title: Phase I first-in-human study of TAK-285, a novel investigational dual HER2/EGFR inhibitor, in cancer patients.
abstract: BACKGROUND
  This phase I first-in-human study was conducted in Japanese patients to investigate the safety, pharmacokinetics (PKs), and determine the maximum tolerated dose (MTD) of oral TAK-285, a novel dual erbB protein kinase inhibitor that specifically targets human epidermal growth factor receptor (EGFR) and HER2.
  
  
  METHODS
  The TAK-285 dose was escalated until MTD was determined. A second patient cohort received TAK-285 at the MTD for at least 4 weeks.
  
  
  RESULTS
  In all, 26 patients received TAK-285 at doses ranging from 50 to 400 mg once daily (q.d.) or twice daily (b.i.d.); 20 patients made up the dose escalation cohort and the remaining 6 patients were the repeated administration cohort. TAK-285 was well tolerated. Dose-limiting toxicities noted in two patients who received 400 mg b.i.d. were grade 3 increases in aminotransferases and grade 3 decreased appetite. Consequently, the MTD was determined to be 300 mg b.i.d. Absorption of TAK-285 was rapid after oral dosing, and plasma exposure at steady-state increased in a dose-proportional fashion for doses ranging from 50 to 300 mg b.i.d. A partial response was observed for one patient with parotid cancer who received 300 mg b.i.d.
  
  
  CONCLUSIONS
  The toxicity profile and PK properties of oral TAK-285 warrant further evaluation.
authors.affiliation: Division of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. tdoi@east.ncc.go.jp
authors.forename: T
authors.initials: T
authors.lastname: Doi
authors.forename: H
authors.initials: H
authors.lastname: Takiuchi
authors.forename: A
authors.initials: A
authors.lastname: Ohtsu
authors.forename: N
authors.initials: N
authors.lastname: Fuse
authors.forename: M
authors.initials: M
authors.lastname: Goto
authors.forename: M
authors.initials: M
authors.lastname: Yoshida
authors.forename: N
authors.initials: N
authors.lastname: Dote
authors.forename: Y
authors.initials: Y
authors.lastname: Kuze
authors.forename: F
authors.initials: F
authors.lastname: Jinno
authors.forename: M
authors.initials: M
authors.lastname: Fujimoto
authors.forename: T
authors.initials: T
authors.lastname: Takubo
authors.forename: N
authors.initials: N
authors.lastname: Nakayama
authors.forename: R
authors.initials: R
authors.lastname: Tsutsumi
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D015507:Drugs, Investigational / Q000627:therapeutic use; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D006885:Hydroxybutyrates / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D015507:Drugs, Investigational; D066246:ErbB Receptors; D006885:Hydroxybutyrates; D018719:Erb-b2 Receptor Tyrosine Kinases; C570404:N-(2-(4-((3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo(3,2-d)pyrimidin-5-yl)ethyl)-3-hydroxy-3-methylbutanamide