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”

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.

Study Type: Interventional

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

Study Primary Completion Date: February 2011

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.

Intervention(s) in this Clinical Trial

• Drug: montelukast sodium
• Other: flow cytometry
• Other: laboratory biomarker analysis
• Procedure: quality-of-life assessment

Primary Measures

• Comparison of the proportion of patients with stable or improved percentage of predicted FEV1 with published literature
  • Safety Issue?: No
• Comparison of the slope of FEV1 before and after treatment with montelukast sodium
  • Safety Issue?: No

Secondary Measures

• Oxygen saturation and supplementation
  • Safety Issue?: No
• Pulmonary function tests, including FEF25-75, RV or RV/FVC, DLCO2, and the ratio of FEV1/FVC and FEV1/SVC
  • Safety Issue?: No
• Pulmonary endurance as measured by a 2- and 6-minute walk test
  • Safety Issue?: No
• Leukotriene levels in the urine and blood and leukotriene receptor expression on activated circulating immune cells
  • Safety Issue?: No
• Other chronic graft-vs-host disease manifestations
  • Safety Issue?: No
• Quality of life and function parameters
  • Safety Issue?: No
• Overall survival at 2 years
  • Safety Issue?: No

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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 6 Years

Maximum Age for this Clinical Trial: 80 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Cancer Institute (NCI)

Overall Clinical Trial Officials and Contacts

Ronald E. Gress, MD Principal Investigator NCI - Experimental Transplantation and Immunology Branch  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00656058

Study ID Number: CDR0000593080

ClinicalTrials.gov Identifier: NCT00656058

Health Authority: Unspecified

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