First-in-Man Phase I Study of GC33, a Novel Recombinant Humanized Antibody Against Glypican-3, in Patients with Advanced Hepatocellular Carcinoma

Abstract

Purpose: GC33 is a novel recombinant fully humanized monoclonal antibody that binds to human glypican-3 (GPC3). The antitumor activity of GC33 was shown in preclinical models of hepatocellular carcinoma (HCC). This first-in-man clinical trial was conducted to evaluate the safety, pharmacokinetic characteristics, and preliminary efficacy of GC33 in patients with advanced HCC.Experimental Design: Patients with measurable, histologically proven, advanced HCC were enrolled to a dose-escalation study of GC33 (2.5-20 mg/kg) given intravenously weekly. The primary endpoint was to determine the maximum tolerated dose of GC33 for further development. Pharmacokinetic characteristics were measured in serum samples. Immunohistochemistry was conducted on tumor biopsies to evaluate GPC3 expression. Tumor response was assessed every 8 weeks using Response Evaluation Criteria in Solid Tumors criteria.Results: Twenty patients were enrolled and treated with GC33. A maximum tolerated dose was not reached as there were no dose-limiting toxicities (DLT) up to the highest planned dose level. Common adverse events with all grades included fatigue (50%), constipation (35%), headache (35%), and hyponatremia (35%). The incidence of adverse events seemed not to be dose dependent. Trough serum concentrations at steady state were in excess of target concentration at doses of 5 mg/kg or greater. Median time to progression (TTP) was 26.0 weeks in the GPC3 high expression group and 7.1 weeks in the low expression group (P ¼ 0.033).Conclusion: This study shows that GC33 was well tolerated in advanced HCC and provides preliminary evidence that GPC3 expression in HCC may be associated with the clinical benefit to GC33 that warrants prospective evaluation.

Immunohistochemistry as a surrogate for molecular diagnosis in hepatic tumours

“…A monoclonal antibody against GPC3 showed good antitumour activity in vitro, and a phase one trial subsequently showed increased median time to progression in HCC with high GPC3 expression (26.0 weeks compared to 7.1 weeks for GPC3-low tumours). 21 A score incorporating GPC3 staining intensity and pattern showed good predictive ability in this study.…”

Development of T Cells Redirected to Glypican-3 for the Treatment of Hepatocellular Carcinoma

“…Moreover, the naked antibody could not completely eliminate tumors in mouse models, and no partial or complete response was observed in the 15 patients evaluated during the phase I clinical trial of GC33, suggesting that the therapeutic effects of a naked antibody may not be potent enough for curative treatment of HCC (14). In the phase I clinical trial of a GPC3-derived peptide vaccine for patients with HCC, the median overall survival seemed to positively correlate with the GPC3-specific CTL frequencies, suggesting that GPC3-targeted T cells could be potential agents for HCC treatment (12).…”

Personalized Clinical Trials in Hepatocellular Carcinoma Based on Biomarker Selection

“…GC33 is a humanized monoclonal antibody against GPC3 and it mediates antibody-dependent cell cytotoxicity [72]. A Phase I study demonstrated that GC33 was well tolerated in HCC [73]. In a recent randomized Phase II trial, 185 patients that had advanced HCC and had failed prior systemic therapy were randomized to receive GC33 at 1600 mg intravenously on days 1 and 8 and then every 2 weeks afterwards, or placebo.…”