TROPiCS-04: This Phase III trial is evaluating the effectiveness of a targeted therapy (Sacituzumab Govitecan-hziy) compared to chemotherapy (paclitaxel, docetaxel or vinflunine) in people with bladder cancer that is unable to be treated with surgeryA Randomized Open-Label Phase III Study of Sacituzumab Govitecan Versus Treatment of Physician's Choice in Subjects With Metastatic or Locally Advanced Unresectable Urothelial Cancer (TROPiCS-04)

Inclusion

1. Individuals with histologically documented metastatic or locally advanced unresectable UC defined as

   • Tumor (T) 4b, any node (N) or
   • Any T, N 2-3 Tumors of upper and lower urinary tract are permitted. Mixed histologic types are allowed if urothelial is the predominant histology.
2. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1.

3. Individuals with progression or recurrence following receipt of platinum-containing regimen and anti programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) therapy for metastatic or locally advanced unresectable disease will be enrolled.

   • a. Individuals with recurrence or progression ≤12 months following completion of cisplatin-containing chemotherapy given in the neo-adjuvant/adjuvant setting may utilize that line of therapy to be eligible for the study. The 12-month period is counted from completion of surgical intervention or platinum therapy, respectively. These individuals must receive anti PD-1/PD-L1 therapy in the metastatic or locally advanced unresectable setting to be eligible.
   • b. Individuals who received either carboplatin or anti PD-1/PD-L1 therapy in the neo- adjuvant/adjuvant setting will not be able to count that line of therapy towards eligibility for the study.

   • c. Cisplatin ineligible individuals who meet one of the below criteria and who were treated with carboplatin in the metastatic or locally advanced unresectable settings may count that line of therapy towards eligibility. They must then have received anti PD-1/PD-L1 therapy in metastatic or locally advanced unresectable setting to be eligible for the study.

     • Cisplatin ineligibility is defined as meeting one of the following criteria:

       • 1. Creatinine Clearance < 60 mL/min
       • 2. Grade ≥ 2 Audiometric Hearing Loss
       • 3. Grade ≥ 2 Peripheral Neuropathy
       • 4. New York Heart Association (NYHA) Class III heart failure
       • 5. ECOG PS ≥ 2
   • d. Anti PD-1/PD-L1 therapy administered as part of maintenance therapy may be counted towards eligibility for the study
   • e. Individuals who have progressed after receiving enfortumab vedotin in prior lines of therapy, and individuals who are either ineligible or unable to tolerate enfortumab vedotin therapy, are eligible to enroll in the study
   • f. Individuals who received only concurrent chemoradiation for bladder preservation without further systemic therapy are not eligible to enroll in the study. The substitution of carboplatin for cisplatin does not constitute a new regimen provided no new chemotherapeutic agents were added to the regimen and no progression was noted prior to the change in platinum.
4. Individuals with previously treated brain metastases may participate in the study provided they have stable CNS disease for at least 4 weeks prior to the first dose of study drug and stabilization of all neurologic symptoms, have no evidence of new or enlarging brain metastases, and are not using steroids >20 mg of prednisone (or equivalent) daily for brain metastases for at least 7 days prior to first dose of the study drug.
5. Adequate hematologic counts without transfusion or growth factor support within 2 weeks of study drug initiation (hemoglobin ≥ 9 g/dL, absolute neutrophil count (ANC) ≥1,500/mm^3, and platelets ≥100,000/µL).

6. Adequate hepatic function (bilirubin ≤1.5x institutional upper limit of normal (IULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x IULN or ≤ 5 x IULN if known liver metastases and serum albumin >3 g/dL).

   Docetaxel will only be option in TPC arm for Individuals with a total bilirubin ≤1 x IULN, and an AST and/or ALT ≤1.5x IULN if alkaline phosphatase is also >2.5 x IULN.

7. Creatinine clearance ≥30 mL/min as assessed by the Cockcroft-Gault equation or other validated instruments (e.g. Modification of Diet in Renal Disease (MDRD) equation).
8. Females of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study drug. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
9. Females of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 6 months after the last dose of study drug. Individuals of childbearing potential are those who have not been surgically sterilized or have not been free from menses for >2 years.
10. Males must agree to use an adequate method of contraception starting with the first dose of study therapy through 6 months after the last dose of study therapy.