443PD - Pharmacodynamic (PD) – Pharmacokinetic (PK) Study of Ficlatuzumab(F), A Monoclonal Antibody (MAB) Directed to the Hepatocyte Growth Factor (HGF), in Patients (PTS) with Advanced Solid Tumors who have Liver Metastases (METS)

Abstract

ABSTRACT Background F is a humanized IgG1 mAb directed to HGF that inhibits activation of the c-Met receptor, with potential anti-tumor activity. This study was to define the optimal dose using PD and PK assessments. Methods Pts with solid tumors and liver mets, with phospho (p)-Met expression were sequentially enrolled into 2, 10, or 20 mg/kg (RP2D, defined in a previous study), of F given IV every 2 wks and were evaluated every 8 wks for response using RECIST 1.1. Target pathway modulation was assessed by measuring the following PD markers by IHC in biopsies of liver mets: p-Met, p-Akt, p-ERK, p-S6K, HGF, and c-Met; Ki67 and cleaved caspase-3; and CD31. PD-evaluable pts had measurable p-Met at Cycle 1 Day 1 pre-dose and at least one post-dose timepoint. Serum was collected to measure F, anti-drug antibody (ADA), s-Met, HGF, and HGF/F complex levels by ELISA. Results Nineteen pts received F: 15 male/4 female; median age 60 years; ECOG PS 0/1 (8/11 pts). The most frequent TEAEs, mostly Grade 1 to 3, were asthenia, edema, hepatic pain (32% each), cough (26%). There were no DLTs or ADA. Serum albumin decreased to below normal for most pts at EOT and recovered at the follow up visit. Best overall response was SD (5/18 pts) and disease progression (13/18 pts), and median duration of treatment was 6 wks (range 2-59). PK analysis revealed dose-proportional drug exposure with a low systemic clearance leading to a terminal half-life of 7.4 to 10.0 days, and a low volume of distribution approximating the plasma volume. F treatment increased the total serum HGF and HGF/F complex levels. Increasing dose of F resulted in progressive decreases in p-Met and p-AKT. At RP2D, the majority of pts experienced ≥ 25% decrease from baseline in p-Met, p-ERK, p-Akt, Ki67 and CD31. Conclusions Ficlatuzumab(F) is well tolerated in this population. The PK of F in this study was consistent with that reported previously. Increase in post-dose serum HGF and HGF/F complex levels indicates target engagement. At RP2D, a majority of pts experienced decreases in key cell signaling PD markers. This study supports the selection of 20 mg/kg F dose as RP2D. Disclosure All authors have declared no conflicts of interest.