A phase I clinical and pharmacokinetic study of the camptothecin glycoconjugate, BAY 38-3441, as a daily infusion in patients with advanced solid tumors
Open Access
- 1 August 2004
- journal article
- clinical trial
- Published by Elsevier BV in Annals of Oncology
- Vol. 15 (8), 1284-1294
- https://doi.org/10.1093/annonc/mdh313
Abstract
Background: The aim of this study was to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of the camptothecin glycoconjugate BAY 38-3441, administered as an infusion for 30 min on two separate schedules every 3 weeks. Patients and methods: A total of 81 patients with advanced solid tumors were treated with BAY 38-3441 either at doses of 20, 40, 67, 100, 140, 210, 315, 470 and 600 mg/m2/day for 1 day every 3 weeks (single-dose schedule), or at doses of 126, 189, 246, 320 and 416 mg/m2/day once daily for three consecutive days every 3 weeks (3-day schedule). Plasma sampling was performed to characterize the pharmacokinetics of BAY 38-3441 and camptothecin with these schedules. Results: DLTs included renal toxicity, granulocytopenia and thrombocytopenia on the single-day schedule at doses ≥470 mg/m2/day, and diarrhea and thrombocytopenia on the 3-day schedule at doses ≥320 mg/m2/day. Other non-DLTs were gastrointestinal, dermatological and hematological. Pharmacokinetics of BAY 38-3441 and camptothecin appear to be dose-dependent, but not linear. Conclusions: Renal toxicity was dose-limiting for BAY 38-3441 using 30-min infusions on the single-dose schedule. Dose escalation to 470 mg/m2/day is feasible using a 2-h infusion. However, because of the superior safety profile, we recommend the 3-day schedule for BAY 38-3441 at a dose of 320 mg/m2/day as 30-min infusions for further phase II studies.Keywords
This publication has 21 references indexed in Scilit:
- Recent advances in topoisomerase I-targeting agents, camptothecin analogues.Mini-Reviews in Medicinal Chemistry, 2002
- Cellular roles of DNA topoisomerases: a molecular perspectiveNature Reviews Molecular Cell Biology, 2002
- CamptothecinsDrugs, 2002
- Cellular, pharmacokinetic, and pharmacodynamic aspects of response to camptothecins: can we improve it?Drug Resistance Updates, 2001
- Topoisomerase I Poisons and Suppressors as Anticancer DrugsCurrent Medicinal Chemistry, 2000
- Role of the 20-Hydroxyl Group in Camptothecin Binding by the Topoisomerase I−DNA Binary ComplexBiochemistry, 1999
- Mechanism of action of eukaryotic DNA topoisomerase I and drugs targeted to the enzymeBiochimica et Biophysica Acta (BBA) - Gene Structure and Expression, 1998
- Mechanism of Action of CamptothecinAnnals of the New York Academy of Sciences, 1996
- Discrepancy between the initial DNA damage and cell survival after camptothecin treatment in two murine lymphoma L5178Y sublinesCell Biochemistry and Function, 1996
- Camptothecin cytotoxicity in mammalian cells is associated with the induction of persistent double strand breaks in replicating DNANucleic Acids Research, 1991