Skip to main content

Advertisement

SpringerLink
Log in

Phase I study of cetuximab, erlotinib, and bevacizumab in patients with advanced solid tumors

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Background

Complex interrelationships exist between the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) receptor pathways. EGFR activation elicits cell proliferation and increased VEGF expression. To maximally inhibit EGFR and then downstream VEGF activity, this phase I study was initiated to determine the maximum tolerated dose (MTD) of erlotinib with fixed-dose cetuximab, and then combine with bevacizumab in patients with advanced malignancies.

Patients and methods

Patients with advanced malignancies likely to express EGFR were treated with a full dose of cetuximab intravenous weekly, combined with various doses of oral erlotinib daily (Part 1). Once the MTD was determined in Part 1, escalating doses of bevacizumab were administered intravenously biweekly (Part 2).

Results

Forty patients were enrolled and received 155 courses over four dose levels. In Part 1, dose-limiting grade 3 rash occurred in two patients administered with erlotinib at 100 mg daily, and the MTD of erlotinib for this combination was 50 mg daily with standard-dose cetuximab (11 patients treated). Other adverse events included rash, diarrhea, fatigue, and hypomagnesemia. In Part 2, bevacizumab at 10 mg/kg intravenous every 2 weeks was safely added, with additional nondose-limiting headache, proteinuria, and hypertension. There was one partial response in a patient with renal cell carcinoma. Durable stable disease was observed in five patients for 6–11 months.

Conclusions

The MTD for Part 1 was 50 mg daily of erlotinib combined with standard cetuximab. Bevacizumab at 10 mg/kg biweekly can be safely administered with the MTD for erlotinib and cetuximab combination.

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

Similar content being viewed by others

References

  1. Rowinsky EK (2004) The erbB family: targets for therapeutic development against cancer and therapeutic strategies using monoclonal antibodies and tyrosine kinase inhibitors. Annu Rev Med 55:433–457

    Article  PubMed  CAS  Google Scholar 

  2. Mukohara T, Engelman JA, Hanna NH et al (2005) Differential effects of gefitinib and cetuximab on non-small-cell lung cancers bearing epidermal growth factor receptor mutations. J Natl Cancer Inst 97:1185–1194

    PubMed  CAS  Google Scholar 

  3. Imai K, Takaoka A (2006) Comparing antibody and small-molecule therapies for cancer. Nat Rev Cancer 6:714–727

    Article  PubMed  CAS  Google Scholar 

  4. Huang S, Armstrong EA, Benavente S et al (2004) Dual-agent molecular targeting of the epidermal growth factor receptor (EGFR): combining anti-EGFR antibody with tyrosine kinase inhibitor. Cancer Res 64:5355–5362

    Article  PubMed  CAS  Google Scholar 

  5. Matar P, Rojo F, Cassia R et al (2004) Combined epidermal growth factor receptor targeting with the tyrosine kinase inhibitor gefitinib (ZD1839) and the monoclonal antibody cetuximab (IMC-C225): superiority over single-agent receptor targeting. Clin Cancer Res 10:6487–6501

    Article  PubMed  CAS  Google Scholar 

  6. Jimeno A, Rubio-Viqueira B, Amador ML et al (2005) Epidermal growth factor receptor dynamics influences response to epidermal growth factor receptor targeted agents. Cancer Res 65:3003–3010

    PubMed  CAS  Google Scholar 

  7. Perrotte P, Matsumoto T, Inoue K et al (1999) Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res 5:257–265

    PubMed  CAS  Google Scholar 

  8. Bruns CJ, Solorzano CC, Harbison MT et al (2000) Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma. Cancer Res 60:2926–2935

    PubMed  CAS  Google Scholar 

  9. Ciardiello F, Caputo R, Bianco R et al (2001) Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res 7:1459–1465

    PubMed  CAS  Google Scholar 

  10. Mendelsohn J, Baselga J (2003) Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 21:2787–2799

    Article  PubMed  CAS  Google Scholar 

  11. Jung YD, Mansfield PF, Akagi M et al (2002) Effects of combination anti-vascular endothelial growth factor receptor and anti-epidermal growth factor receptor therapies on the growth of gastric cancer in a nude mouse model. Eur J Cancer 38:1133–1140

