Abstract CT236: MSC2156119J (EMD 1214063), an oral selective c-Met inhibitor, in patients with advanced solid tumors: results of the first-in-human phase I trial
Authors: Falchook Gerald S. , Hong David S. , Amin Hesham M. , Fu Siqing , Piha-Paul Sarina Anne , Janku Filip , Granda J. Gabrielle , Zheng HongXia , Klevesath Manfred B. , Köhler Karola , Bladt Friedhelm , Johne Andreas , Kurzrock Razelle 
Published: May 2015

Abstract
Introduction: Overexpression of the c-Met oncoprotein can enhance invasive tumor behavior and is correlated with poor prognosis. MSC2156119J, a highly selective, ATP-competitive, reversible c-Met inhibitor, suppresses tumor growth and induces regression of HGF-dependent and -independent tumors in preclinical models. Methods: This dose-escalation phase I trial (3+3 design) included patients with advanced solid tumors (NCT01014936). The primary endpoint was to assess the maximum tolerated dose (MTD). Secondary endpoints included safety, antitumor activity, pharmacokinetics (PK), and pharmacodynamics (Pd). Patients were treated once a day with oral MSC2156119J in 21-day cycles: days 1-14 followed by 7 days rest (regimen [R] 1), 3 times per week (R2), or continuously day 1-21 (R3). An optimized formulation was introduced in Aug 2011. Results: Up to Sep 30, 2013, data were available for 125 patients (R1=42; R2=45; R3=38). Doses were escalated from 30-230 mg/day in R1 and 30-115 mg/day in R2 with the initial formulation, and from 30-400 mg/day in R1, 60-315 mg/day in R2, and 300-1400 mg/day in R3 with the optimized formulation. Bioavailability was higher with the optimized formulation; AUC and Cmax increased with dose. Dose-limiting toxicities (DLTs) were reported in 6 patients: asymptomatic G4 lipase and G3 amylase increase (R1; 115 mg/day), asymptomatic G3 lipase increase (R2; 60 and 100 mg/day optimized formulation), G3 nausea and vomiting (R2; 130 mg/day optimized formulation), G3 ALT elevation (R3; 1000 mg/day optimized formulation), and G3 fatigue (R3; 1400 mg/day optimized formulation). Additional ≥G3 drug-related adverse events (AEs) included G3 peripheral edema (1 patient; R3; 300 mg/day optimized formulation), and G3 AST elevation (1 patient; R3; 1000 mg/day optimized formulation). Most frequent G2 drug-related AEs (R1-3) included fatigue (n=8), peripheral edema (n=3), vomiting (n=3), nausea (n=2), asymptomatic lipase elevation (n=2), and neutropenia (n=2). Most patients (80%) had no drug-related AE &gt;G1. In 19/21 evaluable patients, paired tumor biopsies (pre- and on-therapy) revealed phospho-c-Met inhibition. One patient (esophageal adenocarcinoma) achieved confirmed partial response (PR); 2 patients (nasopharyngeal and colorectal carcinoma) had unconfirmed PRs. Eighteen patients had stable disease ≥4 mo, including 1 patient with stable disease &gt;32 mo. Based on preclinical PK/Pd models and clinical Pd data, a dose of 500 mg was considered biologically active and sufficient to achieve target inhibition of ≥95%. Conclusions: MSC2156119J showed antitumor activity and was well tolerated. An MTD has not yet been reached at the doses explored. 500 mg once/day was defined as the recommended phase II dose. Additional Pd and biomarker data will be presented, including c-Met IHC from baseline and on-treatment biopsies, and baseline Met FISH.
Citation Format: Gerald S. Falchook, David S. Hong, Hesham M. Amin, Siqing Fu, Sarina Anne Piha-Paul, Filip Janku, J. Gabrielle Granda, HongXia Zheng, Manfred B. Klevesath, Karola Köhler, Friedhelm Bladt, Andreas Johne, Razelle Kurzrock. MSC2156119J (EMD 1214063), an oral selective c-Met inhibitor, in patients with advanced solid tumors: results of the first-in-human phase I trial. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT236. doi:10.1158/1538-7445.AM2014-CT236