An open, multicenter, phase Ib/II study to evaluate the efficacy, safety and pharmacokinetics of CT041 autologous CAR T-cell injection in patients with advanced gastric/ gastroesophageal junction adenocarcinoma and pancreatic cancer
Rationale: Bile salts are potent signalling molecules influencing various metabolic and functional processes. Bile salts exert these functions by activating nuclear (e.g. FXR ) and plasma cell membrane-bound receptors (e.g. TGR5) which are expressed in several tissues (e.g. liver, small intestine, colon, kidney and gallbladder). Bile salts regulate their own biosynthesis by controlling the transcription of the hepatic bile salt synthetic enzyme CYP7A1. Two pathways are involved in the negative feedback control of bile salt synthesis: i) the hepatic FXR-SHP pathway and ii) the ileal FXR-FGF19 pathway. Studies showed that the latter is more prominent in controlling CYP7A1 transcript levels (viz. bile salt synthesis). Thus, bile salts are synthesized in the liver, excreted in bile and expelled by the gallbladder into the proximal intestine (to aid in lipid absorption and digestion) and reabsorbed in the terminal ileum to recycle back to the liver via portal blood. Bile salts reclaimed from the intestinal lumen by the ileocyte, activate FXR. This induces the expression of an enterokine, FGF19, which signals via portal blood to the liver to activate its receptor which initiates downstream signalling to repress bile salt synthesis. The FXR/FGF19 signalling pathway is the subject of the present study.
Patients with obstructive cholestasis (=accumulation of bile) caused by malignancies (e.g. pancreatic cancer, cholangiocarcinoma) have a perturbed enterohepatic cycle. Obstructive cholestasis is associated with i) gut barrier dysfunction, ii) endotoxemia, iii) bacterial overgrowth and iv) liver injury. Previous study showed that FGF19 is expressed in the liver of patients with obstructive cholestasis. However, knowledge about the contribution of FGF19 protein by the gut in obstructive cholestasis has thus far been unexplored. Preliminary findings revealed that FGF19 is produced by the portal drained viscera (viz. intestine) of non-cholestatic patients undergoing liver surgery. The inter-organ signalling of FGF19 in an obstructed entero-hepatic cycle has not yet been characterized and likewise the metabolic and other functional effects of inflicted FGF19 signalling during cholestasis have not been clarified.
The hypothesis is that the FXR-FGF19 pathway is disturbed in patients with obstructive cholestasis, and this is associated with organ injury and metabolic dysfunction. The investigators postulate that FGF19 is not produced by the terminal ileum under conditions of obstructive cholestatic, but production is shifted to the liver and this affects metabolic processes.
The aim of this study is to investigate FGF19 signalling in patients with cholestasis compared to non-cholestatic patients or post-cholestatic patients (drained patients) by calculating fluxes across the portal drained organs. Secondly, the investigators aim to investigate the metabolic and functional consequences (glucose, lipid homeostasis, cholestatic itch, gut barrier function) of a disturbed FXR-FGF19 pathway in humans. This study will provide insights that may lead to potential therapeutic strategies for patients with a disturbed enterohepatic cycle (e.g. cholestatic liver diseases).
Study population: Adult (>18 years old) cholestatic (cholestasis group), drained (restored enterohepatic cycle) and non-cholestatic patients (controls, normal enterohepatic circulation) undergoing pancreaticoduodenectomy (Whipple procedure) for hepatopancreaticobiliary malignancies (e.g. pancreatic cancer, cholangiocarcinoma) or liver resection for hepatic malignancies (e.g. cholangiocarcinoma, colorectal liver metastases) are eligible for this study.
Study period: inclusion is planned from 1.12.2017 until 1.12.2024
Phase I trial to study the effectiveness of LMB-9 immunotoxin in treating patients who have advanced colon, breast, non-small cell lung, bladder, pancreatic, or ovarian cancer. The LMB-9 immunotoxin can locate tumor cells and kill them without harming normal cells.
This phase I trial is studying the side effects and best dose of sunitinib and gemcitabine in treating patients with pancreatic cancer or other solid tumors. Sunitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in hemotherapy, such as gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving sunitinib together with gemcitabine may kill more tumor cells.
The primary outcome measure for this study is plasma ghrelin level.
The purpose of this study is to determine whether evolution of resting energetic expenditure is a predictive marker of tumoral response for patients suffering from metastatic pancreatic cancer and treated with 1st line of chemotherapy.
The purpose of this study is to evaluate the efficacy of preoperative biliary drainage (PBD) which is performed prior to pancreatoduodenectomy candidates with obstructive jaundice by observing the prevalence of drainage and surgery related complications, hospital stay, medical cost and life quality compared to surgery alone. It is anticipated that PBD can reduce the prevalence of complications and improve the outcome of pancreatoduodenectomy.
The purpose of this study is to test the safety and effectiveness of using brodalumab in patients who develop side effects from cancer immune therapy. Immune-related side effects are due to activation of the immune system in patients who previously received immunotherapy and the goal of this study is to help better control these side effects. Brodalumab is often used to treat patients with autoimmune diseases (diseases where the immune system is activated against normal organs) and safe doses and treatment schedules have been determined in these patients. Immune-related side effects appear to closely mirror these autoimmune conditions. Brodalumab has not been approved by the United States Food and Drug Administration (FDA) for use in immunotherapy side effects but it has been approved for treatment of autoimmune conditions.
The trial evaluates the safety and efficacy of MUC-1/WT-1 peptide and/or tumor lysate-pulsed dendritic cell Immunotherapy for the patients with pancreatic cancer
Long-Term Follow-Up Study for Subjects Enrolled in the Phase I/II Study of Autologous T Cells Engineered using the Sleeping Beauty System to Express T cell Receptors (TCRs) Reactive Against Cancer-specific Mutations in Subjects with Solid Tumors
