Enfortumab Vedotin Plus Pembrolizumab for the Treatment of Locally Advanced or Metastatic Bladder Cancer of Variant Histology

Inclusion Criteria:

• Male or Female

• Age >= 18 years

• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

• Metastatic disease or unresectable locally advanced disease

• Histologically documented variant histology (nested, microcytic, micropapillary,lymphoepithelioma-like, plasmacytoid, giant cell, poorly differentiated, lipid-rich,clear cell, sarcomatoid) bladder cancer and non-urothelial bladder cancer ofepithelial origin including squamous cell carcinoma and adenocarcinoma (urachal andnon-urachal). Variant histology tumors and non-urothelial tumors of ureter, urethra,urachus, or renal pelvis are included. Patients with mixed cell type are eligible ifthe predominant histology (over 50%) is variant or non-urothelial. All histologicalclassifications will follow the 2016 WHO Classifications.

• Untreated or having received any number of lines of prior therapy

• Tumor tissue samples must be available for submission prior to initiation of studytreatment. If not, agree to undergo biopsy

• Patients must have measurable disease as defined by RECIST criteria 1.1 as at leastone lesion that can be accurately measured in at least one dimension (longestdiameter of >= 10 mm for non-nodal lesions or short axis of >= 15 mm for nodallesions) on CT scan, MRI

• Patients must have adequate organ and marrow function, within 28 days of cycle 1 day 1, at the discretion of the investigator

• The effects of study drugs on the developing human fetus are unknown. For thisreason, female of child-bearing potential (FCBP) must have a negative serum or urinepregnancy test prior to starting therapy

• FCBP and men treated or enrolled on this protocol must agree to use adequatecontraception (hormonal or barrier method of birth control; or abstinence) prior tostudy entry and for the duration of study participation. Additionally, FCBP and malesubjects should use effective contraception for 6 months after the last dose. Shoulda woman become pregnant or suspect she is pregnant while she or her partner isparticipating in this study, she should inform her treating physician immediately.Male subjects must not donate sperm and female subjects must not donate ova fromscreening to 6 months after the last dose

• A female of childbearing potential (FCBP) is a sexually mature woman who: 1) has notundergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturallypostmenopausal for at least 24 consecutive months (i.e., has had menses at any timein the preceding 24 consecutive months)

• Completion of all previous therapy (including surgery, radiotherapy, chemotherapy,immunotherapy, or investigational therapy) for the treatment of cancer >= 4 weeksbefore the start of study therapy

• Life expectancy > 12 weeks as determined by the Investigator

• Willingness and ability of the subject to comply with scheduled visits, drugadministration plan, protocol-specified laboratory tests, other study procedures,and study restrictions

• Evidence of a personally signed informed consent indicating that the subject isaware of the neoplastic nature of the disease and has been informed of theprocedures to be followed, the experimental nature of the therapy, alternatives,potential risks and discomforts, potential benefits, and other pertinent aspects ofstudy participation

Exclusion Criteria:

• The neuroendocrine histology (small cell and large cell carcinomas) andnon-epithelial bladder tumors (e.g. bladder sarcoma, carcinosarcoma, paraganglioma,melanoma, primary lymphoma, and lymphoepithelioma-like carcinoma) are excluded.

• Patients who have had chemotherapy or radiotherapy within 4 weeks prior to enteringthe study or those who have not recovered from adverse events due to agentsadministered more than 4 weeks earlier [i.e. ongoing clinically significant toxicity (grade 2 or higher with the exception of alopecia) associated with prior treatment]

• Patients who are receiving any other investigational agents or an investigationaldevice within 21 days before administration of first dose of study drugs

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to the agents used in study

• Patients with ongoing sensory or motor neuropathy grade >= 2

• Prior treatment or enrollment in a study with EV or PD1/PD-L1 immune checkpointinhibitor (including maintenance therapy)

• Known uncontrolled diabetes mellitus with glycated hemoglobin (HbA1c) >= 8% or HbA1c 7% to < 8% with associated diabetes symptoms (polyuria or polydipsia) that are nototherwise explained

• Active central nervous system (CNS) metastases

• Excluding the primary tumor leading to enrollment in this study, any other activemalignancy (except for localized prostate cancer, definitively treated melanomain-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of thebladder or cervix) within the past 24 months

• Currently receiving systemic antimicrobial treatment for active infection or highdose steroids (> 10mg of prednisone or equivalent)

• A FCBP who has a positive urine pregnancy test at baseline or within 72 hours priorto receiving first study dose. If the urine test is positive or cannot be confirmedas negative, a serum pregnancy test will be required

• Breastfeeding females

• History of active autoimmune disease that has required systemic treatment in thepast 2 years (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs), known hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive), known active hepatitis C virus (defined as HCV ribonucleic acid [mRNA] [qualitative] is detected) or tuberculosis

• History of active keratitis or corneal ulcerations

• History of allogenic tissue/solid organ transplant

• Congestive heart failure New York Heart Association Class 3 or 4, unstable anginapectoris, serious cardiac arrhythmias within 6 months prior to first dose ofEV/pembrolizumab

• Other uncontrolled current illness including, but not limited to, cardiac arrhythmiaor psychiatric illness/social situations that would limit compliance with studyrequirements