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 - is a miniature biodegradable polymeric matrix that encompasses anti K-RasG12D siRNA drug, designed to release the drug regionally along 4 months. The siG12D LODER is placed with Endoscopic US biopsy. 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 a dose escalation, dose cohorts were: 0.025mg, 0.75mg and 3.0mg. Gemcitabine 1000 mg/m²IV was given on a weekly basis, following the siG12D LODER insertion, until disease progression. The RP2D (recommended phase II dose) was further examined in highest dose cohort in combination with modified Folfirinox (Oxaliplatin 85mg/m2, Irinotecan 150mg/m2 followed by a Fluorouracil continuous IV 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 with locally advanced PDAC have been enrolled. Two patients were omitted from study but followed for safety 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). No DLTs were observed. CT performed 8-12 weeks following the procedure showed tumor regression in 66% (8 of the first 12 patients, 7/8 from 2nd and 3rd cohorts).Reduction in tumor marker CA 19-9 was observed in 64% (7/11) of patients. Median overall survival was 16.26 months, 14.01 months and 15.11 months in the 0.025 mg, 0.75 mg and the 3 mg treatment groups respectively. Conclusions: The combination of siG12D LODER and chemotherapy is well tolerated. The combination has demonstrated promising efficacy in locally advanced pancreatic cancer with durable responses. NCT01188785. Clinical trial information: NCT01188785.