Official Title: A MULTI-CENTRE RANDOMISED CLINICAL TRIAL OF BIOMARKER-DRIVEN MAINTENANCE TREATMENT FOR FIRST- LINE METASTATIC COLORECTAL CANCER (MODUL) NCT Number: NCT02291289 Document Date: Protocol Version 9: 18-Feb-2020 PROTOCOL TITLE: A MULTI-CENTRE RANDOMISED CLINICAL TRIAL OF BIOMARKER-DRIVEN MAINTENANCE TREATMENT FOR FIRST-LINE METASTATIC COLORECTAL CANCER (MODUL) PROTOCOL NUMBER: MO29112 VERSION NUMBER: 9 EUDRACT NUMBER: 2014-001017-61 IND NUMBER: N/A TEST PRODUCT: Atezolizumab (MPDL3280A, RO5541267) Bevacizumab (RO4876646) Cobimetinib (RO5514041) Pertuzumab (RO4368451) Trastuzumab (RO0452317) Vemurafenib (RO5185426) Cetuximab And combinations thereof MEDICAL MONITOR: Dr. SPONSOR: F. Hoffmann-La Roche Ltd. DATE FINAL: See electronic date stamp below FINAL PROTOCOL APPROVAL Date and Time (UTC) Title Approver's Name 18-Feb-2020 15:44:34 Company Signatory CONFIDENTIAL This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, including Genentech, Inc. in the United States. The information contained in this document, especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as an investigator, potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee or Institutional Review Board. It is understood that this information will not be disclosed to others without written authorization from Roche except to the extent necessary to obtain informed consent from persons to whom the drug may be administered. Bevacizumab — F. Hoffmann-La Roche Ltd. Protocol MO29112, Version 9 DATES AMENDED: Version 1: 5 August 2014 Version 2: 29 October 2014 Version 3: 2 February 2015 Version 4: 30 November 2015 Version 5: 11 April 2016 Version 6: 24 November 2016 Version 7: 8 August 2018 Version 8: 19 December 2018 Bevacizumab — F. Hoffmann-La Roche Ltd Protocol MO29112, Version 9 2 TABLE OF CONTENTS 1. BACKGROUND ............................................................................................................ 44 1.1 Background on Metastatic Colorectal Cancer .................................................... 44 1.1.1 Epidemiology ............................................................................................... 44 1.1.2 Etiology and Risk Factors ............................................................................ 44 1.1.3 Current Treatment of mCRC ........................................................................ 45 1.1.3.1 The Role of Maintenance Therapy in mCRC Treatment ................... 46 1.2 Background on Biomarker-Driven Therapy ........................................................ 46 1.2.1 Biomarkers................................................................................................... 46 1.2.2 Biomarker-driven Therapy ............................................................................ 47 1.2.3 Clinical Experience with Bevacizumab as First-line Treatment of mCRC .......................................................................................................... 48 1.2.4 Clinical Experience with Cetuximab in CRC ................................................. 50 1.2.5 Clinical Experience with Vemurafenib .......................................................... 51 1.2.6 Clinical Experience with Atezolizumab ......................................................... 53 1.2.7 Clinical Experience with Trastuzumab .......................................................... 55 1.2.8 Clinical Experience with Pertuzumab ........................................................... 56 1.2.9 Clinical Experience with Cobimetinib............................................................ 57 1.3 Study Rationale and Benefit-Risk Assessment .................................................. 59 2. OBJECTIVES ................................................................................................................ 62 2.1 Efficacy Objectives ............................................................................................ 62 2.2 Safety Objectives ............................................................................................... 63 2.3 Exploratory Objectives ....................................................................................... 63 3. STUDY DESIGN ........................................................................................................... 63 3.1 Description of Study ........................................................................................... 63 3.1.1 Induction Treatment Phase .......................................................................... 64 3.1.1.1 BRAFmut Patients and Early Disease Progression ............................. 65 3.1.2 Maintenance Treatment Phase .................................................................... 66 3.1.2.1 Maintenance Treatment in Cohort 1 ................................................. 67 3.1.2.2 Maintenance Treatment in Cohort 2 ................................................. 68 3.1.2.3 Maintenance Treatment in Cohort 3 ................................................. 69 3.1.2.4 Maintenance Treatment in Cohort 4 ................................................. 69 3.1.3 Post-Treatment Follow-up Phase ................................................................. 73 3.1.4 Steering Committee ..................................................................................... 73 3.1.5 Independent Data Monitoring Committee ..................................................... 73 Bevacizumab — F. Hoffmann-La Roche Ltd Protocol MO29112, Version 9 3 3.2 End of Study ...................................................................................................... 74 3.3 Rationale for Study Design ................................................................................ 74 3.3.1 Rationale for mRECIST and Allowing Treatment beyond Progression in Atezolizumab-treated Patients .................................................................. 75 3.3.2 Rationale for Investigational Medicinal Product Maintenance Treatment Dosages ..................................................................................... 76 3.3.2.1 Cetuximab ........................................................................................ 76 3.3.2.2 Vemurafenib ..................................................................................... 76 3.3.2.3 Atezolizumab .................................................................................... 77 3.3.2.4 Bevacizumab .................................................................................... 77 3.3.2.5 Trastuzumab .................................................................................... 77 3.3.2.6 Pertuzumab ...................................................................................... 77 3.3.2.7 Cobimetinib ...................................................................................... 78 3.3.3 Rationale for Patient Populations ................................................................. 78 3.3.4 Rationale for Control Group ......................................................................... 78 3.3.5 Rationale for Biomarker Assessments ......................................................... 78 3.4 Outcome Measures ........................................................................................... 79 3.4.1 Efficacy Outcome Measures ........................................................................ 79 3.4.2 Safety Outcome Measures ........................................................................... 79 3.4.3 Exploratory Outcome Measures ................................................................... 80 4. MATERIALS AND METHODS ....................................................................................... 80 4.1 Patients ............................................................................................................. 80 4.1.1 Inclusion Criteria .......................................................................................... 80 4.1.2 Exclusion Criteria ......................................................................................... 81 4.2 Method of Treatment Assignment ...................................................................... 90 4.2.1 Screening procedures .................................................................................. 91 4.3 Study Treatment ................................................................................................ 91 4.3.1 Formulation, Packaging, and Handling ......................................................... 92 4.3.1.1 Induction Treatment Phase .............................................................. 92 4.3.1.2 Maintenance Treatment Phase ......................................................... 92 4.3.1.2.1 Control Arm- All Cohorts ....................................................... 92 4.3.1.2.2 Experimental Arm Cohort 1 ................................................... 92 4.3.1.2.3 Experimental Arm Cohort 2 ................................................... 93 4.3.1.2.4 Experimental Arm Cohort 3 ................................................... 94 4.3.1.2.5 Experimental Arm Cohort 4 ................................................... 95 4.3.2 Dosage and Administration .......................................................................... 95 4.3.2.1 Induction Treatment