MET Inhibitor Drug Discovery Platform: Cancer Cell Signaling Christensen JG, et al1; Eder JP, et al 2
A Randomized, Double-Blind, Phase 2 Study of Ramucirumab or Merestinib or Placebo Plus and Gemcitabine as First-line Treatment in Patients With Advanced or Metastatic Biliary Tract Cancer* Key Inclusion Criteria Nonresectable, recurrent, or metastatic biliary tract adenocarcinoma (eg, of the gallbladder, intra- and extra-hepatic cholangiocarcinoma, or Ampulla of Vater) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Adequate biliary drainage Adequate organ function Willing to provide blood and tissue samples for research purposes Key Exclusion Criteria Previous systemic therapy for locally advanced or metastatic disease History of or current hepatic encephalopathy of any grade, ascites of grade >1, or cirrhosis with Child-Pugh class B or higher Ongoing or recent ( 6 months) hepatorenal syndrome Arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack within 6 months prior to randomization Uncontrolled arterial hypertension despite standard medical management History of gastrointestinal perforation and/or fistulae within 6 months prior to randomization History of uncontrolled hereditary or acquired thrombotic disorder Mixed hepatocellular biliary tract cancer histology Please visit www.clinicaltrials.gov for more information on this clinical trial [NCT02711553]. * This clinical trial is being conducted globally. + ramucirumab Arm A Patients with advanced or metastatic biliary tract cancer Randomization 2:1:2:1 + placebo + merestinib Primary endpoint: Progression-free survival Arm B Participants continue study treatment until disease progression or discontinuation criteria are met. + placebo 2 3
A Phase 1 Study of LY2801653 in Patients With Advanced Cancer* Key Inclusion Criteria Part A: Cancer that is advanced and/or metastatic (solid tumors or non-hodgkin lymphoma) Part B: Colorectal cancer (CRC), head and neck squamous cell carcinoma (HNSCC), cholangiocarcinoma (CCA), or uveal melanoma Part C: HNSCC Parts D and E: CCA Part F: Gastric carcinoma, including gastric adenocarcinoma or gastroesophageal junction adenocarcinoma. Participants must have adequate coagulation function as defined by international normalized ratio 1.5 and a partial thromboplastin time 5 seconds above the upper limit of normal (unless receiving anticoagulation therapy) Parts B, C, D, and E: Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Part F: Measurable and/or evaluable disease Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Key Exclusion Criteria Symptomatic central nervous system malignancy or metastasis Current acute or chronic leukemia Parts B (except uveal melanoma), C, D, E, and F: Tumor sites that are not amenable to tissue sample collection. For participants in these portions of the study, a tumor tissue sample is mandatory, when safe and feasible Part F: The participant has experienced a grade 3 bleeding event within 3 months prior to enrollment, any arterial or venothrombotic or thromboembolic events, including, but not limited to, myocardial infarction, transient ischemic attack, or cerebrovascular accident, within 6 months prior to enrollment Please visit www.clinicaltrials.gov for more information on this clinical trial [NCT01285037]. * This clinical trial is being conducted in the United States. Part C: in HNSCC + cetuximab Part A: Dose escalation of merestinib Part B: Dose confirmation of Cohort B1: CRC Cohort B2: HNSCC Cohort B3: CCA Cohort B4: Uveal melanoma Part D: in CCA + cisplatin Part E: in CCA and cisplatin Part F: in gastric cancer + ramucirumab Primary endpoint: Recommended phase 2 dose and schedule 4 5
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Target MET, the hepatocyte growth factor (HGF) receptor, is a tyrosine kinase receptor. In tumor cells, MET signaling is activated either by binding HGF, its only known ligand, or, in the case of overexpression or amplification of MET, by ligand-independent activation/dimerization. 3 Both ligand-dependent and ligand-independent MET activation trigger downstream signaling pathways known to be involved in tumor cell proliferation, protection from apoptosis, and metastasis. In addition, pathway activation is believed to act as a resistance mechanism to other cancer therapies. 4,5 Dysregulation of the MET pathway is an important feature of many human malignancies, including lung, breast, and colorectal. 1 Molecule Merestinib (LY2801653) is a small molecule that has been shown in vitro to be a reversible type II ATP-competitive inhibitor of MET. Preclinical testing also has shown merestinib to inhibit several other receptor tyrosine oncokinases including MST1R, FLT3, AXL, MERTK, TEK, ROS1, NTRK1/2/3, and DDR1/2 and the serine/threonine kinases MKNK1/2. 6,7 Clinical Development Merestinib is being investigated in a clinical trial in patients with biliary tract cancer and in phase I clinical trials. Study Schemas Not Available [NCT03027284] Early Development A Study of Merestinib (LY2801653) in Japanese Participants With Advanced or Metastatic Cancer References: 1. Christensen JG, et al. Cancer Lett. 2005;225(1):1-26. 2. Eder JP, et al. Clin Cancer Res. 2009;15(7):2207-2214. 3. Gherardi E, et al. Nat Rev Cancer. 2012;12(2):89-103. 4. Yano S, et al. Cancer Sci. 2012;103(7):1189-1194. 5. McDermott U, et al. Cancer Res. 2010;70(4):1625-1634. 6. Yan SB, et al. Invest New Drugs. 2013;31(4):833-844. 7. Konicek BW, et al. AACR Annual Meeting; April 16-20, 2016; New Orleans, LA. Abstract 2647. ON99698 04/2017 PRINTED IN USA Lilly USA, LLC 2017. All rights reserved.