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Study Protocol Full title: A Sequential Phase I study of MEK1/2 inhibitors PD-0325901 or Binimetinib combined with cMET inhibitor PF-02341066 in Patients with RAS Mutant and RAS Wild Type (with aberrant c-MET) Colorectal Cancer Short title: MErCuRIC1: MEK and MET Inhibition in Colorectal Cancer Protocol Version & date: Version 9.0; 29Oct2018 Sponsor Protocol Number: OCTO_049 Ethics Number: 14/SC/1010 EudraCT Number: 2014-000463-40 Funding Reference Number 602901-2 Sponsored by the University of Oxford Funder: European Commission’s Seventh Framework Program (FP7) Confidentiality Statement This document contains confidential information that must not be disclosed to anyone other than the Sponsor, the Trials Office, the Investigator Team, host NHS Trust(s), regulatory authorities, and members of the Research Ethics Committee. MErCuRIC1_Protocol_V9.0_29Oct2018 Protocol Template V3.0_18Feb2013 Page 1 of 121 MErCuRIC1 Confidential GENERAL CONTACT INFORMATION Trial Office (OCTO) MErCuRIC Trial Office Oncology Clinical Trials Office (OCTO) Department of Oncology, The University of Oxford Oxford Cancer and Haematology Centre Churchill Hospital Oxford Tel: +44 (0)1865 227194 Email: [email protected] Website: http://www.oncology.ox.ac.uk/research/oncology- clinical-trials-office-octo Chief Investigator Professor Mark Middleton Department of Oncology, University of Oxford Oxford Cancer and Haematology Centre Churchill Hospital Oxford OX3 7LE Tel: +44 (0)1865 235 315 Email : [email protected] Investigator Professor Richard Wilson and Scientific Project Lead Consultant and Professor in Cancer Medicine Centre for Cancer Research and Cell Biology Queen’s University Belfast, 97 Lisburn Road Belfast BT9 7BL Northern Ireland, UK Tel.: +44 (0) 28 95048492 Email: [email protected] FP7 Co-ordinator Dr Sandra Van Schaeybroeck Senior Lecturer and Honorary Consultant in Medical Oncology Centre for Cancer Research and Cell Biology Lisburn Road 97 Belfast BT9 7BL Northern Ireland Tel: +44 (0) 28 9097 2954 Email: [email protected] Pathology Lead Professor Manuel Salto-Tellez Chair in Molecular Pathology Centre for Cancer Research and Cell Biology Lisburn Road 97 Belfast BT9 7BL Northern Ireland Tel: +44 (0)28 9097 2178 Email: [email protected] Lead NHS Trust Ms Heather House R&D Department, Oxford University Hospitals NHS Foundation Trust Joint Research Department, Block 60, Churchill Hospital Oxford OX3 7LE Fax +44 (0) 1865 572242 E-mail: [email protected] Trial Statisticians MErCuRIC1_Protocol_V9.0_29Oct2018 Protocol Template V3.0_18Feb2013 Page 2 of 121 MErCuRIC1 Confidential Ms Jane Holmes Senior Trial Statistician Oxford Clinical Trials Research Unit (OCTRU) Centre for Statistics in Medicine, The University of Oxford Botnar Research Centre Windmill Road Oxford OX3 7LD Tel: +44 (0) 1865 223452 Email: [email protected] Mr William Sones Statistician Oxford Clinical Trials Research Unit (OCTRU) Centre for Statistics in Medicine, The University of Oxford Botnar Research Centre Windmill Road Oxford OX3 7LD Tel: +44 (0) 1865 227887 Email: [email protected] Patient Representative Mrs Margaret Grayson N. Ireland Cancer Trials Network, Belfast City Hospital, Lisburn Road Belfast BT9 7AB Northern Ireland, UK Tel.: +44 (0) 28 90638468 Email: [email protected] Clinical queries and emergency contact details During office hours: Clinical Queries should be directed to the MErCuRIC Trial Office and contact the Clinical Trial Coordinator. The call will be passed on to the Chief Investigator or to the Clinical Coordinator (medically qualified) or an appropriate member of the Trial Management Group. Out of office hours: call the Churchill Hospital switchboard on Tel: +44 (0) 1865 741 841 and ask to call the MErCuRIC Clinical Coordinator. Patient Registration: See section 4.5 MErCuRIC1_Protocol_V9.0_29Oct2018 Protocol Template V3.0_18Feb2013 Page 3 of 121 MErCuRIC1 Confidential TABLE OF CONTENTS GENERAL CONTACT INFORMATION ............................................................................................................ 2 TABLE OF CONTENTS .................................................................................................................................... 4 PROTOCOL SYNOPSIS ................................................................................................................................... 7 SUMMARY SCHEDULE OF EVENTS ............................................................................................................ 18 DOSE ESCALATION PHASE- SCHEDULE OF EVENTS FOR PF-02341066 WITH BINIMETINIB ............................... 17 DOSE EXPANSION PHASE - SCHEDULE OF EVENTS FOR PF-02341066 WITH BINIMETINIB .............................. 