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Annals of Oncology 14:913-921, 2003
© 2003 European Society for Medical Oncology

Original Paper

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. Braybrooke1, E. Boven2, N. P. Bates1, R. Ruijter2, N. Dobbs1, P. D. Cheverton3, H. M. Pinedo2 and D. C. Talbot1,+

1 Cancer Research UK Medical Oncology Unit, Churchill Hospital, Oxford, UK; 2 Vrije Universiteit Medical Center, Amsterdam, De Boelelaan, Amsterdam, The Netherlands; 3 Daiichi Pharmaceuticals UK Ltd, London, UK

Received 15 November 2002; accepted 3 December 2002

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 2 l/h/m2. The area under the plasma concentration versus time curve (AUC{infty}) 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{infty} 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.

Key words: exatecan mesylate, phase I, topoisomerase inhibitor


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