Enfortumab Vedotin and Pembrolizumab Combined With Radiotherapy in Muscle Invasive Bladder Cancer

Inclusion Criteria

• •Biopsy-confirmed muscle-invasive bladder cancer (cT2,T3,T4a). (Note: Tissue samples are required.) (Participants with cT3/T4a staged disease will be capped at 25% of patients treated at RP2D).
• •Urothelial histology present. Mixed histologies other than small cell/neuroendocrine are allowed as long as some urothelial histology is present. Neuroendocrine histology of any component and pure variant (non-urothelial) histology tumors will be excluded. (Patients with \< 50% urothelial histology will be capped at 25% of patients treated at RP2D).
• •Must be judged by the investigator to be ineligible for radical cystectomy or electing not to undergo radical cystectomy.
• •Must be eligible for and agree to receive bladder irradiation as determined by the treating investigator.
• •Must have a TURBT within 8 weeks of combination treatment start with viable tumor content. If no viable tumor content is present on TURBT, the patient will be replaced in the study.
• •Patients who have autoimmune disease will be evaluated on a case-by-case basis and can only enroll so long as participants are not on active immunosuppression with a corticoid steroid allowance exceeding 10mg of prednisone or equivalent per day.
• •Age \>= 18 years.
• •Eastern Cooperative Oncology Group (ECOG) performance status \<= 1.
• •Absolute neutrophil count ≥ 1,500/microliter (mcL).
• •Platelets \>= 100,000/mcL.
• •Hemoglobin \>= 9.0 g/dL or ≥ 5.6 mmol/L.
• •\* Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
• •Total bilirubin \<= 1.5 × upper limit of normal, unless elevated due to Gilbert's syndrome and direct bilirubin is within normal limits.
• •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase (SGOT)) \<= 2.5 X institutional upper limit of normal.
• •Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase (SGPT)) \<= 2.5 X institutional upper limit of normal.
• •Creatinine clearance glomerular filtration rate (GFR) \>= 30 mL/min/1.73 m\^2, calculated by Cockcroft-Gault or measured using 24-hour creatinine clearance.
• •International normalized ratio (INR) OR prothrombin time (PT) \<= 1.5 × upper limit of normal (ULN).
• •\* If participant is receiving anticoagulant therapy, as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants, participant is eligible.
• •Activated partial thromboplastin time (aPTT) \<= 1.5 × ULN.
• •\* If participant is receiving anticoagulant therapy, as long as PT or aPTT is within therapeutic range of intended use of anticoagulants, participant is eligible.
• •Ability to understand and the willingness to sign a written informed consent document.
• •Human immunodeficiency virus (HIV)-infected individuals on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• •\* Note: Hepatitis B screening tests are not required unless patients have a known history of HBV infection.
• •\* Note: Participants must have completed curative anti-viral therapy at least 4 weeks prior to cycle 1 day 1.
• •Women of child-bearing potential and men with sexual partners of childbearing potential must agree to use adequate contraception for the duration of study participation. Enfortumab vedotin (EV) may cause fetal harm. Women of child-bearing potential must use contraception during treatment with EV and for 120 days after the last dose. Men with female partners who are women of child-bearing potential must use contraception during treatment with EV and for 120 days after the last dose. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Acceptable methods include barrier method, hormonal method, as well as intrauterine devices
• •Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 8 weeks after last administration of study treatment.
• •\* Note: Testing for Hepatitis B or C is not required unless clinically indicated or if there is a known history of hepatitis infection. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• •Pregnant and breast feeding participants are excluded from this study because targeted chemotherapy and radiation have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with EV+pembrolizumab, breastfeeding should be discontinued if the mother is treated with these investigational products.