Enfortumab Vedotin and Stereotactic Radiation for Localized, Cisplatin Ineligible Muscle Invasive Bladder Cancer

Eligibility Criteria

• 1. Urothelial carcinoma of the urinary bladder stage cT2-4a (AJCC 8th edition) N0M0 planned for radical cystectomy. Mixed cell types are allowed as long as urothelial component is \>50% AND no small cell/neuroendocrine or plasmacytoid/signet ring component.
• 2. Ineligibility for cisplatin-based chemotherapy based on treating physician assessment and any of the following "Galsky criteria": renal insufficiency (Creatinine Clearance \<60ml/min by standard institutional calculation method), \>=grade 2 peripheral neuropathy, \>=grade 2 hearing loss, New York Heart Association (NYHA) class III heart failure; a combination of these; or patient refusal.
• 3. Age \>=18.
• 4. Performance status Eastern Cooperative Oncology Group (ECOG) 0-1
• 5. Adequate organ and marrow function as defined below:
• * Platelet count \>=100x109/L
• * Hemoglobin ≥ 9 g/dL
• * Serum bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for subjects with Gilbert's disease
• * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN
• * No end stage renal disease requiring dialysis allowed
• 6. All men, as well as women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 3 months following completion of study neoadjuvant therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• * Has not undergone a hysterectomy or bilateral oophorectomy; or
• * Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
• 7.Ability to understand and the willingness to sign a written informed consent.
• 1. No prior systemic therapy (except prior therapy for non-muscle invasive bladder cancer \>12 prior to registration) for bladder cancer or prior pelvic radiotherapy. Prior intra-vesical therapies are allowed, including Bacillus Calmette-Guerin (BCG) for non-muscle invasive bladder cancer. Prior chemotherapy for other cancers is allowed if given \>=1 year prior to study registration.
• 2. Baseline \>= Grade 2 sensory or motor neuropathy
• 3. Subjects may not be receiving any other investigational agents for the treatment of the cancer under study.
• 4. History of allergic reactions attributed to compounds of similar chemical or biologic composition to enfortumab vedotin or other agents used in study.
• 5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirements.
• 6. Subjects must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.