Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 81, Issue 5, pp 957–963 | Cite as

A phase I trial of escalating doses of cixutumumab (IMC-A12) and sorafenib in the treatment of advanced hepatocellular carcinoma

  • Anthony B. El-KhoueiryEmail author
  • Robert O’Donnell
  • Thomas J. Semrad
  • Philip Mack
  • Suzette Blanchard
  • Nathan Bahary
  • Yixing Jiang
  • Yun Yen
  • John Wright
  • Helen Chen
  • Heinz-Josef Lenz
  • David R. Gandara
Clinical Trial Report

Abstract

Purpose

The insulin-like growth factor (IGF) pathway is activated in hepatocarcinogenesis. Cixutumumab is a monoclonal antibody against human insulin-like growth factor-1 receptor (IGF-1R). Given the cross-talk between the IGF and VEGF pathways, we performed a phase I study of the combination of cixutumumab and sorafenib in hepatocellular cancer (HCC).

Methods

Eligible patients with no prior systemic therapy for advanced HCC and Child–Pugh A to B7 were treated with sorafenib 400 mg BID and escalating doses of cixutumumab (2, 4, or 6 mg/kg IV weekly) in a 3 + 3 design. Dose limiting toxicity (DLT) was defined as treatment-related grade 3 or 4 non-hematologic toxicity (except for a subset of manageable toxicities) or any grade 4 hematologic toxicities.

Results

In 21 patients enrolled, there were 3 DLTs; grade 3 hyperglycemia, grade 3 hypophosphatemia, and grade 5 peritonitis. The maximum tolerated dose of cixutumumab was 4 mg/kg IV weekly with standard dose sorafenib. Eighteen of 21 (86%) patients had grade 3 or above toxicities attributed to treatment. One patient also experienced grade 4 colonic perforation and grade 5 peritonitis. The median number of cycles completed was 4 (0–26). Of 16 patients evaluable for response, 81% achieved stable disease. The median progression free survival was 6.0 months (95% CI 3.6–undefined) and the median overall survival was 10.5 months (95% CI 7.1–undefined).

Conclusions

While the combination of cixutumumab and sorafenib had a toxicity profile similar to that of sorafenib monotherapy, it manifested limited clinical efficacy in unselected patients with HCC.

Keywords

Hepatocellular cancer Sorafenib IMC-A12 Cixutumumab Phase I 

Notes

Funding

This study was supported by the NCI under NO1-CM-62209 (California Cancer Consortium). T. S. is supported by the National Cancer Institute of the National Institutes of Health under award number K12CA138464.

Compliance with ethical standards

Conflict of interest

Dr. Anthony El-Khoueiry and Dr. Heinz-Josef Lenz both have received honoraria for advisory board participation from Bayer. No potential conflicts of interest were disclosed by other authors.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants involved in the study.

