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Annals of Oncology Advance Access originally published online on December 5, 2006
Annals of Oncology 2007 18(3):561-568; doi:10.1093/annonc/mdl418
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© 2006 European Society for Medical Oncology

phase I and pharmacokinetics

Concerted escalation of dose and dosing duration in a phase I study of the oral camptothecin gimatecan (ST1481) in patients with advanced solid tumors

C Sessa1, S Cresta2, T Cerny3, J Baselga4, E Rota Caremoli2, A Malossi1, D Hess3, J Trigo4, M Zucchetti6, M D'Incalci6, A Zaniboni7, G Capri2, B Gatti5, P Carminati8, C Zanna8, S Marsoni5 and L Gianni2,*

1 Istituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland
2 Istituto Nazionale Tumori, Milan, Italy
3 Kantonsspital, St.Gallen, Switzerland
4 Hospital General Vall d'Hebron, Barcelona, Spain
5 SENDO
6 Mario Negri, Milan
7 Casa di Cura Poliambulanza, Brescia
8 Sigma Tau SpA, Rome, Italy

* Correspondence to: Dr L. Gianni, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy. E-mail: luca.gianni{at}istitutotumori.mi.it

Background: Gimatecan is an orally bioavailable camptothecin analogue with preclinical findings of promising antitumor activity. A phase I design of concerted dose escalation and dosing duration was implemented to assess the potential schedule dependency of tolerability that emerged from animal studies.

Patients and methods: Gimatecan was given daily for five consecutive days per week for 1, 2 or 3 weeks every 28 days. Plasma levels of total gimatecan were measured on the first and the last day of treatment in each schedule.

Results: Overall, 108 patients were treated with 0.8–7.2 mg/m2 of gimatecan per cycle. The main toxicity was myelosuppression with dose-limiting thrombocytopenia. In the 1-, 2- and 3-week schedule, the maximum tolerated doses were 4.5, 5.6 and 6.4 mg/m2. Diarrhea and asthenia were of low grade and of minor clinical relevance, while the higher incidence of nausea and vomiting in the 1-week schedule required the use of antiemetic prophylaxis. Due to the prolonged half-life (~77 h), the plasma concentration of gimatecan increased from the first to the last day of dosing. Six partial responses were observed.

Conclusions: Tolerability of gimatecan was schedule dependent. Further testing with schedules taking into account its long persistence in human plasma is worthwhile.

Key words: concerted dose escalation, gimatecan, oral camptothecin, pharmacokinetics, phase I

Received for publication June 13, 2006. Revision received September 4, 2006. Accepted for publication September 22, 2006.


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