Phase 1 study of weekly anti-vascular endothelial growth factor receptor-1 (VEGFR-1) monoclonal antibody IMC-18F1 in patients with advanced solid malignancies

Abstract

14630 Background: VEGFR-1 is expressed on both tumor vasculature and a wide range of human tumors. IMC-18F1 is a recombinant human monoclonal IgG1 antibody that directly targets VEGFR-1 so as to block ligand binding and, in turn, downstream VEGFR-1 signaling. VEGFR-1 activation is also critical for epithelial-mesenchymal transformation and is a mediator of circulating hematopoietic progenitor cells that condition the microenvironment enabling the growth of tumor metastases. Methods: This Phase 1 study of IMC- 18F1 was designed to evaluate the safety, pharmacokinetics (PK), pharmacodynamics, and immunogenicity of IMC-18F1 administered weekly at doses of 2, 3, 6, and 12 mg/kg IV (Cohorts 1–4). If safety, PK, and pharmacodynamic data supported less frequent dosing, then schedules of 15 mg/kg every 2 weeks and 20 mg/kg every 3 weeks (Cohorts 5 and 6) were to be evaluated. Results: A total of 14 patients have received treatment as part of Cohorts 1–4. To date, there have not been IMC-18F1-related, grade > 2 adverse events (AE) nor dose- limiting toxicities observed. The most common AEs considered at least possibly-related to study drug include fatigue (n = 5), nausea (n = 3), and anemia (n = 2). Following the final infusion in Cycle 1; the mean half-life of IMC-18F1 increased with increasing dose (85.9 - 205.4 hrs); the mean clearance decreased with increasing dose (0.208–0.067 mL/hr/kg), suggesting that saturation of elimination was being approached. Cmax and AUCinf increased in a greater-than-dose-proportional manner, indicating that the PK of IMC-18F1 was nonlinear. Conclusions: Enrollment on this study continues, with an evaluation of 15 mg/kg every-2-week and 20 mg/kg every-3- week schedules based on supportive PK and toxicity profiles. The preliminary safety, PK, and biological activity data support further disease- directed development of IMC-18F1. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration ImClone Systems Incorporated ImClone Systems Incorporated