Background: Cis-based combination chemotherapy regimens with gemcitabine or methotrexate, vinblastine, and doxorubicin are commonly used as initial treatment for mUC. However, only a fraction of pts maintain a durable response. Alternative Cis-based combinations with improved efficacy while maintaining tolerability are needed. SG is an antibody-drug conjugate (ADC) composed of an anti-trophoblast cell-surface antigen-2 (Trop-2) antibody coupled to SN-38 (a topoisomerase-I inhibitor) via a proprietary hydrolyzable linker. In vitro/in vivo urinary bladder cancer models suggest that the combination of SG and Cis resulted in additive antitumor activity over either agent alone (data on file). In the phase 2 registrational TROPHY-U-01 study, SG monotherapy resulted in a 27% objective response rate (ORR) and a median overall survival (OS) of 10.9 months with a manageable, mostly non–Cis-overlapping toxicity profile in heavily pretreated pts with mUC (Tagawa et al, J Clin Oncol. 2021). These results led to accelerated approval of SG by the FDA in 2021 for pts with locally advanced or mUC who previously received PLT-containing chemotherapy and a checkpoint inhibitor. We hypothesized that SG and Cis in combination may improve efficacy/safety over available first-line mUC regimens. TROPHY-U-01 Cohort 4 study will evaluate the safety, tolerability, and clinical activity of this novel combination. Methods: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, global phase 2 trial. Cohort 4 will evaluate combination SG and Cis in PLT-naive pts with mUC or unresectable locally advanced disease. Key eligibility requirements include Eastern Cooperative Oncology Group performance status 0–1; no prior anticancer monoclonal antibody or ADC therapy within 4 weeks of study drug initiation; no history of active interstitial lung disease or noninfectious pneumonitis; adequate hematologic, hepatic, and renal function. Pts will be treated with Cis at 70 mg/m² on day 1 of a 21-day cycle (if creatinine clearance [CrCl] ≥60 mL/min) or at a split dose of Cis at 35 mg/m² on days 1 and 8 of a 21-day cycle (if CrCl 50-59 mL/min) followed by SG (5, 7.5, or 10 mg/kg) on days 1 and 8 of a 21-day cycle. The recommended phase 2 dose will be the dose in which ≤30% dose-limiting toxicities are noted in cycle 1. Combination therapy will continue for up to 6 cycles, followed by SG and avelumab maintenance given until progression. Prophylactic granulocyte colony-stimulating factor is not allowed in cycle 1 of the safety lead-in phase. Primary endpoint is ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints include progression-free survival, duration of response, and clinical benefit rate per BICR and investigator assessment. OS and safety will be assessed. Enrollment is ongoing; ̃60 pts expected across ̃30 sites in North America and Europe. Clinical trial information: NCT03547973.