This time, we are sharing with you a phase I clinical trial on KRAS inhibitor siRNA in combination with chemotherapy for advanced pancreatic adenocarcinoma at ASCO 2013. Background: KRAS G12D mutations are common in patients with pancreatiadenocarcinoma (PDAC), and siRNA as KRAS G12D (siG12D) inhibitors have shown significant oncogenic effects in non-clinical trials. siG12D LODER is a compressed anti-KRAS G12D siRNA drug used to small, biodegradable polymer matrix that enters the patient’s body via US endoscopy and can release the drug into the patient’s implanted matrix for up to 4 months. METHODS: Local patients with advanced inoperable PDAC were recruited for a phase I open-label clinical trial. Patients were divided into three groups with siG12D doses of 0.025 mg, 0.75 mg and 3.0 mg. patients were also treated with weekly intravenous gemcitabine 1000 mg/m2 after siG12D Loder implantation. the group with siG12D 3.0 mg was combined with an improved Folfirinox regimen (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2). Irinotecan 150 mg/m2 and fluorouracil infusion 2,400 mg/m2 for 46 hours, every two weeks). Follow-up began at week 8 after treatment and ended with patient death. The primary objective of this trial was to detect dose-limiting toxicities (DLT) and maximum tolerated doses (MTD). RESULTS: Fifteen patients were enrolled and two patients were excluded due to metastasis on the first day after siG12D LODER implant imaging. The mean age of the patients was 70 years (52-85), with a male-to-female ratio of 8:7. The majority of the 13 patients seen had grade 1-2 toxicities, and 4 patients had serious adverse events (SAEs), one of which was due to disease progression. No DLTs were present in the patients and no MTD was reached. patients were monitored for disease progression using CT starting after 8-10 weeks and all patients were found to have stable disease. 64% (7/11) of patients had reduced expression of the tumor marker CA 19-9. the median survival of the 13 patients was 16 months (8/13 patients are still alive to date). CONCLUSIONS: siG12D LODER combination chemotherapy is a patient-tolerated treatment regimen. Combination therapy is highly effective in patients with advanced PDAC with only primary foci, and the toxicities are within the tolerable range. Currently, pharmacokinetic endpoints are determined by patients who are operable in an extension trial. A phase II randomized clinical trial is also now in preparation to facilitate exploration of the efficacy of siG12D LODER in patients with advanced inoperable PDAC.