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

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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.

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Acknowledgments

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

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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
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  2. J. M. Tourani
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  3. F. Lefresne
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  4. A. Pétain
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  5. J.-C. Pouget
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  6. A. Ravaud
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Correspondence to J. P. Delord.

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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

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

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