Annals of Oncology 10:339-344, 1999
© 1999 European Society for Medical Oncology
research-article |
Phase I/pharmacokinetic study of the topoisomerase I inhibitor GG211 administered as a 21-day continuous infusion
1University of Pennsylvania Cancer Center USA
2Fox Chase Cancer Center Philadelphia, PA, USA
3CRC Department of Medical Oncology, University of Glasgow Western Infirmary Hospital, Glasgow, UK
4Johns Hopkins Oncology Center Baltimore, MD
5Glaxo Wellcome Research Inc. Research Triangle Park, NC, USA
J. P. Stevenson, MD, University of Pennsylvania, Presbyterian Medical Center, 51 North 39th Street, MAB- Suite 103, Philadelphia, PA 19104, USA E-mail: jpsteven{at}mail.med.upenn.edu
Background: Preclinical results support a prolonged schedule of administration for topoisomerase I inhibitors, and we have previously demonstrated the safety and activity of the novel water-soluble topoisomerase I inhibitor GG211 when given as a 72-hour continuous infusion to cancer patients.
Patients and methods: In a three-center international phase I trial, 38 patients received GG211 doses from 0.3 to 0.5 mg/m2/day by continuous intravenous infusions for seven, 14, and 21 days. Patients' median performance status was 1; nearly half had colorectal cancer, and 35 patients had prior chemotherapy.
Results: The first patient cohort received 0.3 mg/m/day for seven days with no significant toxicities. Subsequent cohorts received continuous infusions for 14 and 21 days at this dose level with only mild myelosuppression noted. Dose-escalation on the 21-day schedule was then performed. No dose-limiting toxicity occurred at the 0.4 mg/m2/day dose level. Thrombo-cytopenia was dose-limiting with 0.5 mg/m2/day dosing but was not cumulative. Other grade 3–4 toxicities included neu-tropenia, nausea, vomiting, diarrhea, and fatigue. Partial responses occurred with 21-day infusion in two patients with breast and ovarian cancer at the 0.3 and 0.4 mg/m2/day dose levels, respectively. Mean GG211 lactone Css ranged from 0.17 to 0.64 ng/ml.
Conclusion: The maximum tolerated dose of GG211 administered as a 21-day continuous infusion is 0.4 mg/m2/day with antitumor activity noted at tolerable doses.
camptothecin analogues, GG211, continuous infusion, phase I trial, topoisomerase I inhibitors
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