Skip to main content

Advertisement

Springer Nature Link
Log in

Phase I dose-escalation study of oral vinflunine administered once daily for 6 weeks every 8 weeks in patients with advanced/metastatic solid tumours

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

Abstract

Purpose

Vinflunine ditartrate is a microtubule inhibitor belonging to the vinca alkaloid family. This phase I study was carried out to evaluate the maximal tolerated dose, the safety profile, the pharmacokinetics and the activity of oral vinflunine (VFL) given daily in patients with advanced/metastatic solid tumours and who have failed standard therapy.

Methods

Patients were treated with oral VFL administered once daily for 6 weeks followed by a two-week rest. Sequential dose-escalating cohorts of patients were enrolled into 5 dose levels: 20, 40, 60, 75 and 95 mg/day.

Results

In total, 27 patients received 53 cycles. Dose-limiting toxicities (DLT) were observed from 60 mg/day. The dose levels 75 and 95 mg/day were both assessed as maximal tolerated dose. The most frequent dose-limiting toxicities were of haematological origin. The recommended dose was defined as 60 mg/day, dose at which 4 patients experienced long stabilizations (≥4 months) and also received longer treatment duration in comparison with the other dose levels. Blood exposure of VFL and its active metabolite 4-O-deacetyl vinflunine (DVFL) increased proportionally to the dose levels. The concentrations of VFL and DVFL reached a steady state at, respectively, 5 and 20 days and remained stable for the rest of the cycle. Increased incidence of DLT/SAE was consistent with the increase of VFL dose and drug exposure.

Conclusions

These results showed the feasibility of daily oral vinflunine administration on a 6-week treatment duration. This new schedule of administrations enabled sustained and stable blood concentrations of both VFL and DVFL. The recommended dose was defined at 60 mg/day, dose at which 4 patients experienced clinical benefit.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

References

  1. Bennouna J, Campone M, Delord JP, Pinel MC (2005) Vinflunine: a novel antitubulin agent in solid malignancies. Expert Opin Investig Drugs 14(10):1259–1267

    Article  PubMed  CAS  Google Scholar 

  2. Bennouna J, Delord JP, Campone M (2008) Vinflunine: a new microtubule inhibitor agent. Clin Cancer Res 14(6):1625–1632

    Article  PubMed  CAS  Google Scholar 

  3. Kruczynski A, Barret JM, Etievant C, Colpaert F, Fahy J, Hill BT (1998) Antimitotic and tubulin-interacting properties of vinflunine, a novel fluorinated Vinca alkaloid. Biochem Pharmacol 55(5):635–648

    Article  PubMed  CAS  Google Scholar 

  4. Bellmunt J, Theodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G et al (2009) Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol 27(27):4454–4461

    Article  PubMed  CAS  Google Scholar 

  5. Delord JP, Bennouna J, Favreau E, Brandely M, Puozzo C (2007) Absolute bioavailability of an oral form of vinflunine, a first phase I trial. AACR Meeting Abstracts 2007; (3_Molecular_Targets_Meeting):C145

  6. Nguyen L, Petain A., Puozzo C (2009) Validation of neutropenia PK/PD model built from intravenous vinflunine and its application to design phase I trials with oral vinflunine. Abstracts of the Annual Meeting of the Population Approach Group in Europe 2009:18

  7. Pasquier E, Kavallaris M, Andre N (2010) Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol 7(8):455–465

    Article  PubMed  Google Scholar 

  8. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L 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(3):205–216

    Article  PubMed  CAS  Google Scholar 

  9. Vermorken JB, Stupp R, Nguyen L (2003) Phase I study of IV vinflunine given on a weekly schedule in previously untreated patients with advanced solid tumours. Proc Am Soc Clin Oncol 22:221 (Abstract 887) 2003

    Google Scholar 

  10. Zorza G, Van Heugen JC, De Graeve J, Puozzo C (2007) Development of a sensitive liquid chromatography method coupled with a tandem mass spectrometric detection for the clinical analysis of vinflunine and 4-O-deacetyl vinflunine in blood, urine and faeces. J Chromatogr B 853:294–302

