Phase Ib study of codrituzumab in combination with sorafenib in patients with non-curable advanced hepatocellular carcinoma (HCC)

Ghassan K. Abou-Alfa, Chia-Jui Yen, Chih-Hung Hsu, Joseph O’Donoghue, Volkan Beylergil, Shutian Ruan, Neeta Pandit-Taskar, Bolorsukh Gansukh, Serge K. Lyashchenko, Jennifer Ma, Peter Wan, Yu-Yun Shao, Zhong-Zhe Lin, Catherine Frenette, Bert O’Neil, Lawrence Schwartz, Peter M. Smith-Jones, Toshihiko Ohtomo, Takayoshi Tanaka, Hideo Morikawa, Yuko Maki, Norihisa Ohishi, Ya-Chi Chen, Tamara Agajanov, Frederic Boisserie, Laura Di Laurenzio, Ray Lee, Steven M. Larson, Ann-Lii Cheng, Jorge A. Carrasquilo

Codrituzumab, a humanized antibody against glypican-3, is highly expressed in HCC. A phase I study evaluated the combination with sorafenib in HCC. In a 3 + 3 design, codrituzumab was given intravenously in various doses with sorafenib 400 mg twice daily to patients with advanced HCC, age ≥18, ECOG 0-1, Child-Pugh A and B7, adequate organ functions, and no prior systemic therapy, with tumor assessment by RECIST 1.0 and safety by CTCAE 3.0. PK and pre, during, and post-therapy (124)I radiolabeled codrituzumab PET scan imaging were performed. 41 patients were enrolled: 2.5 mg/kg weekly (qw) (12), 5 mg/kg qw (12), 10 mg/kg qw (3), 1600 mg every 2 weeks (q2w) (6), and 1600 mg qw (7). Two drug limiting toxicities occurred: grade 3 hyponatremia at 5 mg/kg and grade 3 hyponatremia and hyperglycemia at 1600 mg q2w. Adverse events occurred in 80% of patients, including at least one ≥grade 3: ten (25%) increased AST, three (7.5%) increased ALT, and ten (25%) increased lipase. There were no responses and nine (25.7%) had stable disease. PK C max and AUCt of codrituzumab and sorafenib were comparable to single-agent data. Thirteen out of 14 patients showed (124)I radiolabeled codrituzumab uptake in tumor. In all three patients who underwent a post-progression PET, glypican-3 remained expressed. Codrituzumab plus sorafenib were tolerated at 1600 mg q2w and 400 mg bid, respectively, with no responses. Codrituzumab exerts selective distribution to HCC cells, and GPC3 does not show any down-regulation post-progression (NCT00976170).