Background: Pancreatic cancer remains a deadly disease and despite advances in chemotherapy treatment, survival for most patients is still less than one year. Over 80% of pancreatic cancers are KRAS mutant which activates the PI3K/AKT pathway and signals downstream to mTOR leading to cell growth, proliferation and survival. Recent data has shown that blocking both the PI3K/AKT and MEK pathways simultaneously is effective in KRASmutant tumors. Our trial is a novel, molecular targeted treatment approach for patients with metastatic pancreatic cancer that has the potential to establish a new treatment paradigm. Methods: S1115 was activated in SWOG in August 2012 and is currently IRB approved at 130 institutions within SWOG and the Clinical Trials Support Unit (CTSU). Patients (performance status 0 or 1) with metastatic pancreatic cancer failing standard gemcitabine chemotherapy are randomized to MK-2206 135 mg orally weekly plus selumetinib 100 mg orally daily or mFOLFOX IV every 2 weeks. Eligibility criteria allow metastatic patients who have progressed within 6 months of receiving adjuvant gemcitabine. Patients receiving prior 5-fluorouracil (excluding radiation-sensitizing doses), capecitabine, oxaliplatin, MEK or PI3K/AKT inhibitors are not eligible. Stratification factors include duration of prior systemic therapy and presence of liver metastases. The primary endpoint of this study is overall survival (OS) in patients treated with the combination of MK-2206 and selumetinib compared with those treated with mFOLFOX. Based on previous studies, median OS in the control group is approximately 6 months. Assuming a one-sided type 1 error of 10%, 80% power, approximately 2 years of accrual and 1.5 years of follow-up, 120 eligible patients will be accrued to detect an improvement in median survival from 6 to 9 months (corresponding to a 1.5 hazard ratio). Prospective tumoral tissue collection will be undertaken. ClinicalTrials.gov Identifier: NCT01658943. Support: NCI grants CA32102 & CA38926 Clinical trial information: NCT01658943.