Inclusion Criteria:
General Inclusion Criteria for Both Arms
* Willing and able to provide informed consent.
* Men and women 18 years of age, or older.
* Must provide the cell block or a minimum of 15 slides from the diagnostic biopsy or archival tissue.
* Tumor tissue must be submitted for molecular profile through a commercial service such as Tempus, CARIS, Foundation One, etc. This must include a PD-L1 assay.
* Tumor must express EphrinB2 as assessed by USC Norris Core Lab.
* Zubrod performance status of less than or equal to 1.
* Women of childbearing potential must use method(s) of contraception. The individual methods of contraception should be determined in consultation with the treating physician or investigator.
* Women of childbearing potential are eligible if serum pregnancy test obtained during screening is negative. Women are also eligible if one of the following criteria is met:
* Have undergone a documented hysterectomy and/or bilateral oophorectomy; OR
* Have medically confirmed ovarian failure; OR
* Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; OR
* A serum follicle stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal women.
* Women must not be breastfeeding.
* Men who are sexually active with women of childbearing potential must agree to use 2 contraceptive methods with a failure rate of less than 1% per year.
o NOTE: Contraception should be continued using two highly effective methods for a period of 120 days after the last dose of treatment.
* Adequate organ function as defined below using baseline laboratory requirements obtained within 14 days prior to randomization:
* Measured or calculated creatinine clearance (CrCl) greater than or equal to 30 mL/min using the Cockcroft-Gault formula using actual weight (NOT ideal or adjusted weights).
* WBC ≥2000/uL
* Neutrophils ≥1500/uL
* Platelets ≥100x103/uL
* Hemoglobin ≥9g/dL
* AST ≤3 x ULN
* ALT ≤3 x ULN
* Bilirubin ≤1.5 x ULN
Module A Inclusion Criteria
* Urothelial carcinoma, variant components and differentiations allowed. Pure small cell not allowed.
* cT2 to cT4a N0M0, by TURBT or imaging.
* No systemic therapy for cancer in the previous 12 months.
* Choice of treatment if randomized to the control arm must be declared prior to randomization. If cisplatin ineligible or refusing, pembrolizumab must be approved by patient's insurance prior to randomization.
Module B inclusion Criteria
* Urothelial carcinoma, variant components and differentiations allowed. Pure small cell not allowed.
* Tumor must be Nectin4 non-amplified- testing performed during pre-screening assessment.
* No systemic therapy for cancer in the previous 12 months.
* Measurable disease as defined by RECIST1.1 criteria
Exclusion Criteria:
* Patients with known symptomatic brain metastases requiring systemic corticosteroids. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to the start of study medication, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable. Mild neurological deficit is allowed, if it does not interfere with the ability to judge the safety on the trial.
* History of or active autoimmune disorders (including but not limited to: Crohn's Disease, rheumatoid arthritis, scleroderma, systemic lupus erythematosus, Grave's disease) and other conditions that compromise or impair the immune system.
* Known active bacterial, fungal or viral infection including hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) -related illness. Routine testing is not required; however, treating physicians may use their discretion to determine whether testing is necessary.
* Uncontrolled adrenal insufficiency.
* Any known active chronic liver disease.
* Concurrent or active second malignancy requiring systemic therapy is excluded.
* Known medical condition (eg, a condition associated with diarrhea or acute diverticulitis) that, in the investigator's opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results.
* Major surgery less than 6 weeks prior to the first dose of study drug. Minor surgery less than 4 weeks prior to the first dose of study drug. Insertion of vascular access device ≥ 7 days prior to 1st dose of study drug is allowed.
* History of severe hypersensitivity reaction to any monoclonal antibody.
