Purpose:
Endoglin (CD105) is an endothelial cell membrane receptor highly expressed on proliferating
tumor vasculature, including that of
hepatocellular carcinoma (HCC), and is associated with poor prognosis.
Endoglin is essential for angiogenesis, and its expression is induced by
hypoxia and
VEGF pathway inhibition.
TRC105 is a chimeric
IgG1 CD105 mAb that inhibits angiogenesis and causes antibody-dependent cellular cytotoxicity and apoptosis of proliferating endothelium.Experimental Design: Patients with HCC (Child-Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of
TRC105 at 3, 6, 10, and 15 mg/kg every 2 weeks given with
sorafenib 400 mg twice daily. Correlative
biomarkers included DCE-MRI and plasma levels of angiogenic factors, including soluble
endoglin. Pharmacokinetics were assessed in serum.Results: Twenty-six patients were enrolled, of whom 25 received treatment, 15 with
cirrhosis. Hep B/C: 3/15; M:F 19:6; mean age of 60 (range, 18-76); 1 DLT (grade 3 AST) occurred
at 10 mg/kg. The most frequent toxicity was low-grade
epistaxis, a known toxicity of
TRC105. One patient experienced an infusion reaction and was replaced. One patient with
coronary stenosis developed a fatal
myocardial infarction, and one patient developed G3 cerebral
tumor hemorrhage. MTD was not established and DL4 (15 mg/kg) was expanded. The overall response rate in 24 evaluable patients at all 4 dose levels was 21% [95% confidence interval (CI), 7.1-42.2], and 25% (95% CI, 8.7-49.1) in patients with measureable disease. Four patients had confirmed stable disease, one of whom was treated for 22 months. Median progression-free survival (PFS) for 24 patients evaluable for PFS was 3.8 months (95% CI, 3.2-5.6 months); median overall survival was 15.5 months (95% CI, 8.5-26.3 months).Conclusions:
TRC105 combined with
sorafenib was well tolerated at the recommended single agent doses of both drugs. Encouraging evidence of activity to date (PR rate 25%) was observed, and the study is now continuing to recruit in the phase II stage as a multicenter study to confirm activity of the combination. Clin
Cancer Res; 23(16); 4633-41. ©2017 AACR.