A first-in-human phase Ia open-label dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the humanized monoclonal antibody (huMAb) anti-EGFL7 (MEGF0444A) administered intravenously in patients with advanced solid tumors.

Abstract

2614 Background: Epidermal growth factor-like domain 7 (EGFL7), is a vascular-restricted, tumor selective, extracellular matrix protein that promotes endothelial cell adhesion, survival and re-growth. Anti-EGFL7 (MEGF0444A) is a huMAb that targets and inhibits the adhesive and pro-survival activities of EGFL7 on endothelial cells. Anti-EGFL7 prolongs survival of mice bearing invasive pancreatic islet tumors driven by the large T antigen, and reduces vascular density and perfusion in the tumors. The combination of anti-EGFL7 with an anti-vascular endothelial growth factor antibody had significantly more potent anti-tumor activity than either agent alone. Methods: This was a Phase Ia, open-label, 3+3 dose-escalation study to evaluate the safety, tolerability and PK of MEGF0444A, administered intravenously (IV) every 3 weeks, in patients (pts) with advanced solid tumors. PD markers including levels of circulating progenitor cells (CPC) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) were assessed. Results: Thirty pts were enrolled in 5 dose-escalation and 2 dose-expansion cohorts. The highest planned dose of 15 mg/kg, also the maximum administered dose, was reached without dose-limiting toxicities (DLTs) within the 21-day DLT window. Ten serious and 8 non-serious adverse events >= Grade 3 in severity were reported, none of which were attributed to study drug. Infusion-related reactions were rare. MEGF0444A demonstrated linear PK typical of IgG1 monoclonal antibodies. There were no tumor responses and most patients progressed by end of cycle 4. Enumeration of CPC levels showed a decrease in a subset of pts within 15 days of MEGF0444A therapy. DCE-MRI results were suggestive of anti-angiogenic activity in select pts. Conclusions: MEGF0444A was well tolerated and has good PK properties. Potential vascular targeting by MEGF0444A is suggested by changes in CPC levels and DCE-MRI. MEGF0444A is currently being investigated in combination with bevacizumab and chemotherapy in a Phase Ib clinical trial.