Phase 1 study to test safety and dose of proglumide as an anti-fibrotic agent

胰腺癌和肝癌的发病率正在显著上升，很快将成为第二位。 美国癌症相关死亡的第三个原因。这些癌症的已知风险因素(和其他)包括 慢性炎症和纤维化。此外，在已确诊的癌症中，肿瘤的环境 具有免疫抑制免疫细胞和基质的微环境被认为损害了 化疗和免疫治疗。胰腺和肝脏表达CCK受体 它们也存在于星状细胞、组织成纤维细胞和免疫细胞上。我们有 在小鼠模型中发现用CCK受体拮抗剂丙谷胺阻断这些受体 抑制胰腺肿瘤生长的同时减少肿瘤微环境的纤维化，改变 免疫细胞渗入，使肿瘤易受治疗。在非酒精中毒的小鼠模型中 脂肪性肝炎(NASH)，丙谷胺逆转组织学NASH，降低肝脏转氨酶和胆红素，以及 预防肝细胞癌。丙谷胺30年前被开发用于治疗消化性溃疡疾病， 当时在人体内安全使用，但自从发现质子泵抑制剂后就不再使用了。 我们假设丙谷胺是一种有效的抗炎和抗纤维化药物，可以 为促进胰腺癌的治疗选择而开发，也作为一种预防性治疗 NASH相关肝细胞癌。此应用程序的目的是重新调整丙谷胺治疗慢性 炎症和纤维化(即胰腺癌和NASH)。我们计划用GMP生产丙谷胺 标准，然后在史密斯博士的食品和药物管理局(IND#138481)下进行一期临床研究，以确定 NASH患者丙谷胺的安全性和耐受性及最大耐受量(MTD)。在这 应用GMP级丙谷胺将被制造，并用高效液相色谱法检测纯度，然后进行复合 制成300毫克胶囊，并进行质量控制测试。接下来，将在符合条件的地区进行一期临床试验 NASH受试者使用MS或HPLC法检测丙谷胺的安全性和血药浓度。最初的剂量将 用于溃疡疾病的测试剂量略低，为300 mg Bid，然后在经典的3+3中升级 确定MTD的研究设计。受试者将接受为期12周的治疗。安全性和毒性将通过以下方式进行评估 验血和体检。丙谷胺的血液浓度将在2和4之后进行尖锐的分析 治疗数周，以确定是否存在可能与任何毒性相关的血液水平。符合条件的科目 会有肝脏转氨酶升高和脂肪肝的超声证据。肝脏纤维扫描将是 在治疗前和治疗12周后进行，以收集关于肝脏脂肪变性和 与治疗有关的纤维化。这项早期研究的目标是提供重要的支持性信息 关于将一种旧药物丙谷胺作为癌症治疗的辅助药物或用于未来的使用和再利用 NASH预防肝细胞癌的治疗试验。

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.