Using pharmacokinetic and pharmacodynamic data in early decision making regarding drug development: A phase I clinical trial evaluating tyrosine kinase inhibitor, AEE788

José Baselga, Alain C. Mita, Patrick Schöffski, Herlinde Dumez, Frederico Rojo, Josep Tabernero, Clifford DiLea, William Mietlowski, Christie Low, Jerry Huang, Margaret Dugan, Kathryn Parker, Eric Walk, Allan Van Oosterom, Erika Martinelli, Chris H. Takimoto

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12 Citations (Scopus)

Abstract

Purpose: In this first-in-human study of AEE788, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), HER-2, and 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 to 550 mg/day). 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 μmol/L) and tumor (0.0125 μmol/L) 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 of 96 evaluable patients showed 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. ©2012 AACR.
Original languageEnglish
Pages (from-to)6364-6372
JournalClinical Cancer Research
Volume18
Issue number22
DOIs
Publication statusPublished - 15 Nov 2012

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