title: Phase I and pharmacological study of the broad-spectrum tyrosine kinase inhibitor JNJ-26483327 in patients with advanced solid tumours.
abstract: BACKGROUND
  JNJ-26483327 is an oral, potent, multi-targeted tyrosine kinase inhibitor, inhibiting kinases of epidermal growth factor receptor (EGFR)-1, -2 and -4, rearranged during transfection (RET) receptor, vascular endothelial growth factor receptor (VEGFR)-3 and Src family (Lyn, Fyn, Yes) at low nanomolar concentrations. This phase I, accelerated titration study assessed maximum tolerated dose, safety, pharmacokinetics and pharmacodynamic effects of JNJ-26483327.
  
  
  METHODS
  Nineteen patients with advanced cancers received JNJ-26483327 continuous twice daily (BID) in escalating dose cohorts ranging from 100 to 2100 mg. Pharmacodynamic effects were assessed in paired skin biopsies and blood.
  
  
  RESULTS
  JNJ-26483327 was well tolerated in doses up to 1500 mg BID, with target-inhibition-related toxicity such as diarrhoea and skin rash, and other common reported toxicities being nausea, vomiting, anorexia and fatigue. At 2100 mg, two episodes of dose-limiting toxicity were observed, consisting of grade 3 anorexia and a combination of grade 3 anorexia and fatigue, respectively. Pharmacokinetics were dose proportional up to 1500 mg in which plasma levels were obtained showing anti-tumour activity in xenograft mouse models. Pharmacodynamic analysis did not show a substantial effect on expression of Ki-67, p27(kip1), phosphorylated mitogen-activated protein kinase, phosphorylated Akt and EGFR, and serum levels of sVEGFR-2, VEGF-C and VEGF-D remained unchanged. Stable disease was noted in six patients (32%).
  
  
  CONCLUSIONS
  JNJ-26483327 is well tolerated and shows a predictable pharmacokinetic profile; the recommended dose for further studies is 1500 mg BID.
authors.affiliation: Department of Medical Oncology, Erasmus University Medical Center, Room HE-118, P.O. Box 2040, Rotterdam 3000 CA, The Netherlands. i.konings@erasmusmc.nl
authors.forename: I R H M
authors.initials: IR
authors.lastname: Konings
authors.forename: M J A
authors.initials: MJ
authors.lastname: de Jonge
authors.forename: H
authors.initials: H
authors.lastname: Burger
authors.forename: A
authors.initials: A
authors.lastname: van der Gaast
authors.forename: L E C
authors.initials: LE
authors.lastname: van Beijsterveldt
authors.forename: H
authors.initials: H
authors.lastname: Winkler
authors.forename: J
authors.initials: J
authors.lastname: Verweij
authors.forename: Z
authors.initials: Z
authors.lastname: Yuan
authors.forename: P
authors.initials: P
authors.lastname: Hellemans
authors.forename: F A L M
authors.initials: FA
authors.lastname: Eskens
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D047028:Macrocyclic Compounds / Q000494:pharmacology*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; C553025:JNJ-26483327; D047028:Macrocyclic Compounds; D047428:Protein Kinase Inhibitors
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