Study of Sacituzumab Govitecan in Participants With Urothelial Cancer That Cannot Be Removed or Has Spread

The objective of this study is to evaluate the efficacy and safety of sacituzumab govitecan-hziy monotherapy and with novel combinations in participants with metastatic urothelial cancer (mUC).

Non-Randomized for Cohorts 1,2,3, and 4; Randomized for Cohorts 5, 6, and 7. Cohort 5 has been cancelled, effective December 2023.

Eligibility Criteria:
Key Inclusion Criteria:

Inclusion Criteria for All Cohorts:

* Female or male individuals, ≥ 18 years of age (19 Years old for South Korea).
* Eastern Cooperative Oncology Group (ECOG) Performance status score of 0 or 1.
* Adequate renal and hepatic function.
* Adequate hematologic parameters without transfusional support.
* Individuals must have a 3-month life expectancy.

Additional Inclusion Criteria for Cohorts 1 to 6:

* Cohort 1: Have had progression or recurrence of urothelial cancer following receipt of platinum-containing regimen (cisplatin or carboplatin):

  1. Received a first-line platinum-containing regimen in the metastatic setting or for inoperable locally advanced disease;
  2. Or received neo/adjuvant platinum-containing therapy for localized muscle-invasive urothelial cancer, with recurrence/progression ≤12 months following completion of therapy.
* Cohort 1: In addition to above criterion, have had progression or recurrence of urothelial cancer following receipt of an Anti-programmed Cell Death Protein 1 (anti-PD-1)/ Anti-programmed Death Ligand 1 (PD-L1) therapy.
* Cohort 2: Were ineligible for platinum-based therapy for first line metastatic disease and have had progression or recurrence of urothelial cancer after a first-line therapy for metastatic disease with anti-PD-1/PD-L1 therapy. Individual may not have received any platinum for treatment of recurrent, metastatic or advanced disease.
* Cohort 3: Progression or recurrence of UC following a platinum containing regimen in the metastatic setting, or progression or recurrence of UC within 12 months of completion of platinum-based therapy as neoadjuvant or adjuvant therapy.
* Cohort 4: Individual has not received any platinum-based chemotherapy in the metastatic or unresectable locally advanced setting. Creatinine clearance of at least 50 mL/min calculated by Cockcroft-Gault formula or another validated tool. For individuals receiving cisplatin at 70 mg/m\^2 on Day 1 of every 21-day cycle, a creatinine clearance of least 60 mL/min calculated by Cockcroft -Gault formula or another validated tool is required. Individuals with creatinine clearance between 50 to 59 mL/min are to receive a split dose of cisplatin (35 mg/m\^2 Day 1 and Day 8 of every 21-day cycle).
* Cohorts 4, 5, 6: Archival tumor tissue comprising muscle-invasive or metastatic urothelial carcinoma, or a biopsy of metastatic urothelial carcinoma.
* Cohort 5: Individuals received at least 4 cycles and no more than 6 cycles of GEM + cisplatin. No other chemotherapy regimens are allowed in this cohort, with the exception of prior adjuvant or neoadjuvant systemic therapy with curative intent after \> 12 months from completion of therapy.
* No evidence of progressive disease following completion of first-line chemotherapy (ie, CR, PR, or SD per RECIST v1.1 guidelines as per investigator).
* Treatment-free interval of 4 to 10 weeks since the last dose of chemotherapy.
* Cohort 6: Cis-ineligible and no prior therapy for metastatic disease or for unresectable locally advanced disease. Checkpoint inhibitor therapy naïve or \>12 months from completion of adjuvant therapy are permitted.
* Cohorts 4 and 6: Have measurable disease by CT or MRI as per RECIST 1.1 criteria. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
* Cohorts 1, 2, 3 and 5: Creatinine clearance ≥ 30 mL/min as calculated by the Cockcroft-Gault formula unless otherwise specified

Additional Inclusion Criteria for Cohort 7:

* No prior systemic therapy for locally advanced or metastatic UC. Therapy in the curative setting is allowed provided recurrence is \> 12 months since the last dose of systemic therapy.
* Archival tumor tissue comprising muscle-invasive or metastatic urothelial carcinoma, or a biopsy of metastatic urothelial carcinoma.
* Have measurable disease by CT or MRI as per RECIST 1.1 criteria. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

Key Exclusion Criteria:

Exclusion Criteria for All cohorts:

* Females who are pregnant or lactating.
* Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
* Has an active second malignancy.
* Has known active Hepatitis B or Hepatitis C.
* Has other concurrent medical or psychiatric conditions.
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
* Has an active second malignancy.

Additional Exclusion Criteria for Cohorts 1 to 6:

* For Cohort 5: Alopecia, sensory neuropathy Grade ≤2 is acceptable, or other Grade \<\< 2 adverse events not constituting a safety risk based on the investigator's judgment are acceptable.
* Cohort 3: Has received anti-PD-1/PD-L1 therapy previously.
* Cohorts 3 to 6: Has an active autoimmune disease that required systemic treatment in past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
* Cohorts 3 to 6: Has received a live vaccine within 30 days prior to the first dose of study drug(s), has history or evidence of interstitial lung disease (ILD) or non-infectious pneumonitis.
* Cohort 4: Refractory to platinum (i.e., relapsed ≤ 12 months after completion of chemotherapy) in the neoadjuvant/adjuvant setting.
* Cohorts 4, 5, and 6: For individuals who received prior CPI, a treatment-free interval \>12 months between the last treatment administration and the date of recurrence is required.

Additional Exclusion Criteria for Cohort 7:

* Have had a prior anticancer therapy within 12 months prior to C1D1 or prior radiation therapy within 2 weeks prior to C1D1. Individuals participating in observational studies are eligible. Use of other investigational drugs (drugs not marketed for any indication) within 28 days or 5 half-lives (whichever is longer) of first dose of investigational product.
* Have a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
* Have a Child-Pugh score of B or C.
* Individuals with uncontrolled diabetes.
* Have active keratitis or corneal ulcerations.
* Participants with ongoing sensory or motor neuropathy Grade ≥ 2.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.