Modular Trial of sEphB4-HSA in EphrinB2-High Solid Tumors

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 orarchival tissue.

• Tumor tissue must be submitted for molecular profile through a commercial servicesuch 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 individualmethods of contraception should be determined in consultation with the treatingphysician or investigator.

• Women of childbearing potential are eligible if serum pregnancy test obtained duringscreening is negative. Women are also eligible if one of the following criteria ismet:

• 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 mensesfor at least 12 consecutive months with no alternative pathological orphysiological cause; OR

• A serum follicle stimulating hormone (FSH) level within the laboratory'sreference range for postmenopausal women.

• Women must not be breastfeeding.

• Men who are sexually active with women of childbearing potential must agree to use 2contraceptive methods with a failure rate of less than 1% per year. o NOTE: Contraception should be continued using two highly effective methods for aperiod of 120 days after the last dose of treatment.

• Adequate organ function as defined below using baseline laboratory requirementsobtained within 14 days prior to randomization:

• Measured or calculated creatinine clearance (CrCl) greater than or equal to 30mL/min using the Cockcroft-Gault formula using actual weight (NOT ideal oradjusted 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 smallcell 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 torandomization. If cisplatin ineligible or refusing, pembrolizumab must be approvedby patient's insurance prior to randomization.

Module B inclusion Criteria

• Urothelial carcinoma, variant components and differentiations allowed. Pure smallcell not allowed.

• Tumor must be Nectin4 non-amplified- testing performed during pre-screeningassessment.

• 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 havecompleted their treatment and have recovered from the acute effects of radiationtherapy or surgery prior to the start of study medication, have discontinuedcorticosteroid treatment for these metastases for at least 4 weeks and areneurologically stable. Mild neurological deficit is allowed, if it does notinterfere with the ability to judge the safety on the trial.

• History of or active autoimmune disorders (including but not limited to: Crohn'sDisease, rheumatoid arthritis, scleroderma, systemic lupus erythematosus, Grave'sdisease) 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 acquiredimmunodeficiency syndrome (AIDS) -related illness. Routine testing is not required;however, treating physicians may use their discretion to determine whether testingis 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 acutediverticulitis) that, in the investigator's opinion, would increase the riskassociated with study participation or study drug administration or interfere withthe interpretation of safety results.

• Major surgery less than 6 weeks prior to the first dose of study drug. Minor surgeryless than 4 weeks prior to the first dose of study drug. Insertion of vascularaccess device ≥ 7 days prior to 1st dose of study drug is allowed.

• History of severe hypersensitivity reaction to any monoclonal antibody.