Skip to main content

A phase I and pharmacokinetic study of liposomal vinorelbine in patients with advanced solid tumor

Summary

Purpose This phase I study was performed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of an untargeted liposomal formulation of vinorelbine (NanoVNB®) and to characterize its plasma pharmacokinetics in patients with advanced solid tumors which were refractory to conventional treatment or without an effective treatment. Patients & methods The study incorporated an accelerated titration design. Twenty-two patients with various solid tumors were enrolled. NanoVNB® was administered intravenously at doses of 2.2–23 mg/m2 once every 14 days. Pharmacokinetic endpoints were evaluated in the first cycle. The safety profiles and anti-tumor effects of NanoVNB® were also determined. Results Skin rash was the DLT and the most common non-hematological toxicity. The MTD was 18.5 mg/m2. Drug-related grade 3–4 hematological toxicities were infrequent. Compared with intravenous free vinorelbine, NanoVNB® showed a high Cmax and low plasma clearance. Of the 11 patients completing at least 1 post-treatment tumor assessment, 5 had stable disease. No responders were noted. Conclusion NanoVNB® was well tolerated and exhibited more favorable pharmacokinetic profiles than free vinorelbine. Based on dose-limiting skin toxicity, further evaluation of NanoVNB® starting from 18.5 mg/m2 as a single agent or in combination with other chemotherapeutic agents for vinorelbine-active malignancies is warranted.

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

Fig. 1

References

  1. Mangeney P, Andriamialisoa RZ, Lallemand JY, Langlois N, Langlois Y, Potier P (1979) 5′-Noranhydrovinblastine. Prototype of a new class of vinblastine derivatives. Tetrahedron 35:2175–2179

    Article  CAS  Google Scholar 

  2. Mangeney P, Andriamialisoa RZ, Langlois N, Langlois Y, Potier P (1979) A new class of antitumor compounds: 5′-nor and 5′, 6′-seco derivatives of vinblastine-type alkaloids. J Org Chem 44:3765–3768

    Article  CAS  Google Scholar 

  3. Maral R, Bourut C, Chenu E, Mathé G (1981) Experimental in vivo cross-resistance of vinca alkaloid drugs. Cancer Chemother Pharmacol 5:197–199

    PubMed  Article  CAS  Google Scholar 

  4. Maral R, Bourut C, Chenu E, Mathé G (1984) Experimental antitumor activity of 5′-nor-anhydrovinblastine navelbine. Cancer Lett 22:49–54

    PubMed  Article  CAS  Google Scholar 

  5. Depierre A, Lemarie E, Dabouis G, Garnier G, Jacoulet P, Dalphin JC (1991) A phase II study of Navelbine (vinorelbine) in the treatment of non-small-cell lung cancer. Am J Clin Oncol 14:115–119

    PubMed  Article  CAS  Google Scholar 

  6. Fumoleau P, Delgado FM, Delozier T et al (1993) Phase II trial of weekly intravenous vinorelbine in first-line advanced breast cancer chemotherapy. J Clin Oncol 11:1245–1252

    PubMed  CAS  Google Scholar 

  7. Gebbia V, Testa A, Valenza R et al (1993) A pilot study of vinorelbine on a weekly schedule in recurrent and/or metastatic squamous cell carcinoma of the head and neck. Eur J Cancer 29:1358–1359

    Article  Google Scholar 

  8. Conroy T, Etienne PL, Adenis A et al (1996) Phase II trial of vinorelbine in metastatic squamous cell esophageal carcinoma. European Organization for Research and Treatment of Cancer Gastrointestinal Treat Cancer Cooperative Group. J Clin Oncol 14:164–170

    PubMed  CAS  Google Scholar 

  9. Bajetta E, Di Leo A, Biganzoli L et al (1996) Phase II study of vinorelbine in patients with pretreated advanced ovarian cancer: activity in platinum-resistant disease. J Clin Oncol 14:2546–2551

    PubMed  CAS  Google Scholar 

  10. Lacava JA, Leone BA, Machiavelli M et al (1997) Vinorelbine as neoadjuvant chemotherapy in advanced cervical carcinoma. J Clin Oncol 15:604–609

    PubMed  CAS  Google Scholar 

  11. Nasti G, Errante D, Talamini R et al (2000) Vinorelbine is an effective and safe drug for AIDS-related Kaposi’s sarcoma: results of a phase II study. J Clin Oncol 18:1550–1557

    PubMed  CAS  Google Scholar 

  12. Sharpe M, Easthope SE, Keating GM, Lamb HM (2002) Polyethylene glycol-liposomal doxorubicin: a review of its use in the management of solid and haematological malignancies and AIDS-related Kaposi’s sarcoma. Drugs 62:2089–2126

    PubMed  Article  CAS  Google Scholar 

  13. Drummond DC, Noble CO, Guo Z et al (2009) Improved pharmacokinetics and efficacy of a highly stable nanoliposomal vinorelbine. J Pharmacol Exp Ther 328:321–330

