Clinical trial NCT02291289
Conditions: Colorectal Cancer
Sponsor: Hoffmann-La Roche
Start date: 2015-04-17; Completion date: 2021-03-24
Enrollment: 1044 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized, multi-center, active-controlled, open-label, parallel-group study will investigate the efficacy and safety of biomarker-driven maintenance treatment for first-line mCRC. Participants with mCRC are eligible for entry and cannot have received any prior chemotherapy in the metastatic setting. The entire study duration is anticipated to be approximately 7.5 years.

Detailed description:

Arms: arm 1: Includes participants with v-raf murine sarcoma viral oncogene homolog B1 mutation positive (BRAFmut)/human epidermal growth factor receptor 2 negative (HER2-)/microsatellite stable (MSS)/rat sarcoma wild type (RASwt). All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab. arm 2: Includes participants with BRAFwt. All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab. arm 3: Includes participants with human epidermal growth factor receptor 2 positive (HER2+). All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab. arm 4: Includes participants with HER2-/high microsatellite instability (MSI-H); HER2-/MSS/v-raf murine sarcoma viral oncogene homolog B1 wild type (BRAFwt); HER2-/MSS/BRAFmut/rat sarcoma mutation positive (RASmut). All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab. arm 5: Participants with v-raf murine sarcoma viral oncogene homolog B1 mutation positive (BRAFmut)/human epidermal growth factor receptor 2 negative (HER2-)/microsatellite stable (MSS)/rat sarcoma wild type (RASwt) will receive 1600-2400 milligrams per square meter (mg/m\^2) 5-FU via 46-hour intravenous (IV) infusion in combination with 400 mg/m\^2 LV via 2-hour infusion on Day 1 of every 2-week cycle with 500 mg/m\^2 cetuximab via infusion on Day 1 of every 2-week cycle and 960 milligrams (mg) vemurafenib twice daily (BID) by mouth. arm 6: Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle. arm 7: Participants with BRAFwt will receive fluoropyrimidine (1600-2400 mg/m\^2 5-FU via 46-hour IV infusion in combination with 400 mg/m\^2 LV via 2-hour infusion on Day 1 of every 2-week cycle or 1000 mg/m\^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break) with 5 milligrams per kilogram (mg/kg) bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle and 800 mg atezolizumab via 60-minute IV infusion on Day 1 of every 2-week cycle. arm 8: Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle. arm 9: Participants with human epidermal growth factor receptor 2 positive (HER2+) will receive 1000 mg/m\^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break with trastuzumab by IV infusion on Day 1 of every 3-week treatment cycle at an initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent doses, and pertuzumab by IV infusion on Day 1 of each 3-week treatment cycle at an initial fixed loading dose of 840 mg followed by 420 mg for subsequent doses. arm 10: Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle. arm 11: Participants with HER2-/high microsatellite instability (MSI-H); HER2-/MSS/v-raf murine sarcoma viral oncogene homolog B1 wild type (BRAFwt); HER2-/MSS/BRAFmut/rat sarcoma mutation positive (RASmut) will receive 60 mg cobimetinib orally for 3 weeks followed by a 1-week treatment break and atezolizumab at a fixed dose of 840 mg via 60-minute IV infusion on Day 1 of every 2-week cycle. arm 12: Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle. arm 13: BRAFmut participants experiencing early disease progression during induction treatment will have the option of proceeding immediately to receive second-line treatment with 5-FU/LV, cetuximab and vemurafenib if their primary tumor is MSS, or with a fluoropyrimidine (5-FU/LV or capecitabine), bevacizumab, and atezolizumab if their primary tumor is MSI-H. This cohort will be followed for adverse events during the study, but is not part of the Maintenance Phase study objectives.
Interventions: intervention 1: Cetuximab intervention 2: FOLFOX induction regimen intervention 3: Fluoropyrimidine (5-FU/LV or capecitabine) intervention 4: Atezolizumab intervention 5: Vemurafenib intervention 6: Bevacizumab intervention 7: Trastuzumab intervention 8: Pertuzumab intervention 9: Cobimetinib intervention 10: 5-FU/LV intervention 11: Capecitabine
Intervention descriptions: intervention 1: 500 mg/m\^2 via IV infusion on Day 1 of every 2-week cycle intervention 2: Administered per the Investigator's discretion in accordance with locally approved prescribing information. intervention 3: Per Investigator's discretion: 5-FU 1600-2400 mg/m\^2 administered via 46-hour IV infusion on Day 1 of every 2-week cycle and LV 400 mg/m\^2 administered via a 2-hour infusion on Day 1 every 2 weeks or 1000 mg/m\^2 twice-daily capecitabine (BID) by mouth given days 1-14 every 2 weeks. The chosen fluoropyrimidine should be administered in accordance with local prescribing information. intervention 4: 800 mg atezolizumab via 60-minute IV infusion on Day 1 of every 2-week cycle, or a fixed dose of 840 mg intervention 5: 960 mg vermurafenib BID by mouth intervention 6: 5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information intervention 7: Initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent doses by IV infusion on Day 1 of every 3-week treatment cycle intervention 8: Initial fixed loading dose of 840 mg followed by 420 mg for subsequent doses by IV infusion on Day 1 of each 3-week treatment cycle intervention 9: 60 mg orally once daily for 3 weeks followed by a 1-week treatment break intervention 10: 1600-2400 mg/m\^2 5-FU via 46-hour IV infusion in combination with 400 mg/m\^2 LV via 2-hour infusion on Day 1 of every 2-week cycle until disease progression per the Investigator's assessment using modified Response Evaluation Criteria in Solid Tumors or death from any cause, whichever occurs first. The fluoropyrimidine should be administered in accordance with local prescribing information. intervention 11: 1000 mg/m\^2 twice-daily capecitabine (BID) by mouth given days 1-14 every 2 weeks. The fluoropyrimidine should be administered in accordance with local prescribing information.

Protocol documents:
Prot_000.pdf: 
 
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 
 
 


FINAL PROTOCOL APPROVAL 
 
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 
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 
 
18-Feb-2020 15:44:34
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Bevacizumab — F. Hoffmann-La Roche Ltd 
Protocol MO29112, Version 9 
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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 
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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 


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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 Phase .............................................................. 96 


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4.3.2.2 
Maintenance Treatment Phase ......................................................... 96 
4.3.2.2.1 
Control Arm-All Cohorts ........................................................ 97 
4.3.2.2.2 
Experimental Arm Cohort 1 ................................................... 97 
4.3.2.2.3 
Experimental Arm Cohort 2 ................................................... 98 
4.3.2.2.4 
Experimental Arm Cohort 3 ................................................... 99 
4.3.2.2.5 
Experimental Arm Cohort 4 ................................................. 100 
4.3.2.3 
Post-Treatment Follow-up Phase ................................................... 101 
4.3.3 
Study Treatment Compliance ..................................................................... 101 
4.3.4 
Investigational Medicinal Product Accountability ........................................ 101 
4.3.5 
Continued Access to Roche Investigational Medicinal Products ................. 101 
4.4 
Concomitant Therapy and Food ....................................................................... 102 
4.4.1 
Permitted Therapy ..................................................................................... 102 
4.4.2 
Therapy Permitted with Caution ................................................................. 103 
4.4.2.1 
Induction Treatment Phase ............................................................ 103 
4.4.2.2 
Maintenance Treatment Phase ....................................................... 104 
4.4.2.2.1 
Control Arms ....................................................................... 104 
4.4.2.2.2 
Experimental Arm Cohort 1 ................................................. 104 
4.4.2.2.3 
Experimental Arm Cohort 2 ................................................. 106 
4.4.2.2.4 
Experimental Arm Cohort 3 ................................................. 107 
4.4.2.2.5 
Experimental Arm Cohort 4 ................................................. 107 
4.4.3 
Prohibited Therapy ..................................................................................... 108 
4.4.3.1 
Induction Treatment Phase ............................................................ 108 
4.4.3.2 
Maintenance Treatment Phase ....................................................... 108 
4.4.3.2.1 
All Cohorts .......................................................................... 108 
4.4.3.2.2 
Experimental Arm Cohort 1 ................................................. 109 
4.4.3.2.3 
Experimental Arm Cohort 2 ................................................. 109 
4.4.3.2.4 
Experimental Arm Cohort 3 ................................................. 109 
4.4.3.2.5 
Experimental Arm Cohort 4 ................................................. 110 
4.4.4 
Food .......................................................................................................... 110 
4.5 
Study Assessments ......................................................................................... 111 
4.5.1 
Induction Treatment Phase ........................................................................ 111 
4.5.1.1 
Informed Consent Forms and Screening Log ................................. 111 
4.5.1.2 
Demographic Data and Medical History ......................................... 111 
4.5.1.3 
Vital Signs ...................................................................................... 112 
4.5.1.4 
Physical Examinations .................................................................... 112 
4.5.1.5 
ECOG Performance Status ............................................................ 112 
4.5.1.6 
Concomitant Medications ............................................................... 112 


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4.5.1.7 
Laboratory Samples ....................................................................... 112 
4.5.1.8 
Whole Blood and Plasma Samples ................................................. 113 
4.5.1.9 
Tumour and Response Evaluations ................................................ 113 
4.5.1.10 
Archival Tumour Tissue .................................................................. 113 
4.5.1.11 
Optional Metastatic Tumour Sample ............................................... 114 
4.5.1.12 
Stool Sample-Supplemental Biomarker Program Participants 
Only ................................................................................................ 114 
4.5.2 
Maintenance Treatment Phase .................................................................. 114 
4.5.2.1 
Cohort-Specific Informed Consent .................................................. 114 
4.5.2.2 
Confirmation of Cohort-Specific Eligibility ....................................... 114 
4.5.2.3 
Screening Log ................................................................................ 114 
4.5.2.4 
Randomization ............................................................................... 114 
4.5.2.5 
Vital Signs ...................................................................................... 115 
4.5.2.6 
Physical Examinations .................................................................... 115 
4.5.2.7 
ECOG Performance Status ............................................................ 115 
4.5.2.8 
Concomitant Medications ............................................................... 115 
4.5.2.9 
Laboratory Samples ....................................................................... 115 
4.5.2.9.1 
Experimental Treatment Arm Cohort 1 ................................ 116 
4.5.2.9.2 
Cohort 2 .............................................................................. 116 
4.5.2.9.3 
Experimental Treatment Arm Cohort 2 ................................ 116 
4.5.2.9.4 
Cohort 3 .............................................................................. 116 
4.5.2.9.5 
Cohort 4 .............................................................................. 116 
4.5.2.9.6 
Experimental Treatment Arm Cohort 4 ................................ 117 
4.5.2.10 
Plasma Samples ............................................................................ 117 
4.5.2.11 
Tumour and Stool Samples- Supplemental Biomarker Program 
Participants Only ............................................................................ 117 
4.5.2.12 
Tumour and Response Evaluations ................................................ 117 
4.5.2.12.1 
Cohorts 1 and 3 .................................................................. 117 
4.5.2.12.2 
Cohorts 2 and 4 .................................................................. 118 
4.5.2.13 
Additional Assessments for Cohort 1 .............................................. 118 
4.5.2.14 
Additional Assessments for Experimental Arm Cohort 1 ................. 118 
4.5.2.15 
Additional Assessment for Experimental Arm Cohort 2 ................... 119 
4.5.2.16 
Additional Assessment for Cohort 3 ................................................ 119 
4.5.2.17 
Additional Assessments for Cohort 4 .............................................. 119 
4.5.2.18 
Additional Assessment for Experimental Arm Cohort 4 ................... 120 
4.5.3 
Samples for Roche Clinical Repository ...................................................... 120 
4.5.3.1 
Overview of the Roche Clinical Repository ..................................... 120 


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4.5.3.2 
Approval by the Institutional Review Board or Ethics 
Committee ...................................................................................... 120 
4.5.3.3 
Sample Collection .......................................................................... 120 
4.5.3.4 
Confidentiality ................................................................................. 121 
4.5.3.5 
Consent to Participate in the Roche Clinical Repository ................. 122 
4.5.3.6 
Withdrawal from the Roche Clinical Repository .............................. 122 
4.5.3.7 
Monitoring and Oversight ............................................................... 123 
4.6 
Patient, Treatment, Study, and Site Discontinuation ........................................ 123 
4.6.1 
Patient Discontinuation .............................................................................. 123 
4.6.2 
Study Treatment Discontinuation ............................................................... 123 
4.6.3 
Study and Site Discontinuation .................................................................. 124 
5. ASSESSMENT OF SAFETY ....................................................................................... 125 
5.1 
Safety Plan ...................................................................................................... 125 
5.1.1 
Management of Specific Adverse Events ................................................... 126 
5.1.2 
Induction Treatment Phase ........................................................................ 126 
5.1.3 
Maintenance Treatment Phase .................................................................. 126 
5.1.3.1 
Control Arms .................................................................................. 126 
5.1.3.2 
Experimental Arm Cohort 1 ............................................................ 127 
5.1.3.3 
Experimental Arm Cohort 2 ............................................................ 127 
5.1.3.4 
Experimental Arm Cohort 3 ............................................................ 128 
5.1.3.5 
Experimental Arm Cohort 4 ............................................................ 129 
5.2 
Safety Parameters and Definitions ................................................................... 129 
5.2.1 
Adverse Events .......................................................................................... 130 
5.2.2 
Serious Adverse Events (Immediately Reportable to the Sponsor) ............ 130 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to the 
Sponsor) .................................................................................................... 131 
5.2.3.1 
Adverse Events of Special Interest in Both Induction and 
Maintenance Treatment Phases ..................................................... 131 
5.2.3.2 
Adverse Events of Special Interest in the Induction Treatment 
Phase ............................................................................................. 131 
5.2.3.3 
Adverse Events of Special Interest in the Maintenance 
Treatment Phase ............................................................................ 131 
5.2.3.3.1 
Control Arms ....................................................................... 131 
5.2.3.3.2 
Experimental Arm Cohort 1 ................................................. 132 
5.2.3.3.3 
Experimental Arm Cohort 2 ................................................. 133 
5.2.3.3.4 
Experimental Arm Cohort 3 ................................................. 134 
5.2.3.3.5 
Experimental Arm Cohort 4 ................................................. 134 
5.3 
Methods and Timing for Capturing and Assessing Safety Parameters ............. 134 


