Background: Endoglin (CD105) is an endothelial cell membrane receptor highly expressed on tumor vessels that is essential for angiogenesis and upregulated by hypoxia and VEGF inhibition. TRC105 is an anti-endoglin monoclonal antibody that potentiates bevacizumab and VEGF receptor tyrosine kinase inhibitors (VEGFR TKI) in preclinical models, and has demonstrated activity with bevacizumab in refractory patients with colorectal and ovarian cancer. Methods: Heavily-pretreated mRCC pts with ECOG PS 0-1, and acceptable organ function were treated with intravenously administered TRC105 weekly (8mg/kg and then 10mg/kg) in combination with axitinib (5 mg) given twice daily of each 28 day cycle. Patients were assessed for safety, PK, and response. Results: Six patients (median age = 65; M:F 5:1; all of whom received prior VEGFR TKI, median number of prior therapies = 2.5) have been treated. TRC105 dose escalation proceeded from 8 mg/kg (n=3) to 10mg/kg (n=3) without the development of dose limiting toxicity. Patients experienced expected TRC105 related adverse events of grade 2 infusion reaction and grade 1 epistaxis, gingival bleeding, headache, rash, and fatigue; and expected axitinib adverse events of grade 1-3 hypertension, grade 1 hand-foot syndrome and grade 1 proteinuria. Two patients dosed with 8 mg/kg developed grade 2 creatinine elevations that reversed with hydration. Adverse events characteristic of each drug were not increased in frequency or severity when both drugs were administered concurrently. Four of five evaluable VEGFR TKI refractory patients demonstrated decreases in tumor burden ranging from 6% to 36% (including unconfirmed partial response per RECIST in an ongoing patient) at two to four months following treatment. Pharmacokinetic and immunogenicity studies will be reported. Conclusions: TRC105 at 8 and 10 mg/kg was well tolerated with axitinib in RCC patients. Additional patients will be enrolled at the MTD of both drugs prior to initiating a randomized phase 2 trial of the combination. Clinical trial information: NCT01806064.