A Pilot Study of Circulating Tumor DNA Adaptive Risk Maintenance Approach for Bladder Cancer (CARMA)

Inclusion Criteria: 1. Histologically confirmed, unresectable locally advanced or metastatic transitional cell carcinoma of the urothelium. 2. Subjects must be deemed eligible for standard first-line platinum-based chemotherapy for advanced or metastatic urothelial cancer (e.g., as per NCCN guidelines). Eligible regimens include; dose-dense MVAC, gemcitabine + cisplatin and/or gemcitabine + carboplatin. (split-dose dosing of cisplatin for dose-dense MVAC and gemcitabine + cisplatin is allowed) 3. Must have measureable disease per RECIST v1.1. 4. Male or female participants with age ≥ 18 years 5. ECOG performance status 0 or 1. 6. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (e.g., barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 6 months after the last dose of study treatment 7. Adequate Bone marrow function: 1. Absolute neutrophil count (ANC) ≥ 750 /mm3 or ≥0.5 x 109/L 2. Platelets ≥50,000/mm3 or ≥100 x 109/L 3. Hemoglobin ≥7.5 g/dL (may have been transfused) 8. Adequate renal function, defined as estimated creatinine clearance ≥ 45 mL/min (calculated using the Cockcroft-Gault formula or measured with 24-hour urine collection) 9. Adequate liver function: 1. Total serum bilirubin \< 1.5 X ULN (Pts with Gilbert's can enroll if conjugated bilirubin is within normal limits) 2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 X institutional ULN 10. Ability to understand and willingness to sign a written informed consent and HIPAA consent document Exclusion Criteria: 1. Prior systemic chemotherapy or radiation therapy for advanced or metastatic urothelial carcinoma. 2. Prior immunotherapy with IL-2, IFN-α, or an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or CTLA-4 antibody (including ipilimumab), or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways. 3. Major surgery ≤ 4 weeks or major radiation therapy ≤ 2 weeks prior to enrollment. 4. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided it has not been completed within 48 hours prior to patient enrollment. 5. Participants with known symptomatic central nervous system (CNS) metastases requiring steroids. Participants with previously diagnosed CNS metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to randomization, have discontinued corticosteroid treatment for these metastases for at least 4 weeks, and are neurologically stable 6. Persisting toxicity related to prior therapy NCI CTCAE v5.0 Grade \>1; however, sensory neuropathy Grade ≤ 2 is acceptable. 7. On active treatment for any other malignancy, except for adjuvant hormone therapy for localized breast cancer or castration for hormone sensitive prostate cancer. 8. Participation in other studies involving investigational drug(s) within 4 weeks prior to randomization. Observational studies are permitted. 9. History of uncontrolled autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Patients with well-controlled autoimmune disease and mild symptoms on a stable dose of prednisone (≤ 10 mg daily) are allowed on study. 10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (defined by current oral or intravenous antibiotic therapy), symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. 11. Patients with prior allogeneic hematologic transplant 12. Pregnant or breast-feeding.