title: Safety, efficacy and pharmacokinetics of neratinib (HKI-272) in Japanese patients with advanced solid tumors: a Phase 1 dose-escalation study.
abstract: OBJECTIVE
  Neratinib (HKI-272), a potent, irreversible, small-molecule, orally administered, pan-ErbB inhibitor that blocks signal transduction via inhibition of three epidermal growth factor receptors [ErbB1, ErbB2 (Her2) and ErbB4], is being developed for the treatment of solid tumors, including breast cancer. This Phase 1 dose-escalation study assessed the safety, tolerability, maximum-tolerated dose, antitumor activity and pharmacokinetics of neratinib in Japanese patients with advanced solid tumors.
  
  
  METHODS
  Patients received neratinib 80, 160, 240 or 320 mg orally; each patient enrolled in only one dose cohort. Patients received a single dose in week 1, followed by daily continuous doses. Blood samples collected were on days 1 and 21 for pharmacokinetic analyses.
  
  
  RESULTS
  Twenty-one patients were enrolled (3 breast cancer; 17 colorectal cancer; 1 gastric cancer). Neratinib-related adverse events (all grades) included diarrhea (20 patients), fatigue (14 patients), nausea and abdominal pain (9 patients each) and anorexia (8 patients). Grade ≥3 neratinib-related adverse events in two or more patients were diarrhea and anorexia (two patients each). Dose-limiting toxicities were diarrhea and anorexia (two patients, 320 mg dose). The maximum-tolerated dose and recommended dose was neratinib 240 mg once daily. Of 21 evaluable patients, 2 with breast cancer had partial response, 3 had stable disease ≥24 weeks, 7 had stable disease ≥16 weeks and 9 had progressive disease. Pharmacokinetic analyses indicated that neratinib exposures increased with dose.
  
  
  CONCLUSIONS
  The safety, efficacy and pharmacokinetic profiles of neratinib are consistent with those reported for non-Japanese patients and warrant further investigation of neratinib in Japanese patients with solid tumors.
authors.affiliation: Breast Cancer Division, Department of Medical Oncology, The Cancer Institute of the Japanese Foundation for Cancer Research, 3-8-31 Ariake Koto-ku, Tokyo 135-8550, Japan. yito@jfcr.or.jp
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ito
authors.forename: Mitsukuni
authors.initials: M
authors.lastname: Suenaga
authors.forename: Kiyohiko
authors.initials: K
authors.lastname: Hatake
authors.forename: Shunji
authors.initials: S
authors.lastname: Takahashi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Onozawa
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hironaka
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hashigami
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Nobuko
authors.initials: N
authors.lastname: Takenaka
authors.forename: Narikazu
authors.initials: N
authors.lastname: Boku
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D044466:Asian People; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011804:Quinolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D011804:Quinolines; D066246:ErbB Receptors; C487932:neratinib