A Phase I Pharmacokinetic and Pharmacodynamic Study of TKI258, an Oral, Multitargeted Receptor Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors

摘要: Purpose: To determine the maximum tolerated dose (MTD) dose-limiting toxicity, and pharmacokinetic pharmacodynamic profile of TKI258 (formerly CHIR-258). Experimental Design: A phase I escalating trial in patients with advanced solid tumors was performed. Treatment initially as single daily doses on an intermittent 7-day on/7-day off schedule. Following a protocol amendment, second schedule comprised, during cycle 1, treatment followed by 14 days continuous dosing; subsequent cycles comprised 28 dosing. Pharmacokinetics evaluation phosphorylated extracellular signal-regulated kinase (ERK) peripheral blood mononuclear cells were done first each Results: Thirty-five treated four (25-100 mg/d) three (100-175 dosing cohorts. Observed drug-related toxicities nausea vomiting, fatigue, headache, anorexia, diarrhea. Dose-limiting grade 3 hypertension one patient at 100 mg dosing, anorexia 175 mg, alkaline phosphatase elevation third mg. One had partial response (melanoma) two stable disease >6 months. pharmacokinetics linear over range 25 to Five evaluable modulation ERK levels. Conclusions: The MTD defined 125 mg/d. Evidence antitumor activity melanoma gastrointestinal stromal warrants further investigation, other studies are ongoing. Further is required these evaluate biological effects TKI258.