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Clinical and pharmacological phase I study with accelerated titration design of a daily times five schedule of BBR3464, a novel cationic triplatinum complex

Sessa, C. ; Capri, G. ; Gianni, L. ; Peccatori, F. ; Grasselli, G. ; Bauer, J. ; Zucchetti, M. ; Viganò, L. ; Gatti, A. ; Minoia, C. ; Liati, P. ; Van den Bosch, S. ; Bernareggi, A. ; Camboni, G. ; Marsoni, S.

In: Annals of Oncology, 2000, vol. 11, no. 8, p. 977-983

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    Titel
    • Clinical and pharmacological phase I study with accelerated titration design of a daily times five schedule of BBR3464, a novel cationic triplatinum complex
    Autor
    • Sessa, C.. Istituto Oncologico della Svizzera Italiana Bellinzona, Switzerland
    • Capri, G.. Division of Oncology, Istituto Nazionale dei Tumori Milan
    • Gianni, L.. Division of Oncology, Istituto Nazionale dei Tumori Milan
    • Peccatori, F.. Division of Medical Oncology A. Istituto Europeo di Oncologia Milan
    • Grasselli, G.. Division of Oncology, Istituto Nazionale dei Tumori Milan
    • Bauer, J.. Centre Pluridisciplinaire d'Oncologie, CHUV Lausanne, Switzerland
    • Zucchetti, M.. Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri Milan
    • Viganò, L.. South European New Drug Development Orgamzation (SENDO) Milan, Italy
    • Gatti, A.. Fondazione Maugeri Pavia
    • Minoia, C.. Fondazione Maugeri Pavia
    • Liati, P.. South European New Drug Development Orgamzation (SENDO) Milan, Italy
    • Van den Bosch, S.. Istituto Oncologico della Svizzera Italiana Bellinzona, Switzerland
    • Bernareggi, A.. Novuspharma Monza
    • Camboni, G.. Novuspharma Monza
    • Marsoni, S.. South European New Drug Development Orgamzation (SENDO) Milan, Italy
    Dokumententyp
    • Postprint
    Sprache
    • Englisch
    Veröffentlicht in
    • Annals of Oncology, 2000, vol. 11, no. 8, p. 977-983. Oxford University Press
    Andere elektronische Ausgabe
    OAI-PMH-ID
    • oai:doc.rero.ch:290548
    Summary
    Objectives To define the maximum tolerated dose (MTD), the toxicity and pharmacokinetic profile of BBR3464, a novel triplatinum complex. Patients and methods Fourteen patients with advanced solid tumors not responsive to previous antitumor treatments received BBR 3464 on a daily × 5 schedule every twenty-eighth day. The drug was given as a one-hour infusion with pre-and post-treatment hydration (500 ml in one hour) and no antiemetic prophylaxis. The starting dose was 0.03 mg/m2/day. A modified accelerated titration escalation design was used. Total and free platinum (Pt) concentrations in plasma and urine were assessed by ICP-MS on days 1 and 5 of the first cycle. Results Dose was escalated four times up to 0.17 mg/m2/ day. Short-lasting neutropenia and diarrhea of late onset were dose-limiting and defined the MTD at 0.12 mg/m2 Nausea and vomiting were rare, neither neuro- nor renal toxic effects were observed. BBR3464 showed a rapid distribution phase of 1 hour and a terminal half-life of several days. At 0.17 mg/m2 plasma Cmax and AUC on day 5 were higher than on day 1, indicating drug accumulation. Approximately 10% of the equivalent dose of BBR3464 (2.2%-13.4%) was recovered in a 24-hour urine collection. Conclusions The higher than expected incidence of neutropenia and GI toxicity might be related to the prolonged half-life and accumulation of total and free Pt after daily administrations. Lack of nephrotoxicity and the low urinary excretion support the use of the drug without hydration. The single intermittent schedule has been selected for clinical development