    Article  PubMed  CAS  Google Scholar 

  12. Ciardiello F, Bianco R, Damiano V et al (2000) Antiangiogenic and antitumor activity of anti-epidermal growth factor receptor C225 monoclonal antibody in combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells. Clin Cancer Res 6:3739–3747

    PubMed  CAS  Google Scholar 

  13. Shaheen RM, Ahmad SA, Liu W et al (2001) Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors. Br J Cancer 85:584–589

    Article  PubMed  CAS  Google Scholar 

  14. Schrag D, Chung KY, Flombaum C et al (2005) Cetuximab therapy and symptomatic hypomagnesemia. J Natl Cancer Inst 97:1221–1224

    Article  PubMed  CAS  Google Scholar 

  15. Tejpar S, Piessevaux H, Claes K et al (2007) Magnesium wasting associated with epidermal-growth-factor receptor-targeting antibodies in colorectal cancer: a prospective study. Lancet Oncol 8:387–394

    Article  PubMed  CAS  Google Scholar 

  16. Therasse P, Arbuck SG, Eisenhauer EA 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 92:205–216

    Article  PubMed  CAS  Google Scholar 

  17. Hirsch FR, Varella-Garcia M, Bunn PA Jr et al (2003) Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 21:3798–3807

    Article  PubMed  CAS  Google Scholar 

  18. Dancey JE, Chen HX (2006) Strategies for optimizing combinations of molecularly targeted anticancer agents. Nat Rev Drug Discov 5:649–659

    Article  PubMed  CAS  Google Scholar 

  19. Baselga J, Schoffski P, Rojo F et al (2006) A phase I pharmacokinetic (PK) and molecular pharmacodynamic (PD) study of the combination of two anti-EGFR therapies, the monoclonal antibody (MAb) cetuximab (C) and the tyrosine kinase inhibitor (TKI) gefitinib (G), in patients (pts) with advanced colorectal (CRC), head and neck (HNC) and non-small cell lung cancer (NSCLC). J Clin Oncol (Meet Abstr) 24:3006

    Google Scholar 

  20. Naret CL, Ramalingam S, Beattie L et al (2006) Total blockade of the epidermal growth factor receptor with the combination of cetuximab and gefitinib: a phase I study for patients with recurrent non-small cell lung cancer (NSCLC). J Clin Oncol (Meet Abstr) 24:17045

    Google Scholar 

  21. Guarino MJ, Schneider CJ, Hosford MA et al (2007) Dual inhibition of the epidermal growth factor receptor (EGFR) pathway with the combination of cetuximab and erlotinib: a phase I study in patients with advanced solid malignancies. Proc AACR-NCI-EORTC Mol Targets Cancer Ther 2007; abstract A147

  22. Vokes EE, Cohen EEW, Mauer AM et al (2005) A phase I study of erlotinib and bevacizumab for recurrent or metastatic squamous cell carcinoma of the head and neck (HNC). J Clin Oncol (Meet Abstr) 23:5504

    Google Scholar 

  23. Herbst RS, Johnson DH, Mininberg E et al (2005) Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer. J Clin Oncol 23:2544–2555

    Article  PubMed  CAS  Google Scholar 

  24. Hainsworth JD, Sosman JA, Spigel DR et al (2005) Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol 23:7889–7896

    Article  PubMed  CAS  Google Scholar 

  25. Fehrenbacher L, O’Neill V, Belani CP et al (2006) A phase II, multicenter, randomized clinical trial to evaluate the efficacy and safety of bevacizumab in combination with either chemotherapy (docetaxel or pemetrexed) or erlotinib hydrochloride compared with chemotherapy alone for treatment of recurrent or refractory non-small cell lung cancer. J Clin Oncol (Meet Abstr) 24:7062

    Google Scholar 

  26. Friberg G, Oza AM, Morgan RJ et al (2006) Bevacizumab (B) plus erlotinib (E) for patients (pts) with recurrent ovarian (OC) and fallopian tube (FT) cancer: preliminary results of a multi-center phase II trial. J Clin Oncol (Meet Abstr) 24:5018

