Skip to main content

Advertisement

SpringerLink
Log in

Endostar in combination with modified FOLFOX6 as an initial therapy in advanced colorectal cancer patients: a phase I clinical trial

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

Abstract

Purpose

Endostar is a recombinant human endostatin with antiangiogenic properties that has been useful in treating a wide range of cancers and shows promise for use in combination treatment for advanced colorectal cancer. This study aimed to evaluate the drug safety and tolerability of continuous intravenous infusion (CIV) of endostar in combination with modified FOLFOX6 (mFOLFOX6) as an initial therapy in advanced colorectal cancer patients.

Methods

This was a single-center, single-arm, open, dose-escalation study in patients with advanced colorectal cancer at Fudan University Shanghai Cancer Center between August 2010 and January 2012. A total of 21 patients were included. Standard dosage of mFOLFOX6 was used. CIV endostar commenced on day 4 to day 14 ascending from 7.5 to 15, 30, 45, 60, and 75 mg/m2/day. Primary outcomes were dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of CIV endostar in combination with mFOLFOX6. Secondary outcomes were pharmacokinetic parameters. Physical examination, performance status, standard blood tests and electrocardiograms were performed.

Results

MTD was 75 mg/m2/day. Adverse events included leucopenia (n = 17, 81 %), neutropenia (n = 12, 57.1 %), anemia (n = 5, 23.8 %), anorexia (n = 6, 28.6 %) and constipation (n = 4, 19.0 %). One patient with an allergic reaction stopped chemotherapy. Two patients stopped endostar treatment, one with level 3 ventricular premature beat (DLT at 15 mg/m2/day) and one with a level 1 ventricular arrhythmia (30 mg/m2/day). The main ECG changes were ST-segment and T wave changes. Exposure to endostar and CIV dose was linear between 7.5 and 30 mg/m2/day (R 2 = 0.974).

Conclusions

Endostar in combination with mFOLFOX6 was generally safe and well tolerated.

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. Chen W, Zheng R, Zhang S, Zhao P, Zeng H, Zou X, He J (2014) Annual report on status of cancer in China, 2010. Chin J Cancer Res 26(1):48–58. doi:10.3978/j.issn.1000-9604.2014.01.08

    PubMed Central  PubMed  Google Scholar 

  2. Goss PE, Strasser-Weippl K, Lee-Bychkovsky BL, Fan L, Li J, Chavarri-Guerra Y, Liedke PE, Pramesh CS, Badovinac-Crnjevic T, Sheikine Y, Chen Z, Qiao YL, Shao Z, Wu YL, Fan D, Chow LW, Wang J, Zhang Q, Yu S, Shen G, He J, Purushotham A, Sullivan R, Badwe R, Banavali SD, Nair R, Kumar L, Parikh P, Subramanian S, Chaturvedi P, Iyer S, Shastri SS, Digumarti R, Soto-Perez-de-Celis E, Adilbay D, Semiglazov V, Orlov S, Kaidarova D, Tsimafeyeu I, Tatishchev S, Danishevskiy KD, Hurlbert M, Vail C, St. Louis J, Chan A (2014) Challenges to effective cancer control in China, India, and Russia. Lancet Oncol 15(5):489–538. doi:10.1016/S1470-2045(14)70029-4

    Article  PubMed  Google Scholar 

  3. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127(12):2893–2917. doi:10.1002/ijc.25516

    Article  CAS  PubMed  Google Scholar 

  4. Brenner H, Kloor M, Pox CP (2014) Colorectal cancer. Lancet 383(9927):1490–1502. doi:10.1016/S0140-6736(13)61649-9

    Article  PubMed  Google Scholar 

  5. Benson AB, 3rd, Bekaii-Saab T, Chan E, Chen YJ, Choti MA, Cooper HS, Engstrom PF, Enzinger PC, Fakih MG, Fenton MJ, Fuchs CS, Grem JL, Hunt S, Kamel A, Leong LA, Lin E, May KS, Mulcahy MF, Murphy K, Rohren E, Ryan DP, Saltz L, Sharma S, Shibata D, Skibber JM, Small W, Jr, Sofocleous CT, Venook AP, Willett CG, Gregory KM, Freedman-Cass DA (2013) Metastatic colon cancer, version 3.2013: featured updates to the NCCN Guidelines. J Natl Compr Canc Netw 11(2):141–152; quiz 152

  6. Engstrom PF, Arnoletti JP, Benson AB 3rd, Chen YJ, Choti MA, Cooper HS, Covey A, Dilawari RA, Early DS, Enzinger PC, Fakih MG, Fleshman J Jr, Fuchs C, Grem JL, Kiel K, Knol JA, Leong LA, Lin E, Mulcahy MF, Rao S, Ryan DP, Saltz L, Shibata D, Skibber JM, Sofocleous C, Thomas J, Venook AP, Willett C, National Comprehensive Cancer N (2009) NCCN clinical practice guidelines in oncology: rectal cancer. J Natl Compr Canc Netw 7(8):838–881

