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Stevenson JP, DeMaria D, Sludden J, Kaye SB, Paz-Ares L, Grochow LB, McDonald A, Selinger K, Wissel P, O'Dwyer PJ, Twelves C
Phase I pharmacokinetic study of the topoisomerase I inhibitor GG211 administered as a 21-day continuous infusion
Annals of Oncology (1999) 10:339-344.
Abstract
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/m(2)/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(2)/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/m(2)/day dose level. Thrombocytopenia was dose-limiting with 0.5 mg/m(2)/day dosing but was not cumulative. Other grade 3-4 toxicities included neutropenia, 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/m(2)/day dose levels, respectively. Mean GG211 lactone C-ss 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/m(2)/day with antitumor activity noted at tolerable doses.
Note
Publication Date: 1999-03-01.
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