A phase i dose-escalation study of edotecarin (J-107088) combined with infusional 5-fluorouracil and leucovorin in patients with advanced/metastatic solid tumors

Muhammad Wasif Saif, Sandra Sellers, Robert B. Diasio, Jean Yves Douillard

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Edotecarin (J-107088), a novel inhibitor of topoisomerase I has an additive effect on colon cell lines (HCT-116) when combined with 5-fluorouracil (5-FU). We conducted a phase I study to determine the maximum tolerated dose and recommended a phase II dose of edotecarin in combination with infusional 5-FU/leucovorin (LV) in patients with advanced solid tumors. Patients and cohorts of three to six patients were sequentially enrolled at progressively higher dose levels of edotecarin administered as a 1-h intravenous (IV) infusion every 2 weeks. The edotecarin starting dose was 6mg/m, followed by 200mg/m LV IV infusion administered over 2h, then 400mg/m bolus dose of 5-FU before the start of 2400mg/m 5-FU continuous infusion for a further 46h. Patients were evaluated for safety, pharmacokinetics, and tumor response according to the Response Evaluation Criteria in Solid Tumors criteria. Fourteen patients (10 male; four female) received a total of 90 cycles (range 3-18). Dose-limiting toxicities were observed in five of the 14 patients treated in the study. All dose-limiting toxicities were related to neutropenia. Only the 6 and 8mg/m edotecarin dose levels were explored; however, no maximum tolerated dose was declared. One confirmed complete response in a patient with hepatocellular carcinoma and seven stable disease responses were achieved in the 14 treated patients. Pharmacokinetic analysis showed that edotecarin achieved and maintained apparent steady-state plasma concentrations during the IV administration in both the cycles. The administration of edotecarin in combination with infusional 5-FU/LV once every 14 days, even without the 5-FU bolus, did not permit adequate time for recovery from neutropenia.

Original languageEnglish (US)
Pages (from-to)716-723
Number of pages8
JournalAnti-cancer drugs
Volume21
Issue number7
DOIs
StatePublished - Aug 2010

Keywords

  • J-107088
  • edotecarin
  • maximum tolerated dose
  • pharmacokinetics
  • solid tumor
  • topoisomerase I inhibitor

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Cancer Research

Fingerprint Dive into the research topics of 'A phase i dose-escalation study of edotecarin (J-107088) combined with infusional 5-fluorouracil and leucovorin in patients with advanced/metastatic solid tumors'. Together they form a unique fingerprint.

Cite this