444PD - Phase I dose-escalation study of oral selective c-MET inhibitor EMD 1214063 in patients with advanced solid tumors

Date 30 September 2012
Event ESMO Congress 2012
Session Developmental therapeutics
Topics Drug Development
Presenter Gerald Falchook
Authors G.S. Falchook1, D.S. Hong2, H.M. Amin3, S. Fu2, S.A. Piha-Paul2, M.B. Klevesath4, V. Jego5, A. Johne6, S. Stinchi7, R. Kurzrock2
  • 1Investigational Cancer Therapeutics, UT MD Anderson Cancer Center, 77030-4095 - Houston/US
  • 2Department Of Investigational Cancer Therapeutics, UT MD Anderson Cancer Center, 77030-4095 - Houston/US
  • 3Department Of Hematopathology, UT MD Anderson Cancer Center, 77030-4095 - Houston/US
  • 4Global Early Development Unit - Oncology, Merck KGaA, 64293 - Darmstadt/DE
  • 5Biostatistics Geneva, Merck Serono, Geneva/CH
  • 6Clinical Pharmacology, Merck KGaA, 64293 - Darmstadt/DE
  • 7Istituto Di Ricerche Biomediche, Merck Serono RBM, 10010 - Colleretto Giacosa/IT

Abstract

Purpose

The cell surface receptor tyrosine kinase c-Met and its ligand, hepatocyte growth factor (HGF), mediate cell migration, survival and proliferation. EMD 1214063 is a highly selective, reversible and ATP-competitive c-Met inhibitor that causes growth inhibition and regression of HGF-dependent and HGF-independent tumors in pre-clinical models.

Methods

This is a first-in-man dose-escalation study to establish the MTD of EMD 1214063. Eligible pts had advanced solid tumors not amenable to standard therapy. Following a 3 + 3 dose escalation scheme, pts were treated with once-daily oral EMD 1214063 according to two 21-day-cycle schedules, either days 1-14 followed by a 7-day rest (regimen 1, [R1]), or continuous 3 times weekly (regimen 2, [R2]). An optimised formulation was introduced in August 2011. Pd markers were evaluated in paired tumor biopsies using immunohistochemistry (IHC) and a Luminex based assay.

Results

Until 3 November 2011, 50 pts had been treated; 27 in R1 and 23 in R2. The dose was escalated from 30 mg/day to 230 mg/day in R1 and to 115 mg/day in R2 with the initial formulation. For the optimised formulation, data are available for 30 mg and 60 mg/day for R1, and for 60 mg/day in R2. Cmax and AUC increased with dose. The optimised formulation showed higher oral bioavailability. Two DLTs were reported, a G4 lipase and G3 amylase elevation in 1 pt in R1 at 115 mg/day, and a G3 lipase elevation in R2 at 115 mg/day. No treatment-related SAEs were observed. Treatment-related AEs of ≥G2 included nausea (n = 1), vomiting (n = 1), decreased appetite (n = 2), diarrhea (n = 1), and fatigue (n = 1) in R1, and neutropenia (n = 1) and fatigue (n = 1) in R2. Forty-four patients (88%) had no drug-related AE >G1. Analysis of pre- and on-treatment biopsies showed decreased phospho-c-Met staining intensity under treatment on IHC and >80% reduction in phospho-c-Met levels on the Luminex assay. Preliminary anti-tumor activity included an unconfirmed PR in 1 pt and SD ≥4 months in 7 pts. One pt with sarcomatoid bladder cancer and multiple MET copies due to polysomy of Chr 7 achieved SD for 12+ months.

Conclusion

The MTD has not yet been reached and dose escalation of EMD 1214063 continues. Updated results will be presented.

Disclosure

G.S. Falchook: Has a consultant/advisory relationship with EMS Serono, received research funding of EMD Serono, received travel reimbursement from EMD Serono.

H.M. Amin: Received research funding of EMD Serono

M.B. Klevesath: Merck KGaA employee

V. Jego: Merck Serono employee

A. Johne: Merck Serono employee

S. Stinchi: Merck Serono employee

R. Kurzrock: Received research funding of EMD Serono and Merck KGaA

All other authors have declared no conflicts of interest.