    Google Scholar 

  27. Dickler M, Rugo H, Caravelli J et al (2004) Phase II trial of erlotinib (OSI-774), an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor, and bevacizumab, a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF), in patients (pts) with metastatic breast cancer (MBC). J Clin Oncol (Meet Abstr) 22:2001

    Google Scholar 

  28. Hainsworth JD, Spigel DR, Farley C et al (2007) Phase II trial of bevacizumab and erlotinib in carcinomas of unknown primary site: the Minnie Pearl Cancer Research Network. J Clin Oncol 25:1747–1752

    Article  PubMed  CAS  Google Scholar 

  29. Bukowski RM, Kabbinavar FF, Figlin RA et al (2007) Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol 25:4536–4541

    Article  PubMed  CAS  Google Scholar 

  30. Saltz LB, Lenz HJ, Kindler HL et al (2007) Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol 25:4557–4561

    Article  PubMed  CAS  Google Scholar 

  31. Clark GM, Zborowski DM, Culbertson JL et al (2006) Clinical utility of epidermal growth factor receptor expression for selecting patients with advanced non-small cell lung cancer for treatment with erlotinib. J Thorac Oncol 1:837–846

    Article  PubMed  Google Scholar 

  32. Paez JG, Janne PA, Lee JC et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500

    Article  PubMed  CAS  Google Scholar 

  33. Lynch TJ, Bell DW, Sordella R et al (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139

    Article  PubMed  CAS  Google Scholar 

  34. Pao W, Miller V, Zakowski M et al (2004) EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 101:13306–13311

    Article  PubMed  CAS  Google Scholar 

  35. Wainberg Z, Hecht JR (2006) A phase III randomized, open-label, controlled trial of chemotherapy and bevacizumab with or without panitumumab in the first-line treatment of patients with metastatic colorectal cancer. Clin Colorectal Cancer 5:363–367

    Article  PubMed  CAS  Google Scholar 

  36. Heymach JV, Johnson BE, Prager D et al (2007) Randomized, placebo-controlled phase II study of vandetanib plus docetaxel in previously treated non small-cell lung cancer. J Clin Oncol 25:4270–4277

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was funded by National Cancer Institute (U01-CA069853).

Author information

Author notes

  1. Chia-Chi Lin

    Present address: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan

  2. Emiliano Calvo & Jordi Rodon

    Present address: Department of Medical Oncology, Vall d’Hebron University Hospital, Barcelona, Spain

  3. Kyriakos P. Papadopoulos, Amita Patnaik, Theresa Mays, Chris H. Takimoto & Anthony W. Tolcher

    Present address: South Texas Accelerated Research Therapeutics, 4319 Medical Dr, Suite 205, San Antonio, TX, 78229, USA

Authors and Affiliations

  1. Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX, USA

    Chia-Chi Lin, Emiliano Calvo, Kyriakos P. Papadopoulos, Amita Patnaik, John Sarantopoulos, Alain C. Mita, Monica M. Mita, Jordi Rodon, Theresa Mays, Pat O’Rourke, Chris H. Takimoto & Anthony W. Tolcher

  2. Brooke Army Medical Center, Fort Sam Houston, TX, USA

    Glenn G. Preston

  3. University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    I-Tien Yeh

  4. Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD, USA

    Janet E. Dancey & Helen Chen

Authors
  1. Chia-Chi Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emiliano Calvo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kyriakos P. Papadopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amita Patnaik
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John Sarantopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alain C. Mita
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Glenn G. Preston
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Monica M. Mita
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jordi Rodon
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Theresa Mays
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. I-Tien Yeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Pat O’Rourke
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Chris H. Takimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Janet E. Dancey
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Helen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Anthony W. Tolcher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anthony W. Tolcher.

Additional information

Chia-Chi Lin and Emiliano Calvo contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lin, CC., Calvo, E., Papadopoulos, K.P. et al. Phase I study of cetuximab, erlotinib, and bevacizumab in patients with advanced solid tumors. Cancer Chemother Pharmacol 63, 1065–1071 (2009). https://doi.org/10.1007/s00280-008-0811-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-008-0811-x

Keywords

Search

Navigation