DOCSLIB.ORG

Clinical Trial Protocol

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Clinical Trial Protocol MSC2156119J (tepotinib) Efficacy, Safety, and PK of MSC2156119J in Asian Subjects with EMR200095-004 HCC Clinical Trial Protocol Clinical Trial Protocol Number EMR200095-004 Title A Multicenter, Randomized, Phase Ib/II Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of MSC2156119J as Monotherapy Versus Sorafenib in Asian Subjects with MET+ Advanced Hepatocellular Carcinoma and Child-Pugh Class A Liver Function Short Title: Efficacy, Safety, and PK of MSC2156119J in Asian Subjects with HCC Phase Ib/II Coordinating Investigator 33' Sponsor Merck KGaA Frankfurter Strasse 250 64293 Darmstadt, Germany Medical Responsible: 33' EMD Serono, Inc. 45A Middlesex Turnpike Billerica MA 01821 United States of America Tel: 33' Fax: 33' Clinical Trial Protocol Version 19 May 2017/Version 4.0, Amendment No. 4.0 Replaces Version 24 June 2016/Version 3.0 This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It is intended for restricted use only and may not – in full or part – be passed on, reproduced, 'RFXPHQW1R&&, 1/146 2EMHFW1R&&, MSC2156119J (tepotinib) Efficacy, Safety, and PK of MSC2156119J in Asian Subjects with EMR200095-004 HCC published or used without express permission of Merck KGaA, Darmstadt, Germany, or its subsidiary. Copyright © 2017 by Merck KGaA, Darmstadt, Germany, or its subsidiary. All rights reserved. 'RFXPHQW1R&&, 2/146 2EMHFW1R&&, MSC2156119J (tepotinib) Efficacy, Safety, and PK of MSC2156119J in Asian Subjects with EMR200095-004 HCC Signature Page Protocol Lead responsible for designing the clinical trial: I approve the design of the clinical trial. _____________________________________ ____________________________ Signature Date of Signature Name, academic degree 33' Function Medical Responsible Institution EMD Serono, Inc. Address 45A Middlesex Turnpike Billerica MA 01821 United States of America Telephone number 33' Fax number 33' E-mail address 33' 'RFXPHQW1R&&, 3/146 2EMHFW1R&&, MSC2156119J (tepotinib) Efficacy, Safety, and PK of MSC2156119J in Asian Subjects with EMR200095-004 HCC Coordinating Investigator I agree to conduct the clinical trial in accordance with this clinical trial protocol and in compliance with Good Clinical Practice and all applicable regulatory requirements. _____________________________________ ____________________________ Signature Date of Signature Name, academic degree 33' Function 33' Institution 33' Address 33' Telephone number 33' Fax number 33' E-mail address 33' 'RFXPHQW1R&&, 4/146 2EMHFW1R&&, MSC2156119J (tepotinib) Efficacy, Safety, and PK of MSC2156119J in Asian Subjects with EMR200095-004 HCC Further Sponsor Responsible Persons Biostatistician Name 33' Function 33' Institution Merck-Serono (Beijing), Pharmaceutical R&D Co., Ltd. Telephone number 33' Fax number 33' E-mail address 33' Clinical Trial Leader Name 33' Function 33' Institution Merck-Serono (Beijing), Pharmaceutical R&D Co., Ltd. Telephone number 33' Fax number 33' E-mail address 33' 'RFXPHQW1R&&, 5/146 2EMHFW1R&&, MSC2156119J (tepotinib) Efficacy, Safety, and PK of MSC2156119J in Asian Subjects with EMR200095-004 HCC Principal Investigator Signature Trial Title A Multicenter, Randomized, Phase Ib/II Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of MSC2156119J as Monotherapy Versus Sorafenib in Asian Subjects with MET+ Advanced Hepatocellular Carcinoma and Child-Pugh Class A Liver Function Clinical Trial Protocol 19 May 2017/Version 4.0 Version/Date Center Number Principal Investigator I, the undersigned, am responsible for the conduct of the trial at this site and affirm that: ! I understand and will conduct the trial according to the clinical trial protocol, any approved protocol amendments, ICH Good Clinical Practice (ICH Topic E6 GCP) and all applicable Health Authority requirements and national laws. I understand that some Health Authorities require the Sponsors of clinical trials to obtain and supply, when required, details about the Investigators’ ownership interests in the Sponsor or Investigational Medicinal Product and information regarding any financial ties with the Sponsor. The Sponsor will use any such information that is collected solely for the purpose of complying with the regulatory requirements. I therefore agree to supply the Sponsor with any necessary information regarding ownership