Skip to main content
SpringerLink
Log in

Phase 1 Study of Monotherapy with KHK2866, an Anti-Heparin-Binding Epidermal Growth Factor-Like Growth Factor Monoclonal Antibody, in Patients with Advanced Cancer

  • Original Research Article
  • Published:
Targeted Oncology Aims and scope Submit manuscript

Abstract

Background

KHK2866 is a recombinant, humanized, non-fucosylated, monoclonal antibody directed at heparin-binding epidermal growth factor-like growth factor (HB-EGF).

Objective

To determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, potential immunogenicity, and preliminary clinical efficacy of KHK2866 monotherapy in patients with advanced and refractory cancer in a first-in-human, phase 1 study.

Materials and Methods

Using a standard 3 + 3 dose-escalation design, 20 patients received KHK2866 (0.3, 1, and 3 mg/kg) intravenously once weekly. Two additional patients received 0.1 mg/kg in a cohort which was subsequently added following protocol amendment.

Results

The first three patients enrolled experienced grade 2 hypersensitivity (acute infusion reactions) after the first dose of KHK2866. After prophylactic treatment with an H1-blocker and corticosteroids in subsequently recruited patients, two grade 2 hypersensitivity reactions were observed in the remaining 19 patients. Grade 2/3 neurotoxicity appeared to be dose-limiting at 3 mg/kg in the original dose-escalation cohorts (n = 2), at 1 mg/kg in the MTD dose expansion cohort (n = 1), and at 0.1 mg/kg (n = 1). Neurotoxicity was manifested as complex partial seizure activity, aphasia, and confusion after first-dose administration. Pharmacokinetic exposure to KHK2866 increased proportionally to dose. Mean elimination half-life was 71.9–118 h over the dose range from 0.3 to 3 mg/kg. All KHK2866 doses decreased serum free HB-EGF levels, generally below the lower limit of quantification.

Conclusions

The study was terminated because of neuropsychiatric toxicity. The only predictive factor for neuropsychiatric toxicity was administration of KHK2866. These effects were reversible, but were not predictable. Their etiology is not presently understood. [Study registered at ClinicalTrials.gov #NCT0179291]

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Pegram MD, Konecny G, Slamon DJ (2000) The molecular and cellular biology of HER2/neu gene amplification/over-expression and the clinical development of herceptin (trastuzumab) therapy for breast cancer. Cancer Treat Res 103:57–75

    Article  CAS  PubMed  Google Scholar 

  2. Mendelsohn J, Baselga J (2006) Epidermal growth factor receptor targeting in cancer. Sem Oncol 33:369–85

    Article  CAS  Google Scholar 

  3. Slamon DJ, Leyland-Jones I, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that over-expressed HER2. N Engl J Med 344:783–92

    Article  CAS  PubMed  Google Scholar 

  4. Fukuoka M, Yano S, Giaccone G et al (2003) Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial). J Clin Oncol 21:2237–46

    Article  CAS  PubMed  Google Scholar 

  5. Cunningham D, Humblet Y, Siena S et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–45

    Article  CAS  PubMed  Google Scholar 

  6. Shepherd F, Pereira JR, Ciuleanu T, National Cancer Institute of Canada Clinical Trials Group et al (2005) Erlotinib in previously treated non-small cell lung cancer. N Engl J Med 353:123–32

    Article  CAS  PubMed  Google Scholar 

  7. Geyer CE, Forster J, Lindquist D et al (2006) Lapatinib plus capecitabine for HER-2 positive advanced breast cancer. N Engl J Med 355:2733–43

    Article  CAS  PubMed  Google Scholar 

  8. Van Cutsem E, Peeters M, Siena S et al (2007) Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25:1658–64

    Article  PubMed  Google Scholar 

  9. Higashiyama S, Iwabuki H, Morimoto C, Hieda M, Inoue H, Matsushita N (2008) Membrane-anchored growth factors, the epidermal growth factor family: beyond receptor ligands. Cancer Sci 99:214–20

    Article  CAS  PubMed  Google Scholar 

  10. Yotsumoto F, Yagi H, Suzuki SO et al (2008) Validation of HB-EGF and amphiregulin as targets for human cancer therapy. Biochem Biophys Res Comm 365:555–61

    Article  CAS  PubMed  Google Scholar 

  11. Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–42

    Article  CAS  PubMed  Google Scholar 

  12. Sandler A, Gray R, Perry MC et al (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small cell lung cancer. N Engl J Med 355:2542–50

    Article  CAS  PubMed  Google Scholar 

  13. Rini BI, Halabi S, Rosenberg JE et al (2008) Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 26:5422–8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Friedman HS, Prados MD, Wen PY et al (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27:4733–40

    Article  CAS  PubMed  Google Scholar 

  15. Bublil EM, Yarden Y (2007) The EGF receptor family: spearheading a merger of signaling and therapeutics. Curr Opin Cell Biol 19:124–34

