title: Phase I/pharmacokinetic study of the topoisomerase I inhibitor GG211 administered as a 21-day continuous infusion.
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.
  
  
  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 Css ranged from 0.17 to 0.64 ng/ml.
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of Pennsylvania Cancer Center, Philadelphia, USA. jpsteven@mail.med.upenn.edu
authors.forename: J P
authors.initials: JP
authors.lastname: Stevenson
authors.forename: D
authors.initials: D
authors.lastname: DeMaria
authors.forename: J
authors.initials: J
authors.lastname: Sludden
authors.forename: S B
authors.initials: SB
authors.lastname: Kaye
authors.forename: L
authors.initials: L
authors.lastname: Paz-Ares
authors.forename: L B
authors.initials: LB
authors.lastname: Grochow
authors.forename: A
authors.initials: A
authors.lastname: McDonald
authors.forename: K
authors.initials: K
authors.lastname: Selinger
authors.forename: P
authors.initials: P
authors.lastname: Wissel
authors.forename: P J
authors.initials: PJ
authors.lastname: O'Dwyer
authors.forename: C
authors.initials: C
authors.lastname: Twelves
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C091719:lurtotecan; D002166:Camptothecin