P-0105 - Oral c-Met inhibitor MSC2156119J as monotherapy versus sorafenib in first-line treatment of Asian patients with MET-positive advanced hepatocellular...

Date 28 June 2014
Event World GI 2014
Session Poster Session
Topics Anti-Cancer Agents & Biologic Therapy
Hepatobiliary Cancers
Presenter A.L. Cheng
Citation Annals of Oncology (2014) 25 (suppl_2): ii14-ii104. 10.1093/annonc/mdu165
Authors Y. Lim Ho1, L. Xu2, C. Li3, G. Massimini4
  • 1Department of Medicine, Samsung Medical Center, Sungkyunkwan University, Seoul/KR
  • 2Global Biostatistics, Merck Serono Pharmaceutical R&D Co., Ltd., Beijing/CN
  • 3Global Clinical Development, R&D Beijing Hub, Beijing/CN
  • 4Global Research and Early Development, Merck KGaA, Darmstadt/DE

Abstract

Introduction

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death, particularly in Asia, where about 80% of HCC incidences occur. Patients with HCC have a poor prognosis and there are few effective treatments. MSC2156119J is a highly selective, ATP-competitive, reversible, oral c-Met inhibitor. It was found to inhibit tumor growth in preclinical tumor models. In a Phase I study (Falchook et al. J Clin Oncol 2013:31(Suppl):2506), MSC2156119J demonstrated antitumor activity in patients with advanced solid tumors. The recommended dose for Phase II trials was determined to be 500 mg/day. This Phase Ib/II, randomized, open-label, multicenter trial (NCT01988493) evaluates the efficacy, safety, and pharmacokinetics of MSC2156119J monotherapy compared with sorafenib as first-line treatment for Asian patients with MET+ advanced HCC.

Methods

The Phase Ib part is an open-label, single-arm, dose-escalation trial that follows the 3 + 3 design (MSC2156119J 300 or 500 mg/d; 21-d cycle); up to 18 patients in total are planned for the 2 dose cohorts. The Phase II part is a randomized, open-label, active-controlled trial; 140 patients from 30–35 sites in mainland China, South Korea, Taiwan, and other Asian countries will be randomized on a 1:1 basis to receive either MSC2156119J at the recommended Phase II dose determined in Phase Ib, or 400 mg sorafenib twice daily until disease progression, intolerable toxicity, or consent withdrawal. The primary objective for Phase Ib is to confirm 500 mg as the recommended Phase II dose of MSC2156119J; for the Phase II part it is to determine time to progression (TTP) per independent read of patients treated with MSC2156119J vs sorafenib. The secondary objectives of Phase Ib include the assessment of pharmacokinetics, preliminary antitumor activity, and biochemical response; for the Phase II part they include the determination of safety and tolerability (adverse events will be graded as per the National Cancer Institute's Common Terminology Criteria for Adverse Events version 4.0) and antitumor activity (TTP and progression-free survival per investigator read, overall survival, time to symptomatic progression, objective response, and disease control). The main inclusion criteria are Asian adults with confirmed, advanced HCC of Barcelona Clinic Liver Cancer stage C, Child-Pugh class A liver function with no encephalopathy, estimated life expectancy of ≥3 months, and Eastern Cooperative Oncology Group performance status 0–2 (Phase II only: eligible for sorafenib treatment; measurable disease according to Response Evaluation Criteria In Solid Tumors version 1.1; systemic treatment-naive advanced HCC, and MET+ status, defined as moderate or strong c-Met protein overexpression). The key exclusion criteria include prior treatment with an agent targeting the HGF/c-Met pathway, prior local-regional therapy <4 weeks before the first day of trial treatment, history of liver transplant or neoplasms other than HCC, known symptomatic or untreated central nervous system or brain metastasis, clinically significant gastrointestinal bleeding <4 weeks before trial entry, grade ≥2 peripheral neuropathy, uncontrolled hypertension, known human immunodeficiency virus infection, impaired cardiac function, chronic gastrointestinal disease, and participation in another clinical trial <4 weeks before trial entry. Enrollment for this trial in progress began on January 9, 2014.