Title: Using Pharmacokinetic and Pharmacodynamic Data in Decision Making Regarding Drug Development: A Phase I Clinical Trial Evaluating Tyrosine Kinase Inhibitor, AEE788
Authors: Baselga, José ×
Mita, Alain C
Schöffski, Patrick
Dumez, Herlinde
Rojo, Frederico
Tabernero, Josep
Dilea, Clifford
Mietlowski, William
Low, Christie
Huang, Jerry
Dugan, Margaret
Parker, Kathryn
Walk, Eric
Van Oosterom, Allan
Martinelli, Erika
Takimoto, Chris H #
Issue Date: Nov-2012
Publisher: Association for Cancer Research
Series Title: Clinical Cancer Research vol:18 issue:22 pages:6364-6372
Abstract: PURPOSE: In this first-in-human study of AEE788, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), HER-2, and vascular endothelial growth factor (VEGFR-2), a comprehensive pharmacodynamic program was implemented in addition to the evaluation of safety, pharmacokinetics, and preliminary efficacy of AEE788 in cancer patients. EXPERIMENTAL DESIGN: Patients with advanced, solid tumors received escalating doses of oral AEE788 once daily. Primary endpoints were to determine dose-limiting toxicities (DLTs) and maximum-tolerated dose (MTD). A nonlinear model (Emax model) was used to describe the relationship between AEE788 exposure and target-pathway modulation in skin and tumor tissues. RESULTS: Overall, 111 patients were treated (25 mg/d-550 mg/d). DLTs included rash and diarrhea; MTD was 450 mg/day. Effects on biomarkers correlated to serum AEE788 concentrations. The concentration at 50% inhibition (IC50) for EGFR in skin (0.033 µM) and tumor (0.0125 µM) were similar to IC50 in vitro suggesting skin may be surrogate tissue for estimating tumor EGFR inhibition. No inhibition of p-MAPK and Ki67 was observed in skin vessels at ≤ MTD. Hence, AEE788 inhibited EGFR, but not VEGFR, at doses ≤ MTD. A total of 16/96 evaluable patients demonstrated a > 10% shrinkage of tumor size; one partial response was observed. CONCLUSION: Our pharmacodynamic-based study showed effective inhibition of EGFR, but not of VEGFR at tolerable AEE788 doses. Emax modeling integrated with biomarker data effectively guided real-time decision making in the early development of AEE788. Despite clinical activity, target inhibition of only EGFR led to discontinuation of further AEE788 development.
ISSN: 1078-0432
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Experimental Oncology
× corresponding author
# (joint) last author

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