A phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) in combination with bevacizumab (BEV) for advanced solid tumors.

Abstract

3059 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 an anti-CD105 monoclonal antibody that potentiates VEGF inhibitors in preclinical models. This study assessed safety, PK and preliminary efficacy of TRC105 in combination with BEV. Methods: Pts with advanced solid tumors, ECOG PS 0-1, and normal organ function were treated with escalating doses of IV TRC105 (3, 6, 8 or 10 mg/kg/wk) plus bevacizumab (BEV) at 15 mg/kg q3wk or 10 mg/kg q2wk. Results: Thirty one pts (median age = 62; M:F 14:17; median 4 prior regimens; primarily metastatic colorectal or ovarian cancer) were treated with TRC105 wkly + BEV. TRC105 3 mg/kg wkly + 15 mg/kg q3wk BEV was well tolerated. Concurrent administration of TRC105 6 mg/kg wkly + 15 mg/kg BEV q3wk resulted in headaches in 4 of 5 pts on cycle 1 day 1 (two grade 3). Dose escalation to the recommended single-agent phase II dose of 10 mg/kg TRC105 weekly + BEV (10 mg/kg q2wk) was tolerated when the initial TRC105 dose was introduced one week after BEV dosing and administered over 2 days. Headache was the only serious adverse drug reaction observed. Adverse events characteristic of each individual drug were not increased in frequency or severity. Target TRC105 serum concentrations were achieved at 6 mg/kg. Mucocutaneous telangiectasia, a marker of TRC105 target modulation, was observed beginning at 6 mg/kg and was dose proportional. Five of 19 heavily pretreated, BEV or VEGF receptor tyrosine kinase inhibitor (TKI) refractory pts with colorectal and ovarian cancer, each with marked tumor burden, experienced radiographic reductions in tumor volume (10-17%). Three of these patients remained on study longer than the prior VEGF inhibitor treatment and two are ongoing. Seven ongoing patients have been treated for 2-8 months. Conclusions: TRC105 10 mg/kg wkly was well tolerated with BEV 10 mg/kg q2wk. The combination demonstrated activity in BEV and VEGF TKI refractory pts. Randomized phase II trials of BEV +/- TRC105 have commenced in renal cell cancer and glioblastoma. Clinical trial information: NCT01332721.