title: Phase Ib study of codrituzumab in combination with sorafenib in patients with non-curable advanced hepatocellular carcinoma (HCC).
abstract: OBJECTIVE
  Codrituzumab, a humanized antibody against glypican-3, is highly expressed in HCC. A phase I study evaluated the combination with sorafenib in HCC.
  
  
  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-therapy124I radiolabeled codrituzumab PET scan imaging were performed.
  
  
  RESULTS
  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 Cmaxand AUCtof codrituzumab and sorafenib were comparable to single-agent data. Thirteen out of 14 patients showed124I radiolabeled codrituzumab uptake in tumor. In all three patients who underwent a post-progression PET, glypican-3 remained expressed.
  
  
  CONCLUSIONS
  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).
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. abou-alg@mskcc.org.|Weill Cornell Medical College, New York, NY, USA. abou-alg@mskcc.org.
authors.forename: Ghassan K
authors.initials: GK
authors.lastname: Abou-Alfa
authors.affiliation: National Cheng-Kung University Hospital, Tainan, Taiwan, Republic of China.
authors.forename: Chia-Jui
authors.initials: CJ
authors.lastname: Yen
authors.affiliation: National Taiwan University Hospital, Taipei, Taiwan, Republic of China.
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Hsu
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: O'Donoghue
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Volkan
authors.initials: V
authors.lastname: Beylergil
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Shutian
authors.initials: S
authors.lastname: Ruan
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Neeta
authors.initials: N
authors.lastname: Pandit-Taskar
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Bolorsukh
authors.initials: B
authors.lastname: Gansukh
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Serge K
authors.initials: SK
authors.lastname: Lyashchenko
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ma
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Wan
authors.affiliation: National Taiwan University Hospital, Taipei, Taiwan, Republic of China.
authors.forename: Yu-Yun
authors.initials: YY
authors.lastname: Shao
authors.affiliation: National Taiwan University Hospital, Taipei, Taiwan, Republic of China.
authors.forename: Zhong-Zhe
authors.initials: ZZ
authors.lastname: Lin
authors.affiliation: Scripps Clinic, San Diego, CA, USA.
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authors.initials: C
authors.lastname: Frenette
authors.affiliation: Indiana University Simon Cancer Center, Indianapolis, IN, USA.
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authors.initials: B
authors.lastname: O'Neil
authors.affiliation: Columbia University Hospital, New York, USA.
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authors.lastname: Schwartz
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Smith-Jones
authors.affiliation: Chugai Pharmaceutical Co. Ltd., Tokyo, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ohtomo
authors.affiliation: Chugai Pharmaceutical Co. Ltd., Tokyo, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Chugai Pharmaceutical Co. Ltd., Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Morikawa
authors.affiliation: Chugai Pharmaceutical Co. Ltd., Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Maki
authors.affiliation: Chugai Pharmaceutical Co. Ltd., Tokyo, Japan.
authors.forename: Norihisa
authors.initials: N
authors.lastname: Ohishi
authors.affiliation: Translational and Clinical Research Center, Hoffmann-La Roche Inc., New York, USA.
authors.forename: Ya-Chi
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Translational and Clinical Research Center, Hoffmann-La Roche Inc., New York, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Agajanov
authors.affiliation: Translational and Clinical Research Center, Hoffmann-La Roche Inc., New York, USA.
authors.forename: Frederic
authors.initials: F
authors.lastname: Boisserie
authors.affiliation: Translational and Clinical Research Center, Hoffmann-La Roche Inc., New York, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Di Laurenzio
authors.affiliation: Translational and Clinical Research Center, Hoffmann-La Roche Inc., New York, USA.
authors.forename: Ray
authors.initials: R
authors.lastname: Lee
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.|Weill Cornell Medical College, New York, NY, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Larson
authors.affiliation: National Taiwan University Hospital, Taipei, Taiwan, Republic of China.
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.|Weill Cornell Medical College, New York, NY, USA.
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authors.initials: JA
authors.lastname: Carrasquilo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D005260:Female; D053673:Glypicans / Q000037:antagonists & inhibitors*; D006801:Humans; D007457:Iodine Radioisotopes; D008113:Liver Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D000077157:Sorafenib
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D053673:Glypicans; D007457:Iodine Radioisotopes; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; C000619938:codrituzumab