Inclusion Criteria:

• Patients must have histologically documented urothelial (previously known as transitional cell) carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra).
• Patients with squamous differentiation or mixed cell types are eligible. Patients with resectable locally advanced disease are ineligible.
• Patient must have received prior treatment with a CPI in the locally advanced or metastatic urothelial cancer setting. Patients who received CPI therapy in the neoadjuvant/adjuvant setting and had recurrent or progressive disease either during
• therapy or within 3 months of therapy completion are eligible. A CPI is defined as a PD-1 inhibitor or PD-L1 inhibitor (including, but not limited to: atezolizumab, pembrolizumab, durvalumab, avelumab, and nivolumab).
• Patients must be one of the following:
  • Platinum-treated (Cohort 1):
    • Patients who received prior treatment with platinum containing chemotherapy defined as those who received platinum in the adjuvant/neoadjuvant setting and had recurrent or progressive disease within 12 months of completion OR received treatment with platinum in the locally advanced (defined as unresectable with curative intent) or metastatic setting;
• OR
  • Platinum-naïve and cisplatin ineligible (Cohort 2): Patients who have not received prior treatment with platinum-containing or other chemotherapy in the locally advanced or metastatic setting and are ineligible for treatment with   cisplatin at time of enrollment due to one of the following: impaired renal function (defined as creatinine clearance [CrCl] ≥30 and <60 mL/min), or a hearing loss of 25 decibels (dB) at two contiguous frequencies. Patients who  received platinum in the adjuvant/neoadjuvant setting and did not progress within 12 months of completion will be considered platinum-naïve.
• Patients must have had progression or recurrence of urothelial cancer during or following receipt of most recent therapy.
• Tumor tissue samples must be available for submission to the sponsor prior to study treatment.
• Legally an adult according to local regulation at the time of signing informed consent, and minimum age of 18 years.
• Patients must have measurable disease according to RECIST (Version 1.1) (Eisenhauer 2009). Lesions in a prior radiation field must have progressed subsequent to radiotherapy to be considered measurable.
• An ECOG Performance Status score of 0 or 1.
• The following baseline laboratory data, assessed locally (no transfusions are permitted within 2 weeks prior to screening):
  • absolute neutrophil count ≥1.0 × 109/L;
  • platelet count ≥100 × 109/L;
  • hemoglobin ≥9 g/dL;
  • serum bilirubin ≤1.5 × upper limit of normal (ULN) or ≤ × ULN for patients with Gilbert’s disease;
  • CrCl ≥30 mL/min as measured by 24-hour urine collection or estimated by the Cockcroft-Gault criteria;
  • alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 × ULN.
• Female patient must either:
  • Of nonchildbearing potential:
    • Postmenopausal* (defined as at least 1 year without any menses) prior to screening; or
    • Documented surgically sterile (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy, bilateral tubal occlusion);
    • *Those who are amenorrheic due to an alternative medical cause are not considered postmenopausal and must follow the criteria for childbearing potential patients.
  • Or, if of childbearing potential:
    • Agree not to try to become pregnant during the study and for at least 6 months after the final study drug administration;
    • And have a negative urine or serum pregnancy test within 7 days prior to Day 1 (Females with false positive results and documented verification of negative pregnancy status are eligible for participation);
    • And if heterosexually active, agree to abstinence (if in line with the usual preferred lifestyle of the patient) or consistently use a condom plus 1 form of highly effective birth control† per locally accepted standards starting at screening and throughout the study period and for at least 6 months after the final study drug administration.
• Female patient must agree not to breastfeed or donate ova starting at screening and throughout the study period, and for at least 6 months after the final study drug administration.
• A sexually active male patient with female partner(s) who are of childbearing potential is eligible if:
  • Agree to abstinence (if in line with the usual preferred lifestyle of the patient) or to use a male condom starting at screening and continue throughout study treatment and for at least 6 months after the final study drug administration. If the male patient has not had a vasectomy or is not sterile as defined below their female partner(s) is utilizing 1 form of highly effective birth control† per locally accepted standards starting at screening and continuing throughout study treatment and for at least 6 months after the male patient receives their final study drug administration.
• Male patient must not donate sperm starting at screening and throughout the study period, and for at least 6 months after the final study drug administration.
• Male patient with a pregnant or breastfeeding partner(s) must agree to abstinence or use a condom for the duration of the pregnancy or time their partner is breastfeeding throughout the study period and for at least 6 months after the final study drug administration.
  • †Highly effective forms of birth control include:
    • Consistent and correct usage of established hormonal contraceptives that inhibit ovulation;
    • Established intrauterine device (IUD) or intrauterine hormone releasing system (IUS);
    • Vasectomy (a vasectomy is a highly effective contraception method provided the absence of sperm has been confirmed. If not, an additional highly effective ethod of contraception should be used);
    • Male is sterile due to a bilateral orchiectomy or radical cystoprostatectomy/removal of seminal vesicles.
• The patient must provide written informed consent.