interest and financial ties (including those of my spouse and dependent children), and to provide updates as necessary. _____________________________________ ____________________________ Signature Date of Signature Name, academic qualifications Position (job title) Address of Institution Telephone number Fax number E-mail address 'RFXPHQW1R&&, 6/146 2EMHFW1R&&, MSC2156119J (tepotinib) Efficacy, Safety, and PK of MSC2156119J in Asian Subjects with EMR200095-004 HCC Table of Contents Signature Page .....................................................................................................................3 Table of Contents.................................................................................................................7 Table of In-Text Tables .....................................................................................................11 Table of In-Text Figures ....................................................................................................11 List of Abbreviations .........................................................................................................12 1 Synopsis..............................................................................................16 2 Sponsor, Investigators, and Trial Administrative Structure ...............35 2.1 Sponsor ...............................................................................................35 2.2 Trial Administrative Structure............................................................35 2.2.1 Safety Monitoring Committee ............................................................35 2.2.2 Independent Data Monitoring Committee..........................................36 2.2.3 Independent Review Committee.........................................................36 3 Background Information.....................................................................36 3.1 Hepatocellular Carcinoma ..................................................................36 3.2 c-Met...................................................................................................37 3.3 MSC2156119J ....................................................................................37 3.3.1 Nonclinical Evaluation .......................................................................37 3.3.2 Clinical Experience.............................................................................38 3.4 Rationale for the Current Trial ...........................................................40 3.5 Risk-Benefit Evaluation......................................................................41 4 Trial Objectives ..................................................................................42 4.1 Primary Objectives .............................................................................42 4.2 Secondary Objectives .........................................................................42 4.3 Exploratory Objectives .......................................................................43 5 Investigational Plan ............................................................................43 5.1 Overall Trial Design and Plan ............................................................43 5.2 Discussion of Trial Design .................................................................47 5.2.1 Inclusion of Special Populations ........................................................48 5.3 Selection of Trial Population..............................................................48 5.3.1 Inclusion Criteria ................................................................................48 5.3.2 Exclusion Criteria ...............................................................................49 'RFXPHQW1R&&, 7/146 2EMHFW1R&&, MSC2156119J (tepotinib) Efficacy, Safety, and PK of MSC2156119J in Asian Subjects with EMR200095-004 HCC 5.4 Criteria for Randomization/Initiation of Treatment with the Investigational Medicinal Product......................................................52 5.5 Criteria for Subject Withdrawal..........................................................52 5.5.1 Withdrawal from the Trial..................................................................52 5.5.2 Replacement of Discontinued Subjects ..............................................53 5.5.3 Withdrawal from Trial Therapy..........................................................53 5.6 