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Clinical Protocol
OncoMed Pharmaceuticals, Inc. Demcizumab CLINICAL PROTOCOL Protocol No. M18-006 Title: YOSEMITE: A 3-Arm Phase 2 Double-Blind Randomized StudY of Gemcitabine, Abraxane® Plus PlacebO versuS GEMcitabIne, Abraxane® plus 1 or 2 TruncatEd Courses of Demcizumab in Subjects with 1st-Line Metastatic Pancreatic Ductal Adenocarcinoma Version: 23 October 2014 Amendment 1: 24 November 2014 Amendment 2: 10 February 2015 Amendment 3: 28 May 2015 Amendment 4: 31 March 2016 Amendment 5: 19 December 2016 EudraCT Number: 2014‐003355‐56 Sponsor: OncoMed Pharmaceuticals, Inc. 800 Chesapeake Drive Redwood City, CA 94063 Phone: 650-995-8200 CONFIDENTIAL This document contains proprietary and confidential information of OncoMed Pharmaceuticals, Inc. Acceptance of this document constitutes agreement by the recipient that no previously unpublished information contained herein will be published or disclosed without the prior written approval of OncoMed Pharmaceuticals, Inc. with the exception that this document may be disclosed to study personnel under your supervision who need to know the contents for conducting the study and appropriate Institutional Review Boards/Ethics Committees under the condition that the personnel have agreed to keep this information confidential. The foregoing shall not apply to disclosure required by governmental regulations or laws; however, OncoMed Pharmaceuticals, Inc. shall be promptly notified of any such disclosure. Protocol M18-006, Amendment 5 Page 1 of 130 CONFIDENTIAL 19 December 2016 OncoMed Pharmaceuticals, Inc. Demcizumab SPONSOR CONTACTS Medical Monitor: ___________________ (Primary) ___________________________ Email: ___________________ Phone: ____________________ Medical Monitor: ___________________ (Secondary) ___________________ Email: ___________________ Phone: ___________________ Safety Reporting: Europe, Australia Phone: ___________________ Fax: ___________________ United States Phone: ___________________ Fax: ___________________ Protocol M18-006, Amendment 5 Page 2 of 130 CONFIDENTIAL 19 December 2016 OncoMed Pharmaceuticals, Inc. -
( 12 ) Patent Application Publication ( 10 ) Pub . No .: US 2020/0121788 A1
US 20200121788A1 IN (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No .: US 2020/0121788 A1 MASSIMINI et al. (43 ) Pub . Date : Apr. 23 , 2020 ( 54 ) ABITUZUMAB FOR THE TREATMENT OF A61K 31/44 (2006.01 ) COLORECTAL CANCER A61P 35/00 (2006.01 ) (52 ) U.S. Cl. ( 71) Applicant: Merck Patent GmbH , Darmstadt (DE ) CPC ... A61K 39/39558 (2013.01 ) ; CO7K 16/2848 ( 2013.01 ) ; CO7K 16/2863 ( 2013.01 ) ; CO7K ( 72 ) Inventors: Giorgio MASSIMINI, Darmstadt (DE ) ; 16/22 (2013.01 ) ; A61K 31/4745 ( 2013.01 ) ; Ilhan Celik , Zwingenberg (DE ) ; Josef A61K 31/513 ( 2013.01 ) ; A61K 2039/505 Straub , Seeheim - Jugenheim (DE ) ; Rolf ( 2013.01) ; A61K 31/519 ( 2013.01 ) ; A61K Bruns, Darmstadt ( DE ) 33/243 (2019.01 ) ; A6IK 38/179 ( 2013.01) ; A61K 31/44 ( 2013.01) ; A61P 35/00 ( 2018.01 ) ; ( 73 ) Assignee: Merck Patent GmbH , Darmstadt (DE ) CO7K 2317/76 ( 2013.01) ; A61K 31/7072 ( 21 ) Appl. No .: 16 /657,828 ( 2013.01) ( 22 ) Filed : Oct. 18 , 2019 (57 ) ABSTRACT Methods of treatment of colorectal cancer can include the Related U.S. Application Data administration of the anti - alpha - v integrin (receptor ) anti (60 ) Provisional application No. 62 / 748,114 , filed on Oct. body Abituzumab . Preferably , the methods of treating col 19 , 2018 . orectal cancer can include treating Stage II - IV colorectal cancer, metastatic colorectal cancer , left - sided colorectal Publication Classification cancer and /or left- sided metastatic colorectal cancer, involv ( 51) Int. Ci. ing the administration of said Abituzumab to patients in need A61K 39/395 ( 2006.01 ) thereof. Abituzumab is also useful for the manufacture of a COZK 16/28 ( 2006.01 ) medicament for treating colorectal cancer , preferably col COOK 16/22 ( 2006.01 ) orectal cancer as defined herein . -
Precision Medicine for Human Cancers with Notch Signaling Dysregulation (Review)
