The incidence of pancreatic cancer and liver cancer are significantly increasing and soon will become the 2nd and 3rd causes of cancer-related deaths in the USA. Known risk factors for these cancers, (and others) include chronic inflammation and fibrosis. Furthermore in established cancers, the milieu of the tumor microenvironment with immunosuppressive immune cells and stroma are thought to impair penetrance of chemotherapy and immunotherapy. Cholecystokinin (CCK) receptors are expressed on pancreatic and hepatic epithelial cells; and they are also found on stellate cells, tissue fibroblasts, and immune cells. We have discovered in murine models that blockade of these receptors with the CCK-receptor antagonist proglumide decreases pancreatic tumor growth while decreasing fibrosis of the tumor microenvironment and altering the immune cell infiltrates rendering the tumor susceptible to therapy. In a murine model of nonalcoholic steatohepatitis (NASH), proglumide reversed histologic NASH, lowered liver transaminases and bilirubin, and prevented hepatocellular cancer (HCC). Proglumide was developed for peptic ulcer disease 30 years ago and safely used in human subjects at that time but is no longer used since the discovery of proton pump inhibitors. We hypothesize that proglumide is an effective anti-inflammatory and anti-fibrotic agent that can be developed to facilitate therapeutic options in pancreatic cancer and also as a preventative therapy in NASH-associated HCC. The purpose of this application is to repurpose proglumide for conditions of chronic inflammation and fibrosis (i.e., pancreatic cancer and NASH). We plan to manufacture proglumide by GMP standards and then conduct a Phase 1 clinical study under Dr. Smith’s FDA (IND #138481) to determine safety and tolerability and the maximum tolerated dose (MTD) of proglumide in subjects with NASH. In this application GMP-grade proglumide will be manufactured and tested for purity by HPLC and then compounded into 300mg capsules and tested for quality control. Next, a Phase 1 clinical trial will be conducted in eligible subjects with NASH to test the safety and blood levels of proglumide using MS or HPLC. The initial dose will be tested at a slightly lower dose used in ulcer disease of 300 mg BID and then escalated in the classic 3+3 study design to determine MTD. Subjects will be treated for 12 weeks. Safety and toxicity will be evaluated by blood tests and physical examinations. Blood levels of proglumide will be analyzed acutely and after 2 and 4 weeks of treatment to determine if there is a blood level that may correlate with any toxicity. Eligible subjects will have elevated liver transaminases and ultrasound evidence of fatty liver disease. A liver FibroScan will be performed before and after 12 weeks of therapy to collect preliminary data on changes in hepatic steatosis and fibrosis with the therapy. The goal of this early phase study is to provide important supportive information to the FDA regarding the use and repurposing an old drug, proglumide as an adjunct to cancer therapy or for future trials in treatment of NASH to prevent HCC.