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

Content Provider	Semantic Scholar
Author	Baselga, José Mita, Alain C. Schöffski, Patrick Dumez, Herlinde Rojo, Federico Cuesta Tabernero, J. J. Pérez Dilea, Clifford Mietlowski, William L. Low, Christie Huang, Jerry J. Dugan, Margaret Han Parker, Kathryn Walk, Eric E. Oosterom, Allan T. Van Martinelli, Elisabetta Takimoto, Chris H. M.
Copyright Year	2012
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 (IC(50)) for EGFR in skin (0.033 μmol/L) and tumor (0.0125 μmol/L) were similar to IC(50) 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.
Starting Page	4664
Ending Page	4679
Page Count	16
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://clincancerres.aacrjournals.org/content/clincanres/early/2012/09/25/1078-0432.CCR-12-1499.full.pdf
Alternate Webpage(s)	http://clincancerres.aacrjournals.org/content/clincanres/18/22/6364.full.pdf
PubMed reference number	23014528v1
Alternate Webpage(s)	https://doi.org/10.1158/1078-0432.CCR-12-1499
DOI	10.1158/1078-0432.ccr-12-1499
Journal	Clinical cancer research : an official journal of the American Association for Cancer Research
Volume Number	18
Issue Number	22
Language	English
Access Restriction	Open
Subject Keyword	AEE 788 Adverse reaction to drug Biological Markers Blood Vessel Body tissue Bok protein, mouse Decision Making Diarrhea EGFR protein, human ERBB2 gene Estimated Evaluable Disease Exanthema Growth Factor Receptors Maximum Tolerated Dose Neoplasms Patients Pharmacodynamics Protein Tyrosine Kinase Protein-tyrosine kinase inhibitor drug development erbB-2 Receptor milligram/day solid tumor
Content Type	Text
Resource Type	Article