Background: Treatment options are suboptimal and limited for cisplatin-ineligible metastatic urothelial carcinoma (mUC) patients. Sacituzumab govitecan (SG) is a Trop-2 directed antibody-drug conjugate (ADC) coupled with SN-38 through a hydrolysable linker. In the phase II TROPHY-U-01 study, SG demonstrated an objective response rate (ORR) of 27% and median overall survival (OS) of 10.5 months in mUC patients who progressed after platinum-based chemotherapy and immune checkpoint inhibitors (ICI), receiving accelerated approval by the US FDA. In CheckMate 032 study, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1+I3) every 3 weeks (Q3W) x 4 cycles followed by nivolumab monotherapy 3mg/kg Q2W showed promising activity post-platinum that led to the ongoing phase III trial in the first-line setting (NCT03036098). Given potential synergism between immunogenic cell death induced by ADC and ICI, we hypothesized that the combination of SG and IPI-NIVO would benefit patients with manageable toxicities. We designed this study to assess the safety and clinical activity of IPI-NIVO with SG as first-line therapy for cisplatin-ineligible mUC patients. Methods: This is an ongoing phase I/II, single arm, multicenter study for cisplatin-ineligible mUC. The Phase I portion enrolled 9 patients using a 3+3 design with safety and RP2D as primary endpoints. In this part, patients received fixed doses of IPI-NIVO (N1+I3) IV Q3Wx 4 cycles combined with SG (DL1 8 mg/kg or DL2 10mg/kg) IV on days 1, 8 Q3W x 4 cycles. This was followed by maintenance nivolumab 360 mg IV Q3W with SG on days 1, 8 Q3W. The RP2D of SG was determined as 8 mg/kg and combination was deemed safe and tolerable. ORR is the primary endpoint in the ongoing phase II portion of the study using Simon 2 stage design (n=34) with a futility interim analysis after 13 patients. The null hypothesis of ORR ≤ 38% will be tested with a desirable ORR of >60% under a statistical power of 80% and a one-sided type I error rate of 5%. Thirteen of the 34 patients have been enrolled and the study has passed the predefined interim analysis for futility. We aim to continue accrual. Exploratory biomarker analyses will be conducted using tumor and blood samples collected during screening and at progression. Clinical trial (NCT04863885). Clinical trial information: NCT04863885.