Premature Discontinuation of the Trial ..............................................54 5.7 Definition of End of Trial...................................................................54 6 Investigational Medicinal Product and Other Drugs Used in the Trial.....................................................................................................55 6.1 Description of Investigational Medicinal Product..............................55 6.2 Dosage and Administration ................................................................55 6.2.1 Dose Escalation Assessment Process .................................................56 6.2.2 Definition of DLT...............................................................................57 6.2.3 MTD/RP2D Definition Process..........................................................59
Load more

Recommended publications
  • Daiichi Sankyo Group Value Report 2019
    External Evaluations (as of June 30,2019) ™ Daiichi Sankyo Group Value Report 2019 Value Daiichi Sankyo Group MSCI Japan Empowering Women Select Index THE INCLUSION OF DAIICHI SANKYO CO.,LTD. IN ANY MSCI INDEX, AND THE USE OF MSCI LOGOS, TRADEMARKS, SERVICE MARKS OR INDEX NAMES HEREIN, DO NOT CONSTITUTE A SPONSORSHIP, ENDORSEMENT OR PROMOTION OF DAIICHI SANKYO CO.,LTD. BY MSCI OR ANY OF ITS AFFILIATES. THE MSCI INDEXES ARE THE EXCLUSIVE PROPERTY OF MSCI. MSCI AND THE MSCI INDEX NAMES AND LOGOS ARE TRADE- MARKS OR SERVICE MARKS OF MSCI OR ITS AFFILIATES. “Eruboshi” Certification Mark “Kurumin” Certification Mark Logo given to Certified Health and Productivity Management Organization (White500) This report uses FSC® certified paper, which indicates that the paper used to print this Paper report was produced from properly managed forests. 3-5-1, Nihonbashi-honcho, Chuo-ku, Tokyo 103-8426, Japan This report was printed using 100% Inks biodegradable printing inks from vegetable Corporate Communications Department oil. Daiichi Sankyo Group Tel: +81-3-6225-1126 CSR Department The waterless printing method used for this Value Report 2019 Tel: +81-3-6225-1067 Printing report minimized the use and release of harmful liquid wastes. https://www.daiichisankyo.com/ Printed in Japan 005_7045687911909.indd 1 2019/09/27 18:22:19 Introduction Our Mission The Core Values and Commitments serve as the criteria for business activities and In addition, we have established the DAIICHI SANKYO Group Corporate Conduct Charter . decision-making used by executive officers and employees in working to fulfill Our Mission . This charter calls on us to fulfill our social responsibilities by acting with the highest ethical Our Corporate Slogan succinctly explains the spirit of Our Mission, Core Values and standards and a good social conscience appropriate for a company engaged in business Commitments.
    [Show full text]
  • Targeted Therapies in Melanoma: Knowledge, Resistance And
    ooggeenneessii iinn ss && rrcc aa MM CC uu tt ff aa Journal ofJournal of oo gg ll ee ee aa aa nn nn nn nn ee ee rr rr ss ss uu uu ii ii Colombino et al., J Carcinog Mutagen 2014, S4:S4 ss ss oo oo JJ JJ ISSN: 2157-2518 CarCarcinogenesiscinogenesis & Mutagenesis DOI: 10.4172/2157-2518.S4-004 Review Article Open Access Targeted Therapies in Melanoma: Knowledge, Resistance and Perspectives Maria Colombino1*, Maria Cristina Sini1, Amelia Lissia2, Antonio Cossu2, and Giuseppe Palmieri1 1Unit of Cancer Genetics, Institute of Biomolecular Chemistry (ICB), National Research Council (CNR), Italy 2University Hospital Health Unit - Azienda Ospedaliero Universitaria (AOU), Via Matteotti, 07100 Sassari, Italy *Corresponding author: Dr. Maria Colombino, Unit of Cancer Genetics, Institute of Biomolecular Chemistry (ICB), National Research Council (CNR), Traversa La Crucca, 3 - Baldinca Li Punti, 07100 Sassari, Italy, Tel. +39 079 2841239; Fax +39 079 2841299; E-mail: [email protected] Received date: Mar 18, 2014, Accepted date: May 25, 2014, Published date: May 31, 2014 Copyright: © 2014 Colombino M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Several molecular mechanisms appear to play a major role in melanoma genesis and progression. Current targeted therapies focus on contrasting the activation of RAS/RAF/MEK/ERK and, to a less extent, PI3K/AKT pathways. Development of inhibitors of key effectors (mainly, BRAF mutant and MEK) has significantly improved treatment of patients with advanced melanoma.
