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

第一阶段研究测试丙谷胺作为抗纤维化药物的安全性和剂量

• 批准号: 10015244
• 负责人: Jill P Smith
• 金额: $ 26.25万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10015244
• 关键词: Abdomen; Acute; Adult; Adverse event; Aftercare; Alcoholic Liver Diseases; Anti-Inflammatory Agents; Bilirubin; Bioavailable; Biochemical; Biological Assay; Blood; Blood Tests; Cancer Etiology; Cells; Cessation of life; Characteristics; Chemistry; Cholecystokinin; Cholecystokinin Receptor; Chronic; Cirrhosis; Clinical Research; Collagen; Data; Development; Diagnostic radiologic examination; Disease; Dose; Drug Kinetics; Epidemiology; Epithelial Cells; Excision; Fatty Liver; Fibroblasts; Fibrosis; Frequencies; Future; Goals; Hematology; Hepatic; High Fat Diet; High Pressure Liquid Chromatography; Histologic; Image; Immune; Immunotherapy; Impairment; Incidence; Inflammation; Laboratories; Liver; Liver Fibrosis; Liver diseases; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of liver; Malignant neoplasm of pancreas; Maximum Tolerated Dose; Modeling; Monitor; Mus; Neoplasm Metastasis; Obesity Epidemic; Operative Surgical Procedures; Oral; Pancreas; Patients; Penetrance; Peptic Ulcer; Peptides; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Physical Examination; Prevention; Preventive therapy; Primary carcinoma of the liver cells; Proglumide; Proton Pump Inhibitors; Quality Control; Reporting; Research; Research Design; Risk; Risk Factors; Role; Safety; Sample Size; Secure; Testing; Therapeutic; Time; Tissues; Toxic effect; Transaminases; Transplantation; Tumor-infiltrating immune cells; Ulcer; Ultrasonography; United States; Viral hepatitis; Work; advanced pancreatic cancer; adverse event monitoring; cancer therapy; capsule; cell stroma; chemotherapy; clinical Diagnosis; cohort; healthy volunteer; human subject; improved; metabolomics; mouse model; nonalcoholic steatohepatitis; open label; pancreatic cancer patients; pancreatic neoplasm; pancreatic tumorigenesis; phase 1 designs; phase 1 study; phase 2 study; prevent; receptor; response; safety study; safety testing; stellate cell; tumor; tumor growth; tumor microenvironment

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.

胰腺癌和肝癌的事件正在显着增加，很快将成为第二 在美国，与癌症相关的死亡的第三名原因。这些癌症的已知危险因素（以及其他）包括 慢性炎症和纤维化。此外，在肿瘤的环境中既定的癌症 具有免疫抑制免疫细胞和基质的微环境被认为会损害 化学疗法和免疫疗法。胆囊动蛋白（CCK）受体在胰腺和肝脏上表达 上皮细胞；它们也在星状细胞，组织成纤维细胞和免疫细胞上发现。我们有 在用CCK受体拮抗剂Proglumide阻断这些受体的鼠模型中发现 减少胰腺肿瘤的生长，同时减少肿瘤微环境的纤维化并改变 免疫细胞浸润，使肿瘤容易受到治疗。在非酒精的鼠模型中 脂肪性肝炎（NASH），proglumide反向组织学NASH，降低肝脏转氨酶和胆红素，以及 预防肝癌（HCC）。 30年前为胡椒溃疡疾病开发了proglumide， 当时安全地用于人类受试者，但由于发现质子泵抑制剂，因此不再使用。 我们假设proglumide是一种有效的抗炎和抗纤维化剂，可以是 开发旨在促进胰腺癌的治疗选择，也是作为预防疗法 NASH相关的HCC。此应用的目的是复制慢性条件的Proglumide 炎症和纤维化（即胰腺癌和NASH）。我们计划通过GMP制造Proglumide 标准，然后在史密斯博士的FDA（IND＃138481）下进行1期临床研究以确定 NASH受试者中前氟胺的安全性和耐受性以及最大耐受剂量（MTD）。在这个 应用GMP级Proglumide将通过HPLC制造并测试纯度，然后复合 进入300mg胶囊，并测试了质量控制。接下来，将在合格的中进行1期临床试验 使用NASH的受试者使用MS或HPLC测试Proglumide的安全和血液水平。初始剂量将 以300 mg竞标的溃疡疾病的剂量略低，然后在经典3+3中升级 研究设计以确定MTD。受试者将接受12周的治疗。安全性和毒性将通过 血液检查和身体检查。前后血液的血液水平将急性分析，并在2和4之后进行。 几周的治疗以确定是否存在血液水平可能与任何毒性相关。合格的主题 将具有升高的肝转印​​酶和脂肪肝病的超声证据。肝纤维骨将是 在治疗12周之前和之后进行的，以收集有关肝脂肪变化和的初步数据 治疗纤维化。这项早期研究的目的是向 关于使用和重新利用旧药物的FDA，proglumide作为癌症治疗的辅助或将来 对NASH治疗的试验，以防止HCC。