Targeted Therapy of Bronchiolitis Obliterans Syndrome

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.

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