    [Show full text]
  • A Phase I Dose Escalation Study of Tivantinib (ARQ 197) in Adult
    Author Manuscript Published OnlineFirst on October 5, 2011; DOI: 10.1158/1078-0432.CCR-11-1002 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. A Phase I Dose Escalation Study of Tivantinib (ARQ 197) in Adult Patients with Metastatic Solid Tumors Lee S. Rosen,1* Neil Senzer,2 Tarek Mekhail,3 Ram Ganapathi,3 Feng Chai,4 Ronald E Savage,4 Carol Waghorne,4 Giovanni Abbadessa,4 Brian Schwartz,4 Robert Dreicer3 1Premiere Oncology, 2020 Santa Monica Boulevard, Suite 600, Santa Monica, CA 90404. 2Mary Crowley Cancer Research Centers, 1700 Pacific St, Suite 1100, Dallas, TX 75201. 3 Department of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue R35, Cleveland, OH 44195. Dr. Mekhail is now with Florida Hospital Cancer Institute, 2501 North Orange Avenue, Orlando FL 32804. 4ArQule, Inc., Woburn, MA. *Corresponding author: Lee Rosen Tel: (310) 633-8400 Fax: (310) 633-8419 E-mail: [email protected] Running Title: Phase I Trial of Tivantinib in Patients with Metastatic Solid Tumors Key words: tivantinib, ARQ 197, pharmacokinetics, phase I, safety Word count: 3657 (not including Abstract and references) 41 references 5 tables and 1 figure 1 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2011 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 5, 2011; DOI: 10.1158/1078-0432.CCR-11-1002 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Translational Relevance Inhibitors of the receptor tyrosine kinase c-MET and its ligand, hepatocyte growth factor (HGF), have demonstrated activity in select cancer types.
    [Show full text]
  • A Systematic Review and Meta-Analysis Comparing The
    EUROPEAN UROLOGY 71 (2017) 426–436 available at www.sciencedirect.com journal homepage: www.europeanurology.com Review – Kidney Cancer A Systematic Review and Meta-analysis Comparing the Effectiveness and Adverse Effects of Different Systemic Treatments for Non-clear[3_TD$IF] Cell Renal Cell Carcinoma Sergio Ferna´ndez-Pello a,[3_TD$IF] Fabian Hofmann b, Rana Tahbaz c, Lorenzo Marconi d, Thomas B. Lam e,f, Laurence Albiges g, Karim Bensalah h, Steven E. Canfield i, Saeed Dabestani j, Rachel H. Giles k, Milan Hora l, Markus A. Kuczyk m, Axel S. Merseburger n, Thomas Powles o, Michael Staehler p, Alessandro Volpe q,Bo¨rje Ljungberg r, Axel Bex s,* a Department of Urology, Cabuen˜es Hospital, Gijo´n, Spain; b Department of Urology, Sunderby Hospital, Sunderby, Sweden; c Department of Urology, University Hospital Hamburg Eppendorf, Hamburg, Germany; d Department of Urology, Coimbra University Hospital, Coimbra, Portugal; e Academic Urology Unit, University of Aberdeen, Aberdeen, UK; f Department of Urology, Aberdeen Royal Infirmary, Aberdeen, UK; g Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France; h Department of Urology, University of Rennes, Rennes, France; i Division of Urology, University of Texas Medical School at Houston, Houston, TX, USA; j Department of Urology, Ska˚ne University Hospital, Malmo¨, Sweden; k Patient Advocate International Kidney Cancer Coalition (IKCC), University Medical Centre Utrecht, Department of Nephrology and Hypertension, Utrecht, The Netherlands; l Department of Urology, Faculty Hospital
    [Show full text]
  • Crusader Q2 2020 Research Edition Download
    Your resource for the latest research into the MET alteration. CRUSADER NEWSLETTER Q2 2020 RESEARCH EDITION MET Crusaders is a community of Lung Cancer patients and care givers collaborating with advocates and medical professionals collectively dedicated to helping patients with a MET alteration live normal lives. Come Join Us! [email protected] In this edition Top-level MET gene copy number gain defines .................... 2 Molecular Mechanisms of Acquired Resistance ................... 5 a subtype of poorly differentiated pulmonary to MET Tyrosine Kinase Inhibitors in Patients adenocarcinomas with poor prognosis with MET Exon 14-Mutant NSCLC EDITOR Characteristics and Clinical Outcomes of ............................. 2 MET Alterations Are a Recurring and Actionable .................. 6 Jessica McKernan, PharmD Non-Small Cell Lung Cancer Patients in Korea Resistance Mechanism in ALK-Positive Lung Cancer with MET Exon 14 Skipping Atrium Health Tepotinib in Non-Small-Cell Lung Cancer with ...................... 6 Charlotte, NC Clinical and molecular correlates of PD-L1 ........................... 2 MET Exon 14 Skipping Mutations (VISION Trial) expression in patients with lung adenocarcinomas Therapeutic Efficacy of ABN401, a Highly ............................. 7 CONTRIBUTING EDITORS Efficacy and Safety of Anti-PD-1 Immunotherapy ................. 3 Potent and Selective MET Inhibitor, Based on Julia Stevens, PharmD in Patients With Advanced NSCLC With BRAF, HER2, Diagnostic Biomarker Test in MET-Addicted Cancer or MET Mutations or RET Translocation: GFPC 01-2018 Beth Israel Deaconess Erlotinib plus tivantinib versus erlotinib alone ..................... 7 Medical Center Alterations in the PI3K Pathway Drive Resistance ................ 3 in patients with previously treated stage IIIb/IV Boston, MA to MET Inhibitors in NSCLC Harboring MET non-small-cell lung cancer: A meta-analysis based Exon 14 Skipping Mutations on randomized controlled trials Laura Schmidt, PharmD Incidence and PD-L1 Expression of MET 14 .........................
