N-803 in Combination With Pembrolizumab and Enfortumab Vedotin for Treatment of Urothelial Cancer

Inclusion Criteria: 1. Age ≥ 18 years 2. Histologically or cytologically confirmed locally advanced (LA)/ metastatic urothelial carcinoma (mUC), including UC originating from the renal pelvis, ureters, bladder, or urethra. Mixed-cell type tumors are eligible as long as \> 50% urothelial component is present (mixed histology other than small cell/ neuroendocrine are allowed). 3. No prior systemic treatment for LA/mUC. 4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) \<= 2. 5. Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. 6. Prior perioperative systemic therapy including neoadjuvant or adjuvant chemotherapy, immune checkpoint inhibitors, and EV is allowed if treatment was completed \> 12 months before trial enrollment. 7. Participants enrolling in the trial must agree with discontinuing EV upon demonstrating confirmed CR/PR/SD at the second or third scan timepoint on treatment (after 5.5 to 8 months of intended EV treatment). 8. Leukocytes ≥ 3,000/microliter (uL). 9. Absolute neutrophil count (ANC) ≥ 1,500/uL. 10. Platelets ≥ 100,000/uL. 11. Total bilirubin \< 1.5 x institutional upper limit of normal (ULN) (if previously abnormal due to non-malignant causes such as Gilbert's disease bilirubin ≤ 2 x ULN will be permitted.) 12. Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase (SGOT))/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal (ULN). 13. Creatinine clearance ≥ 30 mL/min/1.73 m\^2 calculated using the Cockcroft-Gault equation. 14. Must have archival tumor tissue available or have disease amenable to a fresh biopsy for diagnosis confirmation and correlative studies. 15. Human immunodeficiency virus (HIV)-infected individuals with undetectable viral load within 6 months are eligible for this trial. Trial participants who are on antiretroviral therapy (ART) should be on established ART for at least four weeks and have an HIV viral load less than 400 copies/mL prior to enrollment. 16. For participants with history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable and the participant should be on suppressive antiviral therapy, if indicated. Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured, with HCV viral load below the level of quantification. A participant who is HCV antibody (Ab) positive but HCV ribonucleic acid (RNA) negative due to prior treatment or natural resolution is eligible for this trial. For individuals with HCV infection who are currently on treatment, they are eligible if HCV viral load below the level of quantification. Ability to attend required study visits and return for adequate follow-up, as required by this protocol. 17. participants who are on beta blockers can enroll in the trial, but discontinuation of beta-blockers should be strongly considered at the time of initiating N-803. Beta blocker use can continue per physician discretion if necessary. \* Note: Beta-blockers or other antihypertensives may be resumed on treatment when clinically indicated. 18. Agreement to practice effective contraception for female participants of child-bearing potential and non-sterile males. Female participants of child-bearing potential must agree to use effective contraception for up to 4 months after completion of therapy, and non-sterile male participants must agree to use a condom for up to 4 months after treatment. Effective contraception includes surgical sterilization (e.g., vasectomy, tubal ligation), oral and injectable contraceptives, 2 forms of barrier methods (e.g., condom, diaphragm) used with spermicide, intrauterine devices (IUDs), and hormonal therapy. For male participants with a female partner of child-bearing potential, the female partner must also agree to use effective contraception for up to 4 months after therapy was completed. 19. Able to understand and provide a signed informed consent that fulfills the relevant institutional review board (IRB) or independent ethics committee (IEC) guidelines. Exclusion Criteria: 1. Symptomatic or untreated central nervous system (CNS) metastases. \* Note: Participants with previously treated brain or CNS metastases are eligible if the participant has recovered from any acute effects of surgery or radiotherapy and do not require steroids (prednisone equivalent ≥ 10 mg daily), and any whole brain radiation therapy or any stereotactic radiosurgery was completed at least 2 weeks prior to initiation of therapy. 2. Participants with a history of active autoimmune disease and on active management with immunosuppressive agents within the past 2 years 3. Participants with a history of interstitial lung disease 4. Participants with congestive heart failure (New York Heart Association class III or IV) 5. Participants on systemic intravenous or oral corticosteroid therapy (prednisone equivalent ≥ 10 mg daily) or other immunosuppressive agents such as azathioprine or cyclosporin A are excluded. For these participants, these excluded treatments must be discontinued at least 1 week prior to enrollment for recent short course use (≤ 14 days) or discontinued at least 4 weeks prior to enrollment for long term use (\> 14 days). \* Note: The use of corticosteroids as premedication for contrast-enhanced studies is allowed prior to enrollment and on study. participants requiring hormone replacement with corticosteroids if the steroids are administered only for the purpose of hormonal replacement or participants treated at doses ≤ 10 mg of prednisone or equivalent per day are allowed. 6. History of uncontrolled diabetes mellitus defined as hemoglobin A1c (HbA1c) ≥ 8%. 7. Grade ≥ 2 peripheral neuropathy at baseline. 8. Radiotherapy or major surgery within 2 weeks prior to treatment start. 9. History of another significant life-limiting malignancy within 2 years prior to the first dose of study drug. Participants with non-melanoma skin cancer, curatively treated localized prostate cancer, or carcinoma in situ of any type (if complete resection was done) are allowed. 10. History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to EV and/or pembrolizumab and/or N-803. 11. Participants who have received hematopoietic stem cell transplantation or solid organ transplantation. 12. Known active keratitis or corneal ulcerations. 13. Received or will receive a live vaccine within 30 days prior to the first administration of study intervention. \* Note: Seasonal flu vaccines that do not contain a live virus are permitted. Locally approved Coronavirus disease of 2019 (COVID-19) vaccines are permitted. 14. Pregnant and nursing women. 15. Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol. 16. Severe uncontrolled intercurrent illness that would limit compliance with study requirements in the judgement of the investigator.