS | 4.5 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Human Activities Profile (HAP) | Modified HAP AAS | 3.5 units on a scale |
Comparison: HAP maximum activity score - highest item still doingp-value: 0.37Wilcoxon (Mann-Whitney)
Comparison: HAP adjusted activity score - MAS minus stoppedp-value: 0.39Wilcoxon (Mann-Whitney)
Comparison: Modified HAP adjusted activity scorep-value: 0.39Wilcoxon (Mann-Whitney)
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.
Time frame: Baseline and 6 months
Population: 24 of 36 subjects were evaluable at 6mo due to missing patient survey data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale | LSS skin scale | -5.63 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale | LSS energy scale | -7.14 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale | LSS lung scale | -5 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale | LSS eye scale | -8.33 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale | LSS nutrition scale | 0 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale | LSS psychological scale | 0 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale | LSS mouth scale | 0 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale | LSS overall summary scale | -7.77 units on a scale |
Comparison: Lee symptom skin scalep-value: 0.11Wilcoxon (Mann-Whitney)
Comparison: Lee symptom energy scalep-value: 0.007Wilcoxon (Mann-Whitney)
Comparison: Lee symptom lung scalep-value: 0.2Wilcoxon (Mann-Whitney)
Comparison: Lee symptom eye scalep-value: 0.002Wilcoxon (Mann-Whitney)
Comparison: Lee symptom nutrition scalep-value: 0.52Wilcoxon (Mann-Whitney)
Comparison: Lee symptom psychological scalep-value: 0.22Wilcoxon (Mann-Whitney)
Comparison: Lee symptom mouth scalep-value: 0.002Wilcoxon (Mann-Whitney)
Comparison: Lee symptom overall summary scalep-value: <0.001Wilcoxon (Mann-Whitney)
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.
Time frame: Baseline and 6 months
Population: 24 of 36 subjects were evaluable at 6mo due to missing patient survey data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | SF-36 norm-based physical functioning score | 0.0 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | SF-36 norm-based role-physical score | 0.0 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | SF-36 norm-based bodily pain score | 0.0 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | SF-36 norm-based general health score | -2.38 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | SF-36 norm-based vitality score | 1.56 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | SF-36 norm-based social functioning score | 5.45 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | SF-36 norm-based role-emotional score | 0.0 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | SF-36 norm-based mental health score | 0.0 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | SF-36 standardized physical component score | -1.21 units on a scale |
| Treatment (BOS Therapy) | Changes in Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | SF-36 standardized mental component score | 1.64 units on a scale |
Comparison: SF-36 norm-based physical functioning scorep-value: 0.81Wilcoxon (Mann-Whitney)
Comparison: SF-36 norm-based role-physical scorep-value: 0.18Wilcoxon (Mann-Whitney)
Comparison: SF-36 norm-based bodily pain scorep-value: 0.48Wilcoxon (Mann-Whitney)
Comparison: SF-36 norm-based general health scorep-value: 0.26Wilcoxon (Mann-Whitney)
Comparison: SF-36 norm-based vitality scorep-value: 0.23Wilcoxon (Mann-Whitney)
Comparison: SF-36 norm-based social functioning scorep-value: 0.36Wilcoxon (Mann-Whitney)
Comparison: SF-36 norm-based role-emotional scorep-value: 0.41Wilcoxon (Mann-Whitney)
Comparison: SF-36 norm-based mental health scorep-value: 0.8Wilcoxon (Mann-Whitney)
Comparison: SF-36 standardized physical component scorep-value: 0.8Wilcoxon (Mann-Whitney)
Comparison: SF-36 standardized mental component scorep-value: 0.23Wilcoxon (Mann-Whitney)
Secondary
Number of Subjects Were Able to Reduce Their Systemic Steroid Exposure by >=50%
Time frame: Baseline to 6 months
Population: 24 out of 36 subjects were evaluable at 6mo due to missing data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (BOS Therapy) | Number of Subjects Were Able to Reduce Their Systemic Steroid Exposure by >=50% | 17 Participants |
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)
Time frame: From baseline to 6 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (BOS Therapy) | Number of Subjects Who Experienced Grade 3-5 SAEs Attributable to FAM and Number of Subjects Who Stopped FAM as a Result | SAEs attributable to FAM | 11 Participants |
| Treatment (BOS Therapy) | Number of Subjects Who Experienced Grade 3-5 SAEs Attributable to FAM and Number of Subjects Who Stopped FAM as a Result | Stopped FAM during study | 1 Participants |
Secondary
Number of Subjects Who Experienced Statistically Significant Changes in FVC, TLC, RV, DLCO
Time frame: Baseline and 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (BOS Therapy) | Number of Subjects Who Experienced Statistically Significant Changes in FVC, TLC, RV, DLCO | 0 Participants |
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.
Time frame: Baseline and 3 months
Population: 33 of 36 participants were evaluable at 3 months due to missing provider survey data
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (BOS Therapy) | Number of Subjects With Improvements in Other Chronic GVHD Characteristics | 12 Participants |