Faculty Collaboration Database

Phase I clinical and pharmacokinetic trial of irofulven. Cancer Chemother Pharmacol 2001 Dec;48(6):467-72

Date

01/22/2002

Pubmed ID

11800027

DOI

10.1007/s002800100365

Scopus ID

2-s2.0-0035206258 (requires institutional sign-in at Scopus site)   16 Citations

Abstract

PURPOSE: To evaluate the clinical tolerability of a new schedule of 6-hydroxymethylacylfulvene (irofulven, MGI 114, HMAF, NSC 683863), a semisynthetic sesquiterpene derived from the cytotoxic mushroom metabolite illudin S. Irofulven has been shown to induce DNA damage and apoptosis in vitro and has shown activity in a number of human tumor xenograft models. A number of drug-resistant cell lines including those that express the mdr phenotype, retain sensitivity to irofulven.

METHODS: We conducted a phase I trial of irofulven given as an intravenous infusion (30 min) on a daily x5 schedule every 28 days. A total of ten patients were enrolled and treated at three dose levels, 6, 8, and 11 mg/m2 per day.

RESULTS: Irofulven reached steady-state concentrations during the 30-min infusions with biexponential kinetics. Irofulven disappeared rapidly from plasma and was detectable for only 15-30 min after the end of the infusion. The mean half-life was 4.91 min and the mean clearance was 4.57 l/mm per m2. Peak plasma concentrations of irofulven of approximately 300 ng/ml were achieved. Pharmacokinetic parameters did not differ significantly from day 1 to day 5. Irofulven was highly emetogenic. Other prominent toxicities included anorexia and fatigue. One case of delayed-onset metabolic acidosis possibly secondary to irofulven was observed. No other renal or metabolic toxicity was encountered. One patient experienced a late-onset grade 3 extravasation skin injury thought to be secondary to extravasation of irofulven. Minimal marrow suppression was observed. No objective tumor responses were observed.

CONCLUSIONS: The recommended phase II dose on this schedule is 6 mg/m2.

Author List

Thomas JP, Arzoomanian R, Alberti D, Feierabend C, Binger K, Tutsch KD, Steele T, Marnocha R, Smith C, Smith S, MacDonald J, Wilding G, Bailey H

Author

James P. Thomas MD, PhD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acidosis
Aged
Anorexia
Antineoplastic Agents, Alkylating
Dose-Response Relationship, Drug
Fatigue
Female
Half-Life
Humans
Infusions, Intravenous
Male
Middle Aged
Neoplasms
Sesquiterpenes
Vomiting