Cigarette smoking is causally associated with development of cancer of the lung, head & neck region, esophagus, bladder, and other sites by overwhelming epidemiological and biologic evidence. Cessation of smoking results in a slow decline in risk of cancer development that remains elevated compared to never smokers beyond 15 years after smoking cessation. Thus, strategies to reduce the impact of lung cancer in former smokers are needed. The epidermal growth factor receptor (EGFR) and cyclo-oxygenase II (COX-2) have been implicated in the development and maintenance of lung cancer. Clinical trials of the EGFR tyrosine kinase inhibitor, ZD1839, in patients with established cancer have demonstrated biological and anti-tumor effects. In the first part of this application, a Phase I, open-label, dose escalation clinical trial will be conducted to determine the maximal tolerable dose of ZD1839, and the associated effect on EGFR signaling, when used as a chemopreventive agent in former smokers. Former smokers treated with curative intent for early stage lung or head and neck cancer will be treated in cohorts of escalating doses of ZD1839. Measures of drug effect (EGFR, c-fos, apoptosis) and biomarkers of lung cancer risk will be measured in bronchial epithelium before and after taking drug for 12 weeks. Potential efficacy of EGFR and/or COX-2 inhibition (using ZD1839 and Celecoxib, respectively) will then be assessed in a Phase II, placebo-controlled, clinical trial assessing effect on bronchial epithelial genetic loss and other surrogate biomarkers of lung cancer risk.
