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.
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.
Authors: Jethro Hu; Patrick Y Wen; Lauren E Abrey; Camilo E Fadul; Jan Drappatz; Nadia Salem; Jeffrey G Supko; Fred Hochberg Journal: J Neurooncol Date: 2012-12-12 Impact factor: 4.130
Authors: Susanne M Arnold; John J Rinehart; Eleftheria Tsakalozou; John R Eckardt; Scott Z Fields; Brent J Shelton; Philip A DeSimone; Bryan K Kee; Jeffrey A Moscow; Markos Leggas Journal: Clin Cancer Res Date: 2010-01-12 Impact factor: 12.531
Authors: G Del Conte; C Sessa; R von Moos; L Viganò; T Digena; A Locatelli; E Gallerani; A Fasolo; A Tessari; R Cathomas; L Gianni Journal: Br J Cancer Date: 2014-07-15 Impact factor: 7.640