Phase I pharmacokinetic study of the topoisomerase I inhibitor GG211 administered as a 21-day continuous infusion

Background: Preclinical results support a prolonged schedule of administrat ion for topoisomerase I inhibitors, and we have previously demonstrated the safety and activity of the novel water-soluble topoisomerase I inhibitor G G211 when given as a 72-hour continuous infusion to cancer patients. Patients and methods: In a three-center international phase I trial, 38 pat ients received GG211 doses from 0.3 to 0.5 mg/m(2)/day by continuous intrav enous infusions for seven, 14, and 21 days. Patients' median performance st atus was 1; nearly half had colorectal cancer, and 35 patients had prior ch emotherapy. Results. The first patient cohort received 0.3 mg/m(2)/day for seven days w ith no significant toxicities. Subsequent cohorts received continuous infus ions 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-l imiting toxicity occurred at the 0.4 mg/m(2)/day dose level. Thrombocytopen ia was dose-limiting with 0.5 mg/m(2)/day dosing but was not cumulative. Ot her grade 3-4 toxicities included neutropenia, nausea, vomiting, diarrhea, and fatigue. Partial responses occurred with 21-day infusion in two patient s 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 co ntinuous infusion is 0.4 mg/m(2)/day with antitumor activity noted at toler able doses.