Background: MIUBC is a systemic disease and > 40% of pts develop recurrence after Cy. Despite neoadjuvant chemotherapy yields Level 1 evidence, it is underutilized worldwide and a small survival improvement is deemed over Cy alone. PEM is an EMA and FDA-approved therapy for metastatic UC after platinum failure or for cisplatin-ineligible pts. EPA, an anti-IDO1 agent, combined with PEM, safely improved the response-rate in UC in phase 1 trial. Our hypothesis is that PEM+EPA, given neoadjuvantly, could further improve downstaging MIUBC. Methods: Pts with T2-T3b N0 UC with residual disease after transurethral resection of the bladder (TURB, surgical opinion, cystoscopy or radiological presence) will receive 3 cycles of PEM 200mg intravenously, q3 weekly. EPA will be orally taken at the dose of 100 mg BID, from d1 until 10 days before Cy. Cy should be performed within 3 weeks of the last PEM dose. Computed tomography (CT) scan, ¹⁸FDG-PET/CT scan, and multiparametric bladder MRI (mpMRI) will be done during screening and before Cy to stage and evaluate response. After Cy, pts will be managed according to EAU guidelines. Adjuvant anti PD-1 therapy is not allowed. PD-L1 status will be assessed using Dako anti-PD-L1 antibody (clone 22C3), relying on the combined positivity score (CPS). Pathologic complete response (pT0) is the primary endpoint. All pts enrolled who receive at least 1 cycle of study drug will be included in the ITT analysis. The H₁ is pT0≥25% and H₀ pT0≤15%. A MinMax 2-stage design will be used to estimate the number of pts required. Out of 71 total pts, with the first stage of 43 pts, ≥6 pT0 will be required in the first stage, and ≥14 pT0 in the whole study population. Correlative research on blood samples will include immune-cell profiling and cytokine assessment. In tumor samples, genomic analyses will be done with FoundationONE test (Foundation Medicine Inc.). Tumor mutational burden (TMB) will be determined on 1.1 Mbp of sequenced DNA and reported as mutations (mut) per megabase (Mb) and microsatellite instability (MSI) will determined on 114 loci (EudraCT number 2017-002379-24). Clinical trial information: 2017-002379-24.