ASP2138

Claudin 18.2 or CLDN18.2 is a protein found on cells in the digestive system. It is also found in some tumors. Researchers are looking at ways to attack CLDN18.2 to help control tumors. ASP2138 is thought to bind to CLDN18.2 and a type of immune cell called a T cell. This "tells" the immune system to attack the tumor. ASP2138 is a potential treatment for people with gastric cancer (also known as stomach cancer) or gastroesophageal junction cancer (GEJ cancer). GEJ is where the tube that carries food (esophagus) joins the stomach. This study is for people with gastric or GEJ cancer that has spread nearby (locally advanced) and is not removable by surgery (unresectable), or has spread to other parts of the body (metastatic). It is for those whose cancer is human epidermal growth factor receptor 2 (HER2)-negative and CLDN18.2-positive. HER2-negative means the cancer does not have extra HER2 protein, so medicines that target HER2 do not work and are therefore not used. CLDN18.2-positive means people have a certain amount of CLDN18.2 proteins on their cancer cells. In this study, researchers want to learn if ASP2138 given together with standard treatments (chemotherapy and pembrolizumab) help people with HER2-negative and CLDN18.2-positive gastric or GEJ cancer. The main aim is to learn how long people who are given ASP2138 with chemotherapy and pembrolizumab live without their cancer getting worse, compared with placebo given with chemotherapy with or without pembrolizumab, and if they live for longer. Placebo looks like the study treatment but does not have any medicine in it. The main aim of this study is to check how well ASP2138 works when given together with chemotherapy and pembrolizumab compared with placebo plus chemotherapy with or without pembrolizumab. People aged 18 years or older with locally advanced unresectable or metastatic gastric or GEJ cancer can take part. Their tumor should be HER2-negative and CLDN18.2-positive. The study doctors will check people for any health conditions that can exclude them from taking part, interfere with the study procedures, or pose an unacceptable risk. This is a double-blind study. That means the people and the study doctors will not know who will receive which treatment. People will be assigned to one of 2 treatment groups by chance: Group A: People will receive ASP2138 along with chemotherapy and pembrolizumab. Group B: People will receive placebo along with chemotherapy, with or without pembrolizumab. People will keep receiving treatment until their cancer gets worse, they have medical problems that require stopping treatment, or a study rule says they must stop. There will be regular safety checks. People will continue to have scans of their tumor until their cancer becomes worse.

Claudin 18.2 protein, or CLDN18.2 is a protein found on cells in the digestive system. It is also found on some tumors. Researchers are looking at ways to attack CLDN18.2 to help control tumors. ASP2138 is thought to bind to CLDN18.2 and a protein on a type of immune cell called a T-cell. This "tells" the immune system to attack the tumor. ASP2138 is a potential treatment for people with stomach cancer, gastroesophageal junction cancer (GEJ cancer) or pancreatic cancer. GEJ is where the tube that carries food (esophagus) joins the stomach. Before ASP2138 is available as a treatment, the researchers need to understand how it is processed by and acts upon the body. In this study, ASP2138 will either be given by itself, or given together with standard treatments for gastric, GEJ and pancreatic cancer. Pembrolizumab and mFOLFOX6, and ramucirumab and paclitaxel are standard treatments for gastric and GEJ cancer. mFOLFIRINOX is a standard treatment for pancreatic cancer. This information will help find a suitable dose of ASP2138 given by itself and together with the standard cancer treatments and to check for potential medical problems from the treatments. The main aims of the study are: * To check the safety of ASP2138 and how well people can tolerate medical problems during the study. * To find a suitable dose of ASP2138 to be used later in the study. * These are done for ASP2138 given by itself and when given together with the standard cancer treatments. Adults 18 years or older with stomach cancer, GEJ cancer, or pancreatic cancer can take part. Their cancer is locally advanced unresectable or metastatic. Locally advanced means the cancer has spread to nearby tissue. Unresectable means the cancer cannot be removed by surgery. Metastatic means the cancer has spread to other parts of the body. There should also be the CLDN18.2 marker in a tumor sample. People cannot take part if they need to take medicines to suppress their immune system, have blockages or bleeding in their gut, have specific uncontrollable cancers, have specific infections, have a condition such as hemophagocytic lymphohistiocytosis (HLH) which is when the body over-reacts to a "trigger" such as infection, or have a specific heart condition ("New York Heart Association Class III or IV"). Phase 1: Lower to higher doses of ASP2138 * ASP2138 is either given through a vein (intravenous infusion) or just under the skin (subcutaneous injection). * Different small groups are given lower to higher doses of ASAP2138. * ASP2138 is either given by itself, or given with 1 of 3 standard treatments: * Pembrolizumab and mFOLFOX6 (first treatment for gastric GEJ cancer) * Ramacirumab and paclitaxel (Second treatment for gastric or GEJ cancer) * ASP2138 with mFOLFIRINOX (first treatment for pancreatic cancer) Phase 1b: doses of ASP2138 worked out from Phase 1 * ASP2138 is either given through a vein or just under the skin. This depends on the findings from Phase 1. * People with gastric cancer, GEJ cancer or pancreatic cancer are given doses of ASP2138, worked out from Phase 1. * This includes doses of ASP2138 given by itself and ASP2138 given with the standard cancer treatments. * The standard cancer treatments given depends on the type of cancer they have. End of treatment visit: This is 7 days after final dose of study treatment or if the study doctor decides to stop the person's treatment. People who have locally advanced unresectable pancreatic cancer will not receive ASP2138 by itself.

Some people with pancreatic ductal cancer (PDAC) have a protein called Claudin 18.2 (CLDN18.2) in their tumor. ASP2138 is thought to work by binding to CLDN18.2 and a protein on a type of immune cell called a T-cell. The T-cell "tells" the immune system to attack the tumor. This study is for people with resectable PDAC. Resectable means that the tumor can be removed by surgery. In this study, adults with resectable PDAC will receive an ASP2138 injection just below the skin (subcutaneous) 2 weeks before surgery. After surgery, they will be given standard chemotherapy treatments chosen by their study doctor. These include mFOLFIRINOX, gemcitabine with nab-paclitaxel, or gemcitabine with capecitabine. People will receive chemotherapy treatment for up to 6 months, or until their cancer gets worse, they cannot tolerate the chemotherapy, or they or their study doctor thinks they should stop chemotherapy. People will have a final clinic visit about a month after finishing chemotherapy for health checks.