INTERNATIONAL JOURNAL OF MOleCular meDICine 45: 279-297, 2020 Precision medicine for human cancers with Notch signaling dysregulation (Review) MASUKO KATOH1 and MASARU KATOH2 1M & M PrecMed, Tokyo 113-0033; 2Department of Omics Network, National Cancer Center, Tokyo 104-0045, Japan Received September 16, 2019; Accepted November 20, 2019 DOI: 10.3892/ijmm.2019.4418 Abstract. NOTCH1, NOTCH2, NOTCH3 and NOTCH4 are conjugate (ADC) Rova-T, and DLL3-targeting chimeric antigen transmembrane receptors that transduce juxtacrine signals of receptor‑modified T cells (CAR‑Ts), AMG 119, are promising the delta-like canonical Notch ligand (DLL)1, DLL3, DLL4, anti-cancer therapeutics, as are other ADCs or CAR-Ts targeting jagged canonical Notch ligand (JAG)1 and JAG2. Canonical tumor necrosis factor receptor superfamily member 17, Notch signaling activates the transcription of BMI1 proto-onco- CD19, CD22, CD30, CD79B, CD205, Claudin 18.2, fibro- gene polycomb ring finger, cyclin D1, CD44, cyclin dependent blast growth factor receptor (FGFR)2, FGFR3, receptor-type kinase inhibitor 1A, hes family bHLH transcription factor 1, tyrosine-protein kinase FLT3, HER2, hepatocyte growth factor hes related family bHLH transcription factor with YRPW receptor, NECTIN4, inactive tyrosine-protein kinase 7, inac- motif 1, MYC, NOTCH3, RE1 silencing transcription factor and tive tyrosine-protein kinase transmembrane receptor ROR1 transcription factor 7 in a cellular context-dependent manner, and tumor-associated calcium signal transducer 2. ADCs and while non-canonical Notch signaling activates NF-κB and Rac CAR-Ts could alter the therapeutic framework for refractory family small GTPase 1. Notch signaling is aberrantly activated cancers, especially diffuse-type gastric cancer, ovarian cancer in breast cancer, non-small-cell lung cancer and hematological and pancreatic cancer with peritoneal dissemination. -
The Extracellular Matrix: an Accomplice in Gastric Cancer Development and Progression
cells Review The Extracellular Matrix: An Accomplice in Gastric Cancer Development and Progression Ana Margarida Moreira 1,2,3, Joana Pereira 1,2,4, Soraia Melo 1,2,4 , Maria Sofia Fernandes 1,2, Patrícia Carneiro 1,2 , Raquel Seruca 1,2,4 and Joana Figueiredo 1,2,* 1 Epithelial Interactions in Cancer Group, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; [email protected] (A.M.M.); [email protected] (J.P.); [email protected] (S.M.); [email protected] (M.S.F.); [email protected] (P.C.); [email protected] (R.S.) 2 Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135 Porto, Portugal 3 Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal 4 Medical Faculty, University of Porto, 4200-319 Porto, Portugal * Correspondence: jfi[email protected]; Tel.: +351-220408800; Fax: +351-225570799 Received: 15 January 2020; Accepted: 6 February 2020; Published: 8 February 2020 Abstract: The extracellular matrix (ECM) is a dynamic and highly organized tissue structure, providing support and maintaining normal epithelial architecture. In the last decade, increasing evidence has emerged demonstrating that alterations in ECM composition and assembly strongly affect cellular function and behavior. Even though the detailed mechanisms underlying cell-ECM crosstalk are yet to unravel, it is well established that ECM deregulation accompanies the development of many pathological conditions, such as gastric cancer. Notably, gastric cancer remains a worldwide concern, representing the third most frequent cause of cancer-associated deaths. Despite increased surveillance protocols, patients are usually diagnosed at advanced disease stages, urging the identification of novel diagnostic biomarkers and efficient therapeutic strategies. -
Bufadienolides from the Skin Secretions of the Neotropical Toad Rhinella Alata (Anura: Bufonidae): Antiprotozoal Activity Against Trypanosoma Cruzi
molecules Article Bufadienolides from the Skin Secretions of the Neotropical Toad Rhinella alata (Anura: Bufonidae): Antiprotozoal Activity against Trypanosoma cruzi Candelario Rodriguez 1,2,3 , Roberto Ibáñez 4 , Luis Mojica 5, Michelle Ng 6, Carmenza Spadafora 6 , Armando A. Durant-Archibold 1,3,* and Marcelino Gutiérrez 1,* 1 Centro de Biodiversidad y Descubrimiento de Drogas, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Apartado 0843-01103, Panama; [email protected] 2 Department of Biotechnology, Acharya Nagarjuna University, Nagarjuna Nagar, Guntur 522510, India 3 Departamento de Bioquímica, Facultad de Ciencias Naturales, Exactas y Tecnología, Universidad de Panamá, Apartado 0824-03366, Panama 4 Smithsonian Tropical Research Institute (STRI), Balboa, Ancon P.O. Box 0843-03092, Panama; [email protected] 5 Centro Nacional de Metrología de Panamá (CENAMEP AIP), Apartado 0843-01353, Panama; [email protected] 6 Centro de Biología Celular y Molecular de Enfermedades, INDICASAT AIP, Apartado 0843-01103, Panama; [email protected] (M.N.); [email protected] (C.S.) * Correspondence: [email protected] (A.A.D.