A phase I trial of intravenous therapy with tumor suppressor FUS1-nanoparticles for recurrent/metastatic lung cancer

e19065 Background: The tumor suppressor gene FUS1 is frequently inactivated early in lung cancer development. FUS1 mediates apoptosis in cancer cells but not normal cells through its interaction with Apaf1. DOTAP:cholesterol nanoparticles encapsulating a FUS1 expression plasmid showed selective uptake by cancer cells and activity in mouse xenograft metastatic lung cancer models. Methods: Patients with recurrent/metastatic lung cancer previously treated with platinum-based chemotherapy were treated with escalating doses of intravenous DOTAP:cholesterol FUS1 nanoparticles. Nanoparticle-DNA complexes were manufactured in GMP facilities to meet specifications of OD400, size, appearance, and transfection efficiency. Results: Patients have received doses ranging from 0.01–0.09 mg/kg at 3 week intervals. To date 23 patients have been entered on study at 6 dose levels, with 21 patients currently evaluable for the primary endpoint of cycle 1 toxicity. 70% of subjects had received 2 or more prior chemotherapy regimens. Among 4 patients treated without premedications, all 4 developed grade 2 or higher fevers within 24 hours of treatment. Among the 17 patients premedicated with dexamethasone and diphenhydramine, 4 developed grade 1 fever. There have been no other grade 2 or higher drug-related toxicities. Four patients received only one dose because of rapidly progressing disease at a site requiring local treatment. Fifteen patients received two or more doses and are evaluable for response, with 4 patients achieving stable disease and 11 patients progressing. Median survival time for all patients is 10.3 months. A maximum tolerated dose (MTD) has not been reached. Pre and 24 hour posttreatment tumor biopsies were obtained from 4 patients. A quantitative real time reverse transcriptase PCR (RT-PCR) analysis using a plasmid FUS1 sequence-specific probe have been performed on 3 paired-samples blinded to time of biopsy. A high level of plasmid FUS1 expression was detected in all 3 posttreatment samples but not in three pretreatment samples and negative controls by RT-PCR. Conclusions: DOTAP:cholesterol FUS1 nanoparticles can be safely administered intravenously in lung cancer patients with demonstrable gene expression in posttreatement tumor biopsies. [Table: see text]