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Phase I Study of Topoisomerase I Inhibitor Exatecan Mesylate (DX-8951f) Given as Weekly 24-Hour Infusions Three of Every Four Weeks

Division of Gastrointestinal Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [S. S., N. K., G. K. S., D. K., E. O., D. I., S. K., E. H., L. B. S.]; MDS Pharma Services, Montreal, Canada H4R 2N6 [M. P. D.]; and Daiichi Pharmaceutical Corporation, Montvale, New Jersey 07645 [J. C., R. L. D. J.]

Exatecan mesylate (DX-8951f) is a topoisomerase I inhibitor that has increased solubility and antitumor activity compared with other topoisomerase I inhibitors. The purpose of this study was to establish a safe dose of DX-8951f given as a weekly 24-h infusion 3 of every 4 weeks. DX-8951f was administered as a 24-h continuous infusion in escalating doses. Twenty-seven patients were treated with 81 courses of the drug. Dose-limiting toxicities included neutropenia, thrombocytopenia, and inability to administer all three doses in the first cycle. In minimally pretreated patients, a dose of 0.8 mg/m² was tolerable. In patients who were heavily pretreated, a slightly lower dose, 0.53 mg/m², was tolerated without any severe toxicities. Nonhematological toxicities were mild and consisted of mild diarrhea, asthenia, mild nausea, and constipation. Pharmacokinetic parameters could be well described with a one-compartment model in most patients, although the application of the one-compartment model probably resulted in an underestimated elimination half-life. In conclusion, the recommended Phase II dose for DX-8951f administered as a weekly 24-h infusion on a 3-of-4 week schedule is 0.8 mg/m² in minimally pretreated patients and 0.53 mg/m² in patients who are heavily pretreated.

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