Enfortumab Vedotin

This study is being done to learn more about a new medicine called PF-08634404. It is for adults with a type of bladder cancer called locally advanced or metastatic urothelial cancer (LA/mUC), meaning the cancer has spread to nearby tissues or other parts of the body. The purpose of the study is to see if PF-08634404 is safe, how well it works, how it moves through the body, and how it affects the cancer. The study will also look at how the medicine may change certain markers in the body that are linked to cancer. To join the study, participants must: * Be adults (18 years or older) and * Have locally advanced or metastatic urothelial cancer, The study has two groups: * Cohort A: People who have already received treatment for their cancer will get the study medicine ( PF-08634404) alone. * Cohort B: People who have not had treatment before will get the study medicine along with another cancer medicine called enfortumab vedotin. Everyone in the study will get the study medicine through a vein (IV infusion) with or without enfortumab vedotin. Treatment will continue as long as it helps and side effects are manageable. Before starting, participants will go through a screening period to check if they are eligible. During the study, they will have regular visits for treatment, health checks, and tests to see how the cancer is responding. Scans will be done regularly to monitor the cancer. If the cancer gets worse but the treatment is still helping and side effects are manageable, participants may be allowed to continue treatment with their doctor's and the sponsor's agreement.

Enfortumab vedotin (or PADCEV Injection) is a treatment for cancer in the bladder lining (urothelial cancer). PADCEV Injection is now available to treat this cancer. People in this study will be adults in South Korea with locally advanced or metastatic urothelial cancer. Metastatic means the cancer has spread to other parts of the body. During their care, the person's doctor will have prescribed PADCEV Injection and other medicines to treat their cancer. People in the study will be treated according to their clinic's standard practice. This study is about collecting information only. This study will survey people who know they are receiving PADCEV Injection. The aims of the study are to check outcomes of treatment with PADCEV and record any medical problems during the study. Once a doctor has prescribed PADCEV Injection, a person in the study will be observed for up to 48 weeks (about 1 year) after their first dose. During this time, a person's medical records will be reviewed to check for any medical problems and to follow the condition of their cancer. If a person in the study stops taking PADCEV Injection sooner than 48 weeks, records will be reviewed until 30 days (1 month) after each person's last dose of PADCEV Injection or until they start a different medicine for their cancer.

People with a type of bladder cancer called muscle-invasive bladder cancer have cancer that has spread into the muscle wall of the bladder. The standard treatment is to have chemotherapy, followed by surgery to completely remove the bladder. This has a significant impact on people with long-term life-altering changes. There are also limited options for people who cannot have chemotherapy or who do not want their bladder removed. Studies show that enfortumab vedotin, when given with pembrolizumab, can help people with advanced bladder cancer. This treatment has also worked well for people with muscle-invasive bladder cancer who can't receive chemotherapy when it was given before and after bladder-removal surgery. However, some people can't have or won't have this surgery. There is still a need for new treatments that let people keep their bladder. This is especially important for people who respond well to the enfortumab vedotin, when given with pembrolizumab, and may benefit from continuing this study treatment instead of having surgery. The main aims of this study are to check how many people continue to respond well to enfortumab vedotin with pembrolizumab and how many people have their bladder intact after 2 years. People in this study will be adults who have muscle-invasive bladder cancer and are able to have surgery to remove the bladder. People cannot take part if they have nerve damage (sensory or motor neuropathy), have had certain other cancers, have diabetes that is not under control, or have had a transplant. People will receive infusions of enfortumab vedotin on the 1st and 8th day of 3-week (21-day) cycles. They will also receive pembrolizumab on the 1st day of every 3-week cycle. There will be safety checks at each visit with checks of the tumors at some visits. The doctors will continue to check for medical problems throughout the study. People will continue to receive study treatment unless their cancer doesn't improve after 9 cycles of study treatment, or until their cancer gets worse, they can't tolerate the study treatment, they start other cancer treatment, they or the doctor decides the person should stop receiving study treatment, or sadly they pass away. People's whose cancer gets worse or doesn't improve after 9 cycles may need bladder surgery, radiotherapy or chemotherapy. People will visit the clinic after they stop their study treatment, in which they will be asked about any medical problems and have a health check. After this, people will continue to have scans every 12 weeks (3 months) for the first 2 years until their cancer gets worse. After this, if their cancer doesn't get worse, they will continue to have scans every 24 weeks (6 months) for up to 5 years to check for any changes in their cancer. After people's cancer gets worse, they won't have any more scans but will have telephone health checks every 3 months.

Specific proteins found in tumors help the tumors spread and grow. People with solid tumors often have a protein called TROP2 in their tumor. ASP2998 is being developed to attach to TROP2 and then attack the tumor cells in people with solid tumors. ASP2998 will either be given by itself, or given together with one or more of standard cancer treatments pembrolizumab, carboplatin, and enfortumab vedotin. This is an early development study to collect information about ASP2998 in people with solid tumors. In this study ASP2998 will be given to humans for the first time. Early development studies are mostly about safety, but also to find the most suitable dose. Other aims are to check if ASP2998 shows signs of reducing tumor growth, to learn how the body processes ASP2998, and to check if there are changes either in the TROP2 protein or in the immune system. The main aim of the study is to check the safety of ASP2998 when given by itself and given with the standard cancer treatments, and how well it is tolerated. People in this study will be adults with locally advanced, unresectable or metastatic solid tumors. 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. People's cancer came back or became worse after previous treatment or they couldn't receive treatment. Some people who had previously refused treatment may be able to take part. This will depend on which study treatment they receive. People will either have cancer in the bladder lining (urothelial cancer), non-small cell lung cancer (NSCLC), gastric cancer or cancer where the food pipe joins the stomach (gastroesophageal cancer, or GEJ), or certain types of breast cancer. People cannot take part if the cancer cells have spread to the thin tissue covering the brain and spinal cord (leptomeningeal disease), have symptoms of cancer in the brain or nervous system, or need medicines to suppress their immune system. In this study, ASP2998 will be given to humans for the first time. ASP2998 will either be given by itself, or given together with one or more of standard cancer treatments pembrolizumab, carboplatin and enfortumab vedotin. The standard cancer treatment given will depend on which cancer people have. The study will have 2 parts. In Part 1, different small groups of people will receive lower to higher doses of ASP2998 given by itself or together with one or more of the standard cancer treatments. Any medical problems will be recorded for each dose. This is done to find suitable doses of ASP2998 to use in Part 2. In Part 2, other different small groups will receive suitable doses of ASP2998 worked out from Part 1. ASP2998 will either be given by itself or given together with one or more of the standard cancer treatments. This part will also check how each type of cancer responds to ASP2998 when given by itself or together with the standard cancer treatments. In both parts of the study, safety checks will be done at each visit, and the doctors will continue to check for medical problems throughout the study. ASP2998 will be given slowly through a tube into a vein (infusion). People will continue to receive ASP2998 until their cancer gets worse, they can't tolerate ASP2998, they start other cancer treatment, they or the doctor decides the person should stop receiving ASP2998.