Background: KRAS alterations are the most frequent driver alterations identified in pancreas cancer; however, KRAS has remained an elusive therapeutic target. siG12D-LODER is a novel, miniature bio-degradable polymeric matrix encompassing a novel small interfering RNA targeting KRAS G12D and all additional G12X mutations (G12C, G12V...). The siG12D-LODER is inserted directly into the pancreas tumor via endoscopic intervention. A Phase 1/2a dose escalation and expansion study of patients receiving a one-time dose of siG12D-LODER with ongoing chemotherapy demonstrated that the combination was well-tolerated and safe and exhibited promising potential efficacy with 10/12 patients achieving disease control and median overall survival 15.1 months (Golan, Oncotarget 2015). Methods: This phase 2 study was initially designed as a randomized, two arm, open label study of gemcitabine and nab-paclitaxel with or without siG12D-LODER for patients with locally advanced pancreas cancer with planned 40 patients in each arm and primary endpoint of progression-free survival. Eighteen patients were enrolled in the chemotherapy alone arm and 18 in the chemotherapy and siG12D-LODER arm. After an interim analysis, the study design has been amended and is now a single arm study in which patients (N=39) with both borderline resectable and locally advanced pancreas cancer will receive investigator’s choice of chemotherapy (the combination of gemcitabine/nab-paclitaxel or modified FOLFIRINOX) and all patients will receive up to three doses of the siG12D-LODER administered once every 12 weeks. Primary endpoint is overall response rate after final siG12D-LODER insertion. Secondary endpoints include duration of response, progression-free survival, overall survival, time to response, percentage of patients proceeding to surgical resection, and percentage of patients receiving radiation therapy. Exploratory analyses include evaluation of KRAS mutation status and monitoring of circulating free DNA and circulating tumor cells. The amended protocol is now open for accrual and four patients having been enrolled to date. Trial accrual is anticipated to be completed by December 2020. Clinical trial information: NCT01676259.