-A.); [email protected] (M.G.) Abstract: Toads in the family Bufonidae contain bufadienolides in their venom, which are charac- Citation: Rodriguez, C.; Ibáñez, R.; terized by their chemical diversity and high pharmacological potential. American trypanosomiasis Mojica, L.; Ng, M.; Spadafora, C.; is a neglected disease that affects an estimated 8 million people in tropical and subtropical coun- Durant-Archibold, A.A.; Gutiérrez, M. tries. In this research, we investigated the chemical composition and antitrypanosomal activity Bufadienolides from the Skin of toad venom from Rhinella alata collected in Panama. -
The Role of Cancer Stem Cells in Colorectal Cancer: from the Basics to Novel Clinical Trials
cancers Review The Role of Cancer Stem Cells in Colorectal Cancer: From the Basics to Novel Clinical Trials Céline Hervieu 1 , Niki Christou 1,2 , Serge Battu 1 and Muriel Mathonnet 1,2,* 1 EA 3842 CAPTuR “Control of Cell Activation in Tumor Progression and Therapeutic Resistance”, Faculty of Medicine, Genomics, Environment, Immunity, Health and Therapeutics (GEIST) Institute, University of Limoges, 87025 Limoges CEDEX, France; [email protected] (C.H.); [email protected] (N.C.); [email protected] (S.B.) 2 Department of General, Endocrine and Digestive Surgery, University Hospital of Limoges, 87025 Limoges CEDEX, France * Correspondence: [email protected] Simple Summary: Cancer stem cells (CSCs) fuel tumor growth, metastasis and resistance to therapy in colorectal cancer (CRC). These cells therefore represent a promising target for the treatment of CRC but are difficult to study because of the complexity of their isolation. This review presents the methods currently used to isolate colorectal CSCs as well as the techniques for characterizing these cells with their advantages and limitations. The aim of this review is to provide a state-of-the-art on the clinical relevance of CSCs in CRC by outlining current treatments for CRC, the resistance mechanisms developed by CSCs to overcome them, and ongoing clinical trials of drugs targeting CSCs in CRC. Overall, this review addresses the complexity of studying CSCs in CRC research and developing clinically effective treatments to enable CRC patients to achieve a short and long-term therapeutic response. Citation: Hervieu, C.; Christou, N.; Battu, S.; Mathonnet, M. The Role of Abstract: The treatment options available for colorectal cancer (CRC) have increased over the years Cancer Stem Cells in Colorectal and have significantly improved the overall survival of CRC patients. -
Predictive QSAR Tools to Aid in Early Process Development of Monoclonal Antibodies
Predictive QSAR tools to aid in early process development of monoclonal antibodies John Micael Andreas Karlberg Published work submitted to Newcastle University for the degree of Doctor of Philosophy in the School of Engineering November 2019 Abstract Monoclonal antibodies (mAbs) have become one of the fastest growing markets for diagnostic and therapeutic treatments over the last 30 years with a global sales revenue around $89 billion reported in 2017. A popular framework widely used in pharmaceutical industries for designing manufacturing processes for mAbs is Quality by Design (QbD) due to providing a structured and systematic approach in investigation and screening process parameters that might influence the product quality. However, due to the large number of product quality attributes (CQAs) and process parameters that exist in an mAb process platform, extensive investigation is needed to characterise their impact on the product quality which makes the process development costly and time consuming. There is thus an urgent need for methods and tools that can be used for early risk-based selection of critical product properties and process factors to reduce the number of potential factors that have to be investigated, thereby aiding in speeding up the process development and reduce costs. In this study, a framework for predictive model development based on Quantitative Structure- Activity Relationship (QSAR) modelling was developed to link structural features and properties of mAbs to Hydrophobic Interaction Chromatography (HIC) retention times and expressed mAb yield from HEK cells. Model development was based on a structured approach for incremental model refinement and evaluation that aided in increasing model performance until becoming acceptable in accordance to the OECD guidelines for QSAR models. -
