AEE788, a novel multitargeted inhibitor of ErbB and VEGF receptor family tyrosine kinases: Preliminary phase 1 results

• DOI: 10.1200/jco.2005.23.16_suppl.3039
• Publication Date: 2017-02-23T18:55:09Z
• Authors: E. Martinelli; C. H. Takimoto; A. T. van Oosterom; J. Tabernero; E. Rowinsky; P. Schöffski; J. Huang; E. Casado; A. Mita; H. Dumez
• Keywords: Pharmacodynamics

3039 Background: AEE788 is an oral inhibitor with potent activity against multiple tyrosine kinases including EGFR, HER2, and VEGFR2. This phase 1 study was to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), MTD/DLT dose levels, optimal biologic of AEE788. Methods: Patients (pts) advanced solid tumors were enrolled. Doses escalated in a standard Phase I design 3–6 pts/cohort. Safety monitoring included extensive cardiac assessments. All but pt naïve EGFR VEGF inhibitory therapy. Pharmacodynamic markers analyzed pre- post-treatment skin tumor biopsies. A 24-hr PK profile obtained on days 1, 15, 28, trough sampling 8 22. Each cycle (cyc) 28 days. Results: To date, 69 pts, median age 55 years (range 20–78), have been treated once daily at doses 25 (5), 50 (6), 100 150 225 300 (8), 400 (14), 450 500 550 mg (9) per day. Tumor types breast (10), colon (9), medullary thyroid (7), head neck melanoma (4), NSCLC RCC (3), angiosarcoma (3) other (23). Two pts had DLT (grade ([gr] 3 diarrhea) both mg. The most common adverse events (> 20%) diarrhea (67%), fatigue/asthenia (51%), anorexia (49%), rash (43%), nausea (42%), vomiting (28%). Most AEs mild moderate. Six gr LFT elevation. LFTs one remained normal when rechallenged lower dose. Three (2 mg) withdrew < cyc due AEs. There no QTcF > ms change ≥ 60 over 1980 ECGs. Serum concentrations parent (AEE788) active metabolite (AQM674) increase duration. Exposure increases overproportionately increased while AQM674 exposure proportionally. metabolite/parent ratio 0.2 2) appears decline duration average 0.3–0.4 steady state (by day 15). achieved partial response. stable disease 2 cycs 2–10). number <1–10). Conclusions: well tolerated. levels defined Enrollment continues. Author Disclosure Employment or Leadership Consultant Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Aventis, Bristol-Myers Squibb, Lilly, Merck KgaA, Novartis, Pfizer, Pharma Mar, Roche ILEX Oncology,