Japanese phase I study of GC33, a humanized antibody against glypican-3 for advanced hepatocellular carcinoma

Abstract

GC33 is a humanized mAb against human glypican-3 (GPC3). In the first-in-human study carried out in the USA, GC33 was well tolerated and showed preliminary antitumor activity in patients with advanced hepatocellular carcinoma. This study aimed to assess the safety, tolerability, and pharmacokinetic characteristics of GC33 in Japanese patients with advanced hepatocellular carcinoma. The study design was a conventional 3 + 3 dose-escalation design to determine the maximum tolerated dose of GC33 given i.v. at 5, 10, or 20 mg/kg weekly. Immunohistochemistry was carried out on tumor biopsies to evaluate GPC3 expression. Thirteen patients were enrolled across the three dose levels, and no patients observed any dose-limiting toxicity up to the highest planned dose of 20 mg/kg. The most common adverse events were decreased lymphocyte count, decreased natural killer cell count, increased C-reactive protein, and pyrexia. Grade 3 adverse events (increased blood pressure, decreased lymphocyte count, and decreased platelet count) were observed in two or more patients. The AUCinf showed a dose-proportional increase from the 5 mg/kg dose group to the 20 mg/kg dose group. The trough concentrations of GC33 appeared to reach a steady state after the fourth to the sixth dose. Seven of the 13 patients showed stable disease, the other six showed progressive disease. Furthermore, three patients showed long-term stable disease of more than 5 months. In conclusion, GC33 given at up to 20 mg/kg weekly was well tolerated in Japanese patients with advanced hepatocellular carcinoma.

Keywords: GC33; Japanese patients; glypican-3; hepatocellular carcinoma; phase I study.

Fig. 1

Immunohistochemistry (IHC) of glypican-3 (GPC3) in hepatocellular carcinoma. (a) Representative GPC3 staining features observed in matched specimens evaluated using two IHC methods. Method 1 was used in a previous first-in-human study; method 2 was a fully automated IHC assay. Scores are indicated under each photograph. Bar = 50 μm (b) Comparison of total GPC3 staining score by method 1 (0–14) and clinical score by method 2 (0–3). Spearman's correlation was 0.76 (P = 0.00255). (c) Comparison of clinical score and membrane H score. (d) Comparison of clinical score and cytoplasm H score. There was a positive association between the H scores and the GPC3 clinical scores, with R² values of 0.75 and 0.33, respectively.

Fig. 2

Treatment duration in patients with advanced hepatocellular carcinoma treated with humanized antibody against glypican-3 (n = 13). The GPC3 immunohistochemistry (IHC) scores evaluated using two IHC methods (method 1, score 0–14; method 2, score 0–3) and best overall response (BOR) are described to the left of the chart. NE, not evaluable; PD, progressive disease; SD, stable disease.

Fig. 3

Best changes from baseline in α-fetoprotein (AFP) (a) and des-γ-carboxy prothrombin (DCP) (b) in patients with advanced hepatocellular carcinoma treated with humanized antibody against glypican-3 (GC33). Best changes in AFP (11 patients) or DCP (13 patients) are shown as best percent changes from their baseline values. Two patients were excluded from AFP changes because their baseline AFP levels were within the normal range. (c) Computed tomography imaging of lung metastasis before and after (arrow) treatment with GC33. SD, Stable disease.