Background: A growing body of data support that the key to generating anti-tumor immune responses triggered by administration of immuno-oncology (IO) agents, is the activation and invasion of T lymphocytes. Checkpoint inhibitors (CPIs) are being actively explored in the neoadjuvant setting of MIBC. CPIs documented 30-40% pathologic complete response-rates (ypT0N0) in previous trials. Increasingly, novel IO agents are being developed in combinations with anti PD(L)-1 therapies. Understanding the changes in the tumor microenvironment that occur with the addition of novel immunomodulating agents to PD(L)-1 inhibitors can help inform whether a compound is viable for further development. The OPTIMUS trial is a window of opportunity, neoadjuvant platform design study in MIBC patients that are cisplatin-ineligible. The study investigates the addition of the indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor epacadostat to the PD-1 inhibitor retifanlimab. The platform design allows for investigation of other novel immune-modulating combinations. Methods: This is an open-label, randomized, Phase 2, multi-treatment group, window-of-opportunity, platform study for participants with MIBC undergoing radical cystectomy who refuse or are not eligible for cisplatin-based neoadjuvant chemotherapy (NCT04586244). Participants are randomized based on tumor tissue PD-L1 CPS ≥ 10 or PD-L1 CPS < 10 to one of the following treatment groups: Treatment Group A (epacadostat + retifanlimab); Treatment Group B (retifanlimab monotherapy); Treatment Group C (epacadostat monotherapy). 18 patients will be enrolled in each of Treatment Groups A and B. 9 patients will be enrolled into Treatment Group C. Total treatment duration is a maximum of 10 weeks. The platform study design allows for addition of future treatment groups. Pre-treatment biopsy is obtained through transurethral resection of bladder tumor (TURBT), followed by neoadjuvant treatment, followed by radical cystectomy. In all treatment groups, tissue from the surgical specimen(s) is collected and compared with the initial pre-treatment samples. The primary endpoint is the change from baseline in CD8+ lymphocytes within resected tumor. Secondary endpoints include safety and tolerability, rates of ypT0N0 response, and major pathologic response. Exploratory analyses include tumoral changes in gene cell expression profile, immune-cell protein and metabolic marker levels, and spatial relationships between cell types. Plasma is also collected and will be investigated for changes in cytokines and other inflammatory or metabolic markers. Clinical trial information: NCT04586244.