Abstract Introduction: Prostacyclin genetic overexpression or the oral prostacyclin analogue iloprost prevent development of lung cancer in a variety of murine models, including cigarette smoke exposure mice. The mechanism of action is through non-canonical PPARγ activation. PPARγ agonists also prevent development of lung cancer in experimental models. These observations have led to completed ongoing and planned phase II chemoprevention clinical trials using bronchial histology as the primary endpoint. Methods: In the completed randomized Phase II study comparing iloprost to placebo entry criteria included: current or former smoker (> 20 pack years); at least mild cytologic atypia on sputum cytology; no previous history of cancer. Autofluorescence and white light bronchoscopy was performed with 6 standard endobronchial sites biopsied, along with all other abnormally appearing areas. Subjects were then randomized to oral iloprost (in escalating doses) or placebo for 6 months and then a second bronchoscopy with repeat biopsy of all the central airway areas sampled during the first bronchoscopy, as well as any new areas suspicious for dysplasia. The predetermined primary endpoint for the study was average bronchial histologic score (based on the WHO classification of premalignant lesions) in all subjects, as well as in current and ex-smokers separately. In the ongoing study of the PPRAα agonist, pioglitazone, entry criteria, sample size and endpoints are similar. Results: For the iloprost study, 152 subjects were randomized and 125 completed both bronchoscopies (60/75 iloprost, 65/77 placebo). Treatment groups were well matched for age, tobacco exposure and baseline histology. Endobronchial histology was summarized within patients using three separate measures: worst biopsy score (Max), dysplasia index (DI - defined as the percentage of biopsies with a score of at least 4 (mild dysplasia) or worse), and average of all biopsy scores (Avg). 74% of subjects had at least one biopsy displaying mild dysplasia (score 4.0) or worse on the initial bronchoscopy. A reproducibility study with two independent pathologists demonstrated that 85% of readings were within one histologic grade. Baseline histology was significantly worse for current smokers (Avg 3.0) than former smokers (Avg 2.1). Former smokers receiving oral iloprost exhibited a significant improvement in Avg (0.41 better, p=0.010), Max (1.10 units, p=0.002), and an improvement in DI (12.45%, p=0.006). No histologic improvement occurred in current smokers. Proliferation by Ki-67 index was a secondary endpoint and demonstrated no change with iloprost administration. There were no differences in dropout rates or SAEs between treatment groups. In the ongoing pioglitazone study - patients have been enrolled and dropout rates are also very low. Conclusions and Future Directions: Oral iloprost significantly improved endobronchial dysplasia in former heavy smokers with sputum dysplasia. Unfortunately, the oral iloprost studied is no longer available commercially. Since the ultimate goal is to prevent lung cancer and the groups at highest risk and greatest numbers are resected stage I lung cancer and head and neck cancer patients. We are planning a randomized phase II trial in resected stage I NSCLC and SCCHN patients. The study drug will be a new oral prostacyclin or to placebo for one year with bronchial biopsies at times 0, 6 month and 12 months. CT scan will also be obtained at these times with bronchial histology as primary endpoint. When the pioglitazone study and this study are completed, a phase III randomized trial with prevention of secondary lung cancer as the primary endpoint in contemplated. Disclosures: RLK, YEM and MWG hold a patent for the use of prostacylin analogs for the prevention of cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr ED01-03.