Background: Small cell carcinoma of the bladder (SCCB) is a rare, aggressive malignancy accounting for <1% of all bladder malignancies. Given its rarity, few prospective randomized trials have been completed in SCCB. Most therapeutic evidence comes from retrospective case series and due to its histologic similarity to small cell lung cancer (SCLC), current guidelines recommend bladder cancers with any component of small cell histology be treated similarly to SCLC. Lurbinectedin is a novel alkylating agent which recently received accelerated approval from the FDA as a second line treatment for SCLC after demonstrating an overall response rate (ORR) of 35.2% and median duration of response (DoR) of 5.3 months (Trigo et al., Lancet Oncol, 2020). Avelumab is an anti-PD-L1 antibody FDA approved as maintenance treatment for patients with locally advanced or metastatic urothelial cancer (UC) without progression on frontline chemotherapy. Case reports have demonstrated that second line options in SCLC, including immunotherapy, appear to have some efficacy in SCCB. The purpose of this study is to assess the efficacy of lurbinectedin, either alone or in combination with avelumab, in participants with SCCB or other high grade neuroendocrine tumors (HGNETs) of the urinary tract. Methods: LASER (NCT06228066) is a phase II, multisite, open label, nonrandomized study with two cohorts. Eligible patients must have pathologically confirmed SCCB or other HGNETs of the urinary tract. Patients with mixed histologies, with any component of neuroendocrine tumor, are eligible. Patients must have received or be ineligible/refused frontline platinum/etoposide therapy. Participants in Cohort 1 must have received prior immune checkpoint inhibitors (ICIs) or be ineligible for treatment with ICI. These patients will receive lurbinectedin 3.2mg/m2 IV every 21 days. Participants in Cohort 2 must be ICI naïve but eligible to receive them. These patients will receive lurbinectedin 3.2mg/m2 IV and avelumab 800mg IV every 21 days. The primary endpoint for both cohorts is ORR, with key secondary endpoints including clinical benefit rate, PFS, OS, and DoR. The study will be conducted using a Simon minimax two stage design to rule out an ORR of 5% in favor of an ORR of 25% or greater in each cohort. If 1 of the first 12 patients has a response accrual will continue up to 16 evaluable patients per cohort. Accrual ceiling will be set at 35 patients. Exploratory objectives include analyzing peripheral immune subsets, DNA and RNA sequencing of tumors, and measurement of ctDNA and CTCs. Clinical trial information: NCT06228066.