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5.3.1 
Adverse Event Reporting Period ................................................................ 135 
5.3.2 
Eliciting Adverse Event Information ............................................................ 135 
5.3.3 
Assessment of Severity of Adverse Events ................................................ 135 
5.3.4 
Assessment of Causality of Adverse Events .............................................. 136 
5.3.5 
Procedures for Recording Adverse Events................................................. 137 
5.3.5.1 
Infusion-Related Reactions ............................................................ 137 
5.3.5.2 
Diagnosis versus Signs and Symptoms .......................................... 137 
5.3.5.3 
Adverse Events That Are Secondary to Other Events .................... 138 
5.3.5.4 
Persistent or Recurrent Adverse Events ......................................... 138 
5.3.5.5 
Abnormal Laboratory Values .......................................................... 138 
5.3.5.6 
Abnormal Vital Sign Values ............................................................ 139 
5.3.5.7 
Abnormal Liver Function Tests ....................................................... 140 
5.3.5.8 
Deaths ............................................................................................ 140 
5.3.5.9 
Pre-existing Medical Conditions ..................................................... 141 
5.3.5.10 
Lack of Efficacy or Worsening of mCRC ......................................... 141 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ................................... 141 
5.3.5.12 
Adverse Events Associated with an Overdose ............................... 141 
5.4 
Immediate Reporting Requirements from Investigator to Sponsor ................... 142 
5.4.1 
Emergency Medical Contacts .................................................................... 142 
5.4.2 
Reporting Requirements for SAEs and AEs of Special Interest .................. 142 
5.4.2.1 
Events That Occur prior to Study Drug Initiation ............................. 142 
5.4.2.2 
Events That Occur after Study Drug Initiation ................................. 143 
5.4.3 
Reporting Requirements for Pregnancies .................................................. 143 
5.4.3.1 
Pregnancies in Female Patients ..................................................... 143 
5.4.3.2 
Pregnancies in Female Partners of Male Patients .......................... 144 
5.4.3.3 
Abortions ........................................................................................ 144 
5.4.3.4 
Congenital Anomalies/Birth Defects ............................................... 144 
5.5 
Follow-Up of Patients after Adverse Events ..................................................... 144 
5.5.1 
Investigator Follow-Up ............................................................................... 144 
5.5.2 
Sponsor Follow-Up .................................................................................... 144 
5.6 
Post-study Adverse Events .............................................................................. 145 
5.7 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Ethics Committees .......................................................... 145 
6. STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ........................................ 146 
6.1 
Overview ......................................................................................................... 146 
6.1.1 
Analysis Populations .................................................................................. 147 
6.1.2 
Statistical Hypotheses ................................................................................ 147 


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6.2 
Determination of Sample Size ......................................................................... 148 
6.3 
Summaries of Conduct of Study ...................................................................... 149 
6.4 
Summaries of Treatment Group Comparability ................................................ 150 
6.5 
Efficacy Analyses............................................................................................. 150 
6.5.1 
Primary Efficacy Endpoints ........................................................................ 150 
6.5.2 
Secondary Efficacy Endpoints.................................................................... 150 
6.5.3 
Exploratory Efficacy Endpoints................................................................... 151 
6.6 
Safety Analyses ............................................................................................... 151 
6.7 
Exploratory Biomarker Analyses ...................................................................... 152 
6.8 
Interim Analyses .............................................................................................. 152 
6.9 
SubGroup Analyses ......................................................................................... 152 
7. DATA COLLECTION AND MANAGEMENT ................................................................ 152 
7.1 
Data Quality Assurance ................................................................................... 152 
7.2 
Electronic Case Report Forms ......................................................................... 153 
7.3 
Source Data Documentation ............................................................................ 153 
7.4 
Use of Computerised Systems......................................................................... 154 
7.5 
Retention of Records ....................................................................................... 154 
8. ETHICAL CONSIDERATIONS .................................................................................... 154 
8.1 
Compliance with Laws and Regulations ........................................................... 154 
8.2 
Informed Consent ............................................................................................ 154 
8.3 
Institutional Review Board or Ethics Committee ............................................... 156 
8.4 
Confidentiality .................................................................................................. 156 
8.5 
Financial Disclosure ......................................................................................... 156 
9. STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION ...................... 157 
9.1 
Study Documentation ...................................................................................... 157 
9.2 
Protocol Deviations .......................................................................................... 157 
9.3 
Site Inspections ............................................................................................... 157 
9.4 
Administrative Structure ................................................................................... 157 
9.5 
Publication of Data and Protection of Trade Secrets ........................................ 157 
9.6 
Protocol Amendments ..................................................................................... 158 
10. REFERENCES ............................................................................................................ 159 
11. APPENDICES ............................................................................................................. 168 
11.1 
Appendix 1  Schedule of Assessments for All Patients (Screening / 
Baseline and Induction Treatment Phase) ....................................................... 169 
11.2 
Appendix 2  Schedule of Assessments During Maintenance Phase 
(Cohort 1) ........................................................................................................ 174 


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11.3 
Appendix 3  Schedule of Assessments During Maintenance Phase 
(Cohort 2) ........................................................................................................ 179 
11.4 
Appendix 4  Schedule of Assessments During Maintenance Phase 
(Cohort 3) ........................................................................................................ 184 
11.5 
Appendix 5  Schedule of Assessments During Maintenance Phase 
(Cohort 4) ........................................................................................................ 189 
11.6 
Appendix 6  FOLFOX Regimens: Induction Treatment Phase ......................... 194 
11.7 
Appendix 7  Capecitabine Dose Calculation by Body Surface Area ................. 195 
11.8 
Appendix 8  ECOG Performance Status .......................................................... 196 
11.9 
Appendix 9  Pre-Existing Autoimmune Diseases ............................................. 197 
11.10 Appendix 10  RECIST 1.1 ................................................................................ 198 
11.11 Appendix 11  Modified RECIST (mRECIST) .................................................... 209 
11.12 Appendix 12  Medications Affecting QT Intervals ............................................. 215 
11.13 Appendix 13  Agents Metabolised by CYP1A2, CYP2C9 and CYP3A4 ........... 216 
11.14 Appendix 14  Cetuximab Package Insert ......................................................... 218 
11.15 Appendix 15  Cardiac Toxicity Management and Reporting Conventions 
with Trastuzumab and Pertuzumab ................................................................. 219 
11.16 Appendix 16  Guidelines for the Management of Adverse Events With 
Cobimetinib and Atezolizumab......................................................................... 222 
11.17 Appendix 17  Biomarker Assessments ............................................................. 237 
11.17.1 
Archival Primary Tumour Block from Initial Diagnosis ..................... 237 
11.17.2 
Biomarker Testing for Cohort Assignment ...................................... 237 
11.17.3 
Biomarker Stratification Variables ................................................... 238 
11.17.4 
Core Biopsy of Metastases ............................................................. 239 
11.17.5 
Stool Sample .................................................................................. 239 
11.17.6 
Exploratory Biomarker Outcome Measures .................................... 239 
11.17.7 
Whole Blood and Plasma Biomarker Assessments ........................ 240 
11.18 Appendix 18  Supplemental Biomarker Program ............................................. 241 
11.19 Appendix 19  Patient Management and Data Collection After May 31, 
2019 ................................................................................................................ 243 
 


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LIST OF TABLES 
Table 1: 
PFS and Sample Size Estimates per Cohort ................................................ 40 
Table 2: 
Efficacy Outcomes from Phase 3 Clinical Trials of Bevacizumab plus 
Chemotherapy Regimens in First-Line Treatment of mCRC ........................ 49 
Table 3: 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE ................................................................................. 136 
Table 4: 
Causal Attribution Guidance ...................................................................... 137 
Table 5: 
Sample Size Determination per Cohort ...................................................... 149 
 
LIST OF FIGURES 
Figure 1: 
Study Design ............................................................................................... 20 
Figure 2: 
Study Design ............................................................................................... 72 
Figure 3: 
Trastuzumab/Pertuzumab Dose Management for Left Ventricular 
Dysfunction ................................................................................................ 220 
Figure 4: 
Biomarker-based Cohort Assignment Decision Tree .................................. 238 
Figure 5: 
Blood Biomarker Sample Collections ......................................................... 240 
Figure 6: 
Mandatory and Supplemental Biomarker Program Tumour and Stool 
Sampling .................................................................................................... 242 
 


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PROTOCOL ACCEPTANCE FORM 
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 PRODUCTS: 
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. 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files. Please return a copy of this 
form as instructed by your local Roche affiliate.  


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PROTOCOL SYNOPSIS 
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 
PHASE: 
2 
INDICATION: 
Metastatic colorectal cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
Objectives 
Efficacy Objectives 
The primary efficacy objective of the study is to evaluate progression-free survival (PFS) within each 
maintenance treatment cohort. 
Secondary efficacy objectives include the evaluation of efficacy through other endpoints: 
• 
Overall survival (OS) 
• 
Overall response rate (ORR) 
• 
Disease control rate (DCR)  
• 
Time to treatment response (TTR) 
• 
Duration of response (DoR) 
• 
Change in Eastern Cooperative Oncology Group (ECOG) performance status 


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Safety Objectives 
Additional objectives for this study are to assess the safety of each treatment including: 
• 
the incidence, nature and severity of adverse events (AEs) 
• 
Incidence and reasons for any dose reductions, interruptions or premature discontinuation of any 
component of study treatment 
• 
Clinically significant laboratory values  
Adverse events (AEs) refer to all treatment-emergent adverse events occurring after the initiation of 
study medication (i.e. on or after Day 1, Cycle 1 of the Induction Treatment Phase).   AEs will continue 
to be collected during the Maintenance Treatment Phase and Post-Treatment Follow-up Phase as 
applicable. 
Exploratory Objectives 
The exploratory efficacy objective of this study is: 
• 
To evaluate PFS measured according to modified RECIST (mRECIST) in patients treated with 
atezolizumab 
The exploratory biomarker objectives for this study are as follows: 
• 
To explore whether there is differential benefit from treatment in patient subgroups defined by 
different biomarkers, e.g. but not limited to biomarker panels (mutation and expression profiles), 
immune panels etc. 
• 
If applicable, to assess correlations between biomarkers/marker panels and safety  
• 
Where possible, to investigate if changes in expression/mutation panels of biomarkers during 
treatment correlate with treatment efficacy or failure i.e. to explore potential resistance/escape 
mechanisms to (targeted) treatment 
• 
Explore prognostic and potentially predictive effects of markers/marker profiles 
• 
Explore prevalence of specific markers at Baseline and/or salvage/resistance markers to guide 
targeted therapy approaches beyond MODUL, e.g. but not limited to programmed cell death-1 
(PD-L1) 
• 
Explore and correlate microbiome with other biomarkers, baseline characteristics and clinical 
outcome 
Study Design 
Description of Study 
This is a randomised, multi-centre, active-controlled, open-label, parallel-group clinical trial of 
biomarker-driven maintenance treatment for first-line metastatic colorectal cancer (mCRC).  The 
primary study endpoint is PFS according to RECIST 1.1 within each cohort.  Secondary endpoints 
include other efficacy measurements and safety.  In addition, exploratory outcomes will focus on the 
correlations between biomarkers and study outcomes. 
Patients with mCRC who have not received any prior chemotherapy in the metastatic setting are 
eligible for entry. The study will enrol patients in Europe, Asia, Africa, and South America. 
For an individual patient, the study will consist of a Screening Phase (≤ 28 days), a 4-month Induction 
Treatment Phase, a Maintenance Treatment Phase, and finally follow-up during the Post-Treatment 
Follow-up Phase.  
Potential patients will undergo screening assessments to determine study eligibility within 28 days 
prior to starting study induction treatment. Results from routine assessments conducted prior to 
informed consent signature may be used as screening assessments as long as they were done within 


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7 days prior to informed consent signature.  The primary tumour tissue block prepared at the time of 
the initial diagnosis will be used for biomarker assessment for maintenance treatment cohort 
assignment (see Appendix 17).  If the tumour block is not available, ≥ 20 slides cut from the primary 
tumour sample will be accepted as an alternative. The sample (block or slides) must be shipped to the 
designated laboratory and confirmation of sample receipt by the laboratory must be obtained before 
the patient may be enrolled in the study. 
All patients enrolled in the study will be asked to give written informed consent to provide blood 
samples for exploratory biomarker analyses and to allow all available residual samples of tumour, 
blood and plasma samples collected in the study be used for additional exploratory biomarker 
research using the Roche Clinical Sample Repository (RCR). No additional sampling is required for 
RCR samples. Prior to May 2018, an optional metastatic tumour sample was collected from all study 
patients. In addition, patients at selected centres were able to participate in an optional Supplemental 
Biomarker Program (described in Appendix 18). As of May 2018, collection of the optional baseline 
metastatic tumour sample has been discontinued and the Supplemental Biomarker Program has been 
closed. Baseline metastatic tumour samples and Supplemental Biomarker Program samples collected 
up to this time point may still be used for exploratory biomarker analyses.  
Eligible patients will enter a 4-month Induction Treatment Phase.  Treatment during this phase, based 
on Investigator’s choice (see Appendix 6), will be either: 
• 
Eight 2-week cycles of 5-fluorouracil (5-FU), leucovorin (LV) and oxaliplatin (FOLFOX) in 
combination with bevacizumab 
or 
• 
Six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles 
of 5-FU/LV with bevacizumab 
During the Induction Treatment Phase, patients will be assessed for AEs at every cycle. Clinical 
laboratory assessments will be conducted at each cycle, however results from tests conducted every 
second treatment cycle only will be collected in the case report form (CRF). Physical examinations 
and documentation of concomitant medications will be done every two treatment cycles. Tumour 
assessments will be evaluated according to the Response Evaluation Criteria in Solid Tumors version 
1.1 (RECIST 1.1) during the Induction Treatment Phase.  Tumour assessments during treatment will 
be based on local standard of care, but are required at the end of the Induction Treatment Phase (see 
Appendix 1). 
Patients who prematurely discontinue study treatment for any reason during the Induction Treatment 
Phase, or who experience PD at any time during or at the end of the Induction Treatment Phase, or 
who refuse to proceed to the Maintenance Treatment Phase or who are not eligible for any study 
cohort will undergo a Study Treatment Discontinuation Visit within 30 days after the last dose of study 
treatment and will then enter the Post-Treatment Follow-up Phase. All patients need to be evaluated 
for potential resection of metastasis at completion of the induction period. This is of particular 
importance for patients with liver metastases. If the patient is found to be resectable they will undergo 
a Study Treatment Discontinuation Visit within 30 days after the last dose of study treatment and will 
then enter the Post-Treatment Follow-up Phase. Patients completing induction treatment who do not 
have progressive disease and whose disease has not become resectable can proceed to the 
Maintenance Treatment Phase. Informed consent based on the information specific to the assigned 
maintenance cohort will be obtained prior to the conduct of any cohort-specific screening 
assessments (unless the study site has chosen to conduct informed consent including information for 
induction regimens and all potential maintenance regimens prior to study entry).  
Each maintenance treatment cohort will consist of a cohort-specific experimental treatment arm and a 
standard control arm of fluoropyrimidine (5-FU/LV or capecitabine) and bevacizumab.  At completion 
of the Induction Treatment Phase of the study, patients continuing to the biomarker-driven 
Maintenance Treatment Phase will be assigned to a maintenance treatment cohort based on the 
biomarker profile determined from their primary tumour tissue. Biomarkers considered in maintenance 


