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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

From the Institute for Drug Development, Cancer Therapy and Research Center, and Department of Medicine, Division of Oncology, University of Texas Health Science Center at San Antonio, San Antonio, TX, and MGI Pharma, Inc, Bloomington, MN.

Address reprint requests to S. Gail Eckhardt, MD, Division of Oncology, University of Colorado Health Science Center, 4200 East 9th Ave, B171, Denver, CO 80262; email:gail.eckhardt{at}uchsc.edu

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.

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