Results of the first-in-human phase I trial assessing MSC2156119J (EMD 1214063), an oral selective c-Met inhibitor, in patients (pts) with advanced solid tumors.

Abstract

2521^ Background: MSC2156119J, a selective c-Met inhibitor, suppresses tumor growth in preclinical models. Methods: Primary endpoint of this dose-escalation study (3+3 design; NCT01014936): to assess an MTD; secondary endpoints: antitumor activity, safety, pharmacokinetics (PK), and pharmacodynamics (Pd). Pts received 1x/d oral MSC2156119J (21-d cycles; 3 regimens [R]): d1–14 followed by 7-d rest (R1); 3x/wk (R2); or d1–21 (R3). An optimized formulation (OF) was introduced in Aug 2011. Results: Up to Nov 25, 2013,126 pts were analyzed (R1=42; R2=45; R3=39). On the initial formulation, doses were escalated from 30–230 mg/d in R1 and 30–115 mg/d in R2; on the OF (R1–3): 30–400 mg/d, 60–315 mg/d, and 300–1400 mg/d. AUC and Cmax increased with dose; bioavailability was higher with OF. An MTD was not reached. Six pts reported dose-limiting toxicities: asymptomatic G4 lipase and G3 amylase increase (R1; 115 mg/d), G3 nausea and vomiting (R2; 130 mg/d; OF), asymptomatic G3 lipase increase (R2; 60 + 100 mg/d; OF), G3 fatigue (R3; 1400 mg/d; OF), and G3 ALT elevation (R3; 1000 mg/d; OF). Other ≥G3 treatment-related adverse events (trAEs) were G3 peripheral edema (1 pt; R3; 300 mg/d; OF) and G3 AST elevation (1 pt; R3; 1000 mg/d; OF). Most frequent G2 trAEs (R1–3): fatigue (n=8), peripheral edema (n=3), vomiting (n=3), nausea (n=2), asymptomatic lipase increase (n=2), and neutropenia (n=2). 79% of pts had no trAE >G1. Pre- and on-therapy tumor biopsies showed phospho-c-Met inhibition in 19/21 evaluable pts. One pt (esophageal adenocarcinoma) had confirmed partial response (PR); 2 pts (nasopharyngeal and colorectal carcinoma) had unconfirmed PRs. Stable disease (SD) ≥4 mo was seen in 18 pts, incl. 1 pt with SD >32 mo. Based on preclinical PK/Pd models and clinical Pd data, 500 mg was considered biologically active and sufficient to reach ≥95% target inhibition. Conclusions: MSC2156119J was well tolerated and showed antitumor activity. Recommended phase II dose (RP2D) is 500 mg 1x/d. Dose escalation was stopped at 2.8xRP2D (1400 mg/d). An MTD was not reached. Additional Pd and biomarker data (c-Met status by immunohistochemistry [IHC] and in situ hybridization) will be presented. Clinical trial information: NCT01014936.