Background: Kirsten rat sarcoma viral oncogene homolog(KRAS) p.G12C mutation is an oncogenic driver mutation in several solid tumors. Sotorasib is a specific, irreversible, small molecule inhibitor of KRAS^G12C that has demonstrated durable clinical benefit in NSCLC, with mild and manageable toxicities. Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related death in the world, although recent advances in chemotherapeutic regimens for metastatic PDAC provide better clinical outcomes. KRAS p.G12C mutations are found in 1-2% of PDAC. Modest single agent activity of Sotorasib was observed in chemo-refractory PDAC patients (pts). Combination of Sotorasib with approved PDAC chemotherapy regimens is expected to enhance antitumor efficacy. This study is designed to evaluate safety, tolerability and efficacy of Sotorasib in combination with second line chemotherapy in pts with KRASp.G12C mutated advanced PDAC who have progressed on first-line chemotherapy. Methods: This investigator initiated study run through Hoosier Cancer Research Network, is a phase Ib/II study evaluating Sotorasib in combination with either Liposomal Irinotecan/5-Fluorouracil/Leucovorin or Gemcitabine/nab-paclitaxel. Physician choice of chemotherapy based on first line chemotherapy regimen used. Histologically confirmed PDAC pts who have KRAS p.G12C mutation identified through tumor or blood based testing, progressed on first-line chemotherapy, adequate organ function and performance status are eligible. A safety lead-in will be conducted to evaluate the safety of Sotorasib at a dose of 960 mg in combination with each of the two chemotherapy regimens. A “3+3” dose de-escalation design will be used for each combination separately. All patients treated at the RP2D in the initial safety cohort will be evaluable for response and included in the first stage of Simon’s two stage design. The phase II trial conducted at the RP2D follows Simon’s two-stage “minimax” design. The trial is designed to test whether addition of Sotorasib to chemotherapy will improve the objective response rate (ORR), from 16% to 31%. In Stage 1, 22 evaluable patients will be enrolled, and the trial will be stopped if 3 or fewer of the 22 evaluable patients respond. If ≥ 4 responses are observed, an additional 28 patients will be enrolled in Stage 2, for a total of 50 evaluable patients. Up to 59 subjects will be enrolled across 15 academic cancer institutions in order to obtain the required number of 50 evaluable subjects, assuming 15% attrition rate. Primary endpoint is to determine the objective response rate (ORR) by RECIST 1.1. The secondary endpoint to evaluate safety, and further evaluate efficacy in terms of disease control rate, duration of response, progression-free survival and overall survival. Correlative endpoints will determine biomarkers based on analysis of blood and/or tumor on study. Clinical trial information: IND 159412.