Background: UCs are the 6^th most common malignancies in the Western world being localized in the upper (5-10%) or the lower (90-95%) urinary tract. Metastatic UC (mUC), which accounts for 5% of all cases, is associated with a dismal prognosis and prompt progression. So far, the 1^st line therapy for mUC encompassed platinum-based combination regimens. Recent data indicate beneficial patient treatment with immune checkpoint inhibitors. Thus, avelumab was approved for maintenance therapy after progression-free platinum-based chemotherapy for locally advanced (LA) or mUC. Further immune checkpoint inhibitors (e.g. pembrolizumab, atezolizumab, nivolumab) achieved approval or showed promising results for treatment of different patient populations. Eftilagimod alpha (efti) is a soluble LAG-3 fusion protein and a MHC class II agonist activating APCs followed by CD8 T-cell activation. The combination of efti with PD-1/PD-L1 blockade is not yet available and is proposed to enhance efficacy. Based on previous results from the INSIGHT trial and change in treatment landscape we hypothesize that combining avelumab and efti will display clinically relevant efficacy in unresectable LA UC or mUC subgroups with acceptable toxicity. Methods: INSIGHT-005 is a new stratum within the investigator-initiated INSIGHT phase I platform trial ongoing at multiple sites (n=9) in Germany. Patients with unresectable LA UC or mUC will receive efti in combination with avelumab. 30 patients will be enrolled in 3 subgroups: I) Previously untreated, eligible for platinum-based therapy, with PD-L1 CPS≥10; II) Previously untreated, not-eligible for platinum-based therapy, irrespective of the PD-L1 status; III) Suffered disease progression after platinum-based chemotherapy for metastatic disease and did not receive avelumab maintenance therapy, irrespective of the PD-L1 status. Enrolled patients will receive avelumab 800 mg i.v. and efti 30 mg s.c. on the same day Q2W for a maximum of 24 cycles. Tumor evaluation will be performed via CT or MRI every 8 weeks. The primary endpoint of this study is to explore feasibility, safety, and preliminary efficacy of efti when added to avelumab in unresectable LA UC or mUC. Secondary endpoints include safety and efficacy parameters as defined by objective response, time to and duration of response and PFS according to RECIST 1.1, OS and biomarker analyses. First patient was enrolled on 2023-11-29. Currently, recruitment is ongoing. ClinicalTrials.gov ID: NCT03252938 Clinical trial information: NCT03252938.