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treatment assignment include presence or absence of HER2 overexpression (HER2+ or HER2- 
respectively), microsatellite stability status (microsatellite stable [MSS] or high microsatellite instability 
[MSI-H]), wild-type or mutated BRAF gene (BRAFwt or BRAFmut respectively), and presence or 
absence of RAS pathway mutation (RASwt or RASmut respectively; see Appendix 17 for the biomarker-
based cohort assignment decision tree). Patients will be randomised within their assigned cohort on a 
2:1 (experimental:control) basis to either the experimental treatment arm or the control arm of that 
cohort and will begin treatment within 3 weeks of completing induction treatment. Randomisation will 
be stratified according to specific biomarkers identified for each cohort, by geographical region, and/or 
by patient response after the Induction Treatment Phase (CR/PR vs. SD). Stratification variables 
applicable to each cohort are described in Section 4.2 of the protocol. 
The study will follow an adaptive design, where additional cohorts can be added or existing cohorts 
may be modified over the course of the study via protocol amendment (see Figure 1). 
Cohort 1 
Biomarker profile (all patients screened prior to June 3, 2016): BRAFmut  
Biomarker profile (all patients screened after June 3, 2016): HER2-/MSS/BRAFmut/RASwt 
5-FU/LV with cetuximab and vemurafenib 
vs. 
Fluoropyrimidine (5-FU/LV or capecitabine) and bevacizumab 
Cohort 2 - CLOSED TO ENROLMENT 
(No patients screened after June 3, 2016 will be assigned to this cohort) 
Biomarker profile: BRAFwt 
Fluoropyrimidine (5-FU/LV or capecitabine) with bevacizumab and atezolizumab 
vs. 
Fluoropyrimidine (5-FU/LV or capecitabine) and bevacizumab 
Cohort 3 
Biomarker profile: HER2+  
Capecitabine with trastuzumab and pertuzumab 
vs. 
Fluoropyrimidine (5-FU/LV or capecitabine) and bevacizumab 
Cohort 4 - CLOSED TO ENROLMENT  
(As of February 12, 2018, no further patients are assigned to this cohort. See protocol Section 3.1.2.4.)  
Biomarker profiles: HER2-/MSI-H; HER2-/MSS/BRAFwt; HER2-/MSS/BRAFmut/RASmut 
Cobimetinib and atezolizumab 
vs. 
Fluoropyrimidine (5-FU/LV or capecitabine) and bevacizumab 
See Appendix 17 for additional information on biomarker testing and biomarker-based cohort 
assignment. 
Study Enrolment and Cohort Status Update:  
• 
Accrual to Cohort 2 was completed in November 2016.  


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• 
Study enrolment and accrual into Cohort 4 were suspended in February 2018 as a result of an 
unfavourable benefit-risk evaluation of Cohort 4 by the independent Data Monitoring Committee 
(iDMC). Accrual to Cohort 4 was not re-opened after February 2018 due to iDMC 
recommendations. See protocol Section 3.1.2.4.  
• 
Cohort assignment and randomization of any patients who were already enrolled and eligible for 
Cohorts 1 and 3 were continued following the February 2018 suspension of study enrolment. 
• 
No new or modified cohorts have been identified for addition to the study. In the absence of a 
cohort with broad biomarker eligibility criteria (i.e. to replace Cohort 4), the majority of patients 
would not be eligible for maintenance cohort assignment. For this reason, study enrolment will not 
be re-opened following the February 2018 suspension. 
All Cohorts 
No other anti-cancer therapy is permitted during the study with the following exceptions: 
• 
local ablation for liver metastases during Induction Treatment Phase only and only if there are 
other non-ablated sites of measurable disease that have been followed from baseline tumour 
assessment (i.e. prior to start of induction treatment)  
• 
radiotherapy for pain control during the either Induction or Maintenance Treatment Phases 
For all patients who are not receiving atezolizumab, study maintenance treatment will continue until 
disease progression (based on Investigator’s assessment), unacceptable toxicity, initiation of another 
anti-cancer therapy, patient or physician decision to discontinue, or patient death, whichever occurs 
first.  
For all patients who are receiving atezolizumab, study maintenance treatment may continue after the 
first tumour assessment showing progression per RECIST 1.1 as long as patients meet the following 
criteria as assessed by the Investigator: 
• 
Evidence of clinical benefit  
• 
Absence of symptoms and signs (including worsening of laboratory values, e.g. new or worsening 
hypercalcaemia) indicating unequivocal progression of disease 
• 
No decline in ECOG performance status that can be attributed to disease progression 
• 
Absence of tumour progression at critical anatomical sites (e.g. leptomeningeal disease) that 
cannot be managed by protocol-allowed medical interventions 
Treatment should be discontinued if the next follow-up tumour assessment continues to demonstrate 
progression per RECIST 1.1 (as compared to the assessment at the end of induction treatment). If the 
next tumour assessment does not show progression per RECIST 1.1, the patient may continue 
maintenance treatment until such time as the treatment continuation criteria above are no longer met 
and/or two sequential tumour assessments show progression per RECIST 1.1. 
Atezolizumab treated patients may be discontinued from study treatment for the following reasons 
other than loss of clinical benefit or persistent progression: unacceptable toxicity, initiation of another 
anti-cancer therapy, patient or physician decision to discontinue, or patient death, whichever occurs 
first. 
Efficacy, safety and tolerability will be assessed during the entire Maintenance Treatment Phase. 
While receiving study treatment during the Maintenance Treatment Phase, patients will be assessed 
for AEs and concomitant medications at every treatment cycle. Clinical laboratory assessments will be 
conducted at every cycle. For regimens with two week treatment cycles, clinical laboratory results 
from every second treatment cycle only will be collected in the CRF. For regimens with three week 
treatment cycles (such as Cohort 3 experimental regimen), clinical laboratory results from every cycle 
will be collected in the CRF. Physical examinations will be done every treatment cycle (regimens with 
three week cycles) or every two treatment cycles (regimens with two week cycles). Additional safety 
reviews (safety run-ins) will be conducted by the iDMC, when necessary, for a prespecified number of 
initial patients receiving experimental combinations with inadequate prior safety experience to assure 


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appropriate dosing (e.g., as required for the initial patients treated with the experimental combination 
of ‘5-FU/LV + cetuximab + vemurafenib’).  Up to and including May 31, 2019, disease status will be 
evaluated during the Maintenance Treatment Phase as compared to the tumour assessment at the 
end of induction treatment and in accordance with RECIST 1.1 (see Appendix 10) for all patients, and 
additionally according to mRECIST (see Appendix 11) for patients treated with atezolizumab. Tumour 
assessments will be conducted every eight weeks. After May 31, 2019, disease status will no longer 
be collected for study analyses and should be evaluated according to local practice. Schedules of 
Assessments for each cohort are provided in Appendices 2 to 5. 
Patients who discontinue study treatment for any reason during the Maintenance Treatment Phase 
will undergo a Study Treatment Discontinuation Visit within 30 days after the last dose of study 
treatment and will then enter the Post-Treatment Follow-up Phase. 
Patients who prematurely discontinue treatment during the Induction Treatment Phase, who did not 
proceed to the Maintenance Treatment Phase or who discontinue treatment during the Maintenance 
Treatment Phase, will be followed for new AEs for 28 days (patients discontinuing before 
maintenance treatment and patients treated in all maintenance cohort control arms and Cohort 1 
experimental arm) or 90 days (patients treated in experimental arms of Cohorts 2, 3 and 4 only) 
following the discontinuation of study treatment. At the time of treatment discontinuation, any ongoing 
AE/SAE will be followed until the event resolves, the Investigator assesses the event as stable, or the 
patient is lost to follow-up, dies or withdraws consent. The Sponsor should be notified if the 
Investigator becomes aware of any SAE or AEs of special interest occurring after the end of the 
adverse event reporting period if the event is believed to be related to prior study treatment. 
All patients will undergo a Study Treatment Discontinuation visit within 30 days following their last 
study treatment and will enter the Post-Treatment Follow-up Phase of the study. Before May 31, 
2019, patients will be followed every 3 months during the Post-Treatment Follow-up Phase for 
subsequent anti-cancer therapies, survival, and AEs (as applicable) including therapy-specific safety 
assessments (e.g., investigations for squamous cell carcinoma in patients who received vemurafenib) 
(see Appendices 1 to 5). After May 31, 2019, patients in Cohorts 2 and 3 who have completed the 
adverse event reporting period and, if applicable, cohort-specific post-treatment follow-up safety 
assessments will be discontinued from the study. Cohorts 2 and 3 patients who have completed the 
adverse event reporting period (and cohort-specific post-treatment follow-up safety assessments if 
applicable) prior to May 31, 2019 will be discontinued at their Post-Treatment Follow-up visit within the 
3 months prior to and including May 31, 2019. See protocol Section 5.3.1 for adverse event reporting 
periods and post-treatment follow-up safety assessments. All patients in Cohorts 1 and 4 will continue 
in the Post-Treatment Follow-up Phase until the end of the study. Refer to Appendix 19 for 
management of patients in each cohort based on their study status on May 31, 2019.  
Patients who discontinue study treatment in either the Induction or Maintenance Treatment Phases 
prior to disease progression will also enter the Post-Treatment Follow-up Phase but will also continue 
to be followed for progression, with disease status followed according to local practice (patients 
discontinuing during the Induction Treatment Phase) or every eight weeks (patients discontinuing 
during the Maintenance Treatment Phase) until progression or May 31, 2019, whichever comes first. 
After May 31, 2019, disease status will no longer be collected for any study patient. Disease 
assessments in any patient who has not yet progressed as of May 31, 2019 should thereafter be 
conducted according to local practice.  
Second-line treatment during the Post-Treatment Follow-up Phase is at the Investigator’s discretion. 
However, patients who received atezolizumab should not receive other immunomodulatory agents for 
10 weeks after maintenance treatment discontinuation. 
BRAFmut Patients and Early Disease Progression 
BRAFmut patients experiencing early disease progression during induction treatment will have the 
option of proceeding immediately to receive second-line treatment with 5-FU/LV, cetuximab and 


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vemurafenib if their primary tumour is MSS, or with a fluoropyrimidine (5-FU/LV or capecitabine), 
bevacizumab, and atezolizumab if their primary tumour is MSI-H. 
If a patient previously indicated to have a BRAFmut primary tumour (e.g. according to local testing) 
progresses prior to the availability of results from the study primary tumour biomarker testing, the 
Investigator may request an expedited biomarker report from the sponsor’s Medical Monitor to confirm 
BRAFmut status and to obtain MS status. Such patients will be allocated to the appropriate second-line 
treatment and may begin treatment following approval from the Medical Monitor.  
Early progressing BRAFmut patients receiving 5-FU/LV, cetuximab and vemurafenib as second-line 
treatment will be followed for safety and efficacy in accordance with the Maintenance Treatment 
Phase Schedule of Assessments (including eligibility, biomarker sampling and post-treatment follow-
up) for Cohort 1 (see Appendix 2) and will be managed according to protocol recommendations and 
requirements for the experimental arm of Cohort 1.  Early progressing BRAFmut patients receiving a 
fluoropyrimidine (5-FU/LV or capecitabine), bevacizumab, and atezolizumab as second-line treatment 
will be followed for safety and efficacy in accordance with the Maintenance Treatment Phase 
Schedule of Assessments (including eligibility, biomarker sampling and post-treatment follow-up) for 
Cohort 2 (see Appendix 3) and will be managed according to protocol recommendations and 
requirements for the experimental arm of Cohort 2. This includes continuation of therapy beyond 
progression per RECIST 1.1 as described for Maintenance Treatment Phase patients receiving 
atezolizumab. 
 


 
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Figure 1: 
Study Design 
 


 
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Study Conduct 
A Steering Committee (SC) will be responsible for overseeing the general conduct of the study.  An 
iDMC will be responsible for evaluating the safety of the patients participating in the trial at regular 
intervals throughout the study.  This includes ongoing evaluation of benefit-risk balance based on 
accumulating safety and, as warranted, efficacy data. The iDMC will make recommendations as to 
whether cohort recruitment should continue based on each interim evaluation.  In addition, when 
necessary due to the nature of prior experience with a particular experimental regimen, the iDMC will 
conduct a safety run-in review of a pre-specified number of initial patients (e.g. as conducted for the 
initial patients treated with ‘5-FU/LV + cetuximab + vemurafenib’). Safety run-ins deemed necessary 
for additional cohorts will be specified in the protocol. The schedule of iDMC reviews will be 
determined by the iDMC and described in the iDMC Charter.  Additional data are provided in the 
respective SC and iDMC Charters.   
Number of Patients 
Before study enrolment was closed prematurely, approximately 1,820 patients were expected to be 
screened and approximately 1,400 patients were expected to be enrolled in the Induction Treatment 
Phase of the study in order to randomise the target sample size in each maintenance cohort. This 
included 405 patients in Cohort 2. Accrual into Cohort 4 was terminated prior to reaching the target 
sample size. Due to early closure of study enrolment, target sample sizes will not be reached for 
Cohorts 1 and 3. 
Screening procedures 
For comparability reasons, only the archival primary tumour sample from the original diagnosis will be 
used for the biomarker assessment which determines treatment assignment during the Maintenance 
Treatment Phase, as this material will be available for all patients. To be eligible for the study, patients 
must have an archival primary tumour sample for biomarker assessment for cohort assignment. If the 
tumour block is not available, ≥ 20 slides cut from the primary tumour sample will be accepted as an 
alternative. The sample (block or slides) must be shipped to the designated lab with confirmation of 
sample receipt provided by the laboratory prior to study enrolment. Biomarker analyses for cohort 
assignment will be conducted during the Induction Treatment Phase and these results will only be 
available during the Induction Treatment Phase and not during Screening. Patients with an adequate 
tumour sample but with unknown biomarker status due to lack of determinant result (e.g. due to 
technical issues) may still be included in the study depending on the addition of future cohorts. 
For enrolment into the study, patients who do not meet the study eligibility criteria (screen failures) 
may be re-screened within 7 days of the date they are determined to be screen failures. Re-screening 
of a patient > 7 days after screen failure is allowed only with prior approval from the Medical Monitor. 
Patients cannot be re-screened for the study more than once. 
Target Population 
The target study population consists of patients with mCRC who have not received any prior 
chemotherapy in the metastatic setting. Cohort-specific target populations are further defined by 
specific biomarker profiles. 
The “All Cohort” eligibility criteria are evaluated prior to initiating the first cycle of study treatment 
during the Induction Treatment Phase.  Cohort-specific exclusion criteria must be assessed within 3 
weeks of completing Induction Treatment Phase. Biomarker assessments will be completed prior to 
randomisation, as the results of the biomarker assessments are required to identify the intended 
cohort in order to complete the appropriate cohort-specific eligibility assessments.  


