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Title: Phase I and pharmacologic study of PKI166, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies
Authors: Hoekstra, Ronald ×
Dumez, Herlinde
Eskens, Ferry A L M
van der Gaast, Ate
Planting, Andre S T
de Heus, Gerda
Sizer, Kurt C
Ravera, Christina
Vaidyanathan, Sujata
Bucana, Corazon
Fidler, Isaiah J
Van Oosterom, Allan
Verweij, Jaap #
Issue Date: Oct-2005
Publisher: Association for Cancer Research
Series Title: Clinical Cancer Research vol:11 issue:19 Pt 1 pages:6908-15
Abstract: PURPOSE: This phase I study was conducted to assess the tolerability, pharmacokinetics, and antitumor activity of the oral, selective epidermal growth factor receptor tyrosine kinase inhibitor PKI166 in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: PKI166 was first given once daily continuously and in the second part of the study once daily for 2 weeks every 4 weeks to establish the maximum tolerated dose (MTD). Ten additional patients were studied at MTD to acquire additional safety information and characterize the effect of food intake on PKI166 pharmacokinetics. Pharmacokinetics of PKI166 were characterized after single and multiple doses at all dose levels. RESULTS: Fifty-four patients received a total of one hundred sixteen 28-day cycles of PKI166. Dose-limiting transaminase elevations were observed in two of seven and two of eight patients using 50 and 100 mg PKI166 continuously. In the second part with PKI166 once daily for 2 weeks every 4 weeks, MTD was set at 750 mg. Dose-limiting toxicity consisted of diarrhea, skin rash, and transaminase elevations. Pharmacokinetic analysis revealed fast absorption, a linear dose-response relationship without drug accumulation after multiple doses. At MTD, no significant influence of food intake on PKI166 pharmacokinetics was observed. Stable disease for more than two cycles was observed in 11 patients. CONCLUSIONS: PKI166 given once daily for 2 weeks every 4 weeks is well tolerated with linear pharmacokinetics, compatible with once daily dosing, and without significant effect of food intake on absorption. The recommended dose for further studies is 750 mg once daily for 2 weeks every 4 weeks.
URI: 
ISSN: 1078-0432
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Experimental Oncology
Department of Oncology - miscellaneous
× corresponding author
# (joint) last author

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