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

Purpose: To evaluate the toxicity and pharmacologic behavior of the novel m ushroom-derived cytotoxin irofulven administered as a 5-minute intravenous (IV) infusion daily for 5 days every 4 weeks to patients with advanced soli d malignancies. Patients and Methods: In this phase I trial, 46 patients were treated with irofulven doses ranging from 1.0 to 17.69 mg/m(2) 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, ph armacokinetic studies were performed on days 1 and 5 to characterize the pl asma 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 d ysfunction. At the 14.15-mg/m(2) dose level, renal dysfunction resembling r enal tubular acidosis occurred in four of 10 patients and was ameliorated b y prophylactic IV hydration. The 17.69-mg/m(2) dose level was not tolerated because of grade 4 neutropenia and renal toxicity, whereas the 14.15-mg/m( 2) dose level wets not tolerable with repetitive dosing because of persiste nt thrombocytopenia. Other common toxicities included mild to moderate naus ea, vomiting, facial erythema, and fatigue. One partial response occurred i n a patient with advanced, refractory metastatic pancreatic cancer lasting 7 months. Pharmacokinetic studies of irofulven revealed dose-proportional i ncreases in both maximum plasma concentrations and area under the concentra tion-time curve, while the agent exhibited ct rapid elimination half-life o f 2 to 10 minutes. Conclusion: Given the results of this study, the recommended dose of iroful ven is 10.64 mg/m(2) as a 5-minute IV infusion daily for 5 days every 4 wee ks. The preliminary antitumor activity documented in a patient with advance d pancreatic cancer and the striking preclinical antitumor effects of irofu lven observed on intermittent dosing schedules support further disease-dire cted evaluations of this agent on the schedule evaluated in this study. J C lin Oncol 18:4086-4097. (C) 2000 by American Society of Clinical Oncology.