Phase I and pharmacokinetic study of fostriecin given as an intravenous bolus daily for five consecutive days.
Fostriecin (CI-920) is a potent inhibitor of protein phosphatase 2A (PP2A) and protein phosphatase 4(PP4) found to have anticancer activity in preclinical testing. A phase I study was conducted to evaluate the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetics (PK) of this drug. Forty-six patients were treated with escalating doses of fostriecin (2-47 mg/m2) administered as a daily bolus infusion for five consecutive days. PK studies were performed at different time points following administration of fostriecin. Dose-limiting toxicities included: elevation of creatinine, bilirubin, and hepatic transaminases; nausea, anorexia, lethargy, and hypotension. PK studies were compatible with a two-compartment model. Regression analysis revealed a significant relationship between dose and clearance; however, the r2 value was only 0.168 indicating a low predictive value for the model. No significant difference was seen in PK parameters with repeated dosing during the same cycle. Although no tumor responses were seen, 16 patients had stable disease with a median duration response of 2.6 months. The study was closed before reaching MTD due to problems with the supply of fostriecin from the National Cancer Institute of the United States (NCI US). New methods for synthesizing fostriecin have recently been described and therefore further development of this unique anticancer agent may be warranted.
Lê
Lyly H
LH
Princess Margaret Hospital, Toronto, ON, Canada.
Erlichman
Charles
C
Pillon
Linda
L
Thiessen
Jake J
JJ
Day
Andrew
A
Wainman
Nancy
N
Eisenhauer
Elizabeth A
EA
Moore
Malcolm J
MJ
D000328:Adult; D000368:Aged; D000475:Alkenes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D000704:Analysis of Variance; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015507:Drugs, Investigational / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D005500:Follow-Up Studies; D005767:Gastrointestinal Diseases / Q000097:blood / Q000139:chemically induced; D006801:Humans; D007275:Injections, Intravenous; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D011090:Polyenes; D011753:Pyrones
D000475:Alkenes; D015507:Drugs, Investigational; D011090:Polyenes; D011753:Pyrones; C040313:fostriecin