Phase I/pharmacokinetic study of the topoisomerase I inhibitor GG211 administered as a 21-day continuous infusion

J. P. Stevenson, D. DeMaria, J. Sludden, S. B. Kaye, L. Paz-Ares, L. B. Grochow, A. McDonald, K. Selinger, P. Wissel, P. J. O'Dwyer, C. Twelves

Research output: Contribution to journalArticle

Abstract

Background: Preclinical results support a prolonged schedule of administration for topoisomerase I inhibitors, and we have previously demonstrated the safety and activity of the novel water-soluble topoisomerase I inhibitor GG211 when given as a 72-hour continuous infusion to cancer patients. Patients and methods: In a three-center international phase I trial, 38 patients received GG211 doses from 0.3 to 0.5 mg/m2/day by continuous intravenous infusions for seven, 14, and 21 days. Patients' median performance status was 1; nearly half had colorectal cancer, and 35 patients had prior chemotherapy. Results: The first patient cohort received 0.3 mg/m2/day for seven days with no significant toxicities. Subsequent cohorts received continuous infusions for 14 and 21 days at this dose level with only mild myelosuppression noted. Dose-escalation on the 21-day schedule was then performed. No dose-limiting toxicity occurred at the 0.4 mg/m2/day dose level. Thrombocytopenia was dose-limiting with 0.5 mg/m2/day dosing but was not cumulative. Other grade 3-4 toxicities included neutropenia, nausea, vomiting, diarrhea, and fatigue. Partial responses occurred with 21-day infusion in two patients with breast and ovarian cancer at the 0.3 and 0.4 mg/m2/day dose levels, respectively. Mean GG211 lactone C(ss) ranged from 0.17 to 0.64 ng/ml. Conclusion: The maximum tolerated dose of GG211 administered as a 21-day continuous infusion is 0.4 mg/m2/day with antitumor activity noted at tolerable doses.

Original languageEnglish (US)
Pages (from-to)339-344
Number of pages6
JournalAnnals of Oncology
Volume10
Issue number3
DOIs
Publication statusPublished - 1999

    Fingerprint

Keywords

  • Camptothecin analogues
  • Continuous infusion
  • GG211
  • Phase I trial
  • Topoisomerase I inhibitors

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Stevenson, J. P., DeMaria, D., Sludden, J., Kaye, S. B., Paz-Ares, L., Grochow, L. B., ... Twelves, C. (1999). Phase I/pharmacokinetic study of the topoisomerase I inhibitor GG211 administered as a 21-day continuous infusion. Annals of Oncology, 10(3), 339-344. https://doi.org/10.1023/A:1008313011289