Phase I clinical and pharmacokinetic trial of irofulven.
OBJECTIVE
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.
Thomas
J P
JP
University of Wisconsin Comprehensive Cancer Center and Department of Medicine, University of Wisconsin, Madison 53792, USA.
Arzoomanian
R
R
Alberti
D
D
Feierabend
C
C
Binger
K
K
Tutsch
K D
KD
Steele
T
T
Marnocha
R
R
Smith
C
C
Smith
S
S
MacDonald
J
J
Wilding
G
G
Bailey
H
H
D000138:Acidosis / Q000139:chemically induced; D000368:Aged; D000855:Anorexia / Q000139:chemically induced; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D014839:Vomiting / Q000139:chemically induced
D018906:Antineoplastic Agents, Alkylating; D012717:Sesquiterpenes; C102714:irofulven