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Phase I and Pharmacokinetic Study of Exatecan Mesylate (DX-8951f): A Novel Camptothecin Analog

From the University of Texas M.D. Anderson Cancer Center, Houston, TX; Daiichi Pharmaceutical Corporation, Montvale, NJ; Phoenix International Life Sciences, Montreal, Canada; and United States Food and Drug Administration, Rockville, MD.

Address reprint requests to Paulo M. Hoff, MD, Box 78, Section of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; email: phoff{at}mdanderson.org

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic (PK) profile, and recommended phase II dose of Exatecan mesylate (DX-8951f) when administered as a 24-hour continuous infusion every 3 weeks to patients with solid tumors.

PATIENTS AND METHODS: Twenty-two patients with advanced solid tumors, all previously treated, and with performance status 2, were entered. The starting dose of DX-8951f was 0.15 mg/m²; the dose was escalated according to the modified continual reassessment method. The drug was administered until disease progression or until unacceptable toxic effects occurred.

RESULTS: Seven dose escalations were completed, and a total of 53 courses were delivered (median, two courses; range, one to eight courses) during the study. At doses 1.2 mg/m² and lower, toxicities were mostly grade 1, primarily hematologic. In the initial cohort of three patients treated at 2.4 mg/m², grade 2 hematologic toxicity was observed. Of the six additional patients entered at 2.4 mg/m², three had grade 3 or 4 granulocytopenia. At doses higher than 2.4 mg/m², DLT granulocytopenia was observed. Nonhematologic toxicities, including nausea, vomiting, diarrhea, fatigue, and alopecia, were mild to moderate. Neither complete nor partial responses were observed, but four patients had stable disease. The PK profile of DX-8951f seemed linear at the doses administered. The plasma clearance, total volume of distribution, and terminal elimination half-life were approximately 3 L/h, 40 L, and 14 hours, respectively.

CONCLUSION: The DLT of this DX-8951f schedule was granulocytopenia for minimally pretreated patients, and both granulocytopenia and thrombocytopenia for heavily pretreated patients. The MTD for both minimally and heavily pretreated patients was 2.4 mg/m². DX-8951f seems to have a linear PK profile on the basis of single-dose administration. The recommended phase II dose with this schedule is 2.4 mg/m² for minimally pretreated patients. A lower dose should be used for heavily pretreated patients.

This article was prepared by Dr Richard Pazdur in his private capacity. No official support or endorsement by the Food and Drug Administration is intended or should be inferred.

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