    Article  CAS  PubMed  Google Scholar 

  16. Goishi K, Higashiyama S, Klagsbrun M et al (1995) Phorbol ester induces the rapid processing of cell surface heparin-binding EGF-like growth factor: conversion from juxtacrine to paracrine growth factor activity. Mol Biol Cell 6:967–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Miyamoto S, Yagi H, Yotsumoto F, Kawarabayashi T, Mekada E (2006) Heparin-binding epidermal growth factor-like growth factor as a novel targeting molecule for cancer therapy. Cancer Sci 97:341–7

    Article  CAS  PubMed  Google Scholar 

  18. Sato M, Narita T, Kawakami-Kimura N et al (1996) Increased expression of integrins by heparin-binding EGF like growth factor in human esophageal cancer cells. Cancer Lett 102:183–91

    Article  CAS  PubMed  Google Scholar 

  19. Mishima K, Higashiyama S, Asai A et al (1998) Heparin-binding epidermal growth factor-like growth factor stimulates mitogenic signaling and is highly expressed in human malignant gliomas. Acta Neuropathol 96:322–8

    Article  CAS  PubMed  Google Scholar 

  20. Ito Y, Higashiyama S, Takeda T, Yamamoto Y, Wakasa KI, Matsuura N (2001) Expression of heparin-binding epidermal growth factor-like growth factor in pancreatic adenocarcinoma. Int J Gastrointest Cancer 29:47–51

    Article  CAS  PubMed  Google Scholar 

  21. Ito Y, Takeda T, Higashiyama S, Noguchi S, Matsuura N (2001) Expression of heparin-binding epidermal growth factor-like growth factor in breast carcinoma. Breast Cancer Res Treat 67:81–5

    Article  CAS  PubMed  Google Scholar 

  22. Ito Y, Takeda T, Higashiyama S et al (2001) Expression of heparin binding epidermal growth factor-like growth factor in hepatocellular carcinoma: an immunohistochemical study. Oncol Rep 8:903–7

    CAS  PubMed  Google Scholar 

  23. Ongusaha PP, Kwak JC, Zwible AJ et al (2004) HB-EGF is a potent inducer of tumor growth and angiogenesis. Cancer Res 64:5283–90

    Article  CAS  PubMed  Google Scholar 

  24. Itoh Y, Joh T, Tanida S et al (2005) IL-8 promotes cell proliferation and migration through metalloproteinase cleavage proHB-EGF in human colon carcinoma cells. Cytokine 29:275–82

    CAS  PubMed  Google Scholar 

  25. Yagi H, Yatsumoto F, Miyamoto S (2008) Heparin-binding epidermal growth factor-like growth factor promotes transcoelomic metastasis in ovarian cancer through epithelial-mesenchymal transition. Mol Cancer Ther 7:3441–51

    Article  CAS  PubMed  Google Scholar 

  26. Tanaka Y, Miyamoto S, Suzuki SO et al (2005) Clinical significance of heparin-binding epidermal growth-like factor and a disintegrin and metalloprotease 17 expression in human ovarian cancer. Clin Cancer Res 11:4783–92

    Article  CAS  PubMed  Google Scholar 

  27. Suganuma K, Kubota T, Saikawa Y et al (2003) Possible chemoresistance-related genes for gastric cancer detected by cDNA microarray. Cancer Sci 94:355–9

    Article  CAS  PubMed  Google Scholar 

  28. Wang F, Liu R, Lee SW, Sloss CM, Couget J, Cusack JC (2007) Heparin-binding EGF-like growth factor is an early response gene to chemotherapy and contributes to chemotherapy resistance. Oncogene 26:2006–16

    Article  CAS  PubMed  Google Scholar 

  29. Yagi H, Yotsumoto F, Sonodo K, Kuroki M, Mekada E, Miyamoto S (2009) Synergistic anti-tumor effect of paclitaxel with CRM197, an inhibitor of HB EGF, in ovarian cancer. Int J Cancer 124:1429–39

    Article  CAS  PubMed  Google Scholar 

  30. Sloss CM, Wang F, Palladino MA, Cusack JC Jr (2010) Activation of EGFR by proteasome inhibition requires HB-EGF in pancreatic cancer cells. Oncogene 29:3146–52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Shinkawa T, Nakamura K, Yamane N et al (2003) The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J Biol Chem 278:3466–73

    Article  CAS  PubMed  Google Scholar 

  32. Miyamoto S, Iwamoto R, Furuya A et al (2011) A novel anti-human HB-EGF monoclonal antibody with multiple antitumor mechanisms against ovarian cancer cells. Clin Cancer Res 17:6733–41

