Phase Ib study of the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of the humanized monoclonal antibody (huMAb) anti-EGFL7 (MEGF0444A) in combination with bevacizumab (bev) with or without paclitaxel.

Abstract

e13000 Background: Epidermal growth factor-like domain 7 (EGFL7), is a vascular-restricted, tumor selective, extracellular matrix protein that forms peri-vascular tracks and promotes endothelial cell adhesion and survival. These activities are inhibited by the huMAb anti-EGFL7 (MEGF0444A), which significantly enhances the efficacy of anti-VEGF in murine tumor models. A Phase Ia dose escalation of single agent MEGF0444A demonstrated no dose-limiting toxicities (DLTs). Methods: A standard 3+3 dose escalation design was used to study safety, PK, PD, and anti-tumor activity of MEGF0444A in a 2-arm Phase Ib trial in patients (pts) with advanced solid tumors. In Arm A, 22 pts received MEGF0444A at doses of 2, 5, or 10 mg/kg with bev 10 mg/kg q2w. In Arm B, 18 pts additionally received paclitaxel 90 mg/m2 weekly. Subsequent Arm A expansion cohorts have examined flat dosing of MEGF0444A (600 mg) as a rapid infusion, serial tumor biopsies, and pts with renal cell carcinoma (RCC), respectively. Circulating progenitor cells (CPCs) and dynamic contrast enhanced MRI (DCE-MRI) were assessed as PD biomarkers. Results: The combination of MEGF0444A and bev with or without paclitaxel was well-tolerated without DLTs, exacerbation of bev-related adverse events (AEs), or AEs attributed to rapid infusion. MEGF0444A demonstrated linear PK, and flat dosing yielded MEGF0444A exposures similar to those predicted using Phase Ia weight-based dosing data. CPCs decreased in a subset of pts at the 5 mg/kg q2w dose. DCE-MRI showed a trend toward decreased Ktrans at this dose, supporting combination activity with bev. Eight partial responses, 2 in Arm A and 6 in Arm B, were observed across multiple tumor types. Conclusions: MEGF0444A has demonstrated safety, favorable PK, and clinical activity in combination with bev and bev/paclitaxel. PD biomarker modulation supports a recommended Phase II dose equivalent to 5 mg/kg q2w. RCC and tumor biopsy cohorts remain active. Randomized Phase II trials of MEGF0444A in combination with chemotherapy and bev in colorectal cancer and non-small cell lung cancer are underway.