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A prospective phase II study of 2-methoxyestradiol administered in combination with bevacizumab in patients with metastatic carcinoid tumors

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Abstract

Purpose

Angiogenesis inhibition has emerged as a potentially promising treatment strategy for neuroendocrine tumors. 2-Methoxyestradiol (2ME2; Panzem®) is a natural derivative of estradiol with demonstrated anti-angiogenic activity in animal models. We performed a prospective, phase II study of 2ME2, administered in combination with bevacizumab, in patients with advanced carcinoid tumors.

Methods

Thirty-one patients with advanced carcinoid tumors were treated with 2ME2, administered orally at a dose of 1,000 mg four times daily. Patients also received bevacizumab 5 mg/kg intravenously every 2 weeks. Patients were observed for evidence of toxicity, tumor response, and survival.

Results

The combination of 2ME2 and bevacizumab was relatively easily tolerated and was associated with anticipated toxicities for these two agents. No confirmed radiologic responses (by RECIST) were observed. However, 68% of the radiologically evaluable patients experienced at least some degree of tumor reduction, and the median progression-free survival (PFS) time was 11.3 months.

Conclusion

2ME2 and bevacizumab can be safely administered to patients with advanced carcinoid tumors. While major tumor regression was not observed with this regimen, the encouraging median progression-free survival time suggests that this regimen has some degree of antitumor activity and supports the further investigation of angiogenesis inhibitors in this disease.

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References

  1. Moertel C, Lefkopoulo M, Lipsitz S et al (1992) Streptozocin-doxorubicin, stretpozocin-fluorouracil, or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med 326:519–523

    Article  PubMed  CAS  Google Scholar 

  2. Kulke M, Hornick J, Frauenhoffer C et al (2009) O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clin Cancer Res 15:338–345

    Article  PubMed  CAS  Google Scholar 

  3. Ekeblad S, Sundin A, Janson ET et al (2007) Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res 13:2986–2991

    Article  PubMed  CAS  Google Scholar 

  4. Arnold R, Muller H, Schade-Brittinger C et al (2009) Placebo-controlled, double blind, prospective, randomized study of the efect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID study group. 2009 Gastrointestinal Cancers Symposium A121

  5. Faiss S, Pape UF, Bohmig M et al (2003) Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors–the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol 21:2689–2696

    Article  PubMed  CAS  Google Scholar 

  6. Zhang J, Jia Z, Li Q et al (2007) Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression-free survival among patients with low-grade neuroendocrine tumors. Cancer 109:1478–1486

    Article  PubMed  CAS  Google Scholar 

  7. Terris B, Scoazec J, Rubbia L (1998) Expression of vascular endothelial growth factor in digestive neuroendocrine tumors. Histopathology 32:133–138

    Article  PubMed  CAS  Google Scholar 

  8. Hobday TJ, Rubin J, Holen K et al (2007) MC044 h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): a Phase II Consortium (P2C) study (abstract). J of Clin Onc ASCO Annual Meeting Proc Part 1 25:4504

  9. Kulke MH, Lenz HJ, Meropol NJ et al (2008) Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 26:3403–3410

    Article  PubMed  CAS  Google Scholar 

  10. Yao JC, Phan A, Hoff PM et al (2008) Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b. J Clin Oncol 26:1316–1323

    Article  PubMed  CAS  Google Scholar 

  11. Hughes RA, Harris T, Altmann E et al (2002) 2-Methoxyestradiol and analogs as novel antiproliferative agents: analysis of three-dimensional quantitative structure-activity relationships for DNA synthesis inhibition and estrogen receptor binding. Mol Pharmacol 61:1053–1069

    Article  PubMed  CAS  Google Scholar 

  12. Fotsis T, Zhang Y, Pepper MS et al (1994) The endogenous oestrogen metabolite 2-methoxyoestradiol inhibits angiogenesis and suppresses tumour growth. Nature 368:237–239

    Article  PubMed  CAS  Google Scholar 

  13. Becker CM, Rohwer N, Funakoshi T et al (2008) 2-methoxyestradiol inhibits hypoxia-inducible factor-1{alpha} and suppresses growth of lesions in a mouse model of endometriosis. Am J Pathol 172:534–544

    Article  PubMed  CAS  Google Scholar 

  14. Dahut WL, Lakhani NJ, Gulley JL et al (2006) Phase I clinical trial of oral 2-methoxyestradiol, an antiangiogenic and apoptotic agent, in patients with solid tumors. Cancer Biol Ther 5:22–27

    Article  PubMed  CAS  Google Scholar 

  15. Sweeney C, Liu G, Yiannoutsos C et al (2005) A phase II multicenter, randomized, double-blind, safety trial assessing the pharmacokinetics, pharmacodynamics, and efficacy of oral 2-methoxyestradiol capsules in hormone-refractory prostate cancer. Clin Cancer Res 11:6625–6633

