Phase I study of AEE788, a novel multitargeted inhibitor of ErbB and VEGF receptor family tyrosine kinases: A pharmacokinetic (PK)-pharmacodynamic (PD) study to identify the optimal therapeutic dose regimen

Abstract

3028 Background: AEE788 is an orally active, small-molecule, multitargeted kinase inhibitor with potent inhibitory activity against multiple tyrosine kinases, including EGFR, HER2, and VEGFR2. This phase I study is being conducted to assess its safety, PK, PD, maximum tolerated dose, and optimal biologic dose in pts with advanced solid tumors. Methods: AEE788 was given PO at 25, 50, 100, 150, 225, 300, 400, 450, 500, and 550 mg/day in 28-day cycles to 3–6 pt cohorts. 24-hr PK profiles were performed on days 1, 15, 28. PK parameters of AEE788 and AQM674 (active metabolite) were computed by model-independent methods. PD markers were analyzed in skin (SK), wound and tumor (TU) biopsies pre- and post-treatment. Emax models were used to characterize concentration-effect relationships. % change in PD markers (%dE=100*1-Et/Eo) were computed, Eo and Et are pre- and post-treatment. Emax and IC50 were estimated by non-linear least squares regression, and doses corresponding to 80% Emax were computed. Results: 69 pts were treated with a median of 2 cycles (range <1–10). AEE788 and AQM674 concentrations varied widely and increased with dose and duration. IC50 values were estimated for pEGFR (42nM), pMAPK (38nM), Ki67 (7nM) in SK and pEGFR (28nM), pMAPK (22nM) in TU; 80% Emax was achieved with 100–300 mg/day. Conclusions: A dose-dependent inhibition of EGFR signaling in SK and TU was observed; profound receptor inhibition is achieved with ≥ 300 mg/day. As expected, inhibition of endothelial pMAPK and Ki67 occurs at higher doses than EGFR inhibition (≥ 300 mg). Exposure dependent effects were observed and estimated IC50 values agree with preclinical data. Integration of PK, PD, and clinical response will suggest a potentially therapeutic regimen for further clinical evaluation. Model development will continue as more data become available. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Aventis, Bristol-Myers Squibb, Lilly Oncology, Merck KgaA (A), Novartis, Pfizer, Pharma Mar, Roche, Roche (A) Novartis Aventis, Novartis, Pfizer, Roche ILEX Oncology, Novartis