189 ABBREVIATIONS ........................................................................................................................................... 22 1 INTRODUCTION ........................................................................................................................... 24 1.1 BACKGROUND .................................................................................................................................. 24 1.2 INVESTIGATIONAL MEDICINAL PRODUCTS USED IN THE STUDY ............................................................. 25 1.3 OTHER RESEARCH INTERVENTIONS .................................................................................................... 30 1.4 RATIONALE FOR THE STUDY .............................................................................................................. 30 1.5 PRIMARY HYPOTHESIS OF THE TRIAL .................................................................................................. 33 2 TRIAL DESIGN ............................................................................................................................. 34 2.1 OUTLINE .......................................................................................................................................... 34 2.2 TREATMENT SCHEDULE AND DURATION.............................................................................................. 34 2.3 PROJECTED NUMBER OF SUBJECTS .................................................................................................. 36 2.4 REPLACEMENT OF SUBJECTS ............................................................................................................ 36 2.5 POST-TRIAL CARE AND FOLLOW-UP .................................................................................................... 36 3 OBJECTIVES AND ENDPOINTS ................................................................................................. 40 4 PATIENT SELECTION .................................................................................................................. 38 4.1 INCLUSION CRITERIA ......................................................................................................................... 38 4.2 EXCLUSION CRITERIA ........................................................................................................................ 39 4.3 PROTOCOL DEVIATIONS AND WAIVERS TO ENTRY CRITERIA .................................................................. 40 4.4 RE-SCREENING IF PATIENT DOES NOT MEET INCLUSION/EXCLUSION CRITERIA FIRST TIME ROUND .......... 40 4.5 PATIENT REGISTRATION PROCEDURE ................................................................................................. 40 5 TRIAL ASSESSMENTS AND PROCEDURES ............................................................................ 41 5.1 PRE-TRIAL SCREENING CONSENT AND PROCEDURE (DOSE-EXPANSION PHASE ONLY) ............................ 41 5.2 INFORMED CONSENT FOR MAIN STUDY ............................................................................................... 41 5.3 INFORMED CONSENT FOR TRANSLATIONAL SUB-STUDIES ..................................................................... 42 5.4 MAIN SCREENING: PRE-DOSING EVALUATIONS .................................................................................... 42 5.5 EVALUATIONS DURING DOSING .......................................................................................................... 43 5.6 END OF TREATMENT EVALUATIONS ..................................................................................................... 46 5.7 POST TREATMENT FOLLOW-UP - EVALUATIONS ................................................................................... 46 5.8 EVALUATIONS ON EARLY WITHDRAWAL ............................................................................................... 46 6. EARLY PATIENT WITHDRAWAL ................................................................................................ 47 6.1 TREATMENT WITHDRAWAL ................................................................................................................ 47 6.2 WITHDRAWAL OF CONSENT ............................................................................................................... 47 6.3 PATIENT EVALUABILITY AND REPLACEMENT ........................................................................................ 47 7. SAMPLES FOR LABORATORY ANALYSIS ............................................................................... 47 7.1 SAMPLES TO BE ANALYSED IN LOCAL LABORATORIES .......................................................................... 48 7.2 SAMPLES TO BE SENT TO AND ANALYSED IN A CENTRAL LABORATORY ................................................. 48 7.3 PHARMACOKINETIC
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