 
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Inclusion Criteria 
Patients must meet the following criteria for study entry: 
All Cohorts 
Patient Status  
1. Have provided written informed consent prior to any study specific procedures 
2. Willing and able to comply with the protocol 
3.  ≥ 18 years of age 
4. ECOG status of ≤ 2 (see Appendix 8) 
5. At least 16 weeks of life expectancy at time of entry into the study 
Disease-related 
6. Histologically confirmed CRC with mCRC confirmed radiologically  
7. Measurable, unresectable disease according to RECIST 1.1 
8. No prior chemotherapy for CRC in the metastatic setting 
9. Archival tumour formalin-fixed paraffin-embedded tissue (FFPET) block from the primary tumour 
obtained at the time of the initial diagnosis must be shipped to the Sponsor’s designated 
laboratory with sample receipt confirmed by the laboratory. If the tumour block is not available, 
≥ 20 slides cut from the primary tumour sample will be accepted as an alternative (see 
Appendix 17). The slides must be shipped with receipt confirmed by the Sponsor’s designated 
laboratory prior to study enrolment.  
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
All Cohorts 
Other Prior or Current Treatments  
1. Less than 6 months from completion of any prior neoadjuvant or adjuvant chemotherapy or 
radiotherapy 
2. Prior or current treatment with bevacizumab or any other anti-angiogenic drug (i.e. anti-VEGF or 
vascular endothelial growth factor receptor [VEGFR] therapies or tyrosine kinase inhibitors) 
3. Current or recent (within 10 days of start of study induction treatment) use of aspirin 
(> 325 mg/day), clopidogrel (> 75 mg/day), therapeutic oral or parenteral anticoagulants, or 
thrombolytic agents for therapeutic purposes.  
Note:  The use of full-dose oral or parenteral anticoagulants is permitted as long as the 
international normalised ratio (INR) or activated partial thromboplastin time (aPTT) is within 
therapeutic limits (according to the medical standard of the institution) and the patient has been 
on a stable dose of anticoagulants for at least two weeks prior to the start of study induction 
treatment. Prophylactic use of anticoagulants is allowed. 
4. Requirement for treatment with any medicinal product that contraindicates the use of any of the 
study medications, may interfere with the planned treatment, affects patient compliance or puts 
the patient at high risk for treatment-related complications 
5. Treatment with any other investigational agent within 28 days or 5 investigational agent half-lives 
(whichever is longer) prior to the start of study induction treatment  


 
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Haematological, Biochemical and Organ Function 
6. Inadequate haematological function indicated by one or more of the following: 
̶ 
Absolute neutrophil count (ANC) < 1.5 x 109/L 
̶ 
Platelet count < 100 x 109/L 
̶ 
Haemoglobin < 9 g/dL (patients may have transfusions and/or growth factors to attain 
adequate haemoglobin) 
7. Inadequate liver function indicated by one or more of the following:  
̶ 
Total bilirubin ≥ 1.5 x upper limit of normal (ULN)  
̶ 
Aspartate transaminase (AST) or alanine aminotransferase (ALT) ≥ 2.5 x ULN (≥ 5 x ULN in 
patients with known liver metastases) 
̶ 
Alkaline phosphatase (ALP) ≥ 2 x ULN (≥ 5 x ULN in patients with known liver metastases) 
8. Inadequate renal function indicated by one or more of the following:  
̶ 
Serum creatinine > 1.25 x ULN or calculated creatinine clearance < 50 ml/min 
̶ 
Urine dipstick for proteinuria ≥ 2+ unless a 24-hour urine protein < 1 g of protein is 
demonstrated 
9. INR > 1.5 or aPTT > 1.5 x ULN within 7 days prior to the start of study induction treatment for 
patients not receiving anti-coagulation. For patients, receiving anticoagulants INR and aPTT must 
be within the medical standard of enrolling institution. 
The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is 
within therapeutic limits (according to the medical standard of the enrolling institution) and the 
patient has been on a stable dose of anticoagulants for at least two weeks prior to the start of 
study induction treatment.  
General Criteria 
10. Active infection requiring intravenous antibiotics at the start of study induction treatment  
11. Previous or concurrent malignancy, except for adequately treated basal or squamous cell skin 
cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for five 
years prior to study entry 
12. Evidence of any other disease, neurologic or metabolic dysfunction, physical examination finding 
or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the 
use of any of the study medications, puts the patient at higher risk for treatment-related 
complications or may affect the interpretation of study results  
13. Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg and/or 
diastolic blood pressure > 100 mmHg) 
14. Prior history of hypertensive crisis or hypertensive encephalopathy   
15. Clinically significant (i.e. active) cardiovascular disease, for example cerebrovascular accidents ≤ 
6 months prior to start of study induction treatment, myocardial infarction ≤ 6 months prior to study 
enrolment, unstable angina, New York Heart Association (NYHA) Functional Classification Grade 
2 or greater congestive heart failure, or serious cardiac arrhythmia uncontrolled by medication or 
potentially interfering with protocol treatment 
16. History or evidence upon physical or neurological examination of central nervous system (CNS) 
disease (e.g. seizures) unrelated to cancer unless adequately treated with standard medical 
therapy 
17. Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent arterial 
thrombosis) within 6 months of start of study induction treatment 
18. Any previous venous thromboembolism > National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) Grade 3 within 12 months prior to start of study induction 
treatment 


 
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19. Active, symptomatic or untreated CNS metastases; CNS disease other than supratentorial or 
cerebellar metastases (i.e. patients with metastases to midbrain, pons, medulla or spinal cord are 
excluded); history of or known carcinomatous meningitis.  
Note:  Treatment of brain metastases, either by surgical or radiation techniques, must have been 
completed > 4 weeks prior to start of study induction treatment. Patients requiring anticonvulsants 
or corticosteroids for symptom control and patients with evidence of interim progression between 
the completion of CNS-directed therapy and study baseline disease assessments are excluded 
from the study.  
Note:  Patients without measurable disease outside the CNS are excluded from the study. 
20. History of haemoptysis ≥ Grade 2 (defined as ≥ 2.5 mL bright red blood per episode) within 1 
month of start of study induction treatment 
21. History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding 
(i.e. in the absence of therapeutic anticoagulation)  
22. Surgical procedure (including open biopsy, surgical resection, wound revision, or any other major 
surgery involving entry into a body cavity) or significant traumatic injury within 28 days prior to 
start of study induction treatment, or anticipation of need for major surgical procedure during the 
course of the study  
23. Minor surgical procedure including placement of a vascular access device, within 2 days of start 
of study induction treatment  
24. History of abdominal fistula, gastrointestinal (GI) perforation, intra-abdominal abscess or active GI 
bleeding within 6 months prior to start of study induction treatment  
25. Serious, non-healing wound, active ulcer, or untreated bone fracture 
26. Known hypersensitivity to any component of any of the study induction or maintenance treatment 
medications 
27. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanised antibodies or fusion proteins 
28. Known dihydropyrimidine dehydrogenase (DPD) deficiency 
29. Pregnancy or lactation. A serum pregnancy test is required within 7 days prior to start of study 
induction treatment, or within 14 days with a confirmatory urine pregnancy test within 7 days prior 
start of study induction treatment 
30. For women who are not post-menopausal (< 12 months of non-therapy-induced amenorrhea) or 
surgically sterile (absence of ovaries and/or uterus): refusal to use a highly effective contraceptive 
method (i.e. with a failure rate of < 1% per year such as sexual abstinence, hormonal implants, 
combined oral contraceptives, vasectomised partner), during both the Induction and Maintenance 
Treatment Phases and for at least 7 months after the last dose of study medication.  Periodic 
abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are 
not acceptable methods of contraception. A combination of male condom with cap, diaphragm or 
sponge with spermicide (double barrier methods) is not considered highly effective, birth control 
methods. Acceptable methods of contraception may include total abstinence in cases where the 
lifestyle of the patient ensures compliance. A vasectomised partner is a highly effective birth 
control method provided that partner is the sole sexual partner of the MODUL trial participant and 
that the vasectomised partner has received medical assessment of the surgical success. Some of 
the study-related medication, such as vemurafenib may decrease the plasma exposure of those 
hormonal contraceptives predominantly metabolised by CYP3A4. In these cases, the use of an 
alternate highly effective method of contraception must be considered. 
31. For men: refusal to use a highly effective contraceptive method (i.e. with a failure rate of < 1% per 
year such as vasectomy, sexual abstinence or female partner use of hormonal implants or 
combined oral contraceptives) during both the Induction and Maintenance Treatment Phases and 
for a period of at least 6 months after the last dose of study medication.  Periodic abstinence [e.g., 
calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable 


 
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methods of contraception. A combination of male condom with either cap, diaphragm or sponge 
with spermicide (double barrier methods) is not considered highly effective, birth control methods. 
Acceptable methods of contraception may include total abstinence in cases where the lifestyle of 
the patient ensures compliance. A vasectomised MODUL trial participant is a highly effective birth 
control method provided that the MODUL trial participant has received medical assessment of the 
surgical success. Men must also agree not to donate sperm for at least 6 months after their last 
dose of study drug.  
Cohort-Specific Exclusion Criteria 
The following criteria will be assessed following biomarker-based cohort assignment: 
Additional criteria for Cohort 1  
1. Have not provided informed consent to participate in Cohort 1. 
Note:  At study centers where a single informed consent form is used, informed consent to 
participate in any maintenance cohort will have already been provided at study entry. Patients 
enrolled at centers using two informed consent forms must provide maintenance cohort-specific 
consent after cohort assignment and prior to cohort-specific eligibility assessments other than 
eligibility assessments already conducted as part of routine care. 
2. Inability to swallow pills. 
3. Refractory nausea and vomiting, malabsorption, external biliary shunt or significant bowel 
resection that would preclude adequate absorption. 
4. History or presence of clinically significant ventricular or atrial dysrhythmias ≥ NCI CTCAE 
Grade 2 
5. Corrected QT (QTc) interval ≥ 450 msec as assessed within 3 weeks prior to randomization, long 
QT syndrome, uncorrectable electrolyte abnormalities (including magnesium) or requirement for 
medicinal products known to prolong the QT interval 
6. For women who are not post-menopausal (< 12 months of non-therapy-induced amenorrhea) or 
surgically sterile (absence of ovaries and/or uterus): refusal to use an alternate highly effective 
contraceptive method (i.e. with a failure rate of < 1% per year such as sexual abstinence, 
vasectomised partner) other than hormonal contraceptives, during both the Induction and 
Maintenance Treatment Phases and for at least 7 months after the last dose of study medication. 
Vemurafenib may decrease the plasma exposure of those hormonal contraceptives 
predominantly metabolised by CYP3A4. 
7. ECOG PS > 2. 
Note:  Due to the potential risks associated with treatment in the experimental arm of Cohort 1, 
patients with ECOG PS = 2 and a low body mass index (BMI) must be judged by the Investigator 
as adequately physically fit to receive treatment with 5-FU/LV + cetuximab + vemurafenib to be 
considered eligible. See protocol Section 4.3.2.2.2. 
Additional criteria for Cohort 2  
1. Have not provided informed consent to participate in Cohort 2  
Note:  At study centers where a single informed consent form is used, informed consent to 
participate in any maintenance cohort will have already been provided at study entry. Patients 
enrolled at centers using two informed consent forms must provide maintenance cohort-specific 
consent after cohort assignment and prior to cohort-specific eligibility assessments other than 
eligibility assessments already conducted as part of routine care. 
2. Known hypersensitivity or allergy to Chinese hamster ovary cell products  
3. History of autoimmune disease including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel 


 
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disease, 
vascular 
thrombosis 
associated 
with 
antiphospholipid 
syndrome, 
Wegener’s 
granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or 
glomerulonephritis (see Appendix 9 for a more comprehensive list of autoimmune diseases) 
Patients with the following are eligible: 
̶ 
a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement 
hormone 
̶ 
controlled Type 1 diabetes mellitus on a stable insulin regimen 
̶ 
eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only 
(e.g. patients with psoriatic arthritis would be excluded) are permitted provided that they 
meet the following conditions: 
o 
rash must cover less than 10% of body surface area (BSA) 
o 
disease is well controlled prior to randomization and only requires low potency topical 
steroids 
o 
no acute exacerbations of underlying condition within the previous 12 months (not 
requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, biologic 
agents, oral calcineurin inhibitors, high potency or oral steroids) 
4. Prior allogeneic bone marrow transplantation or prior solid organ transplantation 
5. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or 
evidence of active pneumonitis on most recent chest imaging (CT scan or MRI) 
Note:  History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
6. Positive test for human immunodeficiency virus (HIV) 
7. Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test prior to 
randomization) or hepatitis C 
Note:  Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as 
having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] 
antibody test) are eligible. 
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction 
(PCR) is negative for HCV RNA. 
8. Active tuberculosis 
9. Severe infection within 4 weeks prior to start of maintenance treatment including, but not limited to, 
hospitalization for complications of infection, bacteremia, or severe pneumonia; has signs or 
symptoms of significant infection or has received oral or IV antibiotics within 2 weeks prior to start 
of maintenance treatment. 
Note: Patients receiving prophylactic antibiotics (e.g. for prevention of a urinary tract infection or 
chronic obstructive pulmonary disease) are eligible. 
10. Administration of a live, attenuated vaccine within 4 weeks prior to start of study maintenance 
treatment or anticipation that such a live attenuated vaccine will be required during the study 
11. Prior treatment with CD137 agonists, anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic antibody 
or pathway-targeting agents 
12. Treatment with systemic immunostimulatory agents (including but not limited to interferons or 
interleukin-2) within 4 weeks or five half-lives of the drug, whichever is longer, prior to start of 
study maintenance treatment 
13. Treatment with systemic corticosteroids or other systemic immunosuppressive medications 
(including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, 
methotrexate, thalidomide, and anti-tumour necrosis factor [TNF] agents) within 2 weeks prior to 


