A phase II study of intravenous exatecan mesylate (DX-8951f) administered daily for 5 days every 3 weeks to patients with advanced ovarian, tubal or peritoneal cancer resistant to platinum, taxane and topotecan

Background: DX-8951f is a water-soluble camptothecin derivative with greater in vivo and in vitro activity than topotecan or irinotecan. The objectives of this phase II study were to determine the antitumor activity, safety and pharmacokinetic profile of DX-8951f administered intravenously for five consecutive days, every 3 weeks in patients with advanced ovarian, tubal and peritoneal cancer resistant to platinum, taxane and topotecan. Methods: Enrolled in the study at The University of Texas M. D. Anderson Cancer Center were 16 patients with measurable cancer resistant to platinum, taxane and topotecan. All 16 patients were assessable for safety and 15 for efficacy analyses. Treatment consisted of a daily infusion of DX-8951f at 0.3 mg/m ² per day (except for one minimally pretreated patient who started at 0.5 mg/m² per day) over 30 min for five consecutive days every 3 weeks. The pharmacokinetic and excretory profiles of DX-8951, the anhydrous form of DX-8951f, were also characterized. Results: Disease was stable in 7 of 16 patients (44%) (4 minor response and 3 stable disease). The median time to tumor progression was 43 days (95% CI 37-92 days). The median overall survival was 117 days (95% CI 90-279 days). The main toxic effect was neutropenia and leukopenia with 50% of patients experiencing grade 3 or 4 neutropenia and leukopenia. One episode of neutropenic fever was observed. Grade 3 or more anemia and thrombocytopenia were seen in 25% and 13% of patients, respectively. Grade 3 nonhematologic side effects included nausea (25% of patients) and fatigue (19%). Other side effects were not more than grade 2, and included gastrointestinal dysfunction, stomatitis, dermatitis, alopecia, liver dysfunction and drug fever. DX-8951 displayed linear pharmacokinetic characteristics at the doses administered. The average plasma clearance, total volume of distribution, and terminal elimination half-life were 2.11/ h per m², 20 1/m² and 9.5 h, respectively. Conclusions: DX-8951f administered parenterally as a single agent daily at a dose of either 0.5 or 0.3 mg/m² per day for 5 days is feasible in patients with advanced ovarian, tubal and peritoneal cancer resistant to platinum, taxane and topotecan. Although no responses were observed, a significant number of patients had stable disease with a decrease in CA-125 levels. In this heavily pretreated population, DX-8951f has clinically relevant hematologic and gastrointestinal toxicities in about 25% of patients. DX-8951 appeared to have linear pharmacokinetic characteristics on the basis of multiple administrations.