Preventive and Therapeutic Effects of Chinese Herbal Compounds Against Hepatocellular Carcinoma
molecules Review Preventive and Therapeutic Effects of Chinese Herbal Compounds against Hepatocellular Carcinoma Bing Hu 1,*, Hong-Mei An 2, Shuang-Shuang Wang 1, Jin-Jun Chen 3 and Ling Xu 1 1 Department of Oncology and Institute of Traditional Chinese Medicine in Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; [email protected] (S.-S.W.); [email protected] (L.X.) 2 Department of Science & Technology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 202032, China; [email protected] 3 Department of Plastic & Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, The Ninth People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China; [email protected] * Correspondence: [email protected]; Tel.: +86-21-64385700 Academic Editor: Derek J. McPhee Received: 16 November 2015 ; Accepted: 20 January 2016 ; Published: 27 January 2016 Abstract: Traditional Chinese Medicines, unique biomedical and pharmaceutical resources, have been widely used for hepatocellular carcinoma (HCC) prevention and treatment. Accumulated Chinese herb-derived compounds with significant anti-cancer effects against HCC have been identified. Chinese herbal compounds are effective in preventing carcinogenesis, inhibiting cell proliferation, arresting cell cycle, inducing apoptosis, autophagy, cell senescence and anoikis, inhibiting epithelial-mesenchymal transition, metastasis and angiogenesis, regulating immune function, reversing drug -
Andrew Lai Thesis
TOWARDS THE DEVELOPMENT OF NOVEL BISPECIFIC ANTIBODIES TO INHIBIT KEY CELL SURFACE RECEPTORS INTEGRAL FOR THE GROWTH AND MIGRATION OF TUMOUR CELLS Andrew Lai Bachelor of Science, UNSW 2008 Master of Biotechnology, QUT 2010 Bachelor of Applied Science (Hons), QUT 2012 Submitted for the degree of Doctor of Philosophy Institute of Health and Biomedical Innovation Faculty of Health Queensland University of Technology 2016 Keywords Breast cancer, extracellular matrix, insulin-like growth factor, metastasis, migration, therapeutics, phage display, single chain variable fragments, vitronectin Towards the development of novel bispecific antibodies to inhibit key cell surface receptors integral for the growth and migration of tumour cells i Abstract Metastatic breast cancer, or breast cancer which has spread from the primary tumour to distal secondary sites, remains a major killer of women today. Researchers have observed that the relationship between tumour cells and its surrounding environment plays an important role in cancer progression. One such interaction is between the Insulin-like growth factor (IGF) system and the integrin system, which has been demonstrated to be involved in cancer cell metabolic activity and migration. Therefore, the aim of this project was to translate this knowledge into the generation of bispecific antibody fragments (BsAb) targeting both systems, in order to disrupt their roles in cancer growth and metastasis. To screen for IGF-1R and αv integrin binding ScFv, a phage display enrichment procedure using the Tomlinson ScFv libraries was conducted. After the panning cycles, 192 clones were screened for binding using ELISA, of which 16 were selected for sequencing. Analysis of the results revealed 1 IGF-R and 3 αv integrin unique binding ScFv, which were all subsequently expressed in a bacterial expression system. -
Cinobufagin Inhibits Tumor Growth by Inducing Apoptosis Through Notch Signaling Pathways in Human Cholangiocarcinoma
