title: A phase I, pharmacokinetic and pharmacodynamic study of nimotuzumab in Japanese patients with advanced solid tumors.
abstract: OBJECTIVE
  Nimotuzumab is a humanized IgG₁ monoclonal antibody to the epidermal growth factor receptor (EGFR) and has demonstrated the absence of severe dermatological toxicity commonly caused by other EGFR-targeting antibodies. We conducted a phase I study to assess toxicities, pharmacokinetics, pharmacodynamics, and predictive biomarkers of nimotuzumab administered in Japanese patients with advanced solid tumors.
  
  
  METHODS
  Three dose levels, 100, 200, and 400 mg, of weekly i.v. nimotuzumab were given until disease progression or drug intolerability. Four patients with solid tumors were enrolled in each dose level. The expression and gene copy number of EGFR or its downstream transducers were investigated using skin biopsy samples and tumor specimens.
  
  
  RESULTS
  Planned dose escalation was completed without dose-limiting toxicity, and maximum tolerated dose was not reached. No allergic reaction and hypomagnesaemia were observed, and grade 3 or 4 toxicity did not occur. The common toxicity was skin rash (58 %); however, all of them were grade 1 or 2. In skin biopsies, no correlation was shown between doses and the phosphorylation of EGFR or its downstream signal transducers. Of 11 evaluable patients, no objective response was obtained, while 8 patients had stable disease (73 %). Patients with a higher-EGFR gene copy number level measured by FISH showed a longer time to progression.
  
  
  CONCLUSIONS
  Nimotuzumab administered weekly was feasible and well tolerated up to 400 mg in Japanese patients. A low dermatological toxicity could be a notable advantage as anti-EGFR mAb, and further evaluation is warranted.
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan, wataru_okamoto@dotd.med.kindai.ac.jp.
authors.forename: Wataru
authors.initials: W
authors.lastname: Okamoto
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshino
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Takahashi
authors.forename: Isamu
authors.initials: I
authors.lastname: Okamoto
authors.forename: Shinya
authors.initials: S
authors.lastname: Ueda
authors.forename: Asuka
authors.initials: A
authors.lastname: Tsuya
authors.forename: Narikazu
authors.initials: N
authors.lastname: Boku
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fukuoka
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D003875:Drug Eruptions / Q000453:epidemiology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D018628:Gene Dosage; D006801:Humans; D015994:Incidence; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D015415:Biomarkers; D009363:Neoplasm Proteins; C501466:nimotuzumab; D066246:ErbB Receptors