Protocol Number: 08-C-0097

Title:

Multi-Institutional Prospective Phase II Study of Montelukast for the Treatment of Bronchiolitis Obliterans Following Allogeneic Stem Cell Transplantation in Children and Adults

Number:

08-C-0097

Summary:

Background:

Bronchiolitis obliterans is a form of chronic graft-versus-host disease (GVHD) that sometimes develops after stem cell transplantation (SCT) or bone marrow transplantation (BMT).

In bronchiolitis obliterans, immune cells that normally fight infections attack the lungs of the transplant recipient, causing destruction of lung tissue and fibrosis (scarring). When fibrosis develops, the lungs cannot work properly.

Montelukast (Singulair) is a drug that has been used for many years to treat asthma. Its use as a treatment for bronchiolitis obliterans is experimental.

Objectives:

To see if montelukast improves or stabilizes lung function in patients who develop bronchiolitis obliterans after BMT or SCT.

To assess the safety of montelukast in patients with bronchiolitis obliterans after BMT or SCT

To see if montelukast affects the cells that damage the lungs.

To see if montelukast improves other forms of chronic GVHD, quality of life, and overall survival in patients with bronchiolitis obliterans after BMT or SCT.

Eligibility:

Patients 6 years of age and older with bronchiolitis obliterans following stem cell transplantation.

Design:

Patients take one montelukast tablet daily for 6 months and undergo the following procedures during this period:

-Lung function tests. The patient breathes into a machine that measures the amount of air that goes into and out of the lungs. This test is done once a month for 3 months, then at 6 months, 12 months and 24 months.

-Medical history and physical examination at the study site about every 3 months for the first year of the study and then at 12 months and 24 months. Patients also have physical examinations monthly for the first 6 months at their primary doctor's office. Tests may include blood and urine tests, chest CT scans, echocardiogram (heart ultrasound), 2- and 6-minute walk tests, and quality-of-life questionnaires.

-Bronchoalveolar lavage in patients 18 years of age and older. The subject's mouth, nose and airways are numbed with lidocaine. Some patients may need sedation or anesthesia for the procedure. A tube (bronchoscope) is then passed through the nose into the airway, and a small amount of fluid is put into the lung. The fluid is then removed and tested for infections or other lung problems.

-Apheresis to collect white blood cells. Whole blood is collected through a tube inserted into a vein in the arm. The white cells are extracted in a cell separator machine, and the rest of the blood is returned to the body through a tube placed in a vein in the other arm. The cells are used to study GVHD and bronchiolitis obliterans.

-Patients who wish to continue montelukast therapy after 6 months may do so under the care of their primary doctor, if both agree to the continuation.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

Age greater than 6 years old.

Diagnosis of bronchiolitis obliterans after allogeneic stem cell transplant. The criteria will be based on the definitions created by the NIH consortium on cGVHD. As part of these criterion, for patients without pathologic evidence of BO, one other sign of chronic GVHD must be present. For diagnosis of cGVHD, a minimum of the following must be present: 1) a process distinct from that diagnosed as acute GVHD, 2) the presence of a diagnostic sign or a distinctive sign supported by another clinical or laboratory test, and 3) the exclusion of other pathologies (i.e. recurrent cancer, drug reaction or infection (see Appendix 5a for a list of diagnostic signs.). To meet criteria for a diagnosis of bronchiolitis obliterans, patients must fulfill all 3 criteria. For NIH subjects, prior lung tissue biopsy will be analyzed and confirmed to show bronchiolitis obliterans by the NCI Laboratory of Pathology. If tissue is not available for confirmation, a new biopsy will not be performed.

For bronchiolitis obliterans:

1. FEV1 less than 75 percent of predicted by pulmonary function evaluation for height and weight.

2. Evidence of air-trapping or small airway thickening or bronchiectasis on high resolution chest CT and RV or RV/FVC greater than 120 percent and evidence of chronic GVHD of another organ, OR FEV1/slow vital capacity ratio less than 5 percent of predicted for age or less than 0.7, OR pathologic evidence of bronchiolar inflammation and obstruction of the lumen consistent with a diagnosis of BO. Pulmonary function tests will utilize body plethysmography not helium studies for pertinent values when there is a discrepancy.

3. Absence of active infection with appropriate investigation of any clinical symptoms to include radiographic, microbiologic, and pathologic studies as determined by the PI or LAI.