    PubMed  Google Scholar 

  7. Arnold D, Seufferlein T (2010) Targeted treatments in colorectal cancer: state of the art and future perspectives. Gut 59(6):838–858. doi:10.1136/gut.2009.196006

    Article  CAS  PubMed  Google Scholar 

  8. Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A (2004) FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22(2):229–237. doi:10.1200/JCO.2004.05.113

    Article  CAS  PubMed  Google Scholar 

  9. Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Cassidy J (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26(12):2013–2019. doi:10.1200/JCO.2007.14.9930

    Article  CAS  PubMed  Google Scholar 

  10. Nishina T, Takano Y, Denda T, Yasui H, Takeda K, Ura T, Esaki T, Okuyama Y, Kondo K, Takahashi Y, Sugiyama Y, Muro K (2013) A phase II clinical study of mFOLFOX6 plus bevacizumab as first-line therapy for Japanese advanced/recurrent colorectal cancer patients. Jpn J Clin Oncol 43(11):1080–1086. doi:10.1093/jjco/hyt127

    Article  PubMed Central  PubMed  Google Scholar 

  11. Ruzzo A, Graziano F, Loupakis F, Rulli E, Canestrari E, Santini D, Catalano V, Ficarelli R, Maltese P, Bisonni R, Masi G, Schiavon G, Giordani P, Giustini L, Falcone A, Tonini G, Silva R, Mattioli R, Floriani I, Magnani M (2007) Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy. J Clin Oncol 25(10):1247–1254. doi:10.1200/JCO.2006.08.1844

    Article  CAS  PubMed  Google Scholar 

  12. Chen YC, Tzeng CH, Chen PM, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, Wang WS (2010) Influence of GSTP1 I105 V polymorphism on cumulative neuropathy and outcome of FOLFOX-4 treatment in Asian patients with colorectal carcinoma. Cancer Sci 101(2):530–535. doi:10.1111/j.1349-7006.2009.01418.x

    Article  CAS  PubMed  Google Scholar 

  13. Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E (2008) Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol 26(21):3523–3529. doi:10.1200/JCO.2007.15.4138

    Article  CAS  PubMed  Google Scholar 

  14. Van Cutsem E, Rivera F, Berry S, Kretzschmar A, Michael M, DiBartolomeo M, Mazier MA, Canon JL, Georgoulias V, Peeters M, Bridgewater J, Cunningham D, First Bi (2009) Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol 20(11):1842–1847. doi:10.1093/annonc/mdp233

    Article  PubMed  Google Scholar 

  15. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23):2335–2342. doi:10.1056/NEJMoa032691

    Article  CAS  PubMed  Google Scholar 

  16. Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd, Eastern Cooperative Oncology Group Study E (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25(12):1539–1544. doi:10.1200/JCO.2006.09.6305

    Article  CAS  PubMed  Google Scholar 

  17. Macedo LT, da Costa Lima AB, Sasse AD (2012) Addition of bevacizumab to first-line chemotherapy in advanced colorectal cancer: a systematic review and meta-analysis, with emphasis on chemotherapy subgroups. BMC Cancer 12:89. doi:10.1186/1471-2407-12-89

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182–1186. doi:10.1056/NEJM197111182852108

    Article  CAS  PubMed  Google Scholar 

  19. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88(2):277–285

    Article  PubMed  Google Scholar 

  20. Folkman J (2006) Antiangiogenesis in cancer therapy–endostatin and its mechanisms of action. Exp Cell Res 312(5):594–607. doi:10.1016/j.yexcr.2005.11.015

    Article  CAS  PubMed  Google Scholar 

  21. Huang X, Wong MK, Zhao Q, Zhu Z, Wang KZ, Huang N, Ye C, Gorelik E, Li M (2001) Soluble recombinant endostatin purified from Escherichia coli: antiangiogenic activity and antitumor effect. Cancer Res 61(2):478–481

    CAS  PubMed  Google Scholar 

  22. Han B, Xiu Q, Wang H, Shen J, Gu A, Luo Y, Bai C, Guo S, Liu W, Zhuang Z, Zhang Y, Zhao Y, Jiang L, Zhou J, Jin X (2011) A multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy of paclitaxel–carboplatin alone or with endostar for advanced non-small cell lung cancer. J Thorac Oncol 6(6):1104–1109. doi:10.1097/JTO.0b013e3182166b6b

    Article  PubMed  Google Scholar 

  23. Sun L, Ye HY, Zhang YH, Guan YS, Wu H (2007) Epidermal growth factor receptor antibody plus recombinant human endostatin in treatment of hepatic metastases after remnant gastric cancer resection. World J Gastroenterol 13(45):6115–6118

    Article  PubMed Central  PubMed  Google Scholar 

  24. Xu HX, Huang XE, Qian ZY, Xu X, Li Y, Li CG (2011) Clinical observation of Endostar(R) combined with chemotherapy in advanced colorectal cancer patients. Asian Pac J Cancer Prev 12(11):3087–3090

    PubMed  Google Scholar 

  25. Zhou JF, Bai CM, Wang YZ, Li XY, Cheng YJ, Chen SC (2011) Endostar combined with chemotherapy for treatment of metastatic colorectal and gastric cancer: a pilot study. Chin Med J (Engl) 124(24):4299–4303

