Background: There have been multiple advances in therapy of advanced urothelial carcinoma following platinum and ICB; SG and EV are both FDA approved in this space though durations of response are short and overall survival limited at < 13 months. Given different mechanisms of action, non-overlapping toxicities and potential for synergy, EV and SG is hypothesized to have manageable toxicities and demonstrate additive anti-tumor activity. Methods: NCT04724018 is a single-center (Dana-Farber/Harvard Cancer Center), open-label, non-randomized phase I trial using a Bayesian Optimal Interval design. SG and EV agents are administered intravenously (IV) on days 1 and 8 every 3 weeks (1 cycle) until progression or intolerable toxicities. Laboratory evaluation is performed on days 1 and 8 every cycle with additional blood collected throughout treatment for pharmacokinetic and antidrug antibody studies. Imaging is performed at baseline and every 6 weeks for the first 4 cycles followed by every 9 weeks thereafter. Up to 4 dose levels of the combination of SG and EV are studied with a starting dose of SG of 8 mg/kg and EV of 1 mg/kg (dose level 1) with additional dose escalations outlined in table. Dose de-escalation of SG to 6 mg/kg with the starting dose of EV 1 mg/kg (dose level -1) is permitted. A total of 3 to 18 patients are expected to be enrolled in current dose level depending on dose limiting toxicities (DLTs). DLT is assessed during cycle 1 of therapy and toxicities are captured up to 4 weeks after the last dose of therapy and being defined by ≥1 of the following: neutropenic fever, thrombocytopenic bleeding, grade 3 neuropathy, of any duration and any other grade ≥3 non-hematologic toxicity to include hyperglycemia (except alopecia) lasting >1 week or requiring >3 weeks interruption of therapy or dose reduction. The first patient per 3-patient cohort is required to complete 1 full cycle (3 weeks) before additional patients can be enrolled in that cohort. Therefore, up to 24 patients may be accrued. Trial continues to enroll at dose level one. Clinical trial information: NCT04724018.