2469 Original Article Cinobufagin inhibits tumor growth by inducing apoptosis through Notch signaling pathways in human cholangiocarcinoma Jiajun Ren1, Shouhua Wang2, Longyang Jin2, Fei Ma3, Di Zhou2, Qiang Cai1 1Department of General Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China; 2Department of General Surgery, 3Department of Oncology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China Contributions: (I) Conception and design: J Ren, D Zhou, Q Cai; (II) Administrative support: D Zhou, Q Cai; (III) Provision of study materials or patients: S Wang, L Jin; (IV) Collection and assembly of data: S Wang, F Ma; (V) Data analysis and interpretation: L Jin, F Ma; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Qiang Cai. Department of General Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin No. 2 Road, Shanghai 200025, China. Email: [email protected]; Di Zhou. Department of General Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China. Email: [email protected]. Background: Many studies have shown that cinobufagin has antitumor effects against many cancers. The aim of this study was to assess the effects of cinobufagin on cholangiocarcinoma (CCA) cells. Methods: Colony formation assay, cell-counting kit-8 (CCK-8) assay, and tumor xenograft experiments were applied to investigate the function of cinobufagin on human CCA cells, in vitro and in vivo. Flow cytometric analysis was performed to validate the effects of cinobufagin on cell apoptosis. -
2015 Post-ASH Report
Datamonitor Healthcare Trialtrove Biomedtracker Pharma intelligence | Pharma intelligence | Pharma intelligence | 2015 Post-ASH Report RACHEL MEIGHAN-MANTHA Principal Analyst, Citeline JOSEPH HEDDEN Senior Analyst, Datamonitor Healthcare Summary Profiled themes at the 57th Annual Meeting and Exposition of the American Society of Hematology (ASH), held December 5-8, 2015, in Orlando, Florida, included Genomic Profiling and Chemical Biology, Genome Editing and Gene Therapy, Epigenetic Mechanisms, Immunologic Treatments, Stem Cell Biology and Regenerative Medicine and Preventing Venous Thromboembolic Disease. This report will mainly focus on the theme of Immunologic Treatments because of the importance and popularity of immunotherapies for many different hematological cancers. Also covered in this report are the results from pivotal trials presented at ASH, as well as highlights from other drugs/therapies of interest. In addition, we felt it was important to cover first-in-human trials since (hopefully) some of these drugs/therapies will be in pivotal trials in a few years. At the end of the report, we’ve included a section showcasing drugs that had top- line results presented at ASH, followed by a list of other data presentations supplied by BioMedTracker (BMT). Accompanying links to BioMedTracker events along with changes to the drugs’ likelihood of approval (LOA) are also provided throughout the report. Finally, additional supplemental material related to ASH is listed in the Appendix. 2 Datamonitor Healthcare Trialtrove Biomedtracker -
Patient Resource Free
PATIENT RESOURCE FREE Third Edition CancerUnderstanding Immunotherapy Published in partnership with CONTENT REVIEWED BY A DISTINGUISHED PRP MEDICAL PATIENT ADVISORY RESOURCE BOARD PUBLISHING® Understanding TABLE OF CONTENTS Cancer Immunotherapy Third Edition IN THIS GUIDE 1 Immunotherapy Today 2 The Immune System 4 Immunotherapy Strategies 6 Melanoma Survivor Story: Jane McNee Chief Executive Officer Mark A. Uhlig I didn’t look sick, so I didn’t want to act sick. Publisher Linette Atwood Having and treating cancer is only one part of your life. Co-Editor-in-Chief Charles M. Balch, MD, FACS Jane McNee, melanoma survivor Co-Editor-in-Chief Howard L. Kaufman, MD, FACS Senior Vice President Debby Easum 7 The Road to Immunotherapy Vice President, Operations Leann Sandifar 8 Cancer Types Managing Editor Lori Alexander, MTPW, ELS, MWC™ 14 Side Effects Senior Editors Dana Campbell Colleen Scherer 15 Glossary Graphic Designer Michael St. George 16 About Clinical Trials Medical Illustrator Todd Smith 16 Cancer Immunotherapy Clinical Trials by Disease Production Manager Jennifer Hiltunen 35 Support & Financial Resources Vice Presidents, Amy Galey Business Development Kathy Hungerford 37 Notes Stephanie Myers Kenney Account Executive Melissa Amaya Office Address 8455 Lenexa Drive CO-EDITORS-IN-CHIEF Overland Park, KS 66214 For Additional Information [email protected] Charles M. Balch, MD, FACS Advisory Board Visit our website at Professor of Surgery, The University of Texas PatientResource.com to read bios of MD Anderson Cancer Center our Medical and Patient Advisory Board. Editor-in-Chief, Patient Resource LLC Editor-in-Chief, Annals of Surgical Oncology Past President, Society of Surgical Oncology For Additional Copies: To order additional copies of Patient Resource Cancer Guide: Understanding Cancer Immunotherapy, Howard L.