A phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors

Debashis Sarker, Rhoda Molife, T. R. Jeffrey Evans, Maryon Hardie, Cheryl Marriott, Priska Butzberger-Zimmerli, Rosemary Morrison, Judith A. Fox, Carla Heise, Sharianne Louie, Natasha Aziz, Felix Garzon, Glenn Michelson, Ian R. Judson, Dalal Jadayel, Edgar Braendle, Johann S. de Bono

Research output: Contribution to journalArticlepeer-review

138 Citations (Scopus)

Abstract

Purpose: To determine the maximum tolerated dose (MTD) dose-limiting toxicity, and pharmacokinetic and pharmacodynamic profile of TKI258 (formerly CHIR-258). Experimental Design: 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.
Original languageEnglish
Pages (from-to)2075 - 2081
Number of pages7
JournalClinical Cancer Research
Volume14
Issue number7
DOIs
Publication statusPublished - 1 Apr 2008

Fingerprint

Dive into the research topics of 'A phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors'. Together they form a unique fingerprint.

Cite this