Purpose TRC105 is a chimeric IgG1 monoclonal antibody that binds CD105 (endoglin). This first-in-human, phase 1, open label study assessed safety, pharmacokinetics, and antitumor activity of TRC105 in patients with advanced refractory solid tumors. Patients and Methods Patients received escalating doses of intravenous TRC105 until disease progression or unacceptable toxicity using a standard 3 + 3 phase 1 design. Results Fifty patients were treated with escalating doses of TRC105. The maximum tolerated dose was exceeded at 15 mg/kg every week due to dose-limiting hypoproliferative anemia. TRC105 exposure increased with increasing dose, and continuous serum concentrations that saturate CD105 receptors were maintained at 10 mg/kg weekly (the maximum tolerated dose) and 15 mg/kg every 2 weeks. Common adverse events including anemia, telangiectasias and infusion reactions reflected the mechanism of action of the drug. Antibodies to TRC105 were not detected in patients treated with TRC105 from Chinese hamster ovary cells being used in ongoing phase 1b and phase 2 studies. Stable disease or better was achieved in 21 of 45 evaluable patients (47%) including two ongoing responses at 48 and 18 months. Conclusion TRC105 was tolerated at 10 mg/kg every week and 15 mg/kg every 2 weeks with a safety profile that was distinct from that of VEGF inhibitors. Evidence of clinical activity was seen in a refractory patient population. Ongoing clinical trials are testing TRC105 in combination with chemotherapy and VEGF inhibitors and as a single agent in prostate, ovarian, bladder, and hepatocellular cancer.