    Article  CAS  Google Scholar 

  11. Krzakowski M, Ramlau R, Jassem J, Szczesna A, Zatloukal P, Von Pawel J et al (2010) Phase III trial comparing vinflunine with docetaxel in second-line advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy. J Clin Oncol 28(13):2167–2173

    Article  PubMed  CAS  Google Scholar 

  12. Bennouna J, Fumoleau P, Armand JP, Raymond E, Campone M, Delgado FM et al (2003) Phase I and pharmacokinetic study of the new vinca alkaloid vinflunine administered as a 10-min infusion every 3 weeks in patients with advanced solid tumours. Ann Oncol 14(4):630–637

    Article  PubMed  CAS  Google Scholar 

  13. Kerbel RS, Kamen BA (2004) The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 4(6):423–436

    Article  PubMed  CAS  Google Scholar 

  14. Pourroy B, Honore S, Pasquier E, Bourgarel-Rey V, Kruczynski A, Briand C et al (2006) Antiangiogenic concentrations of vinflunine increase the interphase microtubule dynamics and decrease the motility of endothelial cells. Cancer Res 66(6):3256–3263

    Article  PubMed  CAS  Google Scholar 

  15. Kruczynski A, Poli M, Dossi R, Chazottes E, Berrichon G, Ricome C et al (2006) Anti-angiogenic, vascular-disrupting and anti-metastatic activities of vinflunine, the latest vinca alkaloid in clinical development. Eur J Cancer 42(16):2821–2832

    Article  PubMed  CAS  Google Scholar 

  16. Briasoulis E, Pappas P, Puozzo C, Tolis C, Fountzilas G, Dafni U et al (2009) Dose-ranging study of metronomic oral vinorelbine in patients with advanced refractory cancer. Clin Cancer Res 15(20):6454–6461

    Article  PubMed  CAS  Google Scholar 

  17. Addeo R, Sgambato A, Cennamo G, Montella L, Faiola V, Abbruzzese A et al (2010) Low-dose metronomic oral administration of vinorelbine in the first-line treatment of elderly patients with metastatic breast cancer. Clin Breast Cancer 10(4):301–306

    Article  PubMed  CAS  Google Scholar 

  18. Sessa C, Guibal A, Del Conte G, Ruegg C (2008) Biomarkers of angiogenesis for the development of antiangiogenic therapies in oncology: tools or decorations? Nat Clin Pract Oncol 5(7):378–391

    Article  PubMed  CAS  Google Scholar 

  19. Jain RK, Duda DG, Willett CG, Sahani DV, Zhu AX, Loeffler JS et al (2009) Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol 6(6):327–338

    Article  PubMed  CAS  Google Scholar 

  20. Maraveyas A, Lam T, Hetherington JW, Greenman J (2005) Can a rational design for metronomic chemotherapy dosing be devised? Br J Cancer 92(8):1588–1590

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study has been sponsored by Institut de Recherche Pierre Fabre.

Author information

Authors and Affiliations

  1. Institut Claudius Regaud, 20-24 rue du Pont Saint-Pierre, 31052, Toulouse Cedex, France

    J. P. Delord

  2. Hôpital Saint-André, CHU Bordeaux, Bordeaux, France

    A. Ravaud

  3. CHU de Poitiers, Université de Poitiers, Poitiers, France

    J. M. Tourani

  4. Institut de Recherche Pierre Fabre, Boulogne Billancourt, France

    F. Lefresne, A. Pétain & J.-C. Pouget

Authors
  1. J. P. Delord
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. J. M. Tourani
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. F. Lefresne
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. A. Pétain
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. J.-C. Pouget
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. A. Ravaud
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to J. P. Delord.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Delord, J.P., Tourani, J.M., Lefresne, F. et al. Phase I dose-escalation study of oral vinflunine administered once daily for 6 weeks every 8 weeks in patients with advanced/metastatic solid tumours. Cancer Chemother Pharmacol 71, 647–656 (2013). https://doi.org/10.1007/s00280-012-2051-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-012-2051-3

Keywords