References

  1. 1.
    Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390CrossRefPubMedGoogle Scholar
  2. 2.
    Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS et al (2009) Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 10:25–34CrossRefPubMedGoogle Scholar
  3. 3.
    Pollak MN, Schernhammer ES, Hankinson SE (2004) Insulin-like growth factors and neoplasia. Nat Rev Cancer 4:505–518CrossRefPubMedGoogle Scholar
  4. 4.
    Baserga R (1999) The IGF-I receptor in cancer research. Exp Cell Res 253:1–6CrossRefPubMedGoogle Scholar
  5. 5.
    Sedlaczek N, Hasilik A, Neuhaus P, Schuppan D, Herbst H (2003) Focal overexpression of insulin-like growth factor 2 by hepatocytes and cholangiocytes in viral liver cirrhosis. Br J Cancer 88:733–739CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    De Souza AT, Hankins GR, Washington MK, Fine RL, Orton TC, Jirtle RL (1995) Frequent loss of heterozygosity on 6q at the mannose 6-phosphate/insulin-like growth factor II receptor locus in human hepatocellular tumors. Oncogene 10:1725–1729PubMedGoogle Scholar
  7. 7.
    Zhang YC, Wang XP, Zhang LY, Song AL, Kou ZM, Li XS (2006) Effect of blocking IGF-I receptor on growth of human hepatocellular carcinoma cells. World J Gastroenterol 12:3977–3982CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Hopfner M, Huether A, Sutter AP, Baradari V, Schuppan D, Scherubl H (2006) Blockade of IGF-1 receptor tyrosine kinase has antineoplastic effects in hepatocellular carcinoma cells. Biochem Pharmacol 71:1435–1448CrossRefPubMedGoogle Scholar
  9. 9.
    Lin RX, Wang ZY, Zhang N, Tuo CW, Liang QD, Sun YN et al (2007) Inhibition of hepatocellular carcinoma growth by antisense oligonucleotides to type I insulin-like growth factor receptor in vitro and in an orthotopic model. Hepatol Res 37:366–375CrossRefPubMedGoogle Scholar
  10. 10.
    Granata R, Trovato L, Lupia E, Sala G, Settanni F, Camussi G et al (2007) Insulin-like growth factor binding protein-3 induces angiogenesis through IGF-I- and SphK1-dependent mechanisms. J Thromb Haemost 5:835–845CrossRefPubMedGoogle Scholar
  11. 11.
    Burtrum D, Zhu Z, Lu D, Anderson DM, Prewett M, Pereira DS et al (2003) A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks ligand-dependent signaling and inhibits human tumor growth in vivo. Cancer Res 63:8912–8921PubMedGoogle Scholar
  12. 12.
    Tovar V, Alsinet C, Villanueva A, Hoshida Y, Chiang DY, Sole M et al (2010) IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage. J Hepatol 52:550–559CrossRefPubMedCentralPubMedGoogle Scholar
  13. 13.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216CrossRefPubMedGoogle Scholar
  14. 14.
    Abou-Alfa GK, Capanu M, O’Reilly EM, Ma J, Chou JF, Gansukh B et al (2014) A phase II study of cixutumumab (IMC-A12, NSC742460) in advanced hepatocellular carcinoma. J Hepatol 60:319–324CrossRefPubMedGoogle Scholar
  15. 15.
    Cainap C, Qin S, Huang WT, Chung IJ, Pan H, Cheng Y et al (2015) Linifanib versus sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol 33:172–179CrossRefPubMedGoogle Scholar
  16. 16.
    Cheng AL, Kang YK, Lin DY, Park JW, Kudo M, Qin S et al (2013) Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol 31:4067–4075CrossRefPubMedGoogle Scholar
  17. 17.
    Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA et al (2013) Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol 31:3517–3524CrossRefPubMedGoogle Scholar
  18. 18.
    Zhu AX, Rosmorduc O, Evans TR, Ross PJ, Santoro A, Carrilho FJ et al (2015) SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol 33:559–566CrossRefPubMedGoogle Scholar
  19. 19.
    Goyal L, Muzumdar MD, Zhu AX (2013) Targeting the HGF/c-MET pathway in hepatocellular carcinoma. Clin Cancer Res 19:2310–2318CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Chau GY, Lui WY, Chi CW, Chau YP, Li AF, Kao HL et al (2008) Significance of serum hepatocyte growth factor levels in patients with hepatocellular carcinoma undergoing hepatic resection. Eur J Surg Oncol 34:333–338CrossRefPubMedGoogle Scholar
  21. 21.
    Karabulut S, Tas F, Akyuz F, Ormeci AC, Serilmez M, Soydinc HO et al (2014) Clinical significance of serum hepatocyte growth factor (HGF) levels in hepatocellular carcinoma. Tumour Biol 35:2327–2333CrossRefPubMedGoogle Scholar
  22. 22.
    Vejchapipat P, Tangkijvanich P, Theamboonlers A, Chongsrisawat V, Chittmittrapap S, Poovorawan Y (2004) Association between serum hepatocyte growth factor and survival in untreated hepatocellular carcinoma. J Gastroenterol 39:1182–1188CrossRefPubMedGoogle Scholar
  23. 23.
    Bauer TW, Somcio RJ, Fan F, Liu W, Johnson M, Lesslie DP et al (2006) Regulatory role of c-Met in insulin-like growth factor-I receptor-mediated migration and invasion of human pancreatic carcinoma cells. Mol Cancer Ther 5:1676–1682CrossRefPubMedGoogle Scholar
  24. 24.
    Price JA, Kovach SJ, Johnson T, Koniaris LG, Cahill PA, Sitzmann JV et al (2002) Insulin-like growth factor I is a comitogen for hepatocyte growth factor in a rat model of hepatocellular carcinoma. Hepatology 36:1089–1097CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Anthony B. El-Khoueiry
    • 1
    Email author
  • Robert O’Donnell
    • 2
  • Thomas J. Semrad
    • 2
  • Philip Mack
    • 2
  • Suzette Blanchard
    • 3
  • Nathan Bahary
    • 4
  • Yixing Jiang
    • 5
  • Yun Yen
    • 3
  • John Wright
    • 6
  • Helen Chen
    • 6
  • Heinz-Josef Lenz
    • 1
  • David R. Gandara
    • 2
  1. 1.University of Southern California Norris Comprehensive Cancer CenterLos AngelesUSA
  2. 2.University of California Davis Comprehensive Cancer CenterSacramentoUSA
  3. 3.City of Hope Comprehensive Cancer CenterDuarteUSA
  4. 4.University of Pittsburgh Comprehensive Cancer CenterPittsburghUSA
  5. 5.University of MarylandBaltimoreUSA
  6. 6.National Cancer Institute at the National Institutes of HealthBethesdaUSA

Personalised recommendations