Background: Few patients with metastatic urothelial carcinoma (UC) achieve a durable response despite early stabilization with chemotherapy or immunotherapy. Mutations in the COMPASS-related proteins KMT2D, KMT2C, and KDM6A are found in 66% of patients with UC, suggesting disruption of histone regulation may be an acquired mechanism of tumor viability. Using a carcinogen-derived mouse model of UC in which 80% of animals have alterations in Kmt2d, Kmt2d or both, we found regression of tumors when treated an enzymatic inhibitor of EZH2 (Tazemetostat). In vivo administration of Tazemetostat enhanced the immune response with more necrosis when combined with an anti-PD1 antibody. Therefore, we hypothesized that treatment of UC with an Tazemetostat may further improve the activity of immunotherapy as only 21% of cisplatin refractory (KN45) and 24% of cisplatin ineligible (KN52) patients achieve an objective response. We hypothesized that restoration of the epigenetic imbalance, combined with immunotherapy may improve survival in patients with metastatic UC. Methods: ETCTN10183 (NCT03854474) is a Phase I/II trial evaluating the efficacy of Tazemetostat at 800 mg BID + Pembrolizumab 200 mg IV every 3 weeks in patients with either cisplatin-refractory (Cohort A) or cisplatin-ineligible (Cohort B) metastatic UC. The safety lead-in portion of the trial will follow a “3+3” design with one dose de-escalation level (800mg or 600mg BID Tazemetostat) and will enroll 6-12 patients to establish the recommended phase II dose (RP2D) of Tazemetostat. All DLTs will be reviewed and if tolerated, two dose expansion cohorts will be initiated and will include 24 patients with 12 in each cohort (cisplatin refractory and ineligible). The primary objectives are to identify the RP2D of Tazemetostat in combination with Pembrolizumab, and secondary objectives are to determine the objective disease response in patients with either cisplatin-refractory or unresponsive UC per RECIST criteria, safety, tolerability and progression-free survival. Translational objectives include evaluation of tumor mutations in COMPASS genes, total mutation burden, T cell infiltration, TCR clonality, tumor subtyping and PD-L1 expression. Clinical trial information: NCT03854474