Background: CD105 (endoglin) is an endothelial cell membrane receptor highly expressed on angiogenic tumor vessels that is essential for angiogenesis and upregulated by hypoxia and VEGF inhibition. TRC105 is a human/mouse chimeric anti-CD105 monoclonal antibody that completed phase I testing and is being studied in multiple phase II trials. Methods: Pts with advanced solid tumors (non-CNS), ECOG PS 0-1, and normal organ function were treated with escalating doses of intravenously administered TRC105 plus bevacizumab (BEV) at 15 mg/kg q3wk or 10 mg/kg q2wk and assessed for safety, PK, and response. Results: Twelve pts were treated (3 with TRC105 at 3 mg/kg q1wk + BEV at 15 mg/kg q3wk, 5 with TRC105 at 6 mg/kg q1wk + BEV at 15 mg/kg q3wk, and 4 with TRC105 at 6 mg/kg q1wk + BEV at 10 mg/kg q2wk), and 10 have completed the DLT evaluation period. TRC105 at 6 mg/kg q1wk + BEV at 15 mg/kg q3wk resulted in grade 1-3 headaches with sinus congestion following the cycle 1 day 1 (C1D1) dose in 5 of 5 pts that improved with continued dosing. Treatment with BEV 10 mg/kg q2wk and sequential dosing with Bev starting on C1D1 and TRC105 on C1D8 resulted in decreased frequency and severity of headaches, allowing dose escalation to continue. TRC105 serum concentrations that saturate CD105 binding sites (>200 ng/mL) were achieved continuously at 6 mg/kg q1wk. At 3 mg/kg q1wk TRC105 + 15 mg/kg q3wk BEV, one pt with BEV-resistant ovarian cancer had stable disease for 6 cycles and one pt with refractory hepatocellular cancer who failed sorafenib and sunitinib had an AFP decrease from 1578 at baseline to 179 at the end of cycle 3. Two of three evaluable pts at 6 mg/kg q1wk TRC105 + 15 mg/kg q3wk BEV with VEGF-refractory tumors (HCC and CRC) are ongoing in C4 with stable disease. Dose escalation continues and TRC105 dose levels of 8 and 10 mg/kg are planned. Conclusions: The combination of TRC105 and BEV was tolerated with early evidence of activity in VEGF-refractory pts by sequential administration during initial dosing in C1.