    Article  PubMed  CAS  Google Scholar 

  16. Liu G, sidor C, Feierabend C et al (2005) Phase Ib trial of 2ME2 administered as a nanocrystal dispersion (NCD) in patients with advanced cancer. Proceedings of EORTC/AACR/NCI B14:129

  17. Sweeney C, Slebe K, Li M et al (2005) A single center open label dose escalation safety and pharmacokinetic study of 2 methoxyestriadiol nanocrystal colloidal dispersion in patients with advanced cancer. Proceedings of EORTC/AACR/NCI B12:157

  18. Matei D, Schilder J, Sutton G et al (2009) Activity of 2 methoxyestradiol (Panzem NCD) in advanced, platinum-resistant ovarian cancer and primary peritoneal carcinomatosis: a Hoosier Oncology Group trial. Gynecol Oncol 115:90–96

    Article  PubMed  CAS  Google Scholar 

  19. Schumacher G, Kataoka M, Roth JA et al (1999) Potent antitumor activity of 2-methoxyestradiol in human pancreatic cancer cell lines. Clin Cancer Res 5:493–499

    PubMed  CAS  Google Scholar 

  20. Sosman J, Puzanov I (2009) Combination targeted therapy in advanced renal cell carcinoma. Cancer 115:2368–2375

    Article  PubMed  CAS  Google Scholar 

  21. Feldman DR, Baum MS, Ginsberg MS et al (2009) Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 27:1432–1439. [see comment]

    Article  PubMed  CAS  Google Scholar 

  22. Korse CM, Bonfrer JM, Aaronson NK et al (2009) Chromogranin A as an alternative to 5-hydroxyindoleacetic acid in the evaluation of symptoms during treatment of patients with neuroendocrine Tumors. Neuroendocrinology 89:296–301

    Article  PubMed  CAS  Google Scholar 

  23. Yao JC, Phan AT, Chang DZ et al (2008) Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. [erratum appears in J Clin Oncol. 2008 Dec 1;26(34):5660] J Clin Oncol 26:4311–4318

    Article  PubMed  Google Scholar 

  24. Raymond E (2009) Phase III randomised double blind trial of suntinib versus placebo in patients with progressive, well-differentiated pancreatic neuroendocrine tumors. World Congress on Gastrointestinal Cancers, Barcelona, Spain

  25. Kulke MH, Bergsland EK, Ryan DP et al (2006) Phase II study of recombinant human endostatin in patients with advanced neuroendocrine tumors. J Clin Oncol 24:3555–3561

    Article  PubMed  CAS  Google Scholar 

  26. Duran I, Kortmansky J, Singh D et al (2006) A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer 95:1148–1154

    Article  PubMed  CAS  Google Scholar 

  27. Yao JC, Zhang JX, Rashid A et al (2007) Clinical and in vitro studies of imatinib in advanced carcinoid tumors. Clin Cancer Res 13:234–240

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Support for this study was provided by Entremed, Inc, NCI grants CA093401 (MHK) and P50 CA127003 (DF/HCC SPORE in Gastrointestinal Cancer). The authors gratefully acknowledge support from the Saul and Gitta Kurlat fund for neuroendocrine tumor research.

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Authors and Affiliations

  1. Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA, 02115, USA

    Matthew H. Kulke, Jennifer A. Chan, Jeffrey A. Meyerhardt, Thomas A. Abrams, Eileen Regan & Charles S. Fuchs

  2. Massachusetts General Hospital, Boston, MA, USA

    Andrew X. Zhu & Lawrence S. Blaszkowsky

  3. EntreMed, Inc, Rockville, MD, USA

    Carolyn Sidor

Authors
  1. Matthew H. Kulke
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  2. Jennifer A. Chan
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  3. Jeffrey A. Meyerhardt
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  4. Andrew X. Zhu
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  5. Thomas A. Abrams
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  6. Lawrence S. Blaszkowsky
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  7. Eileen Regan
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  8. Carolyn Sidor
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  9. Charles S. Fuchs
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Corresponding author

Correspondence to Matthew H. Kulke.

Additional information

Reported in part at the American Society of Clinical Oncology 2008 Gastrointestinal Cancers Symposium.

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Kulke, M.H., Chan, J.A., Meyerhardt, J.A. et al. A prospective phase II study of 2-methoxyestradiol administered in combination with bevacizumab in patients with metastatic carcinoid tumors. Cancer Chemother Pharmacol 68, 293–300 (2011). https://doi.org/10.1007/s00280-010-1478-7

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  • DOI: https://doi.org/10.1007/s00280-010-1478-7

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