title: Phase I and pharmacologic study of irinotecan and amrubicin in advanced non-small cell lung cancer.
abstract: OBJECTIVE
  We conducted a Phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with amrubicin, a topoisomerase II inhibitor. The aim was to determine the maximum tolerated dose (MTD) of amrubicin combined with a fixed dose of CPT-11 as well as the dose-limiting toxicities (DLT) of this combination in patients with advanced non-small cell lung cancer.
  
  
  METHODS
  Eleven patients with stage IIIB or IV disease were treated at 3-week intervals with amrubicin (5-min intravenous injection on days 1-3) plus 60 mg/m2 of CPT-11 (90-min intravenous infusion on days 1 and 8). The starting dose of amrubicin was 25 mg/m2, and it was escalated in 5 mg/m2 increments until the maximum tolerated dose was reached.
  
  
  RESULTS
  The 30 mg/m2 of amrubicin dose was one dose level above the MTD, since three of the five patients experienced DLT during the first cycle of treatment at this dose level. Diarrhea and leukopenia were the DLT, while thrombocytopenia was only a moderate problem. Amrubicin did not affect the pharmacokinetics of CPT-11, SN-38 or SN-38 glucuronide. Except for one patient, the biliary index on day-1 correlated well with the percentage decrease of neutrophils in a sigmoid Emax model. There were five partial responses among 11 patients for an overall response rate of 45%.
  
  
  CONCLUSIONS
  The combination of amrubicin and CPT-11 seems to be active against non-small cell lung cancer with acceptable toxicity. The recommended dose for Phase II studies is 60 mg/m2 of CPT-11 (days 1 and 8) and 25 mg/m2 of amrubicin (days 1-3) administered every 21 days.
authors.affiliation: Department of Respiratory Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato Sagamihara, Kanagawa, 228-8555, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yanaihara
authors.forename: Masanori
authors.initials: M
authors.lastname: Yokoba
authors.forename: Sayaka
authors.initials: S
authors.lastname: Onoda
authors.forename: Michiko
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Ryuge
authors.forename: Shintaro
authors.initials: S
authors.lastname: Hagiri
authors.forename: Masato
authors.initials: M
authors.lastname: Katagiri
authors.forename: Mayuko
authors.initials: M
authors.lastname: Wada
authors.forename: Hisashi
authors.initials: H
authors.lastname: Mitsufuji
authors.forename: Masaru
authors.initials: M
authors.lastname: Kubota
authors.forename: Susumu
authors.initials: S
authors.lastname: Arai
authors.forename: Hirosuke
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Nobuo
authors.initials: N
authors.lastname: Yanase
authors.forename: Tadashi
authors.initials: T
authors.lastname: Abe
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Masuda
mesh_terms: D018943:Anthracyclines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged
chemical_list: D018943:Anthracyclines; D000077146:Irinotecan; C055866:amrubicin; D002166:Camptothecin