Tolerability and safety of EUS-injected adenovirus-mediated double-suicide gene therapy with chemotherapy in locally advanced pancreatic cancer: Phase I Trial

Abstract Background and Aims Locally advanced pancreatic cancer (LAPC) is challenging. Here we aimed to evaluate the tolerability and safety of Ad5-yCD/mutTK(SR39)rep-ADP (Ad5-DS), a replication-competent adenovirus-mediated double-suicide gene therapy in combination with gemcitabine in LAPC patients. Methods Newly diagnosed LAPC patients were enrolled in this single-center, open label, 3+3 dose-escalation phase I trial (NCT02894944). Ad5-DS was injected into the pancreatic mass with endoscopic ultrasonography-guided fine needles combined with oral 5-fluorocytosine and valganciclovir, and standard dose of intravenous gemcitabine. The doses of Ad5-DS in cohorts 1 to 3 were 1 × 1011, 3 × 1011, and 1 × 1012 vp/mL, respectively. Patients were observed for dose-limiting toxicity (DLT) for 8 weeks after Ad5-DS injection. Toxicity within 12 weeks, tumor response in 12 weeks, disease progression in 6.5 months, and detection of adenoviral DNA particle in 8 weeks were also assessed. Results Among the 11 enrolled patients, 9 completed the evaluation period and 2 withdrew their consent. No DLT was reported; thus, the maximum tolerated dose (MTD) was not reached. No additional toxicity was reported in 9 to 12 weeks. One patient showed a partial response and 8 showed stable disease at 12 weeks. Two patients showed disease progression at 6.5 months (median progression-free survival, 11.4 months). At 8 weeks, serum adenoviral DNA particles were detected in 4 patients (median, 55 days). Conclusion Combination of intratumoral Ad5-DS and gemcitabine is safe and well-tolerated in patients with locally advanced pancreatic cancer. This warrants further investigation in a larger clinical trial.