A Phase II Study of Bintrafusp Alfa (M7824) in Checkpoint Inhibitor Naive and Refractory Subjects With Urothelial Carcinoma

Background: * Metastatic urothelial carcinoma is lethal and incurable with a median overall survival of 14 months from diagnosis. * Immune checkpoint inhibitors targeting the Programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway have greatly changed clinical management of metastatic urothelial carcinoma (mUC) improving survival by 3 months in the second-line setting. * Five PD-1/PD-L1 inhibitors are Food and Drug Administration (FDA)-approved for for second-line metastatic urothelial carcinoma (mUC), two agents for first-line cisplatin-ineligible mUC. However, response rates are modest, ranging from15-20% in the second-line and 24% in the first-line cisplatin-ineligible. * Therefore, novel strategies are needed to extend benefit of immunotherapy to the remaining approximately 75% of non-responders. * Higher levels of transforming growth factor-beta (TGF-beta) are associated with immune escape, therapy resistance and poor outcomes in advanced malignancies. Non-responders to anti-PD-1/PD-L1 antibodies have also been found to have increased TGF-beta in the tumor microenvironment. * Bintrafusp alfa (M7824) is a novel first-in-class bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II (TGFbetaRII), which effectively functions to sequester or "trap" all three TGF-beta isoforms. A phase I study of M7824 (NCT02517398) demonstrated a manageable safety profile and clinical efficacy among patients with heavily pre-treated advanced solid tumors. * We hypothesize that M7824 is safe and improves outcomes in patients with checkpoint naive or refractory urothelial carcinoma. Objectives: -To evaluate the activity of M7824 as determined by objective response rate (ORR) in two metastatic urothelial carcinoma cohorts: * Cohort 1: Checkpoint inhibitor naive * Cohort 1A: cisplatin ineligible * Cohort 1B: refractory post-platinum therapy * Cohort 2: Checkpoint inhibitor previously treated patients * Cohort 2A: previously achieved a Complete Response (CR)/Partial Response (PR) * Cohort 2B: previously had Stable Disease (SD)/Progressive Disease (PD) Eligibility: * Patients must have a histologically confirmed diagnosis of metastatic urothelial cancer. * Patients may have been previously treated with prior cytotoxic chemotherapy regimen or targeted agent. Patients may have received any number of prior cytotoxic agents. * 18 years of age or older Design: * This is an open label, non-randomized, single arm phase II trial of M7824 in checkpoint inhibitor naive and previously treated patients with urothelial carcinoma of the bladder. * M7824 (intravenous 1200 mg fixed dose) will be delivered every 2 weeks * Patients will receive treatment in cycles consisting of 4 weeks. * A maximum of 75 subjects will be enrolled in this trial.