Phase I dose-escalation study of vinflunine hard capsules administered twice a day for 2 consecutive days every week in patients with advanced/metastatic solid tumors.

Abstract

BACKGROUND:

Vinflunine is a new microtubule inhibitor of the vinca-alkaloid family. It is marketed in transitional cell carcinoma of urothelial tract as a 20 min infusion given every 3 weeks in Europe.

METHODS:

In this phase I study, vinflunine was administered to patients with advanced malignancies as hard capsules given twice a day on days 1-2 every week, with 3 weeks cycles. Serial blood samples were collected during the first cycle for pharmacokinetic investigations.

RESULTS:

Thirty-six patients (pts) were treated at 6 dose levels 150 (3 pts), 190 (3 pts), 230 (8 pts), 300 mg/day (6 pts) and then 250 (3 pts) and 270 mg/day (13 pts). The Maximal Tolerated Dose (MTD) was reached at 300 mg/day where 2 patients out of 6 experienced a dose limiting toxicity (febrile neutropenia with diarrhea). The lower dose level of 270 mg/day was the recommended dose (RD), the toxicity profile being mainly anaemia, neutropenia, fatigue and constipation. The pharmacokinetic analysis demonstrated the adequacy of the flat-fixed dosing regimen, as no correlation between clearance of vinflunine and body surface area was evidenced. Blood concentrations and exposure increased with dose, and a pharmacokinetic accumulation was observed, which is consistent with the terminal half-life of the compounds. The inter-individual exposure variability at the RD was 35%.

CONCLUSION:

Repeated weekly administration of oral vinflunine is feasible and exhibits a moderate inter-individual PK variability. The MTD was achieved at 300 mg/day given for 2 consecutive days. According to the protocol rules, the RD was established at 270 mg/day.

• Authors: E Calvo, J B Vermorken, S Hiret, J Rodon, J Cortes, H Senellart, J Van den Brande, J Dyck, A Pétain, P Ferre, J Bennouna
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 69 Issue 6 Pg. 1467-75 (Jun 2012) ISSN: 1432-0843 [Electronic] Germany
• PMID: 22382883 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

• Capsules
• Tubulin Modulators
• vinflunine
• Vinblastine

Topics

• Adult
• Aged
• Capsules
• Drug Administration Schedule
• Female
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Metastasis
• Neoplasms (drug therapy, pathology)
• Tubulin Modulators (administration & dosage)
• Vinblastine (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)