Title
An Open-label, Single-Arm, Phase 2 Study to Evaluate Enfortumab Vedotin plus Pembrolizumab for Bladder Preservation in Participants with Muscle-invasive Bladder Cancer (EV-209)

Description
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.

Objective
Primary Objective:
- To evaluate: 1) the overall cCR rate after treatment with enfortumab vedotin in combination with pembrolizumab and 2) the 2-year BI-EFS rate in participants who had cCR

Secondary Objectives:
-To evaluate the: 1) overall cCR rate after 4 cycles of treatment with enfortumab vedotin in combination with pembrolizumab and 2) the 2-year BI-EFS rate in participants who had cCR after 4 cycles
-To evaluate other measures of efficacy of enfortumab vedotin in combination with pembrolizumab in participants who had cCR
-To evaluate the safety and tolerability of enfortumab vedotin in combination with pembrolizumab

Treatment An Open-label, Single-Arm, Phase 2 Study to Evaluate Enfortumab Vedotin Plus Pembrolizumab for Bladder Preservation in Participants With Muscle-invasive Bladder Cancer (EV-209)

Key Eligibility Inclusion Criteria:

- Participant has histologically-confirmed MIBC, stage cT2-T4aN0M0 or T1-T4aN1M0. NOTE: urothelial carcinomas (UCs) not originating from the bladder (e.g., upper tract [ureters, renal pelvis], urethra) are not eligible. UCs invading into the prostatic stroma with no histologic muscle invasion is allowed, provided that the extent of disease is confirmed via imaging.
- Participant has predominant UC histology (>/= 50%). NOTE: Participants with mixed histology are eligible provided the urothelial component is >/= 50% (participants whose tumors contain predominant [>/= 50%] plasmacytoid variant are not eligible). Participants whose tumors contain any neuroendocrine histology are not eligible.
- Participant is deemed eligible for radical cystectomy and pelvic lymph node dissection.
- Participant has accessible archival tumor tissue from the primary tumor, for which source and availability have been confirmed prior to study intervention. If no archival tumor tissue is available, the participant will have a biopsy to obtain tumor tissue prior to study intervention.
- Participant has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
- Have a transurethral resection of a bladder tumor within 60 days (+14 days) prior to, or during screening (from the date of informed consent form signature).

Applicable Disease Sites
Bladder

Participating Institutions
UW Health Eastpark Medical Center; UW Health University Hospital