Background: Pancreatic cancer is the third leading cause of cancer death in the USA. The most effective treatments for first-line metastatic pancreatic cancer are FOLFIRINOX and gemcitabine plus nab-paclitaxel, which provide a median overall survival of 11·1 months and 8·5 months with moderate toxicity. Safer and more effective treatments are needed. The glycolic and mitochondrial metabolism are aberrant in pancreatic cancer and translate into chemoresistance. Inhibition of glutamine metabolism can potentially synergize with therapies that increase intracellular reactive oxygen species such as Nab-Paclitaxel. CPI- 613 is a novel antimitocondrial developed by Rafael Pharmaceuticals that showed preclinical activity in pancreatic cancer cell lines as well as promising clinical activity in combination with modified FOLFIRINOX in patients with stage IV pancreatic cancer. Preclinical data suggests possible synergy of CPI- 613 with nab-paclitaxel. Methods: This is a single arm, open-label, nonblinded phase I study of CPI-613 in combination with gemcitabine and nab-paclitaxel in patients with locally advanced or metastatic pancreatic cancer. Key eligibility criteria include: histologically or cytologically documented and measurable locally advanced or metastatic pancreatic adenocarcinoma, ECOG performance status 0-2, first line treatment for both locally advanced or metastatic. CPI-613 will be infused intravenously with a starting dose of 500 mg/m² followed by 125 mg/m² nab-paclitaxel and 1,000 mg/m² gemcitabine on day 1, 8, 15 of a 28-day cycle. The study is comprised of a two-stage dose-escalation schema to evaluate the MTD of CPI-613. At least six months of treatment is planned for patients who have a response. Primary endpoint of the study is MTD of CPI 613 when combined with gemcitabine and nab-paclitaxel and secondary endpoints of the study are treatment related adverse events, CR and PR. This study was initiated in February 2018 at Atlantic Health System and within first seven months of the study, 11 out of 24 planned patients have been enrolled. Clinical trial information: NCT03435289