 
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start of study maintenance treatment, or requirement for systemic immunosuppressive 
medications during the trial.   
Note:  The use of inhaled corticosteroids for chronic obstructive pulmonary disease (≤ 10 mg oral 
prednisone or equivalent), mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic 
hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are 
allowed. 
Patients who have received acute, low-dose (≤ 10 mg oral prednisone or equivalent), systemic 
immunosuppressant medications may be enrolled in the study after discussion with and approval 
by the Medical Monitor. 
14. If receiving a RANKL inhibitor (e.g. denosumab), unwilling to adopt alternative treatment such as 
(but not limited to) bisphosphonates, while receiving atezolizumab. 
Additional criteria for Cohort 3 
1. Have not provided informed consent to participate in Cohort 3 
Note: At study centers where a single informed consent form is used, informed consent to 
participate in any maintenance cohort will have already been provided at study entry. Patients 
enrolled at centers using two informed consent forms must provide maintenance cohort-specific 
consent after cohort assignment and prior to cohort-specific eligibility assessments other than 
eligibility assessments already conducted as part of routine care. 
2. Inability to swallow pills 
3. Left ventricular ejection fraction (LVEF) < 50% as assessed after completion of induction 
treatment by either 2D echocardiogram (ECHO) or multiple-gated acquisition (MUGA) (ECHO is 
the preferred method). 
4. Clinically significant cardiovascular disease, including unstable angina, history of or active 
congestive heart failure of ≥ NYHA Grade 2, history of or ongoing serious cardiac arrhythmia 
requiring treatment (except for controlled atrial fibrillation and/or paroxysmal supraventricular 
tachycardia).  
5. Current uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg) with or 
without medication 
6. Current dyspnoea at rest due to complications of advanced malignancy or other disease requiring 
continuous oxygen therapy 
7. Insulin-dependent diabetes  
8. Current known infection with HIV, HBV, or HCV (active infection or carriers) 
9. Requirement for concurrent use of the antiviral agent sorivudine (antiviral) or chemically related 
analogues, such as brivudine 
10. Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the 
stomach or small bowel, or ulcerative colitis 
11. Known hypersensitivity to murine proteins 
Additional Criteria for Cohort 4 
1. Have not provided informed consent to participate in Cohort 4 
Note:  At study centers where a single informed consent form is used, informed consent to 
participate in any maintenance cohort will have already been provided at study entry. Patients 
enrolled at centers using two informed consent forms must provide maintenance cohort-specific 
consent after cohort assignment and prior to cohort-specific eligibility assessments other than 
eligibility assessments already conducted as part of routine care. 
2. Inability to swallow medications 
3. Known hypersensitivity or allergy to Chinese hamster ovary cell products 


 
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4. History of autoimmune disease including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel 
disease, 
vascular 
thrombosis 
associated 
with 
antiphospholipid 
syndrome, 
Wegener’s 
granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or 
glomerulonephritis (see Appendix 9 for a more comprehensive list of autoimmune diseases) 
Patients with the following are eligible: 
̶ 
a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement 
hormone 
̶ 
controlled Type 1 diabetes mellitus on a stable insulin regimen 
̶ 
eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only 
(e.g. patients with psoriatic arthritis would be excluded) are permitted provided that they 
meet the following conditions: 
o 
rash must cover less than 10% of body surface area (BSA) 
o 
disease is well controlled prior to randomization and only requires low potency topical 
steroids 
o 
no acute exacerbations of underlying condition within the previous 12 months (not 
requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, biologic 
agents, oral calcineurin inhibitors, high potency or oral steroids) 
5. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or 
evidence of active pneumonitis on most recent chest imaging (CT scan or MRI) 
Note:  History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
6. Malabsorption condition that would alter the absorption of orally administered medications 
7. Amylase or lipase ≥ 1.5 × ULN within 14 days prior to maintenance treatment initiation 
8. Serum albumin < 2.5 g/dL 
9. LVEF < institutional lower limit of normal or < 50%, whichever is lower. 
10. Poorly controlled hypertension, defined as a blood pressure consistently above 150/90 mmHg 
despite optimal medical management. 
11. Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated drainage more 
than once every 28 days. Indwelling drainage catheters (e.g. PleurX®) are allowed. 
12. Unstable angina, new onset angina within last 3 months, myocardial infarction within last 6 
months and current congestive heart failure ≥ NYHA Grade 2 
13. History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 6 
months prior to initiation of maintenance treatment 
14. History or evidence of intracranial hemorrhage or spinal cord hemorrhage 
15. Evidence of clinically significant vasogenic edema 
16. Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 28 days prior to initiation of 
maintenance treatment 
17. History or evidence of retinal pathology on ophthalmologic examination that is considered a risk 
factor for central serous retinopathy, retinal vein occlusion, or neovascular macular degeneration 
Patients will be excluded if they currently have any of the following risk factors for retinal vein 
occlusion: 
̶ 
Uncontrolled glaucoma with intra ocular pressure ≥ 21 mmHg 
̶ 
Uncontrolled hypercholesterolemia > 300 mg/dL or 7.75 mmol/L 
̶ 
Uncontrolled hypertriglyceridemia > 300 mg/dL or 3.42 mmol/L 
̶ 
Fasting hyperglycemia > 160 mg/dL or 8.9 mmol/L 


 
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18. Positive HIV test 
19. Active hepatitis B (defined as having a positive HBsAg test prior to randomization) or hepatitis C 
Note:  Patients with past HBV infection or resolved HBV infection (defined as having a negative 
HBsAg test and a positive anti-HBc antibody test) are eligible. 
Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA. 
20. Active tuberculosis 
21. Severe infection within 4 weeks prior to start of maintenance treatment including, but not limited to, 
hospitalization for complications of infection, bacteremia, or severe pneumonia; has signs or 
symptoms of significant infection or has received oral or IV antibiotics within 2 weeks prior to start 
of maintenance treatment. 
Note: Patients receiving prophylactic antibiotics (e.g. for prevention of a urinary tract infection or 
chronic obstructive pulmonary disease) are eligible. 
22. Prior allogeneic bone marrow transplantation or prior solid organ transplantation 
23. Administration of a live, attenuated vaccine within 4 weeks prior to start of study maintenance 
treatment or anticipation that such a live attenuated vaccine will be required during the study 
24. Prior treatment with CD137 agonists, anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic antibody 
or pathway-targeting agents 
25. Prior treatment with a MEK or ERK inhibitor 
26. Treatment with systemic immunostimulatory agents (including but not limited to interferons or 
interleukin-2) within 4 weeks or five half-lives of the drug, whichever is longer, prior to start of 
study maintenance treatment 
27. Treatment with systemic corticosteroids or other systemic immunosuppressive medications 
(including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, 
methotrexate, thalidomide, and anti-TNF agents) within 2 weeks prior to start of study 
maintenance treatment, or requirement for systemic immunosuppressive medications during the 
trial. 
Note:  The use of inhaled corticosteroids for chronic obstructive pulmonary disease (≤ 10 mg oral 
prednisone or equivalent), and mineralocorticoids (e.g., fludrocortisone) for patients with 
orthostatic 
hypotension, 
and 
low-dose 
supplemental 
corticosteroids 
for 
adrenocortical 
insufficiency are allowed. 
Note:  Patients who have received acute, low-dose (≤ 10 mg oral prednisone or equivalent), 
systemic immunosuppressant medications (e.g. a one-time dose of dexamethasone for nausea) 
may be enrolled in the study after discussion with and approval by the Medical Monitor. 
28. If receiving a RANKL inhibitor (e.g. denosumab), unwilling to adopt alternative treatment such as 
(but not limited to) bisphosphonates, while receiving atezolizumab. 
29. Consumption of foods, supplements or drugs that are potent CYP3A4 enzyme inducers or 
inhibitors ≤ 7 days before initiation of study maintenance treatment or expected concomitant use 
during maintenance treatment. These include St. John’s wort or hyperforin (potent CYP3A4 
enzyme inducer) and grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor). 
Length of Study 
Study recruitment started in April 2015. Patient screening was temporarily suspended beginning in 
June 2016 for the addition of maintenance Cohorts 3 and 4. Screening and enrolment were again 
suspended in February 2018 to accommodate closure of accrual to Cohort 4. Study enrolment will not 
be re-opened. The entire study duration is estimated to be approximately 5 years.  


 
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End of Study 
The end of the study is defined as the date when all study patients have discontinued study treatment 
and completed the adverse event reporting period and, if applicable, cohort-specific post-treatment 
follow-up safety assessments (see protocol Section 5.3.1 for adverse event reporting periods and 
post-treatment follow-up safety assessments).  After this, the trial will end and no further data will be 
collected in the clinical database for this study.  
Continued access to Roche investigational medicinal products (IMPs) used in the study will be in 
accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product. 
Efficacy Outcome Measures 
All Cohorts 
Efficacy outcome measures will be assessed within each cohort (experimental arm vs. control arm) 
during the Maintenance Treatment Phase.   
Primary  
PFS defined as the time from randomisation into the Maintenance Treatment Phase until disease 
progression per Investigator assessment using RECIST 1.1 or death from any cause, whichever 
occurs first.   
Secondary 
• 
OS, defined as the time from randomisation into the Maintenance Treatment Phase to death from 
any cause 
• 
ORR (defined as PR or CR) during the Maintenance Treatment Phase.  Response will be 
determined by the Investigator according to RECIST 1.1 based on comparisons to the tumour 
assessment done at the end of the Induction Treatment Phase. 
• 
DCR (defined as CR, PR or SD) during the Maintenance Treatment Phase. Response will be 
determined by the Investigator according to RECIST 1.1 based on comparisons to the tumour 
assessment done at the end of the Induction Treatment Phase. 
• 
TTR defined as the time from randomisation into the Maintenance Treatment Phase to the first 
subsequent occurrence of a documented objective response (PR or CR), as determined by the 
Investigator according to RECIST 1.1. 
• 
DOR, defined as the time from the first occurrence of a documented objective response (PR or 
CR) during the Maintenance Treatment Phase to the time of progression, as determined by the 
Investigator according to RECIST 1.1, or death from any cause 
• 
ECOG performance status during and after treatment 
Safety Outcome Measures 
All Cohorts 
The safety outcome measures for this study are as follows: 
• 
Incidence, nature and severity of all adverse events (graded according to NCI CTCAE v4.0) 
• 
Incidence and nature of all Grade 3 – 5 AEs 
• 
Grade 5 AEs or AEs leading to death on study treatment 
• 
All SAEs 
• 
Incidence and reasons for any premature discontinuation of any component of study treatment 


 
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• 
Incidence and reasons for any dose reductions or interruptions of any component of study 
treatment 
• 
AEs of special interest  
• 
Clinically significant changes in laboratory values  
Adverse events refer to all treatment-emergent adverse events occurring after the initiation of study 
medication (i.e. on or after Day 1, Cycle 1 of the Induction Treatment Phase).  AEs will continue to be 
collected during the Maintenance Treatment Phase and Post-Treatment Follow-up Phase as 
applicable. 
Exploratory Outcome Measures 
Cohorts 2 and 4- Experimental Arms Only 
PFS in patients treated with atezolizumab defined as the time from randomisation into the 
Maintenance Treatment Phase until disease progression per Investigator assessment using 
mRECIST or death from any cause, whichever occurs first. 
All Cohorts 
The exploratory biomarker and microbiome outcome measures for this study include molecular 
markers/marker profiles and efficacy and/or safety outcomes.  Efficacy outcomes considered for this 
analysis may include, but are not limited to, ORR, PFS and OS, as appropriate. Biomarkers, 
biomarker profiles and microbiomes may be assessed using various methodologies including, but not 
limited to, immunohistochemistry (single and multiplex), RNA and DNA analysis (e.g polymerase 
chain reaction; next generation sequencing; and mutation, expression and microsatellite instability 
analyses) of tumour and blood samples collected from all study patients as well as additional tumour 
samples and stool samples collected from patients participating in the Supplemental Biomarker 
Program.  
Study Treatment 
Induction Treatment Phase 
All Cohorts 
All patients will receive 4 months of study treatment in the Induction Treatment Phase.  Treatment 
during this phase, based on Investigator’s choice, will be either: 
• 
eight 2-week cycles of 5-FU/LV and oxaliplatin (FOLFOX) in combination with bevacizumab 
or 
• 
six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 
5-FU/LV with bevacizumab 
and should be in accordance with locally approved prescribing information including any 
recommendations for pre-treatment (i.e. antiemetic therapies). The Investigator will select the 
FOLFOX regimen (e.g. FOLFOX-4, FOLFOX-6, modified FOLFOX-6, FOLFOX-7 or modified 
FOLFOX-7; see Appendix 6) also in accordance with local standards.   
Maintenance Treatment Phase 
All Cohorts 
Each cohort will contain an experimental treatment arm based specifically on the patient’s biomarker 
status based on the patient’s archival tumour sample from the initial diagnosis (see Appendix 17 for 
additional details on cohort assignment). Patients with an adequate tumour sample but with unknown 


 
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biomarker status due to lack of determinant result (e.g. due to technical issues) may still be eligible 
depending on the addition of future cohorts. Each cohort will also include a control treatment arm 
containing a fluoropyrimidine and bevacizumab. Maintenance treatment will begin within 3 weeks of 
completing induction treatment. 
For patients in Cohorts 1 and 3, and the control arms of Cohorts 2 and 4, study treatment during the 
Maintenance Treatment Phase will continue until disease progression (based on Investigator’s 
assessment according to RECIST 1.1), unacceptable toxicity, initiation of another anti-cancer therapy, 
patient or physician decision to discontinue, or patient death, whichever occurs first.  
For patients randomised to the experimental arms of Cohorts 2 and 4 (i.e. patients who are receiving 
atezolizumab), study treatment during the Maintenance Treatment Phase may continue after the first 
tumour assessment showing progression per RECIST 1.1 as long as they meet the following criteria 
as assessed by the Investigator: 
• 
Evidence of clinical benefit  
• 
Absence of symptoms and signs (including worsening of laboratory values, e.g. new or worsening 
hypercalcaemia) indicating unequivocal progression of disease 
• 
No decline in ECOG performance status that can be attributed to disease progression 
• 
Absence of tumour progression at critical anatomical sites (e.g. leptomeningeal disease) that 
cannot be managed by protocol-allowed medical interventions 
Treatment should be discontinued if the next follow-up tumour assessment continues to demonstrate 
progression per RECIST 1.1 (as compared to the assessment at the end of induction treatment). If the 
next tumour assessment does not show progression per RECIST 1.1, the patient may continue 
maintenance treatment until such time as the treatment continuation criteria above are no longer met 
and/or two sequential tumour assessments show progression per RECIST 1.1. 
Atezolizumab treated patients may be discontinued from study treatment during the Maintenance 
Phase for the following reasons other than loss of clinical benefit or persistent progression: 
unacceptable toxicity, initiation of another anti-cancer therapy, patient or physician decision to 
discontinue, or patient death, whichever occurs first. 
Dose reductions or interruptions of IMPs are only allowed as recommended in the applicable 
Investigator’s Brochure.  If any drug of any study treatment regimen in either the Induction or 
Maintenance Treatment Phase is discontinued or held for > 21 days, approval from the Medical 
Monitor will be required before treatment can be re-initiated. If Medical Monitor approval is not 
obtained, the patient will come off all study treatment and will enter the Post-Treatment Follow-up 
Phase. 
All Cohorts - Control Arms 
The maintenance treatment regimen is the same for the control arms of all cohorts.  
Fluoropyrimidine (5-FU/LV or capecitabine): dose and schedule will be according to local label, 
where applicable, or otherwise will be determined per the Investigator’s discretion. Administration 
should be according to local prescribing information. 
Bevacizumab: 5 mg/kg via 15 – 30 minute IV infusion on Day 1 of every 2-week cycle. 
Bevacizumab should be prepared and administered in accordance with local prescribing 
information.  
Cohort 1 – Experimental Arm 
Patients assigned to the experimental arm of Cohort 1 with an ECOG PS = 2 and a low BMI must be 
carefully assessed by the Investigator for physical fitness adequate for receipt of this regimen prior to 
initiating treatment. Such patients must be closely monitored through the maintenance treatment 
period. 


