Montelukast in Treating Patients With Bronchiolitis Obliterans After Stem Cell Transplant

Condition(s) targeted: Cancer

Intervention: montelukast sodium (Drug); flow cytometry (Other); laboratory biomarker analysis (Other); quality-of-life assessment (Procedure)

Phase: Phase 2

Status: Recruiting

Sponsored by: National Cancer Institute (NCI)

Official(s) and/or principal investigator(s):
Ronald E. Gress, MD, Principal Investigator, Affiliation: NCI - Experimental Transplantation and Immunology Branch

RATIONALE: Montelukast may be effective in treating bronchiolitis obliterans after stem cell transplant.

PURPOSE: This phase II trial is studying how well montelukast works in treating patients with bronchiolitis obliterans after stem cell transplant.

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

Study design: Supportive Care, Non-Randomized, Open Label

Primary outcome:

Comparison of the proportion of patients with stable or improved percentage of predicted FEV1 with published literature

Comparison of the slope of FEV1 before and after treatment with montelukast sodium

Secondary outcome:

Oxygen saturation and supplementation

Pulmonary function tests, including FEF25-75, RV or RV/FVC, DLCO2, and the ratio of FEV1/FVC and FEV1/SVC

Pulmonary endurance as measured by a 2- and 6-minute walk test

Leukotriene levels in the urine and blood and leukotriene receptor expression on activated circulating immune cells

Other chronic graft-vs-host disease manifestations

Quality of life and function parameters

Overall survival at 2 years

Detailed description: OBJECTIVES:

Primary

- To determine if montelukast sodium results in stabilization or improvement in pulmonary

function in patients with bronchiolitis obliterans following allogeneic or autologous stem cell transplantation by comparing the absolute change in predicted FEV_1 in these patients with a benchmark control from publications and by comparing the FEV_1 slope (of the absolute value) before and after treatment with montelukast sodium.

Secondary

- To confirm the safety profile of montelukast sodium in these patients.

- To determine if montelukast sodium improves oxygen saturation or decreases oxygen

requirement in these patients.

- To assess if montelukast sodium improves other pulmonary function parameters, including

FEF25-75, RV, DLC02, and the ratio of FEV_1/FVC and FEV_1/SVC, in these patients.

- To determine if montelukast sodium improves pulmonary endurance in these patients as

measured by a 2- and 6-minute walk test.

- To evaluate if montelukast sodium decreases leukotriene levels (LTB4 and CysLT) in the

urine or blood or leukotriene receptor expression (BLT or CysLT) on activated circulating immune cells.

- To determine if improvement in pulmonary function correlates with decreased leukotriene

levels or leukotriene receptor expression on activated circulating immune cells.

- To investigate whether patients experience improvements in other chronic

graft-versus-host disease manifestations and quality of life and function parameters during treatment with montelukast sodium.

- To evaluate if the introduction of montelukast sodium impacts the 2-year overall

survival of these patients.

OUTLINE: This is a multicenter study.

Patients receive oral montelukast sodium once daily for 6 months in the absence of disease progression or unacceptable toxicity.

Blood and urine samples are collected at baseline and at 3 and 6 months to measure leukotriene levels (cysteinyl and LTB4); leukotriene receptor expression on circulating immune cells (including T-cells, B-cells, eosinophils, neutrophils, and monocytes) by flow cytometry; and cytokine levels by immunofluorescent techniques.

Patients complete quality-of-life questionnaires at baseline and at 1, 3, 6, and 18 months.

After completion of study treatment, patients are followed at 6 and 18 months.

Minimum age: 6 Years. Maximum age: 80 Years. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS:

- Diagnosis of bronchiolitis obliterans (BO) following allogeneic or autologous stem

cell transplantation, meeting all of the following criteria:

- FEV_1 ≤ 75% of predicted by pulmonary function test (PFT) for height and weight

- Patients must have 2 PFT measurements with documented FEV_1 values > 3

months apart to calculate the FEV_1 slope at study entry

- Meets one of the following criteria:

- Evidence of air-trapping or small airway thickening or bronchiectasis on

high resolution chest CT scan; RV or RV/FVC > 120%; and evidence of chronic graft-vs-host disease (cGVHD) of another organ

- FEV_1/SVC ratio < 5% of predicted for age or < 0. 7

- Pathologic evidence of bronchiolar inflammation and obstruction of the

lumen consistent with a diagnosis of BO

- No active infection

- Any clinical symptoms must be evaluated by radiographic, microbiologic, and

pathologic studies as determined by the Principal Investigator or Lead Associate Investigator

- Patients without pathologic evidence of BO must have one other sign of cGVHD present

- For diagnosis of cGVHD, a minimum of the following must be present:

- A process distinct from that diagnosed as acute GVHD

- Presence of a diagnostic sign or a distinctive sign supported by another

clinical or laboratory test

- Exclusion of other pathologies (i. e., recurrent cancer, drug reaction, or

infection)

- Has been on a therapeutic regimen for cGVHD for ≥ 3 months AND has stable or

decreasing FEV_1

- Any patient who has been on a therapy for cGVHD for < 3 months will need to be

monitored for 3 months AND demonstrate no improvement in FEV_1 prior to study enrollment

- No tumor burden greater than minimal residual disease (i. e., tumor burden that can

only be detected by molecular methods)

PATIENT CHARACTERISTICS:

- Karnofsky or Lansky performance status 40-100%

- Total bilirubin < 3 times upper limit of normal (ULN) for age

- Transaminases < 5 times ULN for age

- LVEF > 25%

- FEV_1 ≥ 20% of predicted

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No requirement for ventilation

- No clinically significant systemic illness with manifestations of significant organ

dysfunction that, in the judgment of Principal or Associate Investigator, would render the patient unlikely to tolerate study therapy or complete the study

- No history of allergy to montelukast sodium

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Any prior therapy that has been administered chronically for > 3 months for BO is

allowed provided the patient has not demonstrated improvement attributed to this agent during a 1-month period (or longer) of observation prior to study enrollment

- For patients on steroids, a change exceeding ½ mg/kg/day will be considered for

the start of the 3 month monitoring period

- Documented intercurrent infections that are treated with antimicrobials that

result in improvements to, but not above previous baselines will not be considered an improvement attributable to immunosuppressive therapy

- Prior montelukast sodium or zafirlukast allowed provided the patient has been off

treatment for at least 2 months prior to study and duration of total therapy did not exceed 3 months

- Prior bronchodilators or other pulmonary therapies allowed

- No concurrent rifampin or phenobarbital

- No concurrent ibuprofen or acetylsalicylic acid (aspirin)-containing products that

inhibit cyclooxygenase

- Concurrent local steriod therapy including inhaled steroid therapy during steroid

taper allowed

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231-2410, United States; Recruiting
Clinical Trials Office - Sidney Kimmel Comprehensive Cancer Ce, Phone: 410-955-8804, Email: jhcccro@jhmi.edu

Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office, Bethesda, Maryland 20892-1182, United States; Recruiting
Clinical Trials Office - Warren Grant Magnusen Clinical Center, Phone: 888-NCI-1937

Hackensack University Medical Center Cancer Center, Hackensack, New Jersey 07601, United States; Recruiting
Clinical Trials Office - Hackensack University Medical Center, Phone: 201-996-2879

Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, United States; Recruiting
Paul J. Martin, MD, Phone: 206-667-4798

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: February 2008
Last updated: May 28, 2009