    CAS  Google Scholar 

  26. Jin F, Ji H, Jia C, Brockmeier U, Hermann DM, Metzen E, Zhu Y, Chi B (2012) Synergistic antitumor effects of endostar in combination with oxaliplatin via inhibition of HIF and CXCR4 in the colorectal cell line SW1116. PLoS ONE 7(10):e47161. doi:10.1371/journal.pone.0047161

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Mancuso MR, Davis R, Norberg SM, O’Brien S, Sennino B, Nakahara T, Yao VJ, Inai T, Brooks P, Freimark B, Shalinsky DR, Hu-Lowe DD, McDonald DM (2006) Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest 116(10):2610–2621

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Zuniga RM, Torcuator R, Jain R, Anderson J, Doyle T, Schultz L, Mikkelsen T (2010) Rebound tumour progression after the cessation of bevacizumab therapy in patients with recurrent high-grade glioma. J Neurooncol 99(2):237–242. doi:10.1007/s11060-010-0121-0

    Article  CAS  PubMed  Google Scholar 

  29. Kisker O, Becker CM, Prox D, Fannon M, D’Amato R, Flynn E, Fogler WE, Sim BK, Allred EN, Pirie-Shepherd SR, Folkman J (2001) Continuous administration of endostatin by intraperitoneally implanted osmotic pump improves the efficacy and potency of therapy in a mouse xenograft tumor model. Cancer Res 61(20):7669–7674

    CAS  PubMed  Google Scholar 

  30. Leong S, Eckhardt SG, Chan E, Messersmith WA, Spratlin J, Camidge DR, Diab S, Khosravan R, Lin X, Chow Maneval E, Lockhart AC (2012) A phase I study of sunitinib combined with modified FOLFOX6 in patients with advanced solid tumors. Cancer Chemother Pharmacol 70(1):65–74. doi:10.1007/s00280-012-1880-4

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Yoshino T, Yamazaki K, Hamaguchi T, Shimada Y, Kato K, Yasui H, Boku N, Lechuga MJ, Hirohashi T, Shibata A, Hashigaki S, Li Y, Ohtsu A (2012) Phase I study of sunitinib plus modified FOLFOX6 in Japanese patients with treatment-naive colorectal cancer. Anticancer Res 32(3):973–979

    CAS  PubMed  Google Scholar 

  32. Kato T, Muro K, Yamaguchi K, Bando H, Hazama S, Amagai K, Baba H, Denda T, Shi X, Fukase K, Skamoto J, Mishima H (2012) Cediranib in combination with mFOLFOX6 in Japanese patients with metastatic colorectal cancer: results from the randomised phase II part of a phase I/II study. Ann Oncol 23(4):933–941. doi:10.1093/annonc/mdr359

    Article  CAS  PubMed  Google Scholar 

  33. Sakamoto Y, Beppu T, Miyamoto Y, Okabe H, Ida S, Imai K, Chikamoto A, Watanabe M, Takamori H, Baba H (2013) Feasibility and short-term outcome of adjuvant FOLFOX after resection of colorectal liver metastases. J Hepatobiliary Pancreat Sci 20(3):307–312. doi:10.1007/s00534-012-0523-9

    Article  PubMed  Google Scholar 

  34. Tsutsumi S, Watanabe R, Tabe Y, Fujii T, Morita H, Kigure W, Kato T, Yamauchi H, Asao T, Kuwano H (2011) Scheduled prospective tri-weekly modified FOLFOX6 maintenance chemotherapy in the treatment of metastatic colorectal cancer. Hepatogastroenterology 58(112):1930–1932. doi:10.5754/hge10110

    CAS  PubMed  Google Scholar 

Download references

Conflict of interest

The authors have full control of all primary data and that we agree to allow the journal to review their data if requested. We declare that we have no conflict of interest.

Ethical standard

The study protocol was approved by the ethics committee of Fudan University Shanghai Cancer Center (100585-3) and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All persons gave their informed consent prior to their inclusion in the study.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

    Zhiyu Chen, Weijian Guo, Junning Cao, Fangfang Lv, Wen Zhang, Lixin Qiu, Wenhua Li, Dongmei Ji, Sheng Zhang, Zuguang Xia, Jiachen Wang & Jin Li

  2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Zhiyu Chen, Weijian Guo, Junning Cao, Fangfang Lv, Wen Zhang, Lixin Qiu, Wenhua Li, Dongmei Ji, Sheng Zhang, Zuguang Xia, Jiachen Wang & Jin Li

Authors
  1. Zhiyu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Weijian Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Junning Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fangfang Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lixin Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wenhua Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dongmei Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sheng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zuguang Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jiachen Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jin Li.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 139 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, Z., Guo, W., Cao, J. et al. Endostar in combination with modified FOLFOX6 as an initial therapy in advanced colorectal cancer patients: a phase I clinical trial. Cancer Chemother Pharmacol 75, 547–557 (2015). https://doi.org/10.1007/s00280-014-2656-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-014-2656-9

Keywords

Search

Navigation