TY - JOUR
T1 - Phase I and pharmacokinetic study of fostriecin given as an intravenous bolus daily for five consecutive days
AU - Lê, Lyly H.
AU - Erlichman, Charles
AU - Pillon, Linda
AU - Thiessen, Jake J.
AU - Day, Andrew
AU - Wainman, Nancy
AU - Eisenhauer, Elizabeth A.
AU - Moore, Malcolm J.
N1 - Funding Information:
This study was sponsored by the Cancer Therapy Evaluation Program (CTEP) of the NCI US.
PY - 2004/4
Y1 - 2004/4
N2 - 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/m 2) 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.
AB - 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/m 2) 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.
KW - CI-920
KW - Protein phosphatase inhibitor
KW - Topoisomerase II inhibitor
UR - http://www.scopus.com/inward/record.url?scp=1442277086&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=1442277086&partnerID=8YFLogxK
U2 - 10.1023/B:DRUG.0000011792.13160.b0
DO - 10.1023/B:DRUG.0000011792.13160.b0
M3 - Article
C2 - 14739664
AN - SCOPUS:1442277086
SN - 0167-6997
VL - 22
SP - 159
EP - 167
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 2
ER -