title: A phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors.
abstract: OBJECTIVE
  To determine the maximum tolerated dose (MTD) dose-limiting toxicity, and pharmacokinetic and pharmacodynamic profile of TKI258 (formerly CHIR-258).
  
  
  METHODS
  A phase I dose escalating trial in patients with advanced solid tumors was performed. Treatment was initially as single daily doses on an intermittent 7-day on/7-day off schedule. Following a protocol amendment, a second schedule comprised, during cycle 1, 7-day on/7-day off treatment followed by 14 days of continuous daily dosing; subsequent cycles comprised 28 days of daily dosing. Pharmacokinetics and evaluation of phosphorylated extracellular signal-regulated kinase (ERK) in peripheral blood mononuclear cells were done during the first 28 days of each schedule.
  
  
  RESULTS
  Thirty-five patients were treated in four intermittent (25-100 mg/d) and three continuous (100-175 mg/d) dosing cohorts. Observed drug-related toxicities were nausea and vomiting, fatigue, headache, anorexia, and diarrhea. Dose-limiting toxicities were grade 3 hypertension in one patient at 100 mg continuous dosing, grade 3 anorexia in a second patient at 175 mg, and grade 3 alkaline phosphatase elevation in a third patient at 175 mg. One patient had a partial response (melanoma) and two patients had stable disease >6 months. TKI258 pharmacokinetics were linear over the dose range of 25 to 175 mg. Five of 14 evaluable patients had modulation of phosphorylated ERK levels.
  
  
  CONCLUSIONS
  The MTD was defined as 125 mg/d. Evidence of antitumor activity in melanoma and gastrointestinal stromal tumors warrants further investigation, and other phase I studies are ongoing. Further pharmacodynamic evaluation is required in these studies to evaluate the biological effects of TKI258.
authors.affiliation: Royal Marsden Hospital and Institute of Cancer Research, Sutton, United Kingdom.
authors.forename: Debashis
authors.initials: D
authors.lastname: Sarker
authors.forename: Rhoda
authors.initials: R
authors.lastname: Molife
authors.forename: T R Jeffrey
authors.initials: TR
authors.lastname: Evans
authors.forename: Maryon
authors.initials: M
authors.lastname: Hardie
authors.forename: Cheryl
authors.initials: C
authors.lastname: Marriott
authors.forename: Priska
authors.initials: P
authors.lastname: Butzberger-Zimmerli
authors.forename: Rosemary
authors.initials: R
authors.lastname: Morrison
authors.forename: Judith A
authors.initials: JA
authors.lastname: Fox
authors.forename: Carla
authors.initials: C
authors.lastname: Heise
authors.forename: Sharianne
authors.initials: S
authors.lastname: Louie
authors.forename: Natasha
authors.initials: N
authors.lastname: Aziz
authors.forename: Felix
authors.initials: F
authors.lastname: Garzon
authors.forename: Glenn
authors.initials: G
authors.lastname: Michelson
authors.forename: Ian R
authors.initials: IR
authors.lastname: Judson
authors.forename: Dalal
authors.initials: D
authors.lastname: Jadayel
authors.forename: Edgar
authors.initials: E
authors.lastname: Braendle
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D016896:Treatment Outcome
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D011505:Protein-Tyrosine Kinases