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

Abstract

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