Background: Ontuxizumab is a humanized immunoglobulin G-1-kappa monoclonal antibody (mAb) that is the first clinical stage agent to target endosialin. Endosialin (TEM-1/CD248) is a cell surface glycoprotein expressed on cells involved in the development of tumor vasculature, but has generally limited expression in normal tissue. In some tumors, such as sarcomas, endosialin is expressed directly by the tumor cells and therefore soft tissue sarcomas (STS) may be a suitable treatment target. Methods: This Phase 2 multicenter study in subjects with metastatic STS (0-2 prior regimens) is being conducted in two sequential parts. Part 1 was an open label, dose-escalation, safety lead in: 4, 6 and 8 mg/kg ontuxizumab (administered on days 1 and 8 of a 21 day cycle) combined with gemcitabine and docetaxel (G/D) (900 mg/m² on days 1/8 and 75 mg/m² on day 8, respectively)). Based on the observed safety profile in Part 1, 8 mg/kg was utilized in Part 2 efficacy design. In Part 2 subjects are randomized in a double-blind 2:1 ratio to G/D plus ontuxizumab (8 mg/kg) or G/D plus placebo. Using an adaptive population finder design, randomization is stratified by four histological cohorts (liposarcoma, leiomyosarcoma, undifferentiated pleomorphic sarcoma (UPS) and myxofibrosarcoma, and other STS). An independent unblinded statistical committee (ISC) monitors the trial adaptations for futility, success, or maximal cohort sizes (60). Primary objective is progression-free survival (PFS) by RECIST1.1. Secondary objectives include overall survival (OS), overall response rate (ORR), and predictive/ response biomarkers. Enrollment ended in August 2014 with 209 subjects randomized. Primary result analysis is anticipated in December, 2015. Clinical trial information: NCT01574716