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Safety, efficacy and pharmacokinetics of neratinib (HKI-272) in Japanese patients with advanced solid tumors: a Phase 1 dose-escalation study.

AbstractOBJECTIVE:
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.
AuthorsYoshinori Ito, Mitsukuni Suenaga, Kiyohiko Hatake, Shunji Takahashi, Masahiro Yokoyama, Yusuke Onozawa, Kentaro Yamazaki, Shuichi Hironaka, Kiyoshi Hashigami, Hirotaka Hasegawa, Nobuko Takenaka, Narikazu Boku
JournalJapanese journal of clinical oncology (Jpn J Clin Oncol) Vol. 42 Issue 4 Pg. 278-86 (Apr 2012) ISSN: 1465-3621 [Electronic] England
PMID22371427 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Quinolines
  • ErbB Receptors
  • neratinib
Topics
  • Adult
  • Aged
  • Antineoplastic Agents (adverse effects, pharmacokinetics, therapeutic use)
  • Asian People
  • Drug Administration Schedule
  • ErbB Receptors (antagonists & inhibitors)
  • Female
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Quinolines (adverse effects, pharmacokinetics, therapeutic use)

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