Phase Ib study of codrituzumab in combination with sorafenib in patients with non-curable advanced hepatocellular carcinoma (HCC)
Codrituzumab, a humanized antibody against glypican-3, is highly expressed in HCC. A phase I study evaluated the combination with sorafenib in HCC.
Patients and methods
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 124I 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 124I 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).
KeywordsSorafenib Median Progression Free Survival Relative Dose Intensity High Tumor Uptake Adequate Organ Function
We would like to acknowledge Amabella Lindo and Louise Harris for their expert nursing care, Jing Qiao and Ariel Brown for expert technical assistance in labeling the antibodies, Yiauchung Sheh for production of 124I, and Jiong (Lilly) Wu for handling of pharmacokinetic samples and assays and the radiopharmacy group for dispensing of the radiolabeled antibody. Pathologists, Kevin S. McDorman (Charles River Laboratories Inc., USA), Vikram Deshpande (Massachusetts General Hospital, USA), and Hiroaki Kataoka (University of Miyazaki, Japan) for pathological evaluations of GPC3-IHC, Monica Reinholz for technical assistance (Ventana Medical Systems Inc.), Ikue Suzuki, Sylvia Chiu, and Zhaodi Gu for their assistance. Funding was supported by Chugai Pharmaceutical Co. Ltd. and the Hoffmann-La Roche Inc. The Memorial Sloan Kettering Cancer Center’s Radiochemistry and Molecular Imaging Probes were supported by the radiochemistry core NIH grant P30CA008748) and the Ludwig Center for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center.
Compliance with ethical standards
Conflict of interest
Ghassan K. Abou-Alfa, Chia-Jui Yen, Catherine Frenette, Bert O’Neil, Steven M. Larson, Ann-Lii Cheng, and Jorge A. Carrasquilo report research funding support from Roche and Chugai tot heir institutions. Toshihiko Ohtomo, Takayoshi Tanaka, Hideo Morikawa, Yuko Maki, and Norihisa Ohishi report Chugai employment. Ya-Chi Chen, Tamara Agajanov, Frederic Boisserie, Laura Di Laurenzio, and Ray Lee report Roche employment.
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