Patients must also have 2 PFT measurements with documented FEV1 values greater than 3 months apart to calculate the entry FEV1 slope. For patients enrolled after an acute decline following BMT without 2 post-BMT values greater than 3 months apart, the pre-BMT value may be utilized as the first value and the entry PFT value may be the second for the slope calculation. The baseline and 6-month PFT should be done at the accruing site.

Prior therapy: For patients with a chronic diagnosis of BO who have been on treatments, any prior therapy that has been administered chronically for greater than 3 months will be acceptable for enrollment as long as the patient has not demonstrated improvement on this agent in a one month (or more) period of observation preceding enrollment. Patients who have had improvement in the months preceding trial entry will not be eligible since there will be no way to discern improvement due to montelukast versus another therapy. Alternatively, a patient with a new diagnosis of bronchiolitis obliterans characterized by a new decrease in FEV1 is also eligible for this study. Notably, patients who have received bronchodilators or other pulmonary therapies may be included in this study as long as montelukast has not been part of this regimen.

Performance status: Karnofsky or Lansky performance status greater than 40 percent (Appendix 1).

Ability to give informed consent. For patients less than 18 years of age, their legal guardian must give informed consent. Pediatric patients will be included in an age appropriate discussion in accordance with NIH guidelines.

Hepatic function: Patients must have evidence of adequate liver function prior to enrollment defined by total bilirubin less than 3 x the upper limit of normal and transaminases less than 5 times the upper limit of normal for age appropriate indices.

Cardiac function: Patients must have evidence of adequate cardiac function prior to enrollment defined by ejection fraction greater than 25 percent performed within the last 6 months.

Pulmonary function: Patients must have an FEV1 greater than or equal to 20 percent for inclusion in this study.

EXCLUSION CRITERIA:

Underlying disease status: Patients with tumor burden greater than minimal residual disease (i.e. tumor burden that can only be detected by molecular methods) would be excluded from this study.

Prior treatment with montelukast or zakirlukast within the past 2 months and total duration of therapy does not exceed 3 months.

Clinically significant systemic illness with manifestations of significant organ dysfunction which in the judgment of Principal or Associate Investigator would render the patient unlikely to tolerate the protocol therapy or complete the study.

Patients must have been on their current cGVHD therapeutic regimen for at least 3 months with stable or decreasing FEV1 to be eligible for this trial. Any patient who has been on a therapy for less than 3 months for cGVHD will need to be monitored for 3 months without improvement in FEV1 prior to enrollment.

Ventilated patients are excluded.

Patients taking rifampin or phenobarbital as these medications alter the metabolism of montelukast.

Patients taking greater than one age-appropriate dose of ibuprofen or aspirin containing products per day that inhibit cyclooxygenase will be excluded from this trial. The acceptable upper limit for daily doses of aspirin is 325mg/day and 1200mg/day of ibuprophen.

Patients with a history of allergy to montelukast.

Pregnant females and nursing mothers will be excluded from this trial due to unknown risks to the developing fetus. While on study, patients must be able to consent to utilize effective birth control measures.

Special Instructions:

Currently Not Provided

Keywords:

Leukotriene

Chronic Graft-Versus-Host Disease

Montelukast

Stem Cell Transplant

Bronchiolitis Obliterans

Recruitment Keyword(s):

Bronchiolitis Obliterans

Stem Cell Transplant

Chronic Graft-Versus-Host Disease

Condition(s):

Bronchiolitis Obliterans

Chronic Graft Versus Host Disease

Leukotriene

Montelukast

Stem Cell Transplant

Investigational Drug(s):

None

Investigational Device(s):

None

Intervention(s):

Drug: Montelukast

Supporting Site:

National Cancer Institute

Contact(s):

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s):

Chien JW, Martin PJ, Gooley TA, Flowers ME, Heckbert SR, Nichols WG, Clark JG. Airflow obstruction after myeloablative allogeneic hematopoietic stem cell Transplantation. Am J Respir Crit Care Med. 2003 Jul 15;168(2):146-7.

Dudek AZ, Mahaseth H, DeFor TE, Weisdorf DJ. Bronchiolitis obliterans in chronic graft-versus-host disease: analysis of risk factors and treatment outcomes. Biol Blood Marrow Transplant. 2003 Oct;9(10):657-66.

Santo Tomas LH, Loberiza FR Jr, Klein JP, Layde PM, Lipchik RJ, Rizzo JD,Bredeson CN, Horowitz MM. Risk factors for bronchiolitis obliterans in allogeneic hematopoietic stem-cell transplantation for leukemia. Chest. 2005 Jul;128(1):153-61.

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