Phase I and preliminary Phase II study of TRC105 in combination with Sorafenib in Hepatocellular Carcinoma.

Purpose: Endoglin (CD105) is an endothelial membrane receptor expressed on tumor vasculature. Endoglin expression is induced by VEGF pathway inhibition. TRC105 is a chimeric IgG1 CD105 monoclonal antibody that inhibits angiogenesis, causes antibody-dependent cellular cytotoxicity (ADCC) and apoptosis of proliferating endothelium. <br /><br />Experimental Design: Patients with HCC (Childs Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, 15mg/kg q 2wks given with sorafenib 400mg bid. Correlative biomarkers included plasma levels of angiogenic factors, including soluble endoglin. <br /><br />Results: 26 patients were enrolled, of whom 25 received treatment. Hep B/C: 3/15; M:F 19:6; Mean age 60 (range 18-76); 1 DLT (grade 3 AST) occurred at 10mg/kg. The most frequent toxicity was low grade epistaxis, a known toxicity of TRC105. One patient with coronary stenosis developed a fatal myocardial infarction and one patient developed G3 cerebral tumor hemorrhage. MTD was not established and DL4 (15mg/kg) was expanded. The overall response rate in 24 evaluable patients at all 4 dose levels was 21% (95% CI:  7.1-42.2%). Four patients had confirmed stable disease, one of whom was treated for 22 months. Median PFS was 3.8 months (95% CI: 3.2-5.6 months); median OS 15.5 months (95% CI: 8.5-26.3 months).<br /><br />Conclusions: TRC105 combined with sorafenib was well tolerated at the recommended single agent doses of both drugs. Encouraging evidence of activity was observed and the study is now continuing to recruit in the phase 2 stage as a multicenter study to confirm activity of the combination.

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