    [Show full text]
  • Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0192440 A1
    US 20190192440A1 (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0192440 A1 LI (43 ) Pub . Date : Jun . 27 , 2019 ( 54 ) ORAL DRUG DOSAGE FORM COMPRISING Publication Classification DRUG IN THE FORM OF NANOPARTICLES (51 ) Int . CI. A61K 9 / 20 (2006 .01 ) ( 71 ) Applicant: Triastek , Inc. , Nanjing ( CN ) A61K 9 /00 ( 2006 . 01) A61K 31/ 192 ( 2006 .01 ) (72 ) Inventor : Xiaoling LI , Dublin , CA (US ) A61K 9 / 24 ( 2006 .01 ) ( 52 ) U . S . CI. ( 21 ) Appl. No. : 16 /289 ,499 CPC . .. .. A61K 9 /2031 (2013 . 01 ) ; A61K 9 /0065 ( 22 ) Filed : Feb . 28 , 2019 (2013 .01 ) ; A61K 9 / 209 ( 2013 .01 ) ; A61K 9 /2027 ( 2013 .01 ) ; A61K 31/ 192 ( 2013. 01 ) ; Related U . S . Application Data A61K 9 /2072 ( 2013 .01 ) (63 ) Continuation of application No. 16 /028 ,305 , filed on Jul. 5 , 2018 , now Pat . No . 10 , 258 ,575 , which is a (57 ) ABSTRACT continuation of application No . 15 / 173 ,596 , filed on The present disclosure provides a stable solid pharmaceuti Jun . 3 , 2016 . cal dosage form for oral administration . The dosage form (60 ) Provisional application No . 62 /313 ,092 , filed on Mar. includes a substrate that forms at least one compartment and 24 , 2016 , provisional application No . 62 / 296 , 087 , a drug content loaded into the compartment. The dosage filed on Feb . 17 , 2016 , provisional application No . form is so designed that the active pharmaceutical ingredient 62 / 170, 645 , filed on Jun . 3 , 2015 . of the drug content is released in a controlled manner. Patent Application Publication Jun . 27 , 2019 Sheet 1 of 20 US 2019 /0192440 A1 FIG .
