Background: Immune checkpoint inhibition with antibodies (abs) to cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death 1 (PD-1), and programmed death ligand 1 (PD-L1) have made a significant therapeutic impact in metastatic melanoma. Abs targeting the PD-1/PD-L1 axis also exhibited clinical activity in solid tumors that are not considered “immunogenic”, e.g., lung and bladder cancer. The significance of the PD-1/PD-L1 axis is currently being elucidated in sarcoma. Over 150 sarcomas of various histologic subtypes have been analyzed for PD-L1 tumor expression and the presence of PD-1+ tumor infiltrating lymphocytes (TIL): up to 65% of sarcomas expressed PD-L1 which, along with PD-1 TIL positivity, correlated with poorer overall survival and aggressive tumor features. We seek to determine the efficacy of PD-1 blockade with the anti-PD-1 ab pembrolizumab in pts with advanced soft tissue (STS) and bone sarcomas. Methods: This is an open label, multicenter, single stage, phase II study of P in pts with advanced STS (Arm A) or bone sarcomas (Arm B). P will be given intravenously at 200 mg every 3 weeks. The primary efficacy endpoint is objective response rate (ORR) by RECIST 1.1. 40 pts/arm will provide 82% power to detect an improvement in ORR from 10 to 25% with a one-sided type I error of 4.2%. This design will also have 87% power to detect an improvement in the 4-months progression-free survival rate from 20% to 40% with a one-sided type I error of 4%. Key eligibility criteria include ≥ 12 years of age, ECOG PS of 0 or 1, up to 3 prior therapies, and at least one tumor site accessible for biopsy. Exclusion criteria include low grade sarcoma, prior immunotherapies, and chronic use of corticosteroids or other immunosuppression. Secondary endpoints are safety, overall and progression free survival, and response rates by immune-related response criteria (ir-RC). Mandatory tumor biopsies pre and post-treatment will be obtained to determine PD-L1 expression as well as to perform immune monitoring in the tumor microenvironment. Peripheral blood will also be collected for immune monitoring in the circulation. Enrollment will occur at 10 SARC participating institutions and is expected to be completed in 2015. NCT02301039. Clinical trial information: NCT02301039