A Study of Enfortumab Vedotin in People With Urothelial Carcinoma of the Upper Urinary Tract

Inclusion Criteria: * Histologically confirmed high grade urothelial carcinoma of the upper tract and/or radiographically visible tumor stage T2-T4a N0/x M0 disease with positive selective urinary cytology. Hydronephrosis associated with tumor on imaging or biopsy will be considered invasive by definition. (Variant histology is acceptable if there is a predominant urothelial component. Discussion with PI strongly encouraged.) Retroperitoneal lymph nodes \<15 mm in the short axis will be eligible. * Patients who are o Ineligible for cisplatin based on any of the following criteria: * Estimated or calculated creatinine clearance ≥ 30ml/min but \< 60 ml/min * Grade 2 or above audiometric hearing loss (per CTCAE v5.0) or * Declined cisplatin-based neoadjuvant chemotherapy, as documented in medical chart * Availability of tumor specimen block, cell block or 30 unstained slides from diagnosis. Patients with fewer than 30 slides available may be enrolled after discussion with the Principal Investigator.Additional research biopsy is not required. * Karnofsky performance status ≥ 70%. * Medically appropriate candidate for radical surgery (nephroureterectomy, nephrectomy, or ureterectomy), as per treating Attending Urologic Oncologist * Age ≥ 18 years. * Required initial laboratory values: * Absolute neutrophil count ≥ 1.5 x 10\^9 /L * Platelets ≥ 100 x 109 /L * Bilirubin ≤1.5 times the upper limit of normal (x ULN) * Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN PTT/PT ≤1.5 x ULN or INR \< 1.7 x ULN for patients who are not receiving therapeutic anticoagulation. Patients receiving therapeutic anticoagulation should be on a stable dose * If patients are HIV (+) they are eligible as long as they have: cd4 \>200, undetectable viral load and on HAART therapy. Exclusion Criteria: * Presence of metastatic disease. * Prior treatment with systemic chemotherapy or radiotherapy for urothelial cancer of the bladder within the last 2 years. (Prior intravesical treatment such as BCG is allowed). * Grade 2 or higher peripheral neuropathy. * 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. * Patients with uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobin A1c (HbA1c) ≥8% or HbA1c 7% to \<8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained. * Unstable angina. * New York Heart Association (NYHA) Grade II or greater congestive heart failure. * History of myocardial infarction within 6 months. * History of stroke within 6 months. * Evidence of bleeding diathesis or coagulopathy. Therapeutic anticoagulation is permitted, but patients must be on a stable dose. * Major surgical procedure within 28 days prior to the study. (Transurethral resection of bladder tumor is permitted) * Serious, non-healing wound, ulcer, or bone fracture. * Patients with active tuberculosis. * Other prior malignancy active within the previous 2 years except for local or organ confined early stage cancer that has been definitively treated with curative intent or does not require treatment, does not require ongoing treatment, has no evidence of active disease, and has a negligible risk of recurrence and is therefore unlikely to interfere with the endpoints of the study. * Prior treatment with enfortumab vedotin or other MMAE-based antibody-drug conjugates (ADCs). * No known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected). * Women who are breastfeeding or pregnant as evidenced by a positive pregnancy test within 14 days of first dose. * Known severe (≥ Grade 3) hypersensitivity to enfortumab vedotin or to any excipient contained in the drug formulation of enfortumab vedotin (including histidine, trehalose dihydrate, and polysorbate 20). * Male subjects who are unwilling to use contraception during the treatment and for at least 31 weeks after the last dose of study treatment (5 half-lives of study drug plus 90 days duration of sperm turnover). * Women of childbearing potential (WOCBP) not using a medically acceptable means of contraception throughout the study treatment and for at least 23 weeks following the last dose of study treatment (5 half-lives of study drug plus 30 days duration of ovulatory cycle). °WOCBP are defined as those who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Postmenopausal is defined as: * Amenorrhea ≥ 12 consecutive months without another cause, or * For women with irregular menstrual periods and on hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level \> 35 mIU/mL * Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness. * Inability to comply with study and/or follow-up procedures.