First-in-Man Phase I Study of GC33, A Novel Recombinant Humanized Antibody against Glypican-3, in Patients with Advanced Hepatocellular Carcinoma
Mené sur 20 patients atteints d'un carcinome hépatocellulaire de stade avancé, cet essai évalue la toxicité et les caractéristiques pharmacocinétiques d'un nouvel anticorps monoclonal appelé GC33
Purpose:GC33 is a novel recombinant fully humanized monoclonal antibody that binds to human glypican-3 (GPC3). The anti-tumor activity of GC33 was demonstrated in preclinical models of hepatocellular carcinoma (HCC). This first-in-man clinical trial was conducted to evaluate the safety, pharmacokinetic (PK) 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 to 20 mg/kg) given intravenously weekly. The primary endpoint was to determine the maximum tolerated dose of GC33 for further development. PKs were measured in serum samples. Immunohistochemistry (IHC) was performed on tumor biopsies to evaluate GPC3 expression. Tumor response was assessed every 8 weeks using RECIST criteria. Results:Twenty patients were enrolled and treated with GC33. A maximum tolerated dose was not reached as there were no dose limiting toxicities (DLTs) up to the highest planned dose level. Common adverse events (AEs) with all grades included fatigue (50%), constipation (35%), headache (35%) and hyponatremia (35%). AE incidence 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 = 0.033). Conclusions:This study demonstrates 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.