Background: The VEGFR inhibitor pazopanib is approved for the treatment of advanced STS. Resistance to pazopanib is a challenge in the treatment of STS, and endoglin (CD105) activation may be an important resistance mechanism. Endoglin is an angiogenic receptor expressed on proliferating tumor vessels, which is upregulated following VEGF inhibition and expressed on certain STS subtypes, including angiosarcoma. A phase Ib study of TRC105, an anti-endoglin antibody, in combination with pazopanib was performed in patients (pts) with advanced STS. Methods: Heavily-pretreated STS pts with leiomyosarcoma (11); angiosarcoma (2); synovial sarcoma (2); epithelioid sarcoma (1); myxofibrosarcoma (1); epithelioid hemangioendothelioma (1); and unclassifiable high grade sarcoma (2), ECOG PS 0-1, were treated with infusional TRC105 weekly in two cohorts (8mg/kg and 10mg/kg). TRC105 was initiated following a 2 to 4 week lead-in period of pazopanib starting at 800 mg PO daily. Results: Twenty pts (median age = 57; M:F 9:11; median prior regimens = 2) were treated. Eighteen of twenty pts tolerated pazopanib alone in cycle 1 and received TRC105 beginning with cycle 2. TRC105 dose escalation proceeded from 8 mg/kg (n = 3) to 10 mg/kg (n = 15) without dose limiting toxicity. Grade 1-2 adverse events (AEs) characteristic of each drug were not increased in frequency or severity during concurrent dosing of the two drugs. The most common TRC105 AEs included grade 1-2 telangiectasia (with associated epistaxis and gingival bleeding), while the most common pazopanib AEs included grade 1-2 fatigue and diarrhea. One patient with cutaneous angiosarcoma is ongoing with a complete response, and 5 of 18 pts (28% of those evaluable for efficacy) exhibited > 10% tumor reduction by RECIST 1.1. Duration of therapy ranged from 2 to 12.3+ months. Efficacy endpoints will be correlated with endoglin expression by immunohistochemistry. Conclusions: TRC105 was well tolerated at its recommended phase 2 dose of 10 mg/kg weekly, in combination with daily oral pazopanib, in pts with advanced STS, and the combination exhibited evidence of activity. A multicenter phase 2 trial of TRC105 + pazopanib is ongoing. Clinical trial information: NCT01975519