title: Phase I and pharmacokinetic study of erlotinib administered in combination with amrubicin in patients with previously treated, advanced non-small cell lung cancer.
abstract: OBJECTIVE
  We conducted a phase I trial of erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, combined with amrubicin, a topoisomerase II inhibitor. The aim was to determine the maximum tolerated dose, the dose-limiting toxicities (DLTs), and the pharmacokinetics of this combination in patients with non-small cell lung cancer who had received previous chemotherapy.
  
  
  METHODS
  A total of 9 patients with stage IV disease were treated at 3-week intervals with erlotinib once daily on days 1 through 21 plus a 5-minute intravenous injection of amrubicin on days 1 through 3.
  
  
  RESULTS
  The dose levels evaluated were erlotinib (mg/body)/amrubicin (mg/m): 100/30 (n=3), 100/35 (n=3), and 150/30 (n=3). The maximum tolerated dose of erlotinib and amrubicin was 100 mg/body and 35 mg/m because 2 of the 3 patients experienced DLTs during the first cycle of treatment at the third dose level of 150 mg/body and 30 mg/m. Cessation of erlotinib administration for 8 days because of grade 3 leukopenia and grade 3 skin infection (erysipelas) were the DLTs. No drug-drug interactions between erlotinib and amrubicin were observed in this study. The overall response rate was 33%, including 3 partial responses, in the 9 patients. The median progression-free survival for all patients was quite long, 11.3 months, and the median overall survival has not yet been reached.
  
  
  CONCLUSIONS
  Combined erlotinib plus amrubicin therapy seems to be highly effective, with acceptable toxicity, against non-small cell lung cancer. The recommended dose for phase II studies was erlotinib 100 mg once daily on days 1 through 21, and amrubicin 35 mg/m on days 1 through 3 administered every 21 days.
authors.affiliation: *Department of Respiratory Medicine, Kitasato University School of Medicine ‡Department of Clinical Physiology, Kitasato University School of Allied Health Sciences, Sagamihara, Kanagawa †Division of Integrative Omics and Bioinformatics, National Cancer Center Research Institute, Tokyo §Department of Pharmacy, Kumamoto University Hospital, Kumamoto, Japan.
authors.forename: Sakiko
authors.initials: S
authors.lastname: Otani
authors.forename: Akinobu
authors.initials: A
authors.lastname: Hamada
authors.forename: Jiichiro
authors.initials: J
authors.lastname: Sasaki
authors.forename: Mayuko
authors.initials: M
authors.lastname: Wada
authors.forename: Michiko
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Ryuge
authors.forename: Akira
authors.initials: A
authors.lastname: Takakura
authors.forename: Tomoya
authors.initials: T
authors.lastname: Fukui
authors.forename: Masanori
authors.initials: M
authors.lastname: Yokoba
authors.forename: Hisashi
authors.initials: H
authors.lastname: Mitsufuji
authors.forename: Issei
authors.initials: I
authors.lastname: Toyooka
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Maki
authors.forename: Michiko
authors.initials: M
authors.lastname: Kimura
authors.forename: Nobuatsu
authors.initials: N
authors.lastname: Hayashi
authors.forename: Mikiko
authors.initials: M
authors.lastname: Ishihara
authors.forename: Masashi
authors.initials: M
authors.lastname: Kasajima
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hiyoshi
authors.forename: Ken
authors.initials: K
authors.lastname: Katono
authors.forename: Maiko
authors.initials: M
authors.lastname: Asakuma
authors.forename: Satoshi
authors.initials: S
authors.lastname: Igawa
authors.forename: Masaru
authors.initials: M
authors.lastname: Kubota
authors.forename: Masato
authors.initials: M
authors.lastname: Katagiri
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saito
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Masuda
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D000069347:Erlotinib Hydrochloride; D004886:Erysipelas / Q000139:chemically induced; D005260:Female; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D018943:Anthracyclines; D011799:Quinazolines; C055866:amrubicin; D000069347:Erlotinib Hydrochloride