Phase II clinical trial of zileuton in persons with bronchial dysplasia

A105

Eicosanoids derived from the arachidonic acid cascade have been implicated in the pathogenesis of lung cancer. The most compelling data involve the 5-lipoxygenase (5-LO) pathway. Animal studies found that LO inhibitors have chemopreventive activity in lung carcinogenesis. Therefore, we have conducted a placebo controlled, double-blind, randomized, two-arm phase II chemoprevention trial with zileuton, an asthma drug which inhibits 5-LO, in humans with biopsy proven bronchial dysplasia. Our primary hypothesis was that treatment with zileuton would be associated with regression of bronchial dysplastic lesions and, therefore, with reduced risk of lung cancer. Our secondary hypothesis was that zileuton would modulate biomarkers of cell proliferation and apoptosis, Ki67, Cyclin D1, Bcl-2, Bax and Caspase 3, and lipoxygenase metabolites, 5-HETE and LTB4 in bronchial biopsies, bronchoalveolar lavage (BAL) fluid, brushings and sputum and these changes would be associated with regression of bronchial dysplasia. Study population included current or former smokers who have smoked >30 pack-years and who were over the age of 35. A total of 1041 subjects were screened for study entry. Eighty-six laser induced fluorescence endoscopy (LIFE) bronchoscopies were performed; 47 were negative for dysplasia, 39 had dysplasia. Thirty-eight eligible subjects were entered on the study and 8 subjects dropped out. Thirty-seven subjects were randomly assigned to receive zileuton (n=20) 600 mg or placebo (n=17) po 4 times daily for 6 months, after which they were switched to the opposite arm for 6 months. LIFE bronchoscopies were performed at baseline, 6 months and 12 months and biopsies were taken from pre-designated and abnormal appearing areas and BAL and blood specimens were collected for biomarker studies. Bronchial biopsy readings were consensus opinions of two experienced lung pathologists (LF and AG) and Ki67, Cyclin D1, Bcl-2, Bax and Caspase 3, were evaluated with immunohistochemistry. Serum and BAL levels of 5-HETE and LTB-4 were measured by LC-MS-MS. There were no statistically significant differences between the groups with regard to number and severity of bronchial dysplastic lesions at baseline, 6 months and 12 months. There were no significant differences in any of the immunohistochemical or metabolic biomarkers measured. The study shows that zileuton is inactive in this population of subjects. However the study is underpowered due to small number of subjects. Most adverse events (AE) were mild and did not require interruption of the study drug. There were 174 grade 1, 43 grade 2, 5 grade 3, 4 grade 4 and 2 grade 5 AEs. Most of the grade 1-2 events and all of the grade 3-5 events were felt to be unrelated or unlikely to be related to the study drug. Supported by NCI contract NO1-CN-05022.