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Cancer Chemotherapy and Pharmacology

, Volume 79, Issue 2, pp 421–429 | Cite as

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
Original Article

Abstract

Purpose

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.

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 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.

Conclusion

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).

Keywords

Sorafenib Median Progression Free Survival Relative Dose Intensity High Tumor Uptake Adequate Organ Function 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

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.

Supplementary material

280_2017_3241_MOESM1_ESM.docx (34 kb)
Supplementary material 1 (DOCX 33 KB)
280_2017_3241_MOESM2_ESM.docx (55 kb)
Supplementary material 2 (DOCX 54 KB)
280_2017_3241_MOESM3_ESM.pptx (148 kb)
Supplementary material 3 (PPTX 148 KB)
280_2017_3241_MOESM4_ESM.pptx (124 kb)
Supplementary material 4 (PPTX 124 KB)
280_2017_3241_MOESM5_ESM.pptx (232 kb)
Supplementary material 5 (PPTX 231 KB)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Ghassan K. Abou-Alfa
    • 1
    • 2
  • Chia-Jui Yen
    • 3
  • Chih-Hung Hsu
    • 4
  • Joseph O’Donoghue
    • 1
  • Volkan Beylergil
    • 1
  • Shutian Ruan
    • 1
  • Neeta Pandit-Taskar
    • 1
  • Bolorsukh Gansukh
    • 1
  • Serge K. Lyashchenko
    • 1
  • Jennifer Ma
    • 1
  • Peter Wan
    • 1
  • Yu-Yun Shao
    • 4
  • Zhong-Zhe Lin
    • 4
  • Catherine Frenette
    • 5
  • Bert O’Neil
    • 6
  • Lawrence Schwartz
    • 7
  • Peter M. Smith-Jones
    • 1
  • Toshihiko Ohtomo
    • 8
  • Takayoshi Tanaka
    • 8
  • Hideo Morikawa
    • 8
  • Yuko Maki
    • 8
  • Norihisa Ohishi
    • 8
  • Ya-Chi Chen
    • 9
  • Tamara Agajanov
    • 9
  • Frederic Boisserie
    • 9
  • Laura Di Laurenzio
    • 9
  • Ray Lee
    • 9
  • Steven M. Larson
    • 1
    • 2
  • Ann-Lii Cheng
    • 4
  • Jorge A. Carrasquilo
    • 1
    • 2
  1. 1.Memorial Sloan Kettering Cancer CenterNew YorkUSA
  2. 2.Weill Cornell Medical CollegeNew YorkUSA
  3. 3.National Cheng-Kung University HospitalTainanTaiwan, Republic of China
  4. 4.National Taiwan University HospitalTaipeiTaiwan, Republic of China
  5. 5.Scripps ClinicSan DiegoUSA
  6. 6.Indiana University Simon Cancer CenterIndianapolisUSA
  7. 7.Columbia University HospitalNew YorkUSA
  8. 8.Chugai Pharmaceutical Co. Ltd.TokyoJapan
  9. 9.Translational and Clinical Research CenterHoffmann-La Roche Inc.New YorkUSA

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