Skip to main content

A multicenter phase II study of TSU-68, an oral multiple tyrosine kinase inhibitor, in combination with docetaxel in metastatic breast cancer patients with anthracycline resistance

Abstract

Background

TSU-68 is a novel multiple tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor, and fibroblast growth factor receptor. This open-label, non-comparative, multicenter phase II study evaluated TSU-68 in combination with docetaxel in patients with metastatic breast cancer that had relapsed within 1 year despite prior treatment with an anthracycline-containing regimen.

Methods

TSU-68 was orally administered on days 1–21, and docetaxel was intravenously delivered on day 1. The regimen was repeated every 21 days. Primary endpoint was objective response rate according to the RECIST guidelines version 1.0.

Results

TSU-68 in combination with docetaxel produced objective responses in 21.1% and clinical benefits in 42.1% of the patients, respectively (1 complete response, 3 partial response, and 4 stable disease for at least 24 weeks, n = 19). Median time to progression was 148 days, and median overall survival was 579 days. The common adverse drug reactions were leukopenia, neutropenia, nail disorder, malaise, dysgeusia, alopecia, and edema.

Conclusions

TSU-68 in combination with docetaxel showed a promising antitumor response with manageable toxicity in patients with anthracycline-resistant metastatic breast cancer. Further studies are warranted in a different population of breast cancer or other solid cancers.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

References

  1. Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov. 2011;10:417–27.

    CAS  PubMed  Article  Google Scholar 

  2. Weidner N, Folkman J, Pozza F, Bevilacqua P, Allred EN, Moore DH, et al. Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst. 1992;84:1875–87.

    CAS  PubMed  Article  Google Scholar 

  3. Ferrara N. Pathways mediating VEGF-independent tumor angiogenesis. Cytokine Growth Factor Rev. 2010;21:21–6

    Google Scholar 

  4. Marty M, Pivot X. The potential of anti-vascular endothelial growth factor therapy in metastatic breast cancer: clinical experience with anti-angiogenic agents, focusing on bevacizumab. Eur J Cancer. 2008;44:912–20.

    CAS  PubMed  Article  Google Scholar 

  5. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Davidson NE, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666–76.

    CAS  PubMed  Article  Google Scholar 

  6. Miles D, Chan A, Romieu G, Dirix LY, Cortes J, Pivot X, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010;28:3239–47.

    CAS  PubMed  Article  Google Scholar 

  7. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.

    CAS  PubMed  Article  Google Scholar 

  8. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel–carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–50.

    CAS  PubMed  Article  Google Scholar 

  9. Benjamin LE, Golijanin D, Itin A, Pode D, Keshet E. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest. 1999;103:159–65.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  10. Abramsson A, Lindblom P, Betsholtz C. Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors. J Clin Invest. 2003;112:1142–51

    Google Scholar 

  11. Ostman A, Heldin CH. PDGF receptors as targets in tumor treatment. Adv Cancer Res. 2007;97:247–74.

    PubMed  Article  Google Scholar 

  12. Morikawa S, Baluk P, Kaidoh T, Haskell A, Jain RK, McDonald DM. Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol. 2002;160:985–1000.

    PubMed Central  PubMed  Article  Google Scholar 

  13. Laird AD, Vajkoczy P, Shawver LK, Thurnher A, Liang C, Mohammadi M, et al. SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res. 2000;60:4152–60.

    CAS  PubMed  Google Scholar 

  14. Machida S, Saga Y, Takei Y, Mizuno I, Takayama T, Kohno T, et al. Inhibition of peritoneal dissemination of ovarian cancer by tyrosine kinase receptor inhibitor SU6668 (TSU-68). Int J Cancer. 2005;114(2):224–9.

    CAS  PubMed  Article  Google Scholar 

  15. Naumova E, Ubezio P, Garofalo A, Borsotti P, Cassis L, Riccardi E, et al. The vascular targeting property of paclitaxel is enhanced by SU6668, a receptor tyrosine kinase inhibitor, causing apoptosis of endothelial cells and inhibition of angiogenesis. Clin Cancer Res. 2006;12:1839–49.

