Phase I and pharmacokinetic study of fostriecin given as an intravenous bolus daily for five consecutive days

Lyly H. Lê, Charles Erlichman, Linda Pillon, Jake J. Thiessen, Andrew Day, Nancy Wainman, Elizabeth A. Eisenhauer, Malcolm J. Moore

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)159-167
Number of pages9
JournalInvestigational New Drugs
Volume22
Issue number2
DOIs
StatePublished - Apr 1 2004

Keywords

  • CI-920
  • Protein phosphatase inhibitor
  • Topoisomerase II inhibitor

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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