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 Sessa, S Cresta, T Cerny, J Baselga, E Rota Caremoli, A Malossi, D Hess, J Trigo, M Zucchetti, M D'Incalci, A Zaniboni, G Capri, B Gatti, P Carminati, C Zanna, S Marsoni, L Gianni, C Sessa, S Cresta, T Cerny, J Baselga, E Rota Caremoli, A Malossi, D Hess, J Trigo, M Zucchetti, M D'Incalci, A Zaniboni, G Capri, B Gatti, P Carminati, C Zanna, S Marsoni, L Gianni
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/m(2) 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/m(2). 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 (approximately 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.
Source: PubMed