Cancer Chemotherapy and Pharmacology

, Volume 48, Issue 6, pp 467–472

Phase I clinical and pharmacokinetic trial of irofulven

  • James P. Thomas
  • Rhoda Arzoomanian
  • Dona Alberti
  • Chris Feierabend
  • Kimberly Binger
  • Kendra D. Tutsch
  • Thomas Steele
  • Rebecca Marnocha
  • Charlotte Smith
  • Sheri Smith
  • John MacDonald
  • George Wilding
  • Howard Bailey
Original Article

DOI: 10.1007/s002800100365

Cite this article as:
Thomas, J.P., Arzoomanian, R., Alberti, D. et al. Cancer Chemother Pharmacol (2001) 48: 467. doi:10.1007/s002800100365

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 ×5 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/min 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.

Phase I Irofulven Illudins

Copyright information

© Springer-Verlag 2001

Authors and Affiliations

  • James P. Thomas
    • 1
  • Rhoda Arzoomanian
    • 1
  • Dona Alberti
    • 1
  • Chris Feierabend
    • 1
  • Kimberly Binger
    • 1
  • Kendra D. Tutsch
    • 1
  • Thomas Steele
    • 1
  • Rebecca Marnocha
    • 1
  • Charlotte Smith
    • 2
  • Sheri Smith
    • 2
  • John MacDonald
    • 2
  • George Wilding
    • 1
  • Howard Bailey
    • 1
  1. 1.University of Wisconsin Comprehensive Cancer Center and Department of Medicine, University of Wisconsin, Madison, WI 53792, USA
  2. 2.MGI PHARMA Inc., Bloomington, MN 55438, USA
  3. 3.Correspondence address: K4/336 Clinical Science Center, 600 Highland Ave, Madison, WI 53792, USA, e-mail: hhbailey@facstaff.wisc.edu, Tel.: +1-608-2638600, Fax: +1-608-2638613