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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

基本信息

批准号：
9808375
负责人：
Jill P Smith
金额：
$ 20.29万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-10 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9808375
关键词：
Abdomen Acute Adult Adverse event Aftercare Alcoholic Liver Diseases Anti-Inflammatory Agents Anti-inflammatory 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 Immunosuppressive Agents 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 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

项目摘要

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.

胰腺癌和肝癌的发病率正在显著上升，很快将成为第二大癌症