Exclusion Criteria:

• Ongoing sensory or motor neuropathy Grade ≥2.
• Active central nervous system (CNS) metastases. Patients with treated CNS metastases are permitted on study if all the following are true:
  • CNS metastases have been clinically stable for at least 6 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis;
  • If requiring steroid treatment for CNS metastases, the patient is on a stable dose ≤20 mg/day of prednisone or equivalent for at least 2 weeks;
  • Patient does not have leptomeningeal disease.
• Ongoing clinically significant toxicity (Grade 2 or higher) associated with prior treatment (including systemic therapy, radiotherapy or surgery). Patients with hypothyroidism or panhypopituitarism related to treatment with PD-1 and PD-L1 inhibitors may be enrolled.  Patients on hormone replacement therapy may be enrolled if on a stable dose. Patients with immunotherapy related myocarditis, colitis, uveitis, or pneumonitis are excluded.  Patients with other immunotherapy related adverse events requiring high doses of steroids (>20 mg/day of prednisone or equivalent) are excluded.
• Prior enrollment in an enfortumab vedotin study or prior treatment with other MMAE based ADCs.
• History of another malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Patients with nonmelanoma skin cancer, localized prostate cancer treated with curative intent with no evidence of progression, low-risk or very low-risk (per standard guidelines) localized prostate cancer under active surveillance/watchful waiting without intent to treat, or carcinoma in situ of any type (if complete resection was performed) are allowed.
• Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of first dose of enfortumab vedotin. Routine antimicrobial prophylaxis is permitted.
• Patients with a positive hepatitis B surface antigen and/or antihepatitis B core antibody.  Patients with a negative polymerase chain reaction (PCR) assay are permitted with appropriate antiviral prophylaxis.
• Active hepatitis C infection or known human immunodeficiency virus (HIV) infection.  Patients who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of ≥12 weeks.
• Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms (including congestive heart failure) consistent with New York Heart Association Class III-IV (see Appendix C) within 6 months prior to the first dose of enfortumab vedotin.
• Radiotherapy or major surgery within 2 weeks prior to first dose of study drug.
• Chemotherapy, biologics, investigational agents, and/or antitumor treatment with immunotherapy that is not completed 2 weeks prior to first dose of study drug.
• Known hypersensitivity to enfortumab vedotin or to any excipient contained in the drug formulation of enfortumab vedotin (including histidine, trehalose dihydrate, and polysorbate 20).
• Patients with active keratitis or corneal ulcerations. Patients with superficial punctate keratitis are allowed if the disorder is being adequately treated in the opinion of the investigator.
• Other underlying medical condition that, in the opinion of the investigator, would impair the ability of the patient to receive or tolerate the planned treatment and follow-up.
• Patients with uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c 7–<8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.
• Uncontrolled tumor-related bone pain or impending spinal cord compression. Patients requiring pain medication must be on a stable regimen at the time of enrollment (a minimum of 2 weeks).