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增加，很快将成为第二大癌症。 在美国，癌症相关死亡的第三大原因。这些癌症（和其他癌症）的已知风险因素包括 慢性炎症和纤维化。此外，在确定的癌症中，肿瘤的环境 具有免疫抑制性免疫细胞和间质的微环境被认为损害了 化疗和免疫疗法。胆囊收缩素（CCK）受体表达于胰腺和肝脏 上皮细胞;也见于星状细胞、组织成纤维细胞和免疫细胞。我们有 在用CCK受体拮抗剂丙谷胺阻断这些受体的小鼠模型中发现， 减少胰腺肿瘤生长，同时减少肿瘤微环境的纤维化， 免疫细胞浸润使肿瘤对治疗敏感。在非酒精性的小鼠模型中， 脂肪性肝炎（NASH），丙谷胺逆转组织学NASH，降低肝转氨酶和胆红素， 预防肝细胞癌（HCC）。丙谷胺是30年前开发的用于治疗消化性溃疡的药物， 当时可安全用于人类受试者，但自质子泵抑制剂发现以来已不再使用。 我们假设丙谷胺是一种有效的抗炎和抗纤维化药物， 开发用于促进胰腺癌的治疗选择，也可作为预防性治疗， NASH相关HCC。本申请的目的是将丙谷胺重新用于慢性 炎症和纤维化（即，胰腺癌和NASH）。我公司拟按GMP生产丙谷胺 标准，然后在Smith博士的FDA（IND #138481）下进行1期临床研究，以确定 在NASH受试者中丙谷胺的安全性和耐受性以及最大耐受剂量（MTD）。在这 将生产GMP级丙谷胺，并通过HPLC检测纯度，然后进行混合 制成300毫克胶囊并进行质量控制测试。接下来，将在符合条件的患者中进行1期临床试验。 NASH受试者使用MS或HPLC检测丙谷胺的安全性和血药浓度。初始剂量将 在溃疡病中使用的300 mg BID的稍低剂量下进行测试，然后在经典3+3中递增 确定MTD的研究设计。受试者将接受12周治疗。安全性和毒性将由以下人员进行评价： 血液检查和身体检查。将在急性和2和4小时后分析丙谷胺的血液水平 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。合格受试者 肝脏转氨酶会升高超声检查有脂肪肝的迹象肝脏纤维扫描将 在12周治疗前后进行，以收集关于肝脂肪变性变化的初步数据， 纤维化的治疗这项早期研究的目的是为研究人员提供重要的支持性信息。 FDA关于使用和重新利用旧药物，丙谷胺作为癌症治疗的辅助药物或用于未来 治疗NASH以预防HCC的试验。

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.