Background:K-Ras mutation G12D is most prevalent in pancreatic adenocarcinoma (PDAC). siRNA against the K-Ras^G12D(siG12D) mutant had showed significant preclinical anti-tumor effects. siG12D LODER - miniature biodegradable polymeric matrix that encompasses anti-K-RasG12D siRNA drug, is placed with Endoscopic US biopsy and designed to continuously release the drug regionally over a period of 4 months. Methods: Open label phase I study of patients with locally advanced non-operable PDAC in the first-line setting. Patients were assigned to receive siG12D LODERs in dose escalation cohorts: 0.025mg, 0.75mg and 3.0mg. Gemcitabine 1000 mg/m²IV was given weekly, following siG12D LODER insertion. The RP2D (recommended phase II dose) was further examined in 3.0 mg dose cohort in combination with modified Folfirinox (Oxaliplatin 85mg/m2, Irinotecan 150mg/m2, Fluorouracil infusion 2,400mg/m2 46 hours, every 2 weeks). Follow up period was 8 weeks and survival follow up until death. Primary study objectives were to determine the dose-limiting toxicities (DLT) and maximum tolerated doses (MTD). Results:15 patients have been enrolled. 2 patients were omitted from study due to metastatic disease detected on day 1 post siG12D LODER implant imaging . Median age = 70 (range 52-85); male:female 8:7. Among 13 treated patients, the most frequent adverse events observed in the study were typically grade 1- 2 in severity; 4 patients experienced serious adverse events (SAE), one procedure related. No DLTs were observed. MTD was not reached. CT performed 8-10 weeks following the procedure showed stable disease in all patients. Reduction in tumor marker CA 19-9 was observed in 64% (7/11) of patients. The median survival of 13 patients was 16 months ( 8/13 patients still alive at analysis). Conclusions: The combination of siG12D LODER and chemotherapy is well tolerated. The combination has demonstrated promising efficacy in locally advanced PDAC with durable responses. Phamocodynamic endpoints are currently being examined in an expansion cohort in operable patients. A phase II randomized trial is planned in order to investigate efficacy of siG12D LODER in locally advanced non-operable PDAC. Clinical trial information: NCT01188785.