A multicenter phase I study of adenoviral p53 in Japanese patients with advanced non-small cell lung cancer

Abstract

2564 Adenovirus expressing p53 gene, Advexin (A), has shown antitumor activity in a variety of human cancer in preclinical and clinical studies. The goals of this study were to determine the feasibility, safety, humoral immune response, and biological activity of multiple intratumoral injections of A and to characterize the pharmacokinetics of A in Japanese patients with advanced non-small cell lung cancer (NSCLC). Fifteen patients with histologically confirmed NSCLC and p53 mutations were enrolled into this phase I trial. Nine patients received escalating dose levels of A (1 × 109 to 1 × 1011 plaque-forming units [PFU]) as monotherapy once every 4 weeks. Six patients were treated on a 28-day schedule with A in combination with intravenous administration of cisplatin (80 mg/m2). Patients were monitored for toxicity, tumor response, antibody formation, and vector distribution. Fifteen patients received a total of 63 intratumoral injections of A without dose-limiting toxicity. The most common treatment-related toxicity was a transient fever. Thirteen of 15 patients were assessable for efficacy; one patient had a partial response (squamous cell carcinoma at the carina), 10 patients had stable disease, with three lasting > 9 months, and 2 patients had progressive disease. Distribution studies revealed that the vector was detected in the gargle and plasma, but rarely in the urine. Despite of the presence of neutralizing anti-adenovirus antibody, specific p53 transgene expression was detected in biopsied tumor tissues throughout the period of treatment using reverse-transcriptase polymerase chain reaction We conclude that multiple courses of intratumoral A injection alone or in combination with intravenous administration of cisplatin were feasible and well tolerated in advanced NSCLC patients, and appeared to provide clinical benefit. [Table: see text]