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

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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 22 Pg. 6364-72 (Nov 15 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 23014528 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Ki-67 Antigen
• Protein Kinase Inhibitors
• Purines
• AEE 788

Topics

• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Biomarkers, Tumor (metabolism)
• Decision Making
• Disease-Free Survival
• Dose-Response Relationship, Drug
• Humans
• Inhibitory Concentration 50
• Kaplan-Meier Estimate
• Ki-67 Antigen (metabolism)
• Maximum Tolerated Dose
• Molecular Targeted Therapy
• Neoplasms (drug therapy)
• Proportional Hazards Models
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Purines (administration & dosage, adverse effects, pharmacokinetics)
• Skin (drug effects, pathology)
• Statistics, Nonparametric
• Treatment Outcome