Original Article

Cancer Chemotherapy and Pharmacology

, Volume 48, Issue 6, pp 467-472

Phase I clinical and pharmacokinetic trial of irofulven

  • James P. ThomasAffiliated withUniversity of Wisconsin Comprehensive Cancer Center and Department of Medicine, University of Wisconsin, Madison, WI 53792, USA
  • , Rhoda ArzoomanianAffiliated withUniversity of Wisconsin Comprehensive Cancer Center and Department of Medicine, University of Wisconsin, Madison, WI 53792, USA
  • , Dona AlbertiAffiliated withUniversity of Wisconsin Comprehensive Cancer Center and Department of Medicine, University of Wisconsin, Madison, WI 53792, USA
  • , Chris FeierabendAffiliated withUniversity of Wisconsin Comprehensive Cancer Center and Department of Medicine, University of Wisconsin, Madison, WI 53792, USA
  • , Kimberly BingerAffiliated withUniversity of Wisconsin Comprehensive Cancer Center and Department of Medicine, University of Wisconsin, Madison, WI 53792, USA
  • , Kendra D. TutschAffiliated withUniversity of Wisconsin Comprehensive Cancer Center and Department of Medicine, University of Wisconsin, Madison, WI 53792, USA
  • , Thomas SteeleAffiliated withUniversity of Wisconsin Comprehensive Cancer Center and Department of Medicine, University of Wisconsin, Madison, WI 53792, USA
  • , Rebecca MarnochaAffiliated withUniversity of Wisconsin Comprehensive Cancer Center and Department of Medicine, University of Wisconsin, Madison, WI 53792, USA
  • , Charlotte SmithAffiliated withMGI PHARMA Inc., Bloomington, MN 55438, USA
    • , Sheri SmithAffiliated withMGI PHARMA Inc., Bloomington, MN 55438, USA
    • , John MacDonaldAffiliated withMGI PHARMA Inc., Bloomington, MN 55438, USA
    • , George WildingAffiliated withUniversity of Wisconsin Comprehensive Cancer Center and Department of Medicine, University of Wisconsin, Madison, WI 53792, USA
    • , Howard BaileyAffiliated withUniversity of Wisconsin Comprehensive Cancer Center and Department of Medicine, University of Wisconsin, Madison, WI 53792, USA

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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