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.
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.
Eckhardt
S G
SG
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
Baker
S D
SD
Britten
C D
CD
Hidalgo
M
M
Siu
L
L
Hammond
L A
LA
Villalona-Calero
M A
MA
Felton
S
S
Drengler
R
R
Kuhn
J G
JG
Clark
G M
GM
Smith
S L
SL
MacDonald
J R
JR
Smith
C
C
Moczygemba
J
J
Weitman
S
S
Von Hoff
D D
DD
Rowinsky
E K
EK
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
D018906:Antineoplastic Agents, Alkylating; D012717:Sesquiterpenes; C102714:irofulven