title: Phase I clinical and pharmacokinetic study of pemetrexed and carboplatin in patients with malignant pleural mesothelioma.
abstract: OBJECTIVE
  To determine the maximum tolerated dose (MTD) of pemetrexed and carboplatin given in combination, to derive a recommended dose for phase II studies, and to explore its efficacy. We assessed toxicities and explored the activity of the drug combination exclusively in patients with malignant pleural mesothelioma (MPM). The pharmacokinetics of both agents was investigated.
  
  
  METHODS
  Twenty-seven patients (23 male, four female) with MPM were treated on five escalating dose levels. Doses ranged from pemetrexed 400 mg/m(2) (as a 10-minute intravenous infusion), followed by carboplatin area under the plasma concentration-time curve (AUC) 4 mg/mL.min (as a 30-minute intravenous infusion) to pemetrexed 500 mg/m(2), carboplatin AUC 6 mg/mL.min. All patients had a World Health Organization performance status of 1. A total of 163 courses of treatment were administered (median, six; range, one to 10).
  
  
  RESULTS
  The main toxicity was hematologic, particularly neutropenia, although this was characteristically short-lived and caused few clinical problems. The MTD was pemetrexed 500 mg/m(2), carboplatin AUC 6, because three of the five patients treated at this dose level experienced a dose-limiting toxicity. Eight partial responses (in 25 assessable patients) were observed for a response rate of 32%. Seventy percent of patients noticed an improvement in symptoms, usually (84%) after only two courses. Median time to progression was 305 days, and median survival time was 451 days.
  
  
  CONCLUSIONS
  The MTD was pemetrexed 500 mg/m(2) and carboplatin AUC 6 mg/mL.min. The recommended phase II dose of the combination is pemetrexed 500 mg/m(2) and carboplatin AUC 5 mg/mL.min. The combination is both active and well tolerated in MPM and deserves further exploration.
authors.affiliation: Department of Medical Oncology, Northern Centre for Cancer Treatment, Newcastle General Hospital, Westgate Road, Newcastle Upon Tyne NE4 6BE, United Kingdom. andrew.hughes@newcastle.ac.uk
authors.forename: Andy
authors.initials: A
authors.lastname: Hughes
authors.forename: Paula
authors.initials: P
authors.lastname: Calvert
authors.forename: Ashraf
authors.initials: A
authors.lastname: Azzabi
authors.forename: Ruth
authors.initials: R
authors.lastname: Plummer
authors.forename: Rob
authors.initials: R
authors.lastname: Johnson
authors.forename: Jim
authors.initials: J
authors.lastname: Rusthoven
authors.forename: Melanie
authors.initials: M
authors.lastname: Griffin
authors.forename: Kevin
authors.initials: K
authors.lastname: Fishwick
authors.forename: Alan V
authors.initials: AV
authors.lastname: Boddy
authors.forename: Mark
authors.initials: M
authors.lastname: Verrill
authors.forename: Hilary
authors.initials: H
authors.lastname: Calvert
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D019540:Area Under Curve; D016190:Carboplatin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005260:Female; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008654:Mesothelioma / Q000188:drug therapy* / Q000401:mortality; D008875:Middle Aged; D000068437:Pemetrexed; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000401:mortality; D015996:Survival Rate
chemical_list: D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D016190:Carboplatin