title: A phase I and pharmacokinetic study of pegylated camptothecin as a 1-hour infusion every 3 weeks in patients with advanced solid malignancies.
abstract: OBJECTIVE
  To assess the feasibility of administering camptothecin (CPT), the prototypic topoisomerase I inhibitor, as polyethylene glycol (PEG)-CPT, a macromolecule consisting of CPT conjugated to chemically modified PEG. The study also sought to determine the maximum-tolerated dose (MTD) of PEG-CPT, characterize its pharmacokinetic behavior, and seek preliminary evidence of anticancer activity.
  
  
  METHODS
  Patients with advanced solid malignancies were treated with escalating doses of PEG-CPT as a 1-hour intravenous (IV) infusion every 3 weeks. A modified continual reassessment method was used for dose-level assignment to determine the MTD, which was defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%.
  
  
  RESULTS
  Thirty-seven patients were treated with 144 courses of PEG-CPT at seven dose levels ranging from 600 to 8,750 mg/m(2). Severe myelosuppression was consistently experienced by heavily pretreated (HP) and minimally pretreated (MP) patients at the highest dose level evaluated, 8,750 mg/m(2), whereas both HP and MP patients tolerated repetitive treatment at 7,000 mg/m(2). Cystitis, nausea, vomiting, and diarrhea were also observed but were rarely severe. A partial response was noted in a patient with platinum- and etoposide-resistant small-cell lung carcinoma, and minor responses were noted in one patient each with adenocarcinoma of unknown primary type and osteosarcoma. The pharmacokinetics of free CPT were dose proportional. Free CPT accumulated slowly in plasma, with maximal plasma concentrations achieved at 23 +/- 12.3 hours; the harmonic mean half-life (t(1/2)) of free CPT was long (t(1/2), 77.46 +/- 36.77 hours).
  
  
  CONCLUSIONS
  Clinically relevant doses of CPT can be delivered by administering PEG-CPT. The recommended dose for phase II studies in both MP and HP patients is 7,000 mg/m(2) as 1-hour IV every 3 weeks. The characteristics of the myelosuppressive effects of PEG-CPT, the paucity of severe nonhematologic toxicities with repetitive treatment, the preliminary antitumor activity noted, and the slow clearance of CPT enabling simulation of desirable pharmacokinetic parameters with a convenient single-dosing regimen warrant further disease-directed evaluations.
authors.affiliation: Institute for Drug Development, Cancer Therapy, and Research Center, San Antonio, TX, USA. erowinsk@saci.org
authors.forename: Eric K
authors.initials: EK
authors.lastname: Rowinsky
authors.forename: Jinee
authors.initials: J
authors.lastname: Rizzo
authors.forename: Leonel
authors.initials: L
authors.lastname: Ochoa
authors.forename: Chris H
authors.initials: CH
authors.lastname: Takimoto
authors.forename: Bahram
authors.initials: B
authors.lastname: Forouzesh
authors.forename: Garry
authors.initials: G
authors.lastname: Schwartz
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Hammond
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.forename: Joseph
authors.initials: J
authors.lastname: Kwiatek
authors.forename: Andrew
authors.initials: A
authors.lastname: Goetz
authors.forename: Louis
authors.initials: L
authors.lastname: Denis
authors.forename: Jeffrey
authors.initials: J
authors.lastname: McGuire
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D011092:Polyethylene Glycols; D002166:Camptothecin