Background: Anti-PD 1/PD-L1 blockade alone or in combination with anti-CTLA4 have yielded suboptimal results in most sarcoma subtypes. CD73, an ectonucleotidase, catalyzes the rate-limiting step for adenosine production in the extracellular space, which then aids tumors in evading immune recognition and destruction. Oleclumab, a monoclonal antibody (mAb) selectively binds and inhibits the activity of CD73, and preclinical data suggests additive activity with durvalumab, a mAb that blocks PD-L1. We designed a trial combining oleclumab and durvalumab in certain sarcoma subtypes, selected based on modest activity with anti-PDL-1 and intense staining with CD73 in the tumor microenvironment. Methods: This phase 2 study (NCT04668300) is enrolling patients with age ≥18 years with recurrent/metastatic angiosarcoma (cohort 1) or dedifferentiated liposarcoma (DLPS) (cohort 2) and ≥12 years with recurrent/metastatic osteosarcoma (cohort 3), who have received at least one prior systemic therapy but are checkpoint inhibitor naïve and have measurable disease. Each treatment cycle is 28 days with oleclumab administered at 3000 mg i.v. every 2 weeks x 5 doses, and then every 4 weeks and durvalumab administered at 1500 mg i.v every 4 weeks. Tumor assessments are based on RECIST 1.1 and immune-related response criteria (irRC) and performed at baseline, and every 8 weeks after start of therapy, with an additional scan at 12 weeks for confirmation of response. Planned sample size is ≤ 25 pts in each arm. The primary efficacy endpoint for cohorts 1 and 2 is response rate (RR) at 4 months (per RECIST 1.1). The primary efficacy endpoint for cohort 3 is event free survival (EFS) rate at 4 months. If there is a high probability that the RR4 months is unlikely to be at least 20% for cohorts 1 and 2 or the EFS4 months is unlikely to be at least 40% for cohort 3 then the accrual of the corresponding cohort will be halted. The cohorts will be monitored separately for both futility and toxicity in groups of 5 after a minimum of 10 patients have been enrolled in each cohort. Secondary endpoints for the study include safety, best RR by RECIST and irRC, median PFS, and OS. Core needle biopsies and blood samples are collected at baseline and early on-treatment (week 6). Fresh flow cytometry is being performed to assess changes in T-cell activation, proliferation, and function and CD73 expression in the membrane and cytoplasm is being assessed by immunohistochemistry. Localization of tumor-infiltrating lymphocytes and engagement of the PD-1/PDL1 axis is being assessed using multiplex immunofluorescence staining. As of Jan 30th, 2022, twenty-two patients have initiated study treatment, 3 in cohort 1, 12 in cohort 2, and 7 in cohort 3. Clinical trial information: NCT04668300.