Devimistat (CPI-613^®) is a novel lipoate analog that inhibits the tricarboxcylic acid cycle at two key carbon entry points. Through its inhibition of pyruvate dehydrogenase and a-ketoglutarate dehydrogenase complexes, devimistat inhibits the entry of glucose and glutamine derived carbons, respectively. Pancreatic cancer is dependent on mitochondrial function for enhanced survival and aggressiveness. In a Phase I study of modified FOLFIRINOX, in combination with devimistat for metastatic pancreatic cancer patients, there was a 61% objective response rate including a 17% complete response rate. This report outlines the rationale and design of the AVENGER 500 study, a Phase III clinical trial of devimistat in combination with modified FOLFIRINOX compared with FOLFIRINOX alone for patients with previously untreated metastatic adenocarcinoma of the pancreas. Clinical trial registration: NCT03504423