 
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5-FU:  The first six patients in this cohort received 1,600 mg/m2 5-FU administered via 46-hour IV 
infusion, in combination with LV 400 mg/m2 administered via 2-hour infusion, on Day 1 of every 2-
week cycle.  Subsequent patients in this cohort will receive 1,600 – 2,400 mg/m2 5-FU 
administered via 46-hour IV infusion (IV bolus is not permitted), in combination with LV 400 mg/m2 
administered via 2-hour infusion, on Day 1 of every 2-week cycle. 
Cetuximab:  The dose and scheduling of cetuximab is 500 mg/m2 via IV infusion on Day 1 of 
every 2-week cycle. Cetuximab must be administered in hospital under the supervision of a 
physician experienced in the use of antineoplastic medicinal products. Cetuximab must be 
administered via infusion pump or syringe pump at a rate not exceeding 5 mg/min for the first 
administration and 10 mg/min for subsequent administrations. Close monitoring is required during 
the infusion and for at least 1 hour after the end of the infusion. Availability of resuscitation 
equipment must be ensured. Prior to the first infusion of cetuximab, patients must receive 
premedication with an antihistamine and a corticosteroid. This premedication is recommended 
prior to all subsequent infusions.  Refer to cetuximab Package Insert (Appendix 14). 
Vemurafenib:  The dose and scheduling of vemurafenib is 960 mg b.i.d by mouth. Vemurafenib 
should be taken at approximately the same times each day, the first dose is to be taken in the 
morning and the second dose is to be taken approximately 12 hours later in the evening. Each 
dose should always be taken in the same manner i.e. either with or without a meal. Missed doses 
will not be made up. 
Note:  A safety run-in review of the first six patients treated with the experimental combination of 
‘5-FU/LV + cetuximab + vemurafenib’ was conducted in February 2016. The iDMC recommended 
that patients allocated to this regimen may now receive 5-FU at doses up to 2,400 mg/m2. The 
iDMC will continue to monitor initial patients in this regimen treated with 5-FU doses 
≥ 1,600 mg/m2 and have also recommended that patients with ECOG PS = 2 and a low BMI be 
carefully assessed by the Investigator for physical fitness adequate for receipt of this regimen.   
Cohort 2 - Experimental Arm 
Fluoropyrimidine (5-FU/LV or capecitabine):  1,600 – 2,400 mg/m2 5-FU administered via 46-
hour IV infusion (IV bolus is not permitted) on Day 1 of every 2-week cycle, and LV 400 mg/m2 
administered via a 2-hour infusion on day 1 every 2 weeks; or 1000 mg/m2 twice-daily 
capecitabine (b.i.d.) by mouth given days 1-14 every 2 weeks followed by a one-week treatment 
break.  
Bevacizumab:  The dose and schedule of bevacizumab is 5 mg/kg via 15 – 30 minute IV infusion 
on Day 1 of every 2-week cycle. Bevacizumab should be prepared and administered in 
accordance with local prescribing information. Patients may be at risk of developing infusion / 
hypersensitivity reactions with bevacizumab. Close observation of the patient during and following 
the administration of bevacizumab is recommended as expected for any infusion of a therapeutic 
humanised monoclonal antibody. If a reaction occurs, the infusion should be discontinued and 
appropriate medical therapies should be administered. A systematic premedication is not 
warranted. 
Atezolizumab:  Atezolizumab is administered at a fixed dose of 800 mg via 60-minute IV infusion 
on Day 1 of every 2-week cycle. Atezolizumab must be administered in hospital under the 
supervision of a physician experienced in the use of antineoplastic medicinal products. For the 
first infusion, the patient’s vital signs (heart rate, respiratory rate, blood pressures, and 
temperature) should be determined within 60 minutes before the infusion, every 15 ± 5 minutes 
during the infusion, and 30 ± 10 minutes after the infusion. For subsequent infusions, vital signs 
will be collected within 60 minutes before the infusion and should be collected during or after the 
infusion if clinically indicated or if symptoms occurred in the prior infusion.  If the initial infusion is 
well tolerated, subsequent infusions will be done over a 30-minute time period. No premedication 
is indicated for the first dose of atezolizumab. Patients who experience an infusion-related 
reaction with Cycle 1 of atezolizumab may receive premedication with antihistamines or 


 
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antipyretics/analgesics (e.g. acetaminophen) for subsequent infusions.  The rate of atezolizumab 
infusion should be modified in the event of an infusion-related reaction. 
Cohort 3 - Experimental Arm 
Capecitabine, trastuzumab and pertuzumab will be administered according to the doses and 
schedules described below. For the first treatment cycle, pertuzumab should be administered on 
Day 1, followed by the first dose of trastuzumab and capecitabine on Day 2. If the administration 
of all three agents is well tolerated in the first treatment cycle, they may be given sequentially on 
Day 1 (pertuzumab and trastuzumab should not be mixed in the same infusion bag) in 
subsequent cycles thereafter. If a patient cannot tolerate all three drugs given on the same day, 
pertuzumab should continue to be delivered on Day 1, with trastuzumab and capecitabine 
delivered on Day 2 for subsequent treatment cycles. 
Capecitabine:  1000 mg/m2 twice-daily capecitabine (b.i.d.; for a total daily dose of 2000 mg/m2) 
by mouth given days 1-14 every 2 weeks followed by a one-week treatment break administered in 
accordance with local prescribing information. See Appendix 7 for capecitabine dose calculations 
by body surface area with corresponding tablet counts. 
Trastuzumab:  Trastuzumab is administered by IV infusion on Day 1 of every 3-week treatment 
cycle at an initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent doses. 
Trastuzumab must be administered in hospital under the supervision of a physician experienced 
in the use of antineoplastic medicinal products.  The first infusion should be delivered over 
90 minutes followed by a 60 minute observation period.  If the first infusion is well tolerated 
without infusion-associated AEs, the second and subsequent infusions may be delivered over 
30 minutes with an observation period of 30 minutes.  Longer infusion and/or observation times 
can be maintained if there is any doubt about tolerability. No premedication will be allowed for the 
first dose of trastuzumab. Premedication may be administered for subsequent cycles at the 
discretion of the treating physician.  The rate of trastuzumab infusion should be modified in the 
event of an infusion-related reaction. 
Pertuzumab:  Pertuzumab is administered by IV infusion on Day 1 of each 3-week treatment 
cycle at an initial fixed loading dose of 840 mg followed by 420 mg for subsequent doses. 
Pertuzumab must be administered in hospital under the supervision of a physician experienced in 
the use of antineoplastic medicinal products. The first infusion should be delivered over 
60 minutes followed by a 60 minute observation period.  The observation period for subsequent 
infusions may be between 30 and 60 minutes if the first infusion is well tolerated without infusion-
associated AEs. No premedication will be allowed for the first dose of pertuzumab. Premedication 
may be administered for subsequent cycles at the discretion of the treating physician.  The rate of 
pertuzumab infusion should be modified in the event of an infusion-related reaction. 
Cohort 4 - Experimental Arm 
In an Urgent Safety Measure Letter dated July 25, 2018, the Sponsor advised investigators to strongly 
consider discontinuing treatment in any Cohort 4 patients receiving experimental treatment. 
Investigators were advised to discuss appropriate next treatment options, including combination 
treatment with a fluoropyrimidine plus bevacizumab, with patients discontinuing experimental 
treatment. Please refer to protocol Section 3.1.2.4 for further details of the basis for Sponsor 
decisions for Cohort 4 and management of ongoing patients randomized to the experimental arm. 
Cobimetinib: Cobimetinib is administered orally at a dose of 60 mg for 3 weeks followed by a 
1 week treatment break (21/7 schedule). Treatment cycle length in this arm is 2 weeks. 
Cobimetinib will be administered daily every day of each odd numbered 2-week treatment cycle, 
and for the first 7 days only of each even numbered 2-week treatment cycle.  Cobimetinib should 
be taken at the same time every day with or without food. If a dose is missed or vomiting occurs 
when a dose is taken, dosing should be resumed at the next scheduled dose. 


 
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Atezolizumab:  Atezolizumab is administered at a fixed dose of 840 mg via 60-minute IV infusion 
on Day 1 of every 2-week cycle. Atezolizumab must be administered in hospital under the 
supervision of a physician experienced in the use of antineoplastic medicinal products. For 
anaphylaxis precautions, see Appendix 16.  For the first infusion, the patient’s vital signs (heart 
rate, respiratory rate, blood pressures, and temperature) should be determined within 60 minutes 
before the infusion, every 15 ± 5 minutes during the infusion, and 30 ± 10 minutes after the 
infusion. For subsequent infusions, vital signs will be collected within 60 minutes before the 
infusion and should be collected during or after the infusion if clinically indicated or if symptoms 
occurred in the prior infusion.  If the initial infusion is well tolerated, subsequent infusions will be 
done over a 30-minute time period. No premedication is indicated for the first dose of 
atezolizumab. Patients who experience an infusion-related reaction with Cycle 1 of atezolizumab 
may receive premedication with antihistamines or antipyretics/analgesics (e.g. acetaminophen) 
for subsequent infusions.  The rate of atezolizumab infusion should be modified in the event of an 
infusion-related reaction. 
Post-Treatment Follow-up Phase 
All Cohorts 
Second-line treatment during the Post-Treatment Follow-up Phase is at the Investigator’s discretion. 
However, patients who received atezolizumab should not receive other immunomodulatory agents for 
10 weeks after maintenance treatment discontinuation. 
BRAFmut Patients and Early Disease Progression 
Exceptionally, BRAFmut/MSS patients experiencing early disease progression during the induction 
treatment will have the option of proceeding immediately to receive second-line treatment with 5-
FU/LV, cetuximab and vemurafenib. These patients will be followed for safety and efficacy in 
accordance with the Maintenance Treatment Phase Schedule of Assessments (including eligibility, 
biomarker sampling and post-treatment follow-up) for Cohort 1 (see Appendix 2) and will be managed 
according to protocol recommendations and requirements for the experimental arm of Cohort 1. 
Similarly, BRAFmut/MSI-H patients experiencing early disease progression during induction treatment 
will have the option of proceeding immediately to receive second-line treatment with a 
fluoropyrimidine (5-FU/LV or capecitabine), bevacizumab, and atezolizumab. These patients will be 
followed for safety and efficacy in accordance with the Maintenance Treatment Phase Schedule of 
Assessments (including eligibility, biomarker sampling and post-treatment follow-up) for Cohort 2 (see 
Appendix 3) and will be managed according to protocol recommendations and requirements for the 
experimental arm of Cohort 2. 
Investigational Medicinal Products 
The IMPs used in this study include: 
• 
all non-fluoropyrimidine agents comprising the experimental arms of each maintenance treatment 
cohort (i.e. cetuximab and vemurafenib in Cohort 1, bevacizumab and atezolizumab in Cohort 2, 
trastuzumab and pertuzumab in Cohort 3, cobimetinib and atezolizumab in Cohort 4) 
• 
bevacizumab in the Induction Treatment Phase 
• 
bevacizumab in the control arms of each maintenance treatment cohort   
• 
cetuximab, vemurafenib, bevacizumab and atezolizumab administered as optional second-line 
treatments to early progressing BRAFmut patients 
Non-Investigational Medicinal Products  
Non-IMPs used in this study include all fluoropyrimidine agents (i.e. 5-FU and capecitabine) and 
leucovorin administered during the Induction and Maintenance Treatment Phases and as optional 


 
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second-line treatment to early progressing BRAFmut patients.  Oxaliplatin administered as part of 
induction treatment is also considered a non-IMP. 
Statistical Methods 
All Cohorts 
The cohorts will be based on different biomarkers (see Appendix 17), with each cohort consisting of 
an experimental treatment arm and a control arm. The inclusion of a control group allows 
discrimination of patient outcomes caused by the experimental treatment from outcomes caused by 
other factors. Randomisation avoids systematic differences (bias) between the groups with respect to 
known or unknown baseline variables that could affect outcome. The treatment for patients in the 
control arms represents standard of care. 
The primary objective of the study is to evaluate PFS per RECIST 1.1 within each cohort. 
Provided the iDMC does not recommend discontinuation of enrolment to a cohort or enrolment is not 
otherwise discontinued prior to a cohort reaching its target sample size, the primary analysis will occur 
for each cohort when the target number of PFS events has been reached. Secondary endpoints will 
also be summarised at this time. Analyses of any cohort closed to accrual before its target sample 
size is reached will be described in an SAP and will depend on accrual at the time of closure.  
Update on statistical analysis plans and cohort status following premature closure of study enrolment: 
Accrual to Cohort 2 was completed in November 2016. Accrual to Cohort 4 was closed in February 
2018 due to iDMC recommendations as a result of an unfavourable benefit-risk evaluation (see 
protocol Section 3.1.2.4). Study enrolment was suspended at the time of discontinuation of accrual to 
Cohort 4 (February 2018) and will remain permanently closed to further enrolment. Cohorts 1, 3 and 4 
will not reach their target sample size. As originally planned for cohorts reaching their target number 
of PFS events (applies to Cohort 2 only), an update analysis of efficacy and safety parameters will be 
conducted based on 24 months survival follow-up after the clinical cut-off date (CCOD) for the primary 
analysis. The CCOD for the Cohort 2 primary analysis was May 31, 2017. The Cohort 2 update 
analysis will be conducted based on a CCOD of May 31, 2019. The primary analysis for cohorts 1, 3 
and 4 will be conducted at the same time as the Cohort 2 update analysis (i.e. based on the same 
CCOD of May 31, 2019).  
The final study analysis for all cohorts will be conducted after all patients in the study have 
discontinued study treatment and completed the adverse event reporting period and any applicable 
post-treatment follow-up safety assessments (see protocol Section 5.3.1 for adverse event reporting 
periods and post-treatment follow-up safety assessments). Data will be summarised using appropriate 
summary statistics: mean, standard deviation, median, quartiles and range (minimum and maximum) 
for continuous variables, and number and percentage for categorical variables. 
Analysis Populations 
For each cohort, the Intent-To-Treat (ITT) Population will include patients entered into the 
Maintenance Treatment Phase of the study, irrespective of whether or not they received study 
medication. In this population, patients will be allocated to the study maintenance treatment into which 
they were randomised. The ITT Population will be used for all efficacy analyses. 
The Per Protocol Population will not be defined for this study but major protocol violations will be listed. 
The Safety Population will include all patients who received at least one dose of study medication 
during the Induction or Maintenance Treatment Phases. Patients will be allocated to the treatment 
regimen that they actually received. The Safety Population will be used for all safety analyses. 


