This clinical trial is for patients with locally advanced or metastatic urothelial cancer. 

This is a study that will test how an experimental drug (enfortumab vedotin) combined with a kind of anticancer drug called an immune checkpoint inhibitor (CPI) affects patients with cancer of the urinary system (urothelial cancer). This type of cancer includes cancer of the bladder, renal pelvis, ureter or urethra that has spread to nearby tissues or to other areas of the body. Patients will get the drugs twice every 21-day cycle. Patients will get enfortumab vedotin plus the CPI on day 1. Patients will get enfortumab vedotin only on day 8. 

This study has a Dose Escalation group and a Dose Expansion group. The Expansion group is divided into 3 parts. Depending on what part of the study you are in, you will receive enfortumab vedotin plus other cancer fighting drugs. Your study doctor will let you know which part of the study that you will be in. 

If you are in Escalation or Part 1 of the study, we will treat you with enfortumab vedotin then pembrolizumab on Day 1 and with only enfortumab vedotin again on Day 8. 

If you are in Part 2 of the study, we will treat you with enfortumab vedotin then either cisplatin, carboplatin, or gemcitabine on Day 1. You will receive enfortumab vedotin again on Day 8. If you received gemcitabine on Day 1, you will receive it again on Day 8. 

If you are in Part 3 of the study, we will treat you with enfortumab vedotin followed by cisplatin or carboplatin, and then pembrolizumab on Day 1. You will receive only enfortumab vedotin again on Day 8. 

One year after you join the study, we will reduce the visits or phone calls to about every 12 weeks.