443PD - Pharmacodynamic (PD) - pharmacokinetic (PK) study of ficlatuzumab(F), a monoclonal antibody (MAB) directed to the hepatocyte growth factor (HGF), in...

Date 30 September 2012
Event ESMO Congress 2012
Session Developmental therapeutics
Topics Drug Development
Pharmacology
Presenter Elena Elez
Authors E. Elez1, J. Tabernero2, L. Prudkin3, S. Agarwal4, M. Han4, M. Credi4, W. Yin4, N. Kuriyama4, J. Baselga5
  • 1Medical Oncology, Vall d'Hebron University Hospital, 08035 - Barcelona/ES
  • 2Oncology Department, Vall d'Hebron University HospitalMedical Oncology Service, ES-08035 - Barcelona/ES
  • 3Pathology, Vall d'Hebron University Hospital, Barcelona/ES
  • 4Oncology, AVEO Pharmaceuticals, Inc, Cambridge/US
  • 5Hematology/oncology, MGH Cancer Center, Massachusetts General Hospital, MA 02114 - Boston/US

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.