Phase I and pharmacokinetic study of irofulven, a novel mushroom-derived cytotoxin, administered for five consecutive days every four weeks in patients with advanced solid malignancies

S. G. Eckhardt, S. D. Baker, C. D. Britten, M. Hidalgo, L. Siu, L. A. Hammond, M. A. Villalona-Calero, S. Felton, R. Drengler, J. G. Kuhn, G. M. Clark, S. L. Smith, J. R. MacDonald, C. Smith, J. Moczygemba, S. Weitman, D. D. Von Hoff, E. K. Rowinsky

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Purpose: To evaluate the toxicity and pharmacologic behavior of the novel mushroom-derived cytotoxin irofulven administered as a 5-minute intravenous (IV) infusion daily for 5 days every 4 weeks to patients with advanced solid malignancies. Patients and Methods: In this phase I trial, 46 patients were treated with irofulven doses ranging from 1.0 to 17.69 mg/m2 as a 5-minute IV infusion (two patients received a 1-hour infusion) daily for 5 days every 4 weeks. The modified continual reassessment method was used for dose escalation. Pharmacokinetic studies were performed on days 1 and 5 to characterize the plasma disposition of irofulven. Results: Forty-six patients were treated with 92 courses of irofulven. The dose-limiting toxicities on this schedule were myelosuppression and renal dysfunction. At the 14.15-mg/m2 dose level, renal dysfunction resembling renal tubular acidosis occurred in four of 10 patients and was ameliorated by prophylactic IV hydration. The 17.69-mg/m2 dose level was not tolerated because of grade 4 neutropenia and renal toxicity, whereas the 14.15-mg/m2 dose level was not tolerable with repetitive dosing because of persistent thrombocytopenia. Other common toxicities included mild to moderate nausea, vomiting, facial erythema, and fatigue. One partial response occurred in a patient with advanced, refractory metastatic pancreatic cancer lasting 7 months. Pharmacokinetic studies of irofulven revealed dose-proportional increases in both maximum plasma concentrations and area under the concentration-time curve, while the agent exhibited a rapid elimination half-life of 2 to 10 minutes. Conclusion: Given the results of this study, the recommended dose of irofulven is 10.64 mg/m2 as a 5-minute IV infusion daily for 5 days every 4 weeks. The preliminary antitumor activity documented in a patient with advanced pancreatic cancer and the striking preclinical antitumor effects of irofulven observed on intermittent dosing schedules support further disease-directed evaluations of this agent on the schedule evaluated in this study.

Original languageEnglish (US)
Pages (from-to)4086-4097
Number of pages12
JournalJournal of Clinical Oncology
Volume18
Issue number24
DOIs
StatePublished - Dec 15 2000

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Phase I and pharmacokinetic study of irofulven, a novel mushroom-derived cytotoxin, administered for five consecutive days every four weeks in patients with advanced solid malignancies'. Together they form a unique fingerprint.

Cite this