450PDFIRST-IN-HUMAN PHASE I TRIAL ASSESSING THE HIGHLY SELECTIVE C-MET INHIBITOR MSC2156119J (EMD 1214063) IN PATIENTS WITH ADVANCED SOLID TUMORS

Abstract Aim: c-Met overexpression is associated with poor clinical prognosis. This dose-escalation study (3 + 3 design; NCT01014936) evaluates the selective c-Met inhibitor MSC2156119J in patients (pts) with advanced solid tumors. Methods: Primary endpoint is to assess an MTD. Secondary endpoints are 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, a 500-mg tablet in May 2013. An expansion cohort of 12 pts with c-Met amplification is ongoing at the recommended phase II dose (RP2D). Results: Up to 28 March 2014, 138 pts were analyzed (R1 = 42; R2 = 45; R3 = 51). 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. Treatment-related adverse events (trAEs) observed in ≥5% of pts across all regimens included fatigue (n = 21), peripheral edema (n = 16), decreased appetite (n = 10), nausea (n = 7), lipase and AST elevation (n = 6 and n = 4, resp.), and vomiting (n = 5); 76% of pts had no trAE >G1. Seven pts reported dose-limiting toxicities: fatigue, peripheral edema, nausea, vomiting and AST elevation (all n = 1), and lipase increase (n = 3). Pre- and on-therapy tumor biopsies showed target inhibition in 19/21 evaluable pts. 2 pts (esophageal adenocarcinoma and NSCLC) had confirmed partial response (PR); 2 pts (nasopharyngeal and colorectal carcinoma) had unconfirmed PRs. 22 pts showed stable disease (SD) ≥4 mo, incl. 1 pt with SD 32 mo. c-Met status, scored by immunohistochemistry, was high in 22/72 evaluable pts, of which 2 pts showed PR and 4 pts SD. Based on preclinical PK/Pd models and clinical Pd data, 500 mg was considered biologically active and able to reach ≥90% target inhibition. Conclusions: MSC2156119J was well tolerated and showed antitumor activity. The RP2D is 500 mg 1x/d. Dose escalation was stopped at 1400 mg/d. An MTD was not reached. Additional data from the expansion cohort will be presented. Disclosure: G.S. Falchook: Research funding from EMD Serono, Inc, Rockland, MA, USA.; H.M. Amin: Research funding from EMD Serono, Inc, Rockland, MA, USA.; H. Zheng: Employment by EMD Serono Inc, Rockland, MA, USA and stock ownership of Merck/EMD