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CLINICAL TRIAL PROTOCOL Trial Title Symphogen Clinical Trial Protocol Trial ID: Sym004-13 Version 6.0 CLINICAL TRIAL PROTOCOL Trial Title: A Phase 2, Randomized, Open-Label, Multicenter, Three-Arm Trial of Sym004 versus each of its Component Monoclonal Antibodies, Futuximab and Modotuximab, in Patients with Chemotherapy-Refractory Metastatic Colorectal Carcinoma and Acquired Resistance to Anti-EGFR Monoclonal Antibody Therapy Short Title: Sym004 versus Futuximab or Modotuximab in Patients with mCRC Sponsor: Symphogen A/S Sponsor’s Medical Expert: Coordinating Investigator: Trial ID: Sym004-13 Trial Phase: Phase 2 IND Number: 105953 EudraCT Number: 2018-000618-39 Protocol Version/Date: 6.0 / 18-Jan-2019 (Amendment 5) Previous Protocol 5.0 / 02-Aug-2018 (Amendment 4) Versions/Dates: 4.0 / 08-May-2018 (Amendment 3) 3.0 / 08-Mar-2018 (Amendment 2) 2.0 / 02-Jan-2018 (Amendment 1) 1.0 / 27-Oct-2017 Confidential Page 1 of 169 Symphogen Clinical Trial Protocol Trial ID: Sym004-13 Version 6.0 Sponsor Declarations This confidential document is the property of Symphogen A/S. No unpublished information contained herein may be passed on, reproduced, published or used without prior written approval from Symphogen A/S. Access to this document must be restricted to relevant parties. The trial will be conducted in compliance with this clinical trial protocol, International Council for Harmonisation (ICH) of Technical Requirements for Pharmaceuticals for Human Use E6(R2): Guideline for Good Clinical Practice (GCP) (EMA/CHMP/ICH/135/1995), the Declaration of Helsinki, and applicable regulations. The Sponsor has appointed a Coordinating Investigator for the trial. This Coordinating Investigator will provide input to the trial design and act as overall coordinator for Investigators across all sites. The Coordinating Investigator will furthermore sign off the Clinical Trial Report (CTR) on behalf of all Investigators. Lists of Investigators responsible for conducting the trial, medically qualified physicians responsible for all site-related medical decisions (if other than the Investigators), monitors, clinical laboratories, and other medical and/or technical departments and/or institutions involved in the trial are provided as separate documents. Confidential Page 2 of 169 Symphogen Clinical Trial Protocol Trial ID: Sym004-13 Version 6.0 Principal Investigator Signature Page I, the undersigned, am responsible for the conduct of the trial at this site and agree: To assume responsibility for the proper conduct of the clinical trial at this Investigational Site Not to implement any changes to the clinical trial protocol without agreement from the Sponsor and prior review and written approval from the appropriate Health Authority (as indicated) and the Institutional Review Board/ Ethics Committee, except where necessary to eliminate an immediate hazard to the patients That I am aware of, and will comply with “Good Clinical Practice” (ICH E6(R2) GCP) (EMA/CHMP/ICH/135/1995), the Declaration of Helsinki, and all applicable regulatory requirements That all site staff to which I have delegated tasks for this clinical trial, are appropriately selected and adequately informed about the investigational product(s) and of their trial- related duties and functions as described in the clinical trial protocol ________________________________ ____________________ Signature Date of Signature Name: _________________________ Academic Degree: ________________________ Function: _______________________________ Institution: ______________________________ Confidential Page 3 of 169 Symphogen Clinical Trial Protocol Trial ID: Sym004-13 Version 6.0 TABLE OF CONTENTS LIST OF ABBREVIATIONS AND EXPANDED TERMS .........................................................11 1 SYNOPSIS .............................................................................................................................15 2 SCIENTIFIC BACKGROUND AND RATIONALE ...........................................................25 2.1 Background ........................................................................................................................25 2.1.1 Metastatic Colorectal Carcinoma ....................................................................................25 2.1.2 Current Treatment of Metastatic Colorectal Carcinoma .................................................25 2.1.2.1 Therapy with anti-EGFR Monoclonal Antibodies ........................................................25 2.1.2.2 Resistance to Anti-EGFR Antibodies ...........................................................................25 2.1.3 Target Patient Population ................................................................................................26 2.1.3.1 Current Recommendation for Treatment of mCRC with anti-EGFR mAbs.................26 2.1.3.2 Prior Results with Sym004: Genomic Selection of a Responsive Patient Subset ........27 2.2 Overview of the Product: Sym004 .....................................................................................28 2.2.1 Description of Sym004 ....................................................................................................28 2.2.2 Mechanism of Action of Sym004 and the Individual Antibodies ...................................28 2.3 Summary of Nonclinical Studies .......................................................................................28 2.4 Clinical Experience ............................................................................................................29 2.4.1 Safety ...............................................................................................................................29 2.4.2 Pharmacokinetics .............................................................................................................31 2.4.3 Pharmacodynamic Effects ...............................................................................................32 2.4.4 Antitumor Effects ............................................................................................................32 2.5 Trial Rationale ...................................................................................................................32 2.6 Dose Rationale ...................................................................................................................33 2.7 Summary of Overall Benefit and Risk ...............................................................................33 3 TRIAL OBJECTIVES AND DESIGN ..................................................................................35 3.1 Objectives ..........................................................................................................................35 3.1.1 Primary Objective ............................................................................................................35 3.1.2 Secondary Objective ........................................................................................................35 3.1.3 Exploratory Objective .....................................................................................................35 3.2 Trial Design Summary .......................................................................................................35 4 PATIENT SELECTION ........................................................................................................40 4.1 Number of Patients ............................................................................................................40 4.1.1 Investigational Sites .........................................................................................................40 4.1.2 Planned Sample Size .......................................................................................................40 4.2 Criteria for Inclusion ..........................................................................................................40 4.3 Criteria for Exclusion .........................................................................................................42 4.3.1 Patients to be Excluded ...................................................................................................42 4.3.2 Drugs and Other Treatments to be Excluded ..................................................................45 5 INVESTIGATIONAL MEDICINAL PRODUCT AND COMPARATORS ........................47 5.1 Investigational Medicinal Products....................................................................................47 5.1.1 Formulations ....................................................................................................................47 5.1.2 Formulation Excipients ...................................................................................................47 5.2 Storage and Handling of IMPs ...........................................................................................47 5.3 Stability of IMPs ................................................................................................................48 5.4 Labeling of IMPs ...............................................................................................................48 Confidential Page 4 of 169 Symphogen Clinical Trial Protocol Trial ID: Sym004-13 Version 6.0 5.5 Packaging of IMPs .............................................................................................................48 5.6 Administration of IMPs .....................................................................................................48 5.7 Dose Calculation ................................................................................................................49
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