Background: Metastatic undifferentiated pleomorphic sarcoma (UPS) and the genetically related myxofibrosarcoma (MFS) are soft tissue sarcoma (STS) subtypes with poor prognoses. While responses to first-line chemotherapy can approach 20%, efficacy remains limited in the 2^nd-line setting and beyond. Pazopanib, the only FDA approved treatment in the refractory setting, has demonstrated an objective response rate (ORR) of 4%. Envafolimab is a single domain PD-L1 antibody administered by rapid subcutaneous (SQ) injection that is approved for the treatment of microsatellite instability-high (MSI-H) cancer in China. The activity of envafolimab appears to be similar to other PD-1 antibodies administered intravenously (i.v.). Envafolimab demonstrated a 32% ORR in MSI-H colorectal cancer patients with progressive disease following three approved chemotherapeutics, similar to the ORR of 28% and 33% with nivolumab and pembrolizumab in these patients, respectively. The rationale for the ENVASARC is based on envafolimab activity in STS in phase 1 trials and previously reported activity of checkpoint inhibition in UPS/MFS: single-agent pembrolizumab demonstrated a 23% ORR, while the combination of nivolumab and ipilimumab demonstrated a 29% ORR in refractory UPS/MFS. Methods: ENVASARC (NCT 04480502) is a pivotal multicenter (at 30 U.S. and U.K. centers) open-label, randomized, non-comparative, parallel cohort study of envafolimab 600 mg every 3 weeks by SQ injection (n = 80) or envafolimab 600 mg every 3 weeks by SQ injection combined with ipilimumab 1 mg/kg every 3 weeks i.v. for four doses (n = 80) in patients with locally advanced, unresectable or metastatic UPS/MFS with disease progression on one or two lines of prior therapy. The primary objective of each of parallel cohort is to demonstrate an ORR with a lower limit of the 95% confidence interval that excludes 5.0% in each cohort. If ≥ 9 responders are observed among the 80 patients enrolled in each cohort, then the lower bound of the 95% confidence interval will exclude 5.0%. Secondary endpoints include duration of response, PFS and OS. Key inclusion criteria: ≤ 2 prior lines of therapy ([neo]adjuvant therapy excluded), ECOG ≤ 1. Clinical trial information: NCT04480502.