Enfortumab Vedotin Plus Pembrolizumab With Selective Bladder Sparing for Treatment of Muscle-invasive Bladder Cancer

Inclusion Criteria:

1. Written informed consent and HIPAA authorization for release of personal healthinformation prior to registration. NOTE: HIPAA authorization may be included in theinformed consent or obtained separately.

2. Age ≥ 18 years at the time of consent.

3. ECOG Performance Status of 0-1 within 28 days prior to registration.

4. Histological evidence of clinically localized muscle-invasive urothelial cancer ofthe bladder clinical stage T2-3N0M0. Participants with mixed histology are eligibleprovided the urothelial component is ≥50% with the following exceptions: (a) tumorswith any degree of squamous differentiation are eligible provided there is aurothelial cancer component, (b) tumors that contain any component of neuroendocrinehistology are not eligible. N0 will be considered as the absence of radiographicallyenlarged lymph nodes on baseline imaging (i.e., Patients with lymph nodes ≥1 cm inshort axis on imaging are not eligible).

5. Have undergone a standard of care maximal transurethral resection of bladder tumor ≤ 90 days prior C1D1. A maximal TURBT should be performed when feasible and is definedas a macroscopically complete resection of bladder tumor.

6. All subjects must have adequate transurethral resection of bladder tumor tissueavailable for submission identified during screening. The specimen must includetumor tissue (i.e., if a restaging maximal TURBT was performed and there was nocancer in the specimen, tissue from the most recent prior TURBT that established thediagnosis of muscle-invasive urothelial cancer of the bladder should be submitted).Tissue from both the restaging TURBT and the prior diagnostic TURBT may berequested. Subjects without available archival tissue must be discussed with thesponsor-investigator.

7. Be deemed eligible to undergo radical cystectomy and pelvic lymph node dissection

8. Demonstrate adequate organ function as defined below. All screening labs to beobtained within 28 days prior to registration.

• Absolute neutrophil count (ANC): ≥ 1.5 x 10^9/L

• Hemoglobin (Hgb): ≥ 9 g/dL

• Platelets: ≥ 100 x 10^9/L

• Creatinine clearance: ≥ 30 mL/min

• Bilirubin: ≤ 1.5 ×ULN OR direct bilirubin ≤ ULN for participants with totalbilirubin levels > 1.5 × ULN

• Aspartate aminotransferase (AST): ≤ 2.5 × ULN

• Alanine aminotransferase (ALT): ≤ 2.5 × ULN

• International normalized ratio (INR) or Prothrombin time (PT) or Partialthromboplastin time (PTT): ≤ 1.5 ×ULN unless participant is receivinganticoagulant therapy as long as PT or aPTT is within therapeutic range forintended use of anticoagulants

10. Females of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. WOCBP must agree to use contraception.

11. Male participants able to father a child who are sexually active with female of childbearing potential must be willing to use an effective method(s) of contraception.

Exclusion Criteria:

1. Pre-existing sensory or motor neuropathy Grade ≥ 2

2. Ongoing clinically significant toxicity (Grade 2 or higher with the exception ofalopecia) associated with prior treatment (including systemic therapy, radiotherapyor surgery).

3. Prior systemic chemotherapy for muscle-invasive urothelial cancer of the bladder.

4. Prior malignancy active within the previous 2 years except for locally curablecancers that have been apparently cured. Patients with intermediate or lower riskprostate cancer as defined by the National Comprehensive Cancer Network (NCCN) riskstratification guidelines may be eligible for enrollment.

5. Prior radiation therapy for bladder cancer.

6. Hemoglobin A1c ≥ 8% or hemoglobin A1c 7%-<8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained

7. Active infection requiring systemic therapy.

8. Known active Hepatitis B or C infection. NOTE: Patients with a past or resolved HBVinfection (defined as the presence of hepatitis B core antibody [anti-HBc] andabsence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody areeligible only if polymerase chain reaction is negative for HCV RNA.

9. HIV-infected patients on effective anti-retroviral therapy with an undetectableviral load are eligible.

10. Has a known history of active TB (Bacillus Tuberculosis).

11. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use whilethe mother is being treated on study).

12. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent orwith an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg,CTLA-4, OX 40, CD137).

13. Has received a live or live-attenuated vaccine within 30 days prior to the firstdose of study drug. Administration of killed vaccines is allowed.

14. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 7 days prior to the first dose of study drug.

15. Has severe hypersensitivity (≥ Grade 3) to pembrolizumab or enfortumab vedotinand/or any of their excipients.

16. Has active autoimmune disease that has required systemic treatment in the past 2years (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment and is allowed.

17. Has a history of (non-infectious) pneumonitis/interstitial lung disease thatrequired steroids or has current pneumonitis/interstitial lung disease.

18. Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the study, interfere with thesubject's participation for the full duration of the study, or is not in the bestinterest of the subject to participate, in the opinion of the treating investigator.

19. Has had an allogenic tissue/solid organ transplant.

20. Is currently receiving an investigational agent or has received an investigationalagent or used an investigational device within 28 days of study registration.