title: Phase I and pharmacologic study of oral (PEG-1000) 9-aminocamptothecin in adult patients with solid tumors.
abstract: OBJECTIVE
  9-Amino-20(S)-camptothecin (9-AC) is a specific inhibitor of topoisomerase-I. Recently, a bioavailability of approximately 48% for the oral PEG-1000 formulation was reported. We conducted a phase I and pharmacokinetic study of the oral PEG-1000 formulation of 9-AC to define the maximum-tolerated dose, toxicity profiles, pharmacokinetic-dynamic relationships, and preliminary antitumor activity in patients with solid tumors.
  
  
  METHODS
  Patients were treated with oral (PEG-1000) 9-AC given once a day for 7 or 14 days at doses ranging from 0.25 to 1.1 mg/m(2)/d; cycles were repeated every 21 days. For pharmacokinetic analysis, plasma sampling was performed on days 1 and 6 or 8 of the first course using a validated high-performance liquid chromatographic assay.
  
  
  RESULTS
  Thirty patients were entered onto the study; three patients were not assessable for toxicity and response. Twenty-seven patients received a total of 89 courses. The dose-limiting toxicities (DLTs) were myelosuppression and diarrhea at a dose of 1.1 mg/m(2)/d for 14 days. Pharmacokinetics showed a substantial interpatient variation of the area under the plasma concentration-time curve (AUC) of 9-AC. The intrapatient variability was extremely small. A significant correlation was observed between the percentage decrease in WBC count and the AUC of 9-AC lactone (r(2) = 0.86). One partial response was noted in a patient with metastatic colorectal cancer.
  
  
  CONCLUSIONS
  DLTs in this phase I study of oral 9-AC daily for 14 days every 21 days were myelosuppression and diarrhea. The recommended dose for phase II studies is 0.84 mg/m(2)/d. In view of the substantial interpatient variability in AUC and the availability of a limited sampling model, a pharmacokinetic guided phase II study should be considered.
authors.affiliation: Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital, Rotterdam, The Netherlands. jonge@onch.azr.nl
authors.forename: M J
authors.initials: MJ
authors.lastname: de Jonge
authors.forename: C J
authors.initials: CJ
authors.lastname: Punt
authors.forename: A H
authors.initials: AH
authors.lastname: Gelderblom
authors.forename: W J
authors.initials: WJ
authors.lastname: Loos
authors.forename: V
authors.initials: V
authors.lastname: van Beurden
authors.forename: A S
authors.initials: AS
authors.lastname: Planting
authors.forename: M E
authors.initials: ME
authors.lastname: van der Burg
authors.forename: L W
authors.initials: LW
authors.lastname: van Maanen
authors.forename: B K
authors.initials: BK
authors.lastname: Dallaire
authors.forename: J
authors.initials: J
authors.lastname: Verweij
authors.forename: D J
authors.initials: DJ
authors.lastname: Wagener
authors.forename: A
authors.initials: A
authors.lastname: Sparreboom
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D016018:Least-Squares Analysis; D016013:Likelihood Functions; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D010599:Pharmacokinetics; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D000970:Antineoplastic Agents; C080125:9-aminocamptothecin; D002166:Camptothecin