 
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Statistical Hypotheses 
Cohorts 1 and 3 
The null and alternative hypotheses when comparing PFS between the two randomised treatments in 
Cohort 1 (Arm A: 5-FU/LV with cetuximab and vemurafenib vs. Arm B: fluoropyrimidine and 
bevacizumab) and in Cohort 3 (Arm A: capecitabine with trastuzumab and pertuzumab vs. Arm B: 
fluoropyrimidine and bevacizumab) are: 
H0:  
the distribution of the PFS time is the same in the two treatment groups 
PFS (Arm A) = PFS (Arm B) 
H1:  
the distribution of the PFS time is different in the two treatment groups 
specifically PFS (Arm A) > PFS (Arm B) 
If the hazard ratio (HR) of Arm A compared to Arm B is assumed to be constant over time, then the 
null and alternative hypotheses are: 
H0: HR = 1 vs. H1: HR < 1 
Due to the relatively low prevalence of mCRC patients with HER2+ or BRAFmut disease, the formal 
statistical tests for Cohorts 1 and 3 will be one-sided and performed at an alpha level (type I error rate) 
of 10%. 
Cohorts 2 and 4  
The null and alternative hypotheses when comparing PFS between the two randomised treatments in 
Cohort 2 (Arm A: fluoropyrimidine with bevacizumab and atezolizumab vs. Arm B: fluoropyrimidine 
and bevacizumab) and in Cohort 4 (Arm A: cobimetinib with atezolizumab vs. Arm B: fluoropyrimidine 
and bevacizumab) are: 
H0:  
the distribution of the PFS time is the same in the two treatment groups 
PFS (Arm A) = PFS (Arm B) 
H1:  
the distribution of the PFS time is different in the two treatment groups 
PFS (Arm A) ≠ PFS (Arm B) 
If the HR of Arm A compared to Arm B is assumed to be constant over time, then the null and 
alternative hypotheses are: 
H0: 
HR = 1 vs. H1: HR ≠ 1 
The formal statistical tests for Cohorts 2 and 4 will be two-sided and performed at an alpha level (type 
I error rate) of 5%. 
Primary Endpoint 
All Cohorts 
The primary efficacy endpoint of PFS is defined as the time from randomisation into the Maintenance 
Treatment Phase until disease progression per Investigator assessment using RECIST 1.1 or death 
from any cause, whichever occurs first. Tumour size will be calculated using the sum of the longest 
diameters of all target lesions, and reduction will be based on comparisons to the tumour assessment 
done at the end of the Induction Treatment Phase. 
Patients without an event will be censored at the date of their last evaluable tumour assessment or, if 
this is not available, at the date of randomisation. For each cohort, the primary analysis of PFS will 
occur when the target number of PFS events has been reached. 


 
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Within each cohort, PFS will be presented graphically for each treatment group using the Kaplan-
Meier method. Estimates and the corresponding 95% confidence interval will be reported by treatment 
group for median survival time, and for the 4-, 6- and 12-month PFS rates. 
Within each cohort, the comparison of PFS between the treatment groups will be performed using an 
unstratified log-rank test. In addition, a Cox regression will be performed with treatment and applicable 
stratification variables (biomarkers, geographic region and/or response after induction treatment) as 
terms in the model. The estimated hazard ratio and its corresponding 95% confidence interval will be 
presented.  
The timing and methods of the primary efficacy endpoint analyses for any cohort closed to accrual 
before its target sample size is reached may differ from above. These will be described in the SAP 
applicable to the cohort and will depend on accrual at the time of early closure. 
Secondary Efficacy Endpoints 
All Cohorts 
The secondary efficacy endpoints for each cohort are OS, ORR, DCR, TTR, DoR and ECOG 
performance status. 
OS is defined as the time from randomisation until death from any cause.  Patients who are still alive 
at the time of analysis (clinical cut-off) and patients who are lost to follow-up will be censored at their 
last clinical assessment date. 
Best overall response will be assessed for all patients after randomisation until disease progression. 
ORR will be calculated as the proportion of patients with a best overall response of CR or PR 
determined according to RECIST 1.1. ORR will be summarised and presented along with the 95% 
Clopper-Pearson confidence interval. 
DCR will be calculated as the proportion of patients with a best overall response of CR, PR or SD as 
determined according to RECIST 1.1. DCR will be summarised and presented along with the 95% 
Clopper-Pearson confidence interval. 
TTR will be calculated as the time from randomisation to the first occurrence of a documented 
objective response (CR or PR) determined according to RECIST 1.1. 
DoR will be assessed for all patients after randomisation until PD. Only patients with a best overall 
response of CR or PR per RECIST 1.1 are considered responders. The duration of response is the 
time from the first assessment of CR or PR until disease progression or death from any cause, 
whichever occurs first.  
The secondary time-to-event endpoints will be analysed by the same methods and at the same time 
as the primary endpoint.  
ECOG performance status will be summarised over time. 
Safety Endpoints 
All Cohorts 
Verbatim adverse event (AE) data will be mapped to Medical Dictionary for Regulatory Activities 
(MedDRA) thesaurus terms. 
All treatment-emergent AEs occurring during or after the first dose of study medication will be 
summarised by treatment group in frequency tables, as follows: 
• 
By preferred term and system organ class 
• 
By severity of all adverse events (graded according to NCI CTCAE v4.0) 
• 
Grade 3 – 5 AEs 
• 
Grade 5 AEs or AEs leading to death on study treatment 


 
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• 
All SAEs 
• 
AEs leading to premature discontinuation of any component of study treatment 
• 
AEs leading to dose reduction or interruption of any component of study treatment 
• 
AEs of special interest 
The above safety data will be summarised separately for the Induction and Maintenance Treatment 
Phases overall and by individual maintenance treatment cohort. 
Deaths reported during the study treatment period and those reported during follow-up after treatment 
completion/discontinuation will be summarised.  
Study medication exposure will be separately summarised by number of cycles, duration, dose and 
dose intensity. 
Vital signs data, clinical laboratory parameters, concomitant medication and subsequent anti-cancer 
therapy will also be summarised. 
Analysis for Exploratory Outcome Measures 
Cohorts 2 and 4 - Experimental Arms Only 
The exploratory efficacy endpoint of PFS in patients treated with atezolizumab is defined as the time 
from randomisation into the Maintenance Treatment Phase until disease progression per Investigator 
assessment using mRECIST or death from any cause, whichever occurs first. Patients without an 
event will be censored at the date of their last evaluable tumour assessment or, if this is not available, 
at the date of randomisation. PFS may be presented graphically using the Kaplan-Meier method. 
Estimates and the corresponding 95% confidence interval may be reported for the 4-, 6- and 12-
month PFS rates. 
All Cohorts 
Biomarker analyses will be of exploratory nature only, utilizing all available data obtained from archival 
tumour samples from initial diagnoses, all tumour and blood samples collected during the study 
(including additional tumour samples collected from Supplemental Biomarker Program participants), 
and stool samples collected during the study from Supplemental Biomarker Program participants.  
These analyses will be of exploratory nature only, using descriptive methods with no fixed hypotheses 
testing. 
With the ongoing analyses of the study’s various biomarker-based cohorts, more information on the 
concordance of different biomarkers will be collected and summarised.  Relevant findings will be 
discussed with the study’s SC in order to conduct further exploratory biomarker analyses accordingly. 
Interim Analyses 
The iDMC will evaluate accumulating safety and efficacy data within each cohort to assure these data 
continue to support an early positive benefit-risk ratio and to confirm that continued enrolment into 
each cohort is appropriate. The amount of efficacy data to be assessed in a given cohort will be 
determined by the iDMC at a preceding iDMC meeting. Details of this process are described in the 
iDMC charter. Decisions on what efficacy data have to be evaluated for each cohort will be 
documented in the iDMC meeting minutes. In addition, the iDMC will review data from any safety run-
in patients required for an experimental regimen (e.g. as conducted for the initial patients treated with 
the experimental combination of ‘5-FU/LV + cetuximab + vemurafenib’). These safety run-ins will be 
specified in the protocol.  
Determination of Sample Size 
Before study enrolment was closed prematurely, approximately 1,820 patients were expected to be 
screened and approximately 1,400 patients were expected to be enrolled in the Induction Treatment 
Phase of the study in order to randomise the planned number of patients in each of the maintenance 




 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
5-FU 
5-fluorouracil 
AE 
adverse event 
AKT 
v-akt murine thymoma viral oncogene homolog 
ALT 
alanine aminotransferase  
ALP 
alkaline phosphatase  
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time  
AST 
aspartate transaminase  
AUC 
area under the curve 
b.i.d. 
twice daily 
BMI 
body mass index 
BRAF 
v-raf murine sarcoma viral oncogene homolog B1 
BRAFmut 
BRAF mutation positive 
BRAFV600 
BRAF mutation at codon 600 
BRAFwt 
wild-type BRAF (mutation negative) 
BWFI 
bacteriostatic water for injection 
CA19-9 
carbohydrate antigen 19-9 
CAPIRI 
capecitabine with irinotecan 
CAPOX 
capecitabine with oxaliplatin 
CAPOX-B 
capecitabine with oxaliplatin and bevacizumab 
CHF 
congestive heart failure 
CNS 
central nervous system 
CPK 
creatine phosphokinase 
cSCC 
cutaneous squamous cell carcinoma 
CR 
complete response 
CRC 
colorectal cancer 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE v4.0 
Common Terminology Criteria for Adverse Events version 4.0 
DCR 
disease control rate 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DPD 
dihydropyrimidine dehydrogenase 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EDTA 
ethylenediaminetetraacetic acid 
EGFR 
epidermal growth factor receptor 


 
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Abbreviation 
Definition 
EMA 
European Medicines Agency 
EU 
European Union 
FDA 
Food and Drug Administration 
FFPET 
formalin-fixed paraffin-embedded tissue  
FOLFIRI 
5-fluorouracil, leucovorin and irinotecan 
FOLFOX 
5-fluorouracil, leucovorin and oxaliplatin 
GI 
gastrointestinal 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HER2 
human epidermal growth factor receptor 2 
HER2+ 
human epidermal growth factor receptor 2 positive 
hERG 
human Ether-à-go-go Related Gene 
HIV 
human immunodeficiency virus 
HLH 
hemophagocytic lymphohistiocytosis 
HPV 
human papillomavirus 
HR 
hazard ratio 
ICH 
International Conference on Harmonisation 
iDMC 
independent Data Monitoring Committee 
IHC 
immunohistochemistry  
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
INR 
international normalised ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
intravenous(ly) 
IxRS 
interactive voice or web-based response system 
KA 
keratoacanthoma 
KRAS 
V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog  
LDH 
lactate dehydrogenase 
LFT 
liver function test(s) 
LPLV 
last patient, last visit 
LV 
leucovorin calcium 
LVEF 
left ventricular ejection fraction 
LVSD 
left ventricular systolic dysfunction 
mRECIST 
modified Response Evaluation Criteria in Solid Tumors  
mCRC 
metastatic colorectal cancer 
MAb 
monoclonal antibody 
MAPK 
mitogen-activated protein kinase 
MAS 
macrophage activation syndrome 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
MSI-H 
high microsatellite instability 


