Lurbinectedin With or Without Avelumab in Small Cell Carcinoma of the Bladder (LASER)

Background: Small cell carcinoma of the bladder (SCCB) and other high-grade neuroendocrine tumors (HGNET) of the urinary tract are rare but aggressive cancers. Average survival for people diagnosed with SCCB or HGNET is about 1 year. Lurbinectedin and avelumab are drugs that are approved to treat other cancers. Researchers want to see if these drugs can help people with SCCB or HGNET. Objective: To test lurbinectedin with or without avelumab in people with SCCB or HGNET. Eligibility: Adults aged 18 years and older with SCBB or HGNET that returned and spread after treatment. Design: Participants will be screened. They will have a physical exam. They will have blood tests and imaging scans. They may need to have a new biopsy: A small needle will be used to collect a tissue sample from the tumor. Both study drugs are given through a tube attached to a needle inserted into a vein. If participants have already received a drug like avelumab they will receive only lurbinectedin. If patients have not been previously treated with a drug like avelumab they will receive both lurbinectedin and avelumab. All participants will receive their treatment once every 3 weeks for up to 10 years. They will also receive other drugs to relieve adverse effects. Biopsies, blood tests, and imaging scans will be repeated during some study visits. Participants may also have urine tests and tests of their heart function. Participants may remain in the study as long as the treatment is helping them. If they stop treatment, they will have safety visits 14, 30, and 90 days after their last dose. Additional follow-up visits will continue 5 to 10 years.

Background: * Small cell carcinoma of the bladder (SCCB) is a rare, aggressive form of bladder cancer, accounting for less than 1% of all bladder malignancies. * High grade neuroendocrine tumors (HGNET) of the urinary tract are very rare and include both small cell neuroendocrine carcinomas (SCNEC) and large cell neuroendocrine carcinomas (LCNEC). * Traditionally regimens drawn from the small cell lung cancer literature (cisplatin and etoposide) are used in the frontline setting, and while initially highly responsive to chemotherapy, responses are generally short lived. * There is little evidence to guide therapeutic decisions at time of disease progression. * Lurbinectedin is a selective inhibitor of oncogenic transcription that binds preferentially to guanines located in the GC-rich regulatory areas of DNA gene promoters. * Lurbinectedin prevents binding of transcription factors to their recognition sequences, inhibiting oncogenic transcription and leading to tumor cell apoptosis. * Lurbinectedin was recently approved as a second line agent in small cell lung cancer, where it has shown an overall response rate of 35%. * Immune checkpoint inhibitors (ICIs) have become part of the standard of care for small cell lung cancer, and their use in the community for treatment of SCCB has increased. * However, ICI use in SCCB is still case reportable in the literature, and no prospective studies have been published to date. Objective: -To assess the objective response rate (ORR) of lurbinectedin, either alone or in combination with avelumab, in participants with small cell carcinoma of the bladder (SCCB) or other high grade neuroendocrine tumors (HGNETs) of the urinary tract Eligibility: * Age \>= 18 years * Histologically confirmed diagnosis of metastatic SCCB or HGNET of the urinary tract * Participants must have metastatic disease defined as new or progressive lesions. * Participants must have at least one measurable site of disease * Participants must have received, be ineligible, or refused prior platinum/etoposide chemotherapy for SCCB or HGNET of the urinary tract. Design: * This is a Phase II, multisite, open label, nonrandomized study with two cohorts. * All participants will receive lurbinectedin. * Participants without prior ICI exposure will be eligible to receive concurrent avelumab. * Treatment will be given in 21-day cycles continuously for up to 10 years or until signs of progression or intolerable side effects. * Lurbinectedin will be administered intravenously (I.V.) at 3.2mg/m\^2 every 21 days. * Avelumab will be administered I.V. at 800mg every 21 days. * The accrual ceiling will be set at 35 to allow for a small number of inevaluable participants.