Background: Cabozantinib inhibits c-Met, AXL, RET, and VEGFR and has been FDA and EMA approved for the treatment of medullary thyroid cancer, hepatocellular carcinoma and renal cell carcinoma. In this trial (NCT04066595) we wanted to gain more insights about the potential of Cabozantinib in patients with advanced urothelial carcinoma (UC) ineligible for cisplatin-based chemotherapy and in patients with chemo and/or PD-1- and PD-L1 resistant UC. Methods: This investigator-sponsored Phase II multicenter single-arm trial assessed ORR to Cabozantinib in patients with locally advanced or metastatic UC, who have been pre-treated with checkpoint inhibitors only (cohort 1) or cisplatin-based chemotherapy and checkpoint inhibitors (cohort 2). Secondary outcome measurements were PFS, OS, CBR, DOR, and patient safety. All radiologic findings were determined using RECIST 1.1. Patients commenced treatment with Cabozantinib 60 mg given per os once per day continuously. Participants continued on trial as long as their cancer was not worsened and side effects were not too severe. For the assessment of side effects the severity was qualified in accordance with NCI CTCAE, version 5.0. The primary outcome measure of ORR was reported as percentages and associated 95% confidence interval for each cohort. For planning Simon's two-stage minimax design (Simon, 1989) was used. A total of 44 patients (total 88 patients) were planned to be included into each cohort. Results: Seven patients were included in cohort 2. The patients in cohort 2 (N = 7) had a median age of 69 y, 6 male patients and one female patient. All patients had an ECOG PS 0 (n=2) or 1 (n=5). All tumors were originated from the urinary bladder, two of them showing histological subtypes. PD-L1 status was available in two patients. Visceral metastases were evident in 3 patients. At December 20th 2021 data cutoff no patient was alive. The overall response rate was 0%. The median progression free survival was 2,9 months (range 1-5,4 months). The median overall survival was 3 months (range 1-18,3 months) 3 patients showed a stable disease. All patients (n=7) revealed TRAEs, 3 patients each (43%) showed endocrine disorders, metabolic and nutrition disorders and nervous system disorders. In 5 patients (71%) respiratory AEs and in 86% (n=6) gastrointestinal AEs were evident. In 86% of patients (n=6) SAEs led to treatment dose reduction or discontinuation. In 43% of patients (n=3) grade 5 SAEs were evident. Treatment-related SAEs were notified in 57% of patients (n=4). Conclusions: Cabozantinib was administered in 7 patients without clinical response. Due to low patient recruitment and no adequate response rates the study was discontinued early. Cabozantinib in this study does not reveal a clinical benefit for patients with metastatic UC with prior chemotherapy and IO. Clinical trial information: NCT04066595.