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, Luca Gianni

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 0.8-7.2mg/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.

Original languageEnglish
Pages (from-to)561-568
Number of pages8
JournalAnnals of Oncology
Volume18
Issue number3
DOIs
Publication statusPublished - Mar 2007

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Camptothecin
Appointments and Schedules
Neoplasms
Asthenia
Antiemetics
Maximum Tolerated Dose
Thrombocytopenia
Nausea
Vomiting
Half-Life
ST 1481
Diarrhea
Incidence

Keywords

  • Concerted dose escalation
  • Gimatecan
  • Oral camptothecin
  • Pharmacokinetics
  • Phase I

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Concerted escalation of dose and dosing duration in a phase I study of the oral camptothecin gimatecan (ST1481) in patients with advanced solid tumors. / Sessa, C.; Cresta, S.; Cerny, T.; Baselga, J.; Rota Caremoli, E.; Malossi, A.; Hess, D.; Trigo, J.; Zucchetti, M.; D'Incalci, M.; Zaniboni, A.; Capri, G.; Gatti, B.; Carminati, P.; Zanna, C.; Marsoni, S.; Gianni, Luca.

In: Annals of Oncology, Vol. 18, No. 3, 03.2007, p. 561-568.

Research output: Contribution to journalArticle

Sessa, C, Cresta, S, Cerny, T, Baselga, J, Rota Caremoli, E, Malossi, A, Hess, D, Trigo, J, Zucchetti, M, D'Incalci, M, Zaniboni, A, Capri, G, Gatti, B, Carminati, P, Zanna, C, Marsoni, S & Gianni, L 2007, 'Concerted escalation of dose and dosing duration in a phase I study of the oral camptothecin gimatecan (ST1481) in patients with advanced solid tumors', Annals of Oncology, vol. 18, no. 3, pp. 561-568. https://doi.org/10.1093/annonc/mdl418
Sessa, C. ; Cresta, S. ; Cerny, T. ; Baselga, J. ; Rota Caremoli, E. ; Malossi, A. ; Hess, D. ; Trigo, J. ; Zucchetti, M. ; D'Incalci, M. ; Zaniboni, A. ; Capri, G. ; Gatti, B. ; Carminati, P. ; Zanna, C. ; Marsoni, S. ; Gianni, Luca. / Concerted escalation of dose and dosing duration in a phase I study of the oral camptothecin gimatecan (ST1481) in patients with advanced solid tumors. In: Annals of Oncology. 2007 ; Vol. 18, No. 3. pp. 561-568.
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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 0.8-7.2mg/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.",
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AU - Cresta, S.

AU - Cerny, T.

AU - Baselga, J.

AU - Rota Caremoli, E.

AU - Malossi, A.

AU - Hess, D.

AU - Trigo, J.

AU - Zucchetti, M.

AU - D'Incalci, M.

AU - Zaniboni, A.

AU - Capri, G.

AU - Gatti, B.

AU - Carminati, P.

AU - Zanna, C.

AU - Marsoni, S.

AU - Gianni, Luca

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N2 - 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 0.8-7.2mg/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.

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