Background: Inhibition of vascular endothelial growth factor (VEGF) pathway is effective in mRCC, but resistance inevitably develops. CD105 (endoglin) is highly expressed on endothelial cells and has been shown in preclinical models to mediate resistance to VEGF pathway inhibitors, in part due to TGF-beta signaling. TRC105 is a monoclonal antibody against CD105 which has been shown to be tolerable in combination with Bev at full doses. Methods: Eligible mRCC patients (pts) with any histologic subtype may have received 1-4 prior systemic therapies including cytokines, VEGF, or mTOR agents. Bev was administered at 10 mg/kg IV on day 1 and 15 of 28-day cycles as a single agent (Arm A) or with TRC105 10 mg/kg IV on days 1, 8, 15, and 22 (Arm B). Primary endpoint was progression-free survival (PFS). A total of 88 pts were to be randomized to detect a halving of PFS with 80% power and α = 0.1. An interim analysis for futility was conducted after 44 pts had PFS evaluated. Results: Enrollment was halted after interim analysis with 61 pts randomized; 45 were men. Median age was 60 (24-83). 20 (32%) of pts had received 3 or more prior lines of therapy (median = 2 on both arms). 44 patients had clear cell RCC and 15 had non-clear cell histology. One subject on each arm had a confirmed PR (3%) and 2 patients on each arm had stable disease lasting > 9 cycles. For the 56 evaluable pts, the PFS (including early treatment termination as progression) at 12 weeks was 48% +/- 9% on Bev compared to 50% +/- 9% on Bev + TRC105. Survival did not differ significantly (p = 0.5) between arms, being 81% at 24 weeks for both arms. Grade > 3 toxicities were more common in Arm B and included anemia (8 vs 2 pts), electrolyte abnormalities (6 vs 2 pts), dyspnea (4 vs 2 pts), nausea/vomiting (4 vs 0 pts), hyperglycemia (2 vs 0 pts) and infusion reaction (2 vs 0 pts); hemorrhage, hypertension, and proteinuria were more common in Arm A. Conclusions: TRC105 failed to prolong PFS when added to Bev. Further analysis will examine biomarkers of potential TRC105 benefit in this population. TRC105 is being studied in combination with VEGF receptor tyrosine kinase inhibitors in mRCC to determine whether there is an additive effect on PFS. Clinical trial information: NCT01727089