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • A Abacavir Abacavirum Abakaviiri Abagovomab Abagovomabum
    A abacavir abacavirum abakaviiri abagovomab abagovomabum abagovomabi abamectin abamectinum abamektiini abametapir abametapirum abametapiiri abanoquil abanoquilum abanokiili abaperidone abaperidonum abaperidoni abarelix abarelixum abareliksi abatacept abataceptum abatasepti abciximab abciximabum absiksimabi abecarnil abecarnilum abekarniili abediterol abediterolum abediteroli abetimus abetimusum abetimuusi abexinostat abexinostatum abeksinostaatti abicipar pegol abiciparum pegolum abisipaaripegoli abiraterone abirateronum abirateroni abitesartan abitesartanum abitesartaani ablukast ablukastum ablukasti abrilumab abrilumabum abrilumabi abrineurin abrineurinum abrineuriini abunidazol abunidazolum abunidatsoli acadesine acadesinum akadesiini acamprosate acamprosatum akamprosaatti acarbose acarbosum akarboosi acebrochol acebrocholum asebrokoli aceburic acid acidum aceburicum asebuurihappo acebutolol acebutololum asebutololi acecainide acecainidum asekainidi acecarbromal acecarbromalum asekarbromaali aceclidine aceclidinum aseklidiini aceclofenac aceclofenacum aseklofenaakki acedapsone acedapsonum asedapsoni acediasulfone sodium acediasulfonum natricum asediasulfoninatrium acefluranol acefluranolum asefluranoli acefurtiamine acefurtiaminum asefurtiamiini acefylline clofibrol acefyllinum clofibrolum asefylliiniklofibroli acefylline piperazine acefyllinum piperazinum asefylliinipiperatsiini aceglatone aceglatonum aseglatoni aceglutamide aceglutamidum aseglutamidi acemannan acemannanum asemannaani acemetacin acemetacinum asemetasiini aceneuramic
    [Show full text]
  • Recent Advances in the Management of Advanced Non–Small-Cell Lung Cancer Charu Aggarwal, MD, MPH, and Corey J
    Review Recent advances in the management of advanced non–small-cell lung cancer Charu Aggarwal, MD, MPH, and Corey J. Langer, MD Department of Medicine, Hematology-Oncology Division, University of Pennsylvania, Philadelphia Lung cancer is the leading cause of cancer-related mortality among men and women in the United States. Non–small-cell lung cancer (NSCLC) accounts for about 85% of all lung cancers. Most patients with NSCLC present with advanced disease and median overall survival in this incurable setting remain dismal. Accumulating evidence suggests that both histology and molecular signature have prognostic and predictive value for NSCLC. Recent advances in the molecular characterization of NSCLC tumors have made individualized treatment approaches feasible. Personalized chemotherapy and targeted biological therapy based on a tumor’s individual biologic and molecular profile can optimize efficacy while minimizing toxicity. Molecular testing for activating mutations in the epidermal growth factor receptor (EGFR) domain and EML4-ALK translocation are routinely used to guide therapeutic decisions. Several new treatments that irreversibly target EGFR family members are in development for patients with NSCLC. Novel EML4-ALK inhibitors such as LDK378 are promising agents with encouraging early efficacy data. KRAS mutations are the most common mutation in adenocarcinomas. Although no agents for this subset of NSCLC have been approved, there are several agents in clinical development, including selumetinib, an MEK inhibitor, that seem promising. A growing body of evidence suggests that NSCLC is subject to immune surveillance. Immunotherapeutic interventions, including vaccine therapy and antigen-independent immunomodulatory strategies, may improve outcomes in NSCLC. In this review, we summarize recent advances in non–small-cell lung cancer, with an emphasis on investigational strategies for individualized treatment.
    [Show full text]
  • A Phase I Trial of Topotecan Plus Tivantinib in Patients with Advanced Solid Tumors
    Cancer Chemotherapy and Pharmacology https://doi.org/10.1007/s00280-018-3672-y CLINICAL TRIAL REPORT A phase I trial of topotecan plus tivantinib in patients with advanced solid tumors Stephen V. Liu1 · Susan G. Groshen2 · Karen Kelly3 · Karen L. Reckamp4 · Chandra Belani5 · Timothy W. Synold4 · Amir Goldkorn2 · Barbara J. Gitlitz2,6 · Mihaela C. Cristea4 · I‑Yeh Gong3 · Thomas J. Semrad3 · Yucheng Xu2 · Tong Xu2 · Marianna Koczywas4 · David R. Gandara3 · Edward M. Newman4 Received: 26 April 2018 / Accepted: 17 August 2018 © Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract Purpose Tyrosine kinase inhibitors (TKI) that target MET signaling have shown promise in various types of cancer, includ- ing lung cancer. Combination strategies have been proposed and developed to increase their therapeutic index. Based on preclinical synergy between inhibition of MET and topoisomerase I, a phase I study was designed to explore the combination of topotecan with the MET TKI tivantinib. Methods Eligible patients with advanced solid malignancies for which there was no known effective treatment received topotecan at doses of 1.0–1.5 mg/m2/day for five consecutive days in 21-day cycles with continuous, oral tivantinib given at escalating doses of 120–360 mg orally twice daily. Pharmacokinetic analyses of tivantinib were included. Circulating tumor cells (CTC) were collected serially to identify peripheral changes in MET phosphorylation. Results The trial included 18 patients, 17 of whom received treatment. At the planned doses, the combination of topotecan and tivantinib was not tolerable due to thrombocytopenia and neutropenia. The addition of G-CSF to attenuate neutropenia did not improve tolerability.
