Safety and pharmacokinetics of intravenous VEGF Trap in a phase I clinical trial of patients with advanced solid tumors

Abstract

3029 Background: VEGF Trap is a potent angiogenesis inhibitor comprising portions of human VEGF receptor VEGFR1 (Flt-1) and VEGFR2 (KDR) extracellular domains fused to the Fc portion of human IgG. VEGF Trap binds VEGF-A and neutralizes all VEGF-A isoforms plus placental growth factor. This study was designed to evaluate the safety and pharmacokinetics (PK) of VEGF Trap administered intravenously. Methods: Successive cohorts of patients (pts) with relapsed or refractory solid tumors received intravenous VEGF Trap on Days 1 and 15. Pts without dose-limiting toxicity subsequently entered a long-term extension study. Study endpoints included safety, PK, and immunogenicity. Antitumor activity was assessed by CT scan, and tumor vascular response was assessed by DCE-MRI. Results: Sixteen pts have been treated across 3 dose levels (0.3, 1.0, 2.0 mg/kg every 2 weeks) to date. In the 10 pts treated at the first 2 dose levels, the most common adverse events (AEs) were fatigue (n=9), pain (n=4), and constipation (n=4). Two of these 10 pts had potentially drug-related grade 3 AEs (dose-limiting arthralgia/fatigue/voice changes; non-dose-limiting transient ALT elevation). No grade 4 or 5 AEs were encountered. Peak total VEGF Trap concentrations increased approximately proportionally to dose from 0.3 to 1.0 mg/kg; PK analysis of higher dose levels is ongoing. No pts have developed anti-VEGF Trap antibodies. Fifteen (94%) pts had DCE-MRI scans that were evaluable for tumor vascular response analysis, which is ongoing. One pt with metastatic renal cell carcinoma has maintained stable disease for over 6 months, and 1 pt with advanced uterine leiomyosarcoma had a minor response (both at the 1.0 mg/kg dose level). Conclusions: VEGF Trap has a manageable safety and tolerability profile at the dose levels studied. The maximum tolerated dose has not yet been reached, and dose escalation continues. Updated safety, pharmacokinetic, pharmacodynamic, and preliminary efficacy results from this ongoing study will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Regeneron, sanofi-aventis, tbc sanofi-aventis tbc sanofi-aventis, tbc tbc