Background: 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 antimitochondrial agent developed by Rafael Pharmaceuticals that showed promising clinical activity in combination with modified FOLFIRINOX in patients with stage IV pancreatic cancer. Preclinical data suggested possible synergy of CPI-613 with nab-paclitaxel. Methods: Single arm, open-label, phase I study of CPI-613 with gemcitabine and nab-paclitaxel in patients with locally advanced or metastatic pancreatic cancer to determine MTD, safety, and preliminary efficacy of CPI-613 in combination with chemotherapy. Key eligibility criteria included: histologically documented and measurable locally-advanced or metastatic, PDAC. ECOG performance status 0-2; and first line systemic treatment. CPI-613 was infused intravenously with a starting dose of 500 mg/m² followed by modified dose nab-paclitaxel (100mg/m2) and gemcitabine ( 800 mg/m2) on Days 1, 8, and 15 of a 28-day cycle. The the primary endpoint, the MTD of CPI-613 was determined by a two-stage, dose-escalation schema, with 6-month treatment duration for patients exhibiting treatment response. Secondary endpoints were treatment-related adverse events, complete response (CR) and partial response (PR). Results: From February 2018 to 2020, 26 patients were screened, (23 metastatic and 3 locally advanced), 22 patients enrolled and 18 patients underwent a restaging scan. As of the time of submission 3 patients are still on active treatment. Patient demographics were: median age of 65, ECOG was 0-1, The MTD of CPI- 613 was determined to be 1500 mg/m². The dose limiting toxicities were not achieved. Overall the treatment was well tolerated with toxicities mainly related to chemotherapy; most common grade 3 and 4 toxicities were hematologic toxicity and neuropathy. 1 patient achieved CR, 9 PR, 8 stable disease and 1 progressive disease for an objective response rate of 50% with a CR rate of 5.5%. Conclusions: The results demonstrate that CPI 613 can be safely administered with gemcitabine and nab-paclitaxel at doses up to 1,500 m/g2. Efficacy data suggest synergy with chemotherapy. Further clinical studies of CPI-613 efficacy in pancreatic cancer are in progress. Clinical trial information: NCT03435289..