Phase I and Preliminary Phase II Study of TRC105 in Combination with Sorafenib in Hepatocellular Carcinoma

Abstract

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.

Figure 1

Tumor volume over time following BNL tumor inoculation in BALB/c mice given daily oral gavage of sorafenib (10 mg/kg) with or without anti-CD105 antibody (100 mg/mouse injected i.p. every other day) or no treatment. Tumor sizes are presented as mean ± SEM (n=14 for control, n=10 for sorafenib, n=10 for sorafenib+anti-CD105).

Figure 2

Efficacy data for study population; (A) Swimmer’s plot showing time on study and nature of response; Red line = partial response; Blue = SD; Black = PD; Grey = non-evaluable; (B) Waterfall plot showing magnitude of best response as reflected by change in target lesion sum over time as per RECIST.

Figure 3

(A, B and D): CT scans in a 61 year old gentleman with HCV-related HCC reduction in target lesion (white arrow) over time (A- baseline; B- 8 weeks; D – 12 months). 3C shows peripheral blood aFP measurement over time for the same gentleman; (E–F) MRI scan at baseline and after 4 months of treatment for another responding patient with HCV-related HCC showing marked necrotic response in tumor (denoted T).

Figure 4

Pharmacokinetics. (A) Mean peak TRC105 serum concentrations; (B) Dose proportional increases in mean per patient TRC105 peak serum concentrations

Figure 5

Levels of a) CD105 b) VEGF and c) PlGF in plasma of study patients taken at Cycle 1 days 1 and 15, cycle 2 D1 and at end of study (EOS)