title: 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.
abstract: OBJECTIVE
  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.
  
  
  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. 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/m(2) 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/m(2) dose level was not tolerated because of grade 4 neutropenia and renal toxicity, whereas the 14.15-mg/m(2) 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.
  
  
  CONCLUSIONS
  Given the results of this study, the recommended dose of irofulven is 10.64 mg/m(2) 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.
authors: 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, USA. gail.eckhardt@uchsc.edu
authors: S G
authors: SG
authors: Eckhardt
authors: S D
authors: SD
authors: Baker
authors: C D
authors: CD
authors: Britten
authors: M
authors: M
authors: Hidalgo
authors: L
authors: L
authors: Siu
authors: L A
authors: LA
authors: Hammond
authors: M A
authors: MA
authors: Villalona-Calero
authors: S
authors: S
authors: Felton
authors: R
authors: R
authors: Drengler
authors: J G
authors: JG
authors: Kuhn
authors: G M
authors: GM
authors: Clark
authors: S L
authors: SL
authors: Smith
authors: J R
authors: JR
authors: MacDonald
authors: C
authors: C
authors: Smith
authors: J
authors: J
authors: Moczygemba
authors: S
authors: S
authors: Weitman
authors: D D
authors: DD
authors: Von Hoff
authors: E K
authors: EK
authors: Rowinsky
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D014839:Vomiting / Q000139:chemically induced
chemical_list: D018906:Antineoplastic Agents, Alkylating; D012717:Sesquiterpenes; C102714:irofulven