    [Show full text]
  • Profile of Tivantinib and Its Potential in the Treatment of Hepatocellular Carcinoma: the Evidence to Date
    Journal name: Journal of Hepatocellular Carcinoma Article Designation: REVIEW Year: 2016 Volume: 3 Journal of Hepatocellular Carcinoma Dovepress Running head verso: Pievsky and Pyrsopoulos Running head recto: Tivantinib and its potential in the treatment of HCC open access to scientific and medical research DOI: http://dx.doi.org/10.2147/JHC.S106072 Open Access Full Text Article REVIEW Profile of tivantinib and its potential in the treatment of hepatocellular carcinoma: the evidence to date Daniel Pievsky1 Abstract: Hepatocellular carcinoma (HCC) is the fastest rising cause of cancer-related death Nikolaos Pyrsopoulos2 in the United States and carries a very poor prognosis, with a median survival time of <50% at 1 year for advanced disease. To date, sorafenib is the only therapy approved by the Food 1Department of Internal Medicine, 2Division of Gastroenterology and and Drug Administration for the treatment of advanced HCC. Tivantinib (ARQ-197), a non- Hepatology, Rutgers New Jersey ATP competitive inhibitor of cellular mesenchymal–epithelial transcription factor (c-MET), Medical School, University Hospital, has shown a survival benefit in patients with advanced HCC who have failed or are intolerant Newark, NJ, USA to sorafenib in Phase I and II trials. Those patients who have tumors with high concentra- tions of MET (MET-high) appear to derive the greatest benefit from tivantinib therapy. Cur- rently, two large randomized double-blind placebo-controlled Phase III trials (METIV-HCC For personal use only. [NCT01755767] and JET-HCC [NCT02029157]) are evaluating tivantinib in patients with MET-high advanced HCC, with the primary end points of overall survival and progression-free survival, respectively.
    [Show full text]
  • Phase 1B/2 Trial of Tepotinib in Sorafenib Pretreated Advanced Hepatocellular Carcinoma with MET Overexpression
    www.nature.com/bjc ARTICLE Clinical Study Phase 1b/2 trial of tepotinib in sorafenib pretreated advanced hepatocellular carcinoma with MET overexpression Thomas Decaens 1, Carlo Barone2, Eric Assenat3, Martin Wermke4, Angelica Fasolo5, Philippe Merle6, Jean-Frédéric Blanc7, Véronique Grando8, Angelo Iacobellis9, Erica Villa10, Joerg Trojan11, Josef Straub12, Rolf Bruns13, Karin Berghoff14, Juergen Scheele15, Eric Raymond16 and Sandrine Faivre17 BACKGROUND: This Phase 1b/2 study evaluated tepotinib, a highly selective MET inhibitor, in US/European patients with sorafenib pretreated advanced hepatocellular carcinoma (aHCC) with MET overexpression. METHODS: Eligible adults had aHCC, progression after ≥4 weeks of sorafenib, and, for Phase 2 only, MET overexpression. Tepotinib was administered once daily at 300 or 500 mg in Phase 1b (‘3 + 3’ design), and at the recommended Phase 2 dose (RP2D) in Phase 2. Primary endpoints were dose-liming toxicities (DLTs; Phase 1b) and 12-week investigator-assessed progression-free survival (PFS; Phase 2). RESULTS: In Phase 1b (n = 17), no DLTs occurred and the RP2D was confirmed as 500 mg. In Phase 2 (n = 49), the primary endpoint was met: 12-week PFS was 63.3% (90% CI: 50.5–74.7), which was significantly greater than the predefined null hypothesis of ≤15% (one-sided binomial exact test: P < 0.0001). Median time to progression was 4 months. In Phase 2, 28.6% of patients had treatment- related Grade ≥3 adverse events, including peripheral oedema and lipase increase (both 6.1%). CONCLUSIONS: Tepotinib was generally well tolerated and the RP2D (500 mg) showed promising efficacy and, therefore, a positive benefit–risk balance in sorafenib pretreated aHCC with MET overexpression.
    [Show full text]