DX-8951f, a hexacyclic camptothecin analog, on a daily times-five schedule: A phase I and pharmacokinetic study in patients with advanced solid malignancies

Purpose: To assess the feasibility of administering DX-8951f (exatecan mesy late), ct water-soluble, camptothecin analog, as a 30-minute intravenous in fusion daily for 5 days every 3 weeks, determine the maximum-tolerated dose (MTD) and pharmacokinetic (PK) behavior of DX-8951f, and seek preliminary evidence of anticancer activity. Patients and Methods: patients with advanced solid malignancies were treate d with escalating doses of DX-8951f, After three patients were treated at t he first dose level, doses were to be escalated in increments of 100%, usin g a single patient at each dose level unless moderate toxicity was observed , The MTD, defined as the highest dose level at which the incidence of dose -limiting toxicity did not exceed 20%, was calculated separately for minima lly pretreated (MP) and heavily pretreated (HP) patients. The PK and excret ory profiles of: DX-8951, the anhydrous form of DX-8951f, were also charact erized. Results: Thirty-six patients were treated with 130 courses of DX-8951f at s ix dose levels ranging from 0.1 to 0.6 mg/m(2)/d. Brief, noncumulative neut ropenia was the most common toxicity observed. Severe myelosuppression (neu tropenia that was protracted and/or associated with fever and/or severe thr ombocytopenia) was consistently experienced by HP and MP patients at doses exceeding 0.3 and 0.5 mg/m(2)/d, respectively, Nonhematologic toxicities (n ausea, vomiting, and diarrhea) were also observed, but these effects were r arely severe. Objective antitumor activity included partial responses in on e patient each with platinum-resistant extrapulmonary small-cell and fluoro pyrimidine- and irinotecan-resistant colorectal carcinoma, and minor respon ses in patients with prostate, hepatocellular, thymic, primary peritoneal, and irinotecan-resistant colorectal carcinomas. The PKs of total DX-8951 we re linear and well fit by a three-compartment model. Conclusion: The recommended doses for phase II studies of DX-8951f as a 30- minute infusion daily for 5 days every 3 weeks are 0.5 and 0.3 mg/m2/d for MP and HP patients, respectively, The characteristics of the myelosuppressi ve effects of DX-8951f, paucity of severe nonhematologic toxicities, and an titumor activity against a wide range of malignancies warrant broad disease -directed evaluations of DX-8951f on this schedule. (C) 2000 by American So ciety of Clinical Oncology.