    CAS  PubMed  Article  Google Scholar 

  16. Yonekura K, Basaki Y, Fujita H, Chikahisa L, Hashimoto A, Cherrington J, et al. Inhibition of VEGF/KDR signaling by TSU-68 (SU6668), an oral anti-angiogenic agent, can synergistically enhance the anti-tumor activity of taxol: a new paradigm for breast cancer chemotherapy. Breast Cancer Res Treat. 2001;69(3):216(abstr29).

    Google Scholar 

  17. Murakami H, Ueda Y, Shimoyama T, Yamamoto N, Yamada Y, Arioka H, et al. Phase I, pharmacokinetic, and biological studies of TSU-68, a novel multiple receptor tyrosine kinase inhibitor, administered after meals with solid tumors. Cancer Chemother Pharmacol. 2011;67:1119–28.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  18. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. 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. 2000;92:205–16.

    CAS  PubMed  Article  Google Scholar 

  19. Common Toxicity Criteria v 2.0: cancer therapy evaluation program, National Cancer Institute, Bethesda, MD. 1999.

  20. Ando M, Watanabe T, Nagata K, Narabayashi M, Adachi I, Katsumata N. Efficacy of docetaxel 60 mg/m2 in patients with metastatic breast cancer according to the status of anthracycline resistance. J Clin Oncol. 2001;19:336–42.

    CAS  PubMed  Google Scholar 

  21. Taguchi T, Furue H, Niitani H, Ishitani K, Kanamaru R, Hasegawa K, et al. Phase I clinical trial of RP56976 (docetaxel) a new anticancer drug. Jpn J Cancer Chemother. 1994;21:1997–2005 (in Japanese, abstract in English).

    Google Scholar 

  22. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115–24.

    CAS  PubMed  Article  Google Scholar 

  23. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.

    CAS  PubMed  Article  Google Scholar 

  24. Feldman DR, Baum MS, Ginsberg MS, Hassoun H, Flombaum CD, Velasco S, et al. Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:1432–9.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  25. Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009;27:2823–30.

    CAS  PubMed  Article  Google Scholar 

  26. Azad NS, Posadas EM, Kwitkowski VE, Steinberg SM, Jain L, Annunziata CM, et al. Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. J Clin Oncol. 2008;26:3709–14.

    CAS  PubMed  Article  Google Scholar 

  27. Hecht JR, Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel D, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009;27:672–80.

    CAS  PubMed  Article  Google Scholar 

  28. O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994–1004.

    PubMed  Article  Google Scholar 

  29. Baar J, Silverman P, Lyons J, Fu P, Abdul-Karim F, Ziats N, et al. A vasculature-targeting regimen of preoperative docetaxel with or without bevacizumab for locally advanced breast cancer: impact on angiogenic biomarkers. Clin Cancer Res. 2009;15:3583–90.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

Download references

Acknowledgments

We are grateful to Yutaka Ariyoshi, Yuh Satata, Tomohide Tamura, Kojiro Shimozuma, Seigo Nakamura, and Yuichi Watanabe for extramural review. We thank Junichi Yonezawa Toyomitsu Sato, Masahito Komuro, Kentaro Nagai, Hiroshi Nakayama, Yuji Takami, Itsumi Takaya, Akira Fukushima, Katsuo Ohwada, Kenzo Iizuka, and Kiyoshi Eshima for assistance in data collection and analysis.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Masakazu Toi.

About this article

Cite this article

Toi, M., Saeki, T., Iwata, H. et al. A multicenter phase II study of TSU-68, an oral multiple tyrosine kinase inhibitor, in combination with docetaxel in metastatic breast cancer patients with anthracycline resistance. Breast Cancer 21, 20–27 (2014). https://doi.org/10.1007/s12282-012-0344-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12282-012-0344-3

Keywords

  • Receptor tyrosine kinase inhibitor
  • Phase II study
  • Anthracycline-resistant breast cancer