Background: P, a VEGFR TKI, is approved for advanced STS based on median PFS (mPFS) in the absence of CR. Endoglin is a receptor expressed on tumor vessels that is overexpressed in certain STS, particularly angiosarcoma (AS). It is upregulated following VEGF inhibition and may mediate resistance to P. We performed a phase 1B/2A study of TRC105, an endoglin antibody, in combination with P in pts with advanced STS. Methods: The phase 1 was a dose escalation to determine the RP2D. The phase 2 was a single arm evaluation of TRC105 at the RP2D with P at 800 mg/day PO, with a primary endpoint of increasing PFS beyond that expected with P (HR = .667, power = 86%, one-sided α = 0.05). Secondary endpoints included PFS stratified by histology and tumor endoglin expression. Both phases required progression on chemotherapy, and excluded adipocytic STS and GIST. Results: The RP2D of TRC105 10 mg/kg/week IV was well tolerated with P 800mg/day. 18 pts were enrolled in phase 1B and 63 in phase 2A, (leiomyosarcoma (35); undifferentiated pleomorphic sarcoma (UPS) (18); synovial sarcoma (7); myxofibrosarcoma (6); epithelioid sarcoma (5); AS (5); epithelioid hemangioendothelioma (2)). Median age = 57, M:36 F:45; median prior lines of systemic therapy = 2. mPFS in phase 2 pts was 3.91 mo. (95%CI = 2.53, 5.69) and in all 81 pts was 3.95 mo. (95%CI = 3.72, 5.92), and was not significantly different from mPFS expected with P. mPFS will be stratified by histology and tumor endoglin expression. Three pts have ongoing CR (treatment duration = 44, 51, 75 wks), including 2 of 5 with AS, all of whom had tumor reductions, and 1 pt with multiorgan UPS. Adverse events (AEs) characteristic of each drug were not increased in frequency or severity. Common TRC105 related AEs included grade (g) ≤ 2 telangiectasia (with epistaxis and gingival bleeding) and headache, and g ≤ 3 anemia; common P related AEs included g ≤ 3 fatigue, diarrhea, and hypertension. Conclusions: TRC105 combined with P was well tolerated and exhibited activity, including durable CR in AS, a STS known to densely express endoglin, and UPS. A Phase 3 study in AS is planned. Stratification of PFS by tumor endoglin expression may direct TRC105 treatment in other STS histologies. Clinical trial information: NCT01975519