    Article  CAS  PubMed  Google Scholar 

  33. Kasai N, Yoshikawa Y, Enokizono J (2014) Effect of antigen-dependent clearance on pharmacokinetics of anti-heparin-binding EGF-like growth factor (HB-EGF) monoclonal antibody. MAbs 6:1220–8

    Article  PubMed  PubMed Central  Google Scholar 

  34. Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–47

    Article  CAS  PubMed  Google Scholar 

  35. Rustin GJ, Quinn M, Thigpen T et al (2004) Re: new guidelines to evaluate the response to treatment in solid tumors (ovarian cancer). J Natl Cancer Inst 96:487–8

    Article  PubMed  Google Scholar 

  36. Kasai N, Kobayashi K, Shioya S et al (2012) Soluble heparin-binding EGF-like growth factor (HB-EGF) detected by newly developed immuno-PCR method is a clear-cut serological biomarker for ovarian cancer. Am J Transl Res 4:415–21

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Mishima K, Higashiyama S, Nagashima Y et al (1996) Regional distribution of heparin-binding epidermal growth factor-like growth factor mRNA and protein in adult rat forebrain. Neurosci Lett 213:153–6

    Article  CAS  PubMed  Google Scholar 

  38. Nakagawa T, Sasahara M, Hayase Y et al (1998) Neuronal and glial expression of heparin-binding EGF-like growth factor in central nervous system of prenatal and early postnatal rat. Brain Res Dev Brain Res 108:263–72

    Article  CAS  PubMed  Google Scholar 

  39. Cantarella C, Cayre M, Magalon K, Durbec P (2008) Intranasal HB-EGF administration favors adult SVZ cell mobilization to demyelinated lesions in mouse corpus callosum. Dev Neurobiol 68:223–36

    Article  PubMed  Google Scholar 

  40. Oyagi A, Oida Y, Kakefuda K et al (2009) Generation and characterization of conditional heparin-binding EGF-like growth factor knockout mice. PLoS One 4, e7461

    Article  PubMed  PubMed Central  Google Scholar 

  41. Oyagi A, Moriguchi S, Nitta A et al (2011) Heparin-binding EGF-like growth factor is required for synaptic plasticity and memory formation. Brain Res 1419:97–104

    Article  CAS  PubMed  Google Scholar 

  42. Moore KN, Bendell JC, Olszanski AJ et al. Phase I, first-in-human, dose-escalation study of U3-1565, a fully human anti-HB-EGF monoclonal antibody, in patients with advanced solid tumors. J Clin Oncol. 2013; 31 (suppl; abstr 2519).

Download references

Acknowledgments

Medical writing assistance provided by Peter Todd of Tajut Ltd. (Kaiapoi, New Zealand) was supported financially by Kyowa Hakko Kirin Inc. during the preparation of this manuscript. The Institute for Drug Development, Cancer Therapy, and Research Center at University of Texas Health Science Center San Antonio (San Antonio, TX, USA) received support from Cancer Center Support Grant P30CA054174.

Author information

Authors and Affiliations

  1. Institute for Drug Development, Cancer Therapy and Research Center at University of Texas Health Science Center San Antonio, 4th Floor, Zeller Building, 7979 Wurzbach Road, San Antonio, TX, 78229, USA

    John Sarantopoulos

  2. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Monica M. Mita

  3. Gillette Center of Gynecologic Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Michael J. Birrer

  4. University of Arizona Cancer Center, Tuscon, AZ, USA

    Lee D. Cranmer

  5. Oncology Consultants, Houston, TX, USA

    Luis T. Campos & Luis H. Camacho

  6. Kyowa Hakko Kirin Pharma, Inc., Princeton, NJ, USA

    Xiaoping Zhang, Penelope Bristow, Hidekuni Kaito & Vincent Strout

Authors
  1. John Sarantopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Monica M. Mita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael J. Birrer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lee D. Cranmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Luis T. Campos
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaoping Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Penelope Bristow
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hidekuni Kaito
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Vincent Strout
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Luis H. Camacho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John Sarantopoulos.

Ethics declarations

Funding

Kyowa Hakko Kirin, Inc.

Conflict of Interest

XZ, HK, and VS are employees of Kyowa Hakko Kirin. PB was an employee of Kyowa Hakko Kirin until 29 August 2014. JS, MMM, MJB, LDC, LTC, and LHC declare that they have no conflict of interest

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 40 kb)

ESM 2

(DOCX 36 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sarantopoulos, J., Mita, M.M., Birrer, M.J. et al. Phase 1 Study of Monotherapy with KHK2866, an Anti-Heparin-Binding Epidermal Growth Factor-Like Growth Factor Monoclonal Antibody, in Patients with Advanced Cancer. Targ Oncol 11, 317–327 (2016). https://doi.org/10.1007/s11523-015-0394-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-015-0394-5

Keywords

Search

Navigation