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

Eric K. Rowinsky, Thomas R. Johnson, Charles E. Geyer C.E., Lisa A. Hammond, Gail G. Eckhardt, Ronald Drengler, Leslie Smetzer, John Coyle, Jinee Rizzo, Garry Schwartz, Anthony Tolcher, Daniel D. Von Hoff, Robert L. De Jager

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44 Scopus citations


Purpose: To assess the feasibility of administering DX-8951f (exatecan mesylate), a water-soluble, camptothecin analog, as a 30-minute intravenous infusion daily far 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 treated with escalating doses of DX-8951f. After three patients were treated at the first dose level, doses were to be escalated in increments of 100%, using 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 nat exceed 20%, was calculated separately for minimally, pretreated (MP) and heavily pretreated (HP) patients. The PK and excretory profiles of DX-8951, the anhydrous form of DX-8951f, were also characterized. Results: Thirty-six patients were treated with 130 courses of DX-8951f at six dose levels ranging from 0.1 to 0.6 mg/m2/d. Brief, noncumulative neutropenia was the most common toxicity observed. Severe myelosuppression (neutropenia that was protracted and/or associated with fever and/or severe thrombocytopenia) was consistently experienced by HP and MP patients at doses exceeding 0.3 and 0.5 mg/m2/d, respectively. Nonhematologic toxicities (nausea, vomiting, and diarrhea) were also observed, but these effects were rarely severe. Objective antitumor activity included partial responses in one patient each with platinum-resistant extrapulmonary small-cell and fluoropyrimidine- and irinotecan-resistant colorectal carcinoma, and minor responses in patients with prostate, hepatocellular, thymic, primary peritoneal, and irinotecan-resistant colorectal carcinomas. The PKs of total DX-8951 were 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 far 5 days every 3 weeks are 0.5 and 0.3 mg/m2/d far MP and HP patients, respectively. The characteristics of the myelosuppressive effects of DX-8951f, paucity of severe nonhematologic toxicities, and antitumor activity against a wide range of malignancies warrant broad disease-directed evaluations of DX-8951f on this schedule. (C) 2000 by American Society of Clinical Oncology.

Original languageEnglish (US)
Pages (from-to)3151-3163
Number of pages13
JournalJournal of Clinical Oncology
Issue number17
StatePublished - 2000

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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