450PD - First-in-human phase I trial assessing the highly selective c-Met inhibitor MSC2156119J (EMD 1214063) in patients with advanced solid tumors

Date 28 September 2014
Event ESMO 2014
Session Developmental therapeutics
Topics Drug Development
Translational Research
Presenter Gerald Falchook
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors G.S. Falchook1, D.S. Hong1, H.M. Amin2, S. Fu1, S.A. Piha-Paul1, F. Janku1, H. Zheng3, F. Bladt4, A. Johne5, R. Kurzrock6
  • 1Department Of Investigational Cancer Therapeutics (phase I Clinical Trials Program), MD Anderson Cancer Center, 77030-4095 - Houston/US
  • 2Department Of Hematopathology, MD Anderson Cancer Center, 77030-4095 - Houston/US
  • 3Global Research And Early Development, EMD Serono, Boston/US
  • 4Translational Innovation Platform Oncology, Global Research & Development, Merck KGaA, Darmstadt/DE
  • 5Clinical Pharmacology, Merck KGaA, 64293 - Darmstadt/DE
  • 6San Diego Moores Cancer Center, University of California, San Diego/US

 

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 Serono.; F. Bladt: Employment by Merck KGaA, Darmstadt, Germany; A. Johne: Employment by Merck KGaA, Darmstadt, Germany; R. Kurzrock: Corporate-sponsored research: Merck Serono. All other authors have declared no conflicts of interest.