title: A phase I clinical and pharmacologic study of a carboplatin and irinotecan regimen combined with recombinant human granulocyte-colony stimulating factor in the treatment of patients with advanced nonsmall cell lung carcinoma.
abstract: BACKGROUND
  This Phase I study was designed to determine the toxicity and efficacy of a carboplatin and irinotecan (CPT-11) regimen with recombinant human granulocyte colony-stimulating factor (rhG-CSF) support for patients with advanced nonsmall cell lung carcinoma.
  
  
  METHODS
  Treatment consisted of carboplatin administered intravenously (i.v.) on Day 1 plus CPT-11 i.v. on Days 1, 8, and 15. The carboplatin dose was calculated using Calvert's formula, where the target area under the plasma concentration versus the time curve (AUC) was 5 or 6 mg x min/mL. rhG-CSF (2 microg/kg) was administered daily, except on Days 1, 8, and 15, until the leukocyte count exceeded 20,000/mm3 (10,000/mm3 after Day 16). Cycles were repeated every 4 weeks. Groups entered the trial at escalating CPT-11 and carboplatin dose levels of 60 mg/m2 and 5 mg x min/mL, 70/5 and 60/6.
  
  
  RESULTS
  Twenty-one patients were enrolled in this study, of whom 20 were assessable for toxicity and therapeutic efficacy. Two of 6 patients experienced Grade 4 diarrhea at the 70/5 dose level, suggesting that this was the maximum tolerated dose (MTD). However, the 60/6 dose level was included because toxicities were very mild at the 60/5 dose level. At the 60/6 dose level, 1 of 6 patients experienced severe, life-threatening toxicity. Therefore, subsequent dose escalation was stopped and the study terminated. There were 7 responses (35%) among the 20 patients. At the 60/6 dose level (n=5), the observed carboplatin AUC after aiming for a target AUC of 6 was 5.9+/-0.9 mg x min/mL, as expected, although the AUCs of both CPT-11 and its active metabolite, SN-38, were lower than expected.
  
  
  CONCLUSIONS
  The recommended doses for Phase II studies are 60 mg/m2 of CPT-11 and a target AUC of 5 mg x min/mL for carboplatin, plus rhG-CSF. The combination of AUC-based carboplatin and CPT-11 with rhG-CSF support appears to be an active regimen in the treatment of patients with NSCLC.
authors.affiliation: Division of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, Yokohama City, Kanagawa, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Okamoto
authors.forename: A
authors.initials: A
authors.lastname: Nagatomo
authors.forename: H
authors.initials: H
authors.lastname: Kunitoh
authors.forename: H
authors.initials: H
authors.lastname: Kunikane
authors.forename: K
authors.initials: K
authors.lastname: Watanabe
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016190:Carboplatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins
chemical_list: D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000077146:Irinotecan; D016190:Carboplatin; D002166:Camptothecin