title: A phase I study and pharmacokinetics of irinotecan (CPT-11) and paclitaxel in patients with advanced non-small cell lung cancer.
abstract: OBJECTIVE
  To determine the maximum-tolerated dose (MTD) of irinotecan and paclitaxel in this two-drug combination, and to investigate a sequence-dependent effect in the pharmacokinetics of these drugs, we conducted a phase I study in chemo-naïve patients with advanced non-small cell lung cancer (NSCLC).
  
  
  METHODS
  Patients with stage IIIB/IV NSCLC were enrolled in this study. Both irinotecan and paclitaxel were administered on days 1 and 8, and repeated every 3 weeks. The starting dose of both drugs was 40 mg/m2 which was then alternately increased by 10 mg/m2 increments. In the first cycle, irinotecan was initially administered and followed by paclitaxel infusion, while the sequence of drug administration was reversed in the second cycle. Blood samples for pharmacokinetic analysis were obtained on day 1 of the first and second cycles.
  
  
  RESULTS
  Nine patients received a total of 12 cycles, which were evaluated for toxicity and efficacy. The main hematological toxicity was neutropenia. Grades 3 or more neutropenia was observed in 67% of cycles at dose level 2. The main non-hematological toxicities were grade 3 febrile neutropenia, supraventricular arrhythmia, and grade 2 hepatic dysfunction. The MTD of irinotecan and paclitaxel were 40 and 50 mg/m2, respectively. In the pharmacokinetic analysis, the maximum concentration of paclitaxel was elevated in a dose-dependent manner. There was a trend toward elevation of the area under the plasma concentration-time curve (AUC) of irinotecan and a decline of the AUC of paclitaxel in cycle 1 (irinotecan followed by paclitaxel), compared with those in cycle 2 (paclitaxel followed by irinotecan). Hepatic toxicity was strongly associated with the AUC of irinotecan (r = 0.894, P < 0.0001). The objective response was not observed in the nine patients.
  
  
  CONCLUSIONS
  The combination of irinotecan and paclitaxel with this schedule produced considerable toxicities without any antitumor effect for advanced NSCLC. The different schedule of administration or other combinations should be investigated.
authors.affiliation: Departmnet of Internal Medicine II, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. khotta@md.okayama-u.ac.jp
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Hotta
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ueoka
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kiura
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tabata
authors.forename: Shoichi
authors.initials: S
authors.lastname: Kuyama
authors.forename: Ken
authors.initials: K
authors.lastname: Satoh
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kozuki
authors.forename: Akiko
authors.initials: A
authors.lastname: Hisamoto
authors.forename: Shinobu
authors.initials: S
authors.lastname: Hosokawa
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fujiwara
authors.forename: Mitsune
authors.initials: M
authors.lastname: Tanimoto
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000077146:Irinotecan; D017239:Paclitaxel; D002166:Camptothecin