Phase I and pharmacokinetic study of the topoisomerase I inhibitor, exatecan mesylate (DX-8951f), using a weekly 30-minute intravenous infusion, in patients with advanced solid malignancies

J. P. Braybrooke, E. Boven, N. P. Bates, R. Ruijter, N. Dobbs, P. D. Cheverton, H. M. Pinedo, Denis C. Talbot

Research output: Contribution to journalArticlepeer-review

Abstract

Background: The topoisomerase I inhibitor exatecan mesylate (DX-8951f) is a water-soluble hexacyclic analogue of camptothecin that does not require enzymatic activation. This study determined the toxicity, maximum tolerated dose (MTD), pharmacokinetics and pharmacodynamics of a weekly intravenous (i.v.) schedule of DX-8951f. Patients and methods: Thirty-five patients with advanced solid malignancies, stratified as minimally (MP) or heavily (HP) pre-treated, received escalating doses of DX-8951f as 30-min i.v. infusions for three out of every 4 weeks. Pharmacokinetics were described after the first infusion of DX-8951f. Results: Infusions (244) of DX-8951f were administered with a median of two cycles (range 1-10). The main toxicity observed was haematological. There was no significant gastrointestinal toxicity. Two patients (6%) had confirmed partial responses. Twelve patients (39%) had stable disease. DX-8951f had a terminal elimination half-life of -8 h and a clearance of 21/h/m2. The area under the plasma concentration versus time curve (AUC) and the maximum plasma concentration (Cmax) increased linearly with the dose. A linear relationship was present for the percentage decrease in neutrophil counts or platelet counts and AUC as well as Cmax. Conclusions: The dose-limiting toxicity of DX-8951f is neutropenia for MP patients and neutropenia and thrombocytopenia for HP patients. Evidence for clinical activity was seen, suggesting phase II study of the drug is indicated. Using this schedule the recommended dose is 2.75 mg/m2/week for MP patients and 2.10 mg/m2/week for HP patients.

Original languageEnglish (US)
Pages (from-to)913-921
Number of pages9
JournalAnnals of Oncology
Volume14
Issue number6
DOIs
StatePublished - Jun 1 2003
Externally publishedYes

Keywords

  • Exatecan mesylate
  • Phase I
  • Topoisomerase inhibitor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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