    PubMed  Article  CAS  Google Scholar 

  14. Drummond DC, Meyer O, Hong K, Kirpotin DB, Papahadjopoulos D (1999) Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol Rev 51:691–743

    PubMed  CAS  Google Scholar 

  15. Allen TM (1997) Liposomes. Opportunities in drug delivery. Drugs 54(Suppl 4):8–14

    PubMed  Article  CAS  Google Scholar 

  16. Treat J, Greenspan A, Forst D et al (1990) Antitumor activity of liposome-encapsulated doxorubicin in advanced breast cancer: phase II study. J Natl Cancer Inst 82:1706–1710

    PubMed  Article  CAS  Google Scholar 

  17. Pestalozzi B, Schwendener R, Sauter C (1992) Phase I/II study of liposome-complexed mitoxantrone in patients with advanced breast cancer. Ann Oncol 3:445–449

    PubMed  CAS  Google Scholar 

  18. Gelmon KA, Tolcher A, Diab AR et al (1999) Phase I study of liposomal vincristine. J Clin Oncol 17:697–705

    PubMed  CAS  Google Scholar 

  19. Rosenthal DI, Yom SS, Liu L et al (2002) A phase I study of SPI-077 (Stealth liposomal cisplatin) concurrent with radiation therapy for locally advanced head and neck cancer. Invest New Drugs 20:343–349

    PubMed  Article  CAS  Google Scholar 

  20. Kehrer DF, Bos AM, Verweij J et al (2002) Phase I and pharmacologic study of liposomal lurtotecan, NX 211: urinary excretion predicts hematologic toxicity. J Clin Oncol 20:1222–1231

    PubMed  Article  CAS  Google Scholar 

  21. Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC (1997) Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst 89:1138–1147

    PubMed  Article  CAS  Google Scholar 

  22. 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

    PubMed  Article  CAS  Google Scholar 

  23. Gibaldi M, Perrier D (1982) Pharmacokinetics, 2nd edn. Dekker, New York

    Google Scholar 

  24. Torchilin VP (2005) Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov 4:145–160

    PubMed  Article  CAS  Google Scholar 

  25. Khayat D, Rixe O, Brunet R et al (2004) Pharmacokinetic linearity of i.v. vinorelbine from an intra-patient dose escalation study design. Cancer Chemother Pharmacol 54:193–205

    PubMed  Article  CAS  Google Scholar 

  26. Medical Economics Staff (2003) Physicians’ desk reference, 57th ed. Medical Economics

  27. Semple SC, Leone R, Wang J et al (2005) Optimization and characterization of a sphingomyelin/cholesterol liposome formulation of vinorelbine with promising antitumor activity. J Pharm Sci 94:1024–1038

    PubMed  Article  CAS  Google Scholar 

  28. Zhigaltsev IV, Maurer N, Akhong QF et al (2005) Liposome-encapsulated vincristine, vinblastine and vinorelbine: a comparative study of drug loading and retention. J Control Release 104:103–111

    PubMed  Article  CAS  Google Scholar 

  29. Webb MS, Johnstone S, Morris TJ et al (2007) In vitro and in vivo characterization of a combination chemotherapy formulation consisting of vinorelbine and phosphatidylserine. Eur J Pharm Biopharm 65:289–299

    PubMed  Article  CAS  Google Scholar 

  30. Liu Y, Lu WL, Guo J et al (2008) A potential target associated with both cancer and cancer stem cells: a combination therapy for eradication of breast cancer using vinorelbine stealthy liposomes plus parthenolide stealthy liposomes. J Control Release 129:18–25

    PubMed  Article  CAS  Google Scholar 

  31. Lotem M, Hubert A, Lyass O et al (2000) Skin toxic effects of polyethylene glycol-coated liposomal doxorubicin. Arch Dermatol 136:1475–1480

    PubMed  Article  CAS  Google Scholar 

  32. Gabizon A, Goren D, Horowitz AT, Tzemach D, Lossos A, Siegal T (1997) Long-circulating liposomes for drug delivery in cancer therapy: a review of biodistribution studies in tumor-bearing animals. Adv Drug Deliv Rev 24:337–344

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Taiwan Liposome Co., Ltd. (Taipei, Taiwan).

Conflict of interest statement

No financial or other potential conflicts of interest exist for any of the authors.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ruey-Long Hong.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Yang, SH., Lin, CC., Lin, ZZ. et al. A phase I and pharmacokinetic study of liposomal vinorelbine in patients with advanced solid tumor. Invest New Drugs 30, 282–289 (2012). https://doi.org/10.1007/s10637-010-9522-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-010-9522-3

Keywords

  • Cancer
  • Liposome
  • Pharmacokinetic
  • Phase I study
  • Vinorelbine