Elsevier

Annals of Oncology

Volume 18, Issue 3, March 2007, Pages 561-568
Annals of Oncology

original articles
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

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ABSTRACT

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.

Keywords

concerted dose escalation
gimatecan
oral camptothecin
pharmacokinetics
phase I

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