title: Phase I and pharmacologic study of 9-aminocamptothecin colloidal dispersion formulation given as a 24-hour continuous infusion weekly times four every 5 weeks.
abstract: OBJECTIVE
  9-Aminocamptothecin (9-AC) is a water-insoluble camptothecin (CMP) derivative that inhibits normal topoisomerase I function. Schedule dependency was noted, with the greatest activity seen in the setting of greater than 24 hours exposure to lactone (L) concentrations > or = 10 nmol/L. In this phase I study, 9-AC was given by a continuous intravenous infusion over 24 hours once weekly times four every 5 weeks.
  
  
  METHODS
  Twenty patients, of whom 16 had fluorouracil-refractory colorectal cancer (CRC), entered the study. Dose levels were 0.7 mg/m2 (n = 4), 1.4 mg/m2 (n = 3), 1.9 mg/m2 (n = 6), and 1.65 mg/m2 (n = 7). Detailed pharmacokinetic (PK) measurements of 9-AC L and carboxylate (C) were performed on day 1 of cycles 1 and 2.
  
  
  RESULTS
  At 1.9 mg/m2, dose-limiting toxicity (DLT) was reached, with three of six patients having grade 4 neutropenia. At 1.65 mg/m2, one of seven patients had grade 4 neutropenia. Nonhematologic toxicity was modest, with diarrhea > or = grade 3 in two patients and lethargy > or = grade 3 in eight. PK/pharmacodynamic (PD) analyses showed marked interpatient variability. Steady-state concentrations (Css) of 9-AC L > or = 10 nmol/L (3.6 microg/L) were seen in five of seven patients at 1.65 mg/m2 and five of six patients at 1.9 mg/m2. Using the sigmoidal maximal effect (Emax) model, 9-AC L area under the concentration-time curve (AUC) and Css correlated with day 15 decrease in neutrophils (R2 = .47), but not platelets.
  
  
  CONCLUSIONS
  The recommended phase II dose of 9-AC colloidal dispersion (CD) given as a 24-hour continuous infusion weekly for 4 of every 5 weeks is 1.65 mg/m2.
authors.affiliation: Department of Medicine, Princess Margaret Comprehensive Cancer Centre, Faculty of Pharmacy, University of Toronto, Ontario, Canada.
authors.forename: L L
authors.initials: LL
authors.lastname: Siu
authors.forename: A M
authors.initials: AM
authors.lastname: Oza
authors.forename: E A
authors.initials: EA
authors.lastname: Eisenhauer
authors.forename: P S
authors.initials: PS
authors.lastname: Firby
authors.forename: J J
authors.initials: JJ
authors.lastname: Thiessen
authors.forename: M
authors.initials: M
authors.lastname: Michael
authors.forename: N
authors.initials: N
authors.lastname: Wainman
authors.forename: J
authors.initials: J
authors.lastname: Manzo
authors.forename: R
authors.initials: R
authors.lastname: Feld
authors.forename: R A
authors.initials: RA
authors.lastname: Goldberg
authors.forename: M J
authors.initials: MJ
authors.lastname: Moore
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D003102:Colloids; D015179:Colorectal Neoplasms / Q000188:drug therapy; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D012044:Regression Analysis; D016879:Salvage Therapy
chemical_list: D000970:Antineoplastic Agents; D003102:Colloids; C080125:9-aminocamptothecin; D002166:Camptothecin