 
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Abbreviation 
Definition 
MSS 
microsatellite stable 
MUGA 
multiple-gated acquisition 
NCI 
National Cancer Institute 
NGS 
next generation sequencing 
NRAS 
neuroblastoma RAS viral oncogene homolog 
NSCLC 
non-small cell lung cancer 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PD-L1 
programmed death-ligand 1 
PFS 
progression-free survival 
PR 
partial response 
PRES 
posterior reversible encephalopathy syndrome 
PTEN 
phosphatase and tensin homolog 
QTc 
corrected QT 
QTcF 
Fridericia-corrected QT 
RCR 
Roche Clinical Repository 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
RNA 
ribonucleic acid 
RPLS 
reversible posterior leukoencephalopathy syndrome 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
Steering Committee 
SCC 
squamous cell carcinoma 
SD 
stable disease 
SIA 
systemic immune activation 
SmPC 
summary of product characteristics 
SPF 
sun protection factor 
T3 
triiodothyronine 
T4 
thyroxine 
TSH 
thyroid-stimulating hormone 
TTR 
time to response 
ULN 
upper limit of normal 
VEGF 
vascular endothelial growth factor  
VEGFR 
vascular endothelial growth factor receptor 
WBC 
white blood cell 
XELOX 
capecitabine (Xeloda) and oxaliplatin 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON METASTATIC COLORECTAL CANCER  
1.1.1 
Epidemiology 
Colorectal cancer (CRC) is the second most common cancer in women and the third most 
common in men worldwide (Chawla et al. 2013). It is also the fourth leading cause of cancer 
deaths worldwide, with an estimated 1.36 million cases and 694,000 deaths in the year 2012 
(Ferlay et al. 2013). Unfortunately, these numbers are expected to rise with the worldwide 
incidence reaching 2.44 million by the year 2035. In more developed regions of the world 
(Europe, North America, Australia, New Zealand and Japan), CRC is the third leading cause 
of cancer deaths after lung and prostate cancer. In the European Union (EU), CRC is the 
third leading newly diagnosed cancer after lung cancer and prostate cancer in males, and 
the second after breast cancer in females, and is the second leading cause of overall cancer 
deaths (Karim-Kos 2008). The estimated 2012 EU incidence of CRC is 345,000 cases with 
152,000 deaths for 2012 (Ferlay et al. 2013).  
High CRC mortality rates are fuelled by the large proportion of patients with metastatic 
disease at initial diagnosis (approximately 25%) and the fact that almost 50% of patients will 
develop metastatic disease (Van Cutsem et al. 2010). Treatment and support of CRC 
patients is significant and this, coupled with high disease morbidity and mortality that are 
expected to increase, has resulted in a substantial socio-economic burden and public health 
problem that will worsen (Karsa et al. 2010). 
1.1.2 
Etiology and Risk Factors 
Colorectal cancer represents a paradigm for cancer genetics, as almost all the major-gene 
inﬂuences on CRC have been identiﬁed. There are several syndromes with Mendelian 
dominant inheritance in which there is a primary predisposition for benign or malignant 
tumours of the large bowel, including: familial adenomatous polyposis; hereditary non-
polyposis colon cancer (caused by inheritance of defective deoxyribonucleic acid (DNA) 
mismatch repair genes MLH1, MSH2, PMS2 and MSH6); Peutz–Jeghers syndrome (caused 
by germline mutations of the LKB1/STK11 gene); juvenile polyposis (with the underlying 
mutation of SMAD4 or ALK3), and the MYH-associated polyposis (MAP) syndrome. These 
single gene defects account for up to 2–6% of CRC cases. The great majority of CRCs do 
not have a recognizable inherited cause, but an extensive analysis of twins has suggested 
that 35% of CRCs arise through inherited factors. Inherited predisposition to CRC in humans 
is more likely to be the result of low-penetrance alleles at several or many genetic loci (Kemp 
et al. 2004). Recent genome-wide association studies have identified single-nucleotide 
polymorphisms localizing to multiple chromosomal regions that influence CRC risk. While the 
risk of CRC associated with each of the variants is individually modest, taken together, they 
may significantly contribute to disease burden by virtue of their high frequencies in the 
population (Houlston et al. 2012). Germline genetic testing based on a blood sample is 
recommended to detect potential mutations in those patients whose tumour sample 
demonstrates altered molecular screening (Schmoll et al. 2012).  


 
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Other predisposing factors and common risk factors associated with CRC development 
include long-standing inflammation and augmented inflammatory response, diet and lifestyle, 
altered intestinal microbiota and commensals, and chronic inflammatory bowel diseases 
(Savari et al. 2014). 
1.1.3 
Current Treatment of mCRC 
The management of metastatic CRC (mCRC) remains a significant clinical challenge to 
oncologists worldwide. Even though appropriate screening programmes (implementation of 
faecal occult blood test and colonoscopy) and preventive strategies are in place in many 
countries, a significant number of patients are still diagnosed at late stages of the disease, 
resulting in high disease burden and mortality (Schmoll et al. 2012; Temraz et al. 2014). 
Although care for patients with CRC has improved greatly in the last 20 years, considerable 
variation still exists in cancer management and outcome between European countries, and 
large variation is also apparent between national guidelines and patterns of cancer care in 
Europe (van de Velde et al. 2014). 
While surgery remains the mainstay of curative treatment (5-year survival rates of 20 – 45% 
reported after the surgical resection of R0 resectable colorectal liver metastases), the 
management of mCRC must be a multi-modal approach. Long-term survival, maintained 
quality of life, and even cure can be achieved in selected patients by a combination of 
optimal choice chemotherapy and surgery (Schmoll et al. 2012). The choice of first-line 
treatment for mCRC is influenced by the clinical presentation and patterns of tumour biology 
(e.g., metastases limited to liver and/or lung, or peritoneum; dynamics of progression; 
present or imminent symptoms; prognostic molecular or biochemical markers, like BRAF 
mutation), as well as patient-related factors (e.g. comorbidity and related potential to 
undergo secondary resection), and drug-related factors (availability of targeted drugs; 
predictive markers, e.g. RAS mutation) (Schmoll et al. 2012). 
Pharmacological treatment options for mCRC have increased substantially in the past 
decade (Stein and Bokemeyer, 2014). While combinations of fluoropyrimidines with 
oxaliplatin or irinotecan (such as in 5-FU, leucovorin and oxaliplatin [FOLFOX] / capecitabine 
and oxaliplatin [XELOX] or 5-FU, leucovorin and irinotecan [FOLFIRI]) constitute the main 
treatment of choice in this patient population (Temraz et al. 2014), the addition of novel 
biological therapies targeting cancer-specific molecules to these cytotoxic agents have led to 
significantly improved outcomes and is the current standard treatment for mCRC (Tejpar et 
al. 2014b; Temraz et al. 2014). A broad variety of molecular targeting agents are currently 
available, such as anti-angiogenic agents (bevacizumab) and epidermal growth factor 
receptor (EGFR) antibodies (cetuximab, panitumumab) for first-line treatment of mCRC 
(Stein and Bokemeyer, 2014). A recent systematic review of randomised controlled trials 
concluded that the oral fluoropyrimidine formulation, capecitabine had similar outcomes and 
better safety than 5-fluorouracil (5-FU) with oxaliplatin but not irinotecan; first-line oxaliplatin 
and irinotecan appear equivalent; and that antiangiogenics (bevacizumab, ziv-aflibercept, 
ramucirumab), and EGFR-targeted monoclonal antibodies (MAb) (cetuximab and 
panitumumab) further improved the efficacy of fluoropyrimidine-based regimens in the 
treatment of mCRC (Bekaii-Saab et al. 2014). However, while metastatic CRC patients have 


 
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many treatment options, the optimal use and sequence of targeted agents remain to be 
determined (Temraz et al. 2014). 
1.1.3.1 
The Role of Maintenance Therapy in mCRC Treatment 
Though effective, the toxicity of first-line chemotherapy regimens renders treatments 
untenable for prolonged periods without regimen modifications or complete breaks. 
Oxaliplatin in particular causes debilitating neuropathy which can become irreversible, in 
addition to unacceptable nausea, diarrhoea and asthenia. The results of several studies 
conducted to assess the impact of intermittent chemotherapy regimens with or without 
maintenance treatment with fewer agents as compared to continuous therapy have been 
largely equivocal often due to poor protocol adherence and drug toxicities (Seymour 2012; 
Strickler et al. 2012a). Despite the lack of definitive evidence from these trials, current 
treatment guidelines recommend treatment breaks from combination therapy with continued 
maintenance therapy composed of fewer cytotoxic agents once cumulative toxicity occurs 
(VanCutsem et al. 2010; National Comprehensive Cancer Network 2014). 
More recently, results of the Phase 3 CAIRO3 study comparing maintenance treatment with 
capecitabine and bevacizumab versus observation alone following induction with 
capecitabine and oxaliplatin plus bevacizumab (CAPOX-B) were presented (Koopman et al. 
2014). A significant increase in median PFS was observed in the treatment arm (8.5 vs. 4.1 
months; stratified HR 0.43, 95% CI [0.36-0.52]; p < 0.0001). When patients progressed 
following their initial induction in this study, they were treated again with CAPOX-B. PFS was 
again significantly better in patients who had received maintenance treatment prior to their 
first progression (13.9 vs. 11.1 months; stratified HR 0.68, 95% CI [0.57-0.82]; p < 0.0001). 
A significant difference in OS was not detected in the overall study group but a planned 
subgroup analyses indicated that patients with synchronous disease who underwent 
resection of the primary tumour and patients who had a CR or PR to induction treatment 
experienced a significant survival benefit.  
Recent interim results of an additional study (AIO KRK 0207) evaluating the non-inferiority of 
no therapy or bevacizumab alone as compared to bevacizumab plus fluoropyrimidine as 
maintenance treatment following fluoropyrimidine/oxaliplatin/bevacizumab induction indicate 
that active maintenance treatment (either bevacizumab plus fluoropyrimidine or 
bevacizumab alone) show prolonged first-line progression free survival (Arnold et al. 2014). 
Completion of data collection for the primary analysis of this study is estimated to occur in 
2015.  
1.2 
BACKGROUND ON BIOMARKER-DRIVEN THERAPY 
1.2.1 
Biomarkers 
Biomarkers are characteristics that indicate a normal or pathogenic process or a response to 
a specific therapeutic intervention (Alymani et al. 2010). Cancer biomarkers identified to date 
have a variable range of application for screening, determining diagnosis and prognosis, 
assessing the response to therapy and monitoring for recurrence. Prognostic biomarkers 
provide information on the natural course of the patient’s disease independent of treatment, 
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particular treatment (Alymani et al. 2010). Predictive markers for efficacy are highly relevant, 
in order to avoid unnecessary treatment, toxicity or even detrimental effects, and expenses. 
However, adequate evidence only exists for RAS mutations excluding patients from 
treatment 
with 
EGFR-antibodies. 
There 
is 
a 
clear 
need 
for 
evidence-based 
recommendations regarding predictive molecular markers relevant to decisions regarding 
first-line treatment in mCRC. The potential use of the BRAF mutation in the treatment 
decision-making process also needs further validation (Schmoll et al. 2012). 
1.2.2 
Biomarker-driven Therapy 
As the treatment landscape for mCRC is becoming more complex, the need for 
individualised or personalised therapy based on predictive factors is gaining importance. 
Personalised medicine aims to tailor treatment according to the characteristics of the 
individual patient to increase response rates and survival, and at the same time, reduce 
toxicity (Diamandis et al. 2010). Prognostic and predictive markers have been identified that 
appear to be directly related to sensitivity to targeted therapies, such as those against EGFR. 
However, the sensitivities of individual tumours toward different biological agents appear to 
be more complex, and therefore a more complete molecular signature of the tumour must be 
taken into account when making individual treatment choices (Tejpar et al. 2014b). Recent 
advances, such as extended RAS testing is a further step toward a patient-tailored selection 
of the most beneficial treatment approach (Stein and Bokemeyer, 2014).  
RAS gene mutations in mCRC has been identified as a predictor of response to EGFR MAb 
therapy and to oxaliplatin-based therapy (Lievre et al. 2006; Basso et al. 2013; Lin et al. 
2014). In several randomised clinical trials including the CRYSTAL, OPUS and PRIME 
studies (Van Cutsem et al. 2009; Bokemeyer et al. 2009; Douillard et al. 2010) evaluating 
first-line chemotherapy plus EGFR MAbs in the treatment of mCRC, patients with KRAS 
mutations had an approximately 2-month shorter PFS compared to KRASwt patients. Based 
on the results of these randomised clinical studies, EGFR MAb treatment is not 
recommended in patients with KRASmut mCRC (Roth et al. 2013). More recently, re-analyses 
of samples deemed KRAS wild-type based on exon 2 testing in the OPUS (Tejpar et al. 
2014a) and PRIME (Douillard et al. 2013) studies indicated that other RAS mutations (i.e. in 
exons 3 or 4 of KRAS and/or exons 2, 3 or 4 of NRAS) are also associated with lack of 
benefit from EGFR-targeted therapy. These findings have led to the revision of European 
labelling indications for both cetuximab and panitumumab to patients with RASwt tumours 
(Erbitux® Summary of Product Characteristics [SmPC] 2014; Vectibix® SmPC 2014).  
BRAF mutation has also been investigated as a biomarker, in particular as a prognostic 
indicator in patients with mCRC undergoing anti-EGFR MAb treatment, but current results 
are still inconclusive. A recently published meta-analysis of 21 clinical trials including 5,229 
patients found that BRAF mutation is a predictive biomarker for poor prognosis in mCRC 
patients undergoing anti-EGFR MAb therapy, especially in KRASwt patients (Yuan et al. 
2013).  
Unlike the anti-EGFR MAbs, there is a paucity of biomarkers for bevacizumab as predictors 
of outcome in mCRC patients. A retrospective analysis of the AVF2107 trial investigating the 
influence of the KRAS mutation on the efficacy of bevacizumab in combination with 
chemotherapy showed no differences in terms of treatment efficacy (Hurwitz et al. 2009). 


 
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Similarly, in the AIO KRK-0604 trial, patients with KRAS-mutated tumours showed 
comparable efficacy when treated with bevacizumab plus capecitabine and oxaliplatin 
(CAPOX) or bevacizumab plus capecitabine and irinotecan (CAPIRI), but had a trend 
towards lower overall response rates and shorter survival (Reinacher-Schick et al. 2010).  
A recent study investigating the predictive value of the presence of KRAS and BRAF 
mutations on PFS and OS in 172 patients with mCRC treated with the combination of 
FOLFIRI and bevacizumab did not confirm the predictive value of KRAS and BRAF 
mutations as potential biomarkers for bevacizumab therapy in mCRC (Selcukbiricik et al. 
2013). 
There is clearly a need to further identify and evaluate biomarkers related to treatment 
response in mCRC. Typically, potential biomarkers are identified in studies evaluating 
response in patients that have already undergone treatment or in studies of populations 
enriched for a biomarker that has already been clinically validated. There are many new 
therapies reaching clinical testing that have been developed based on a putative biomarker 
that requires clinical validation. Study designs that incorporate prospective evaluation of new 
therapies with their corresponding biomarkers in confirmatory (Phase 2/3) trial settings are 
important to the integration and application of these new agents in the most effective setting 
as quickly as possible. New trial designs, such as this proposed MODUL study and the 
FOCUS4 study already underway (Kaplan et al. 2013), employ multiple study arms, 
biomarker based- stratification and randomization, and placebo control to achieve these 
goals. 
1.2.3 
Clinical Experience with Bevacizumab as First-line Treatment of 
mCRC 
Bevacizumab (Avastin®) is a vascular endothelial growth factor (VEGF)-specific 
angiogenesis inhibitor approved for use in many countries for the treatment of mCRC, with 
intravenous (IV) 5-FU–based chemotherapy for first- or second-line treatment, and with 
fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second-
line treatment in patients who have progressed on a first-line bevacizumab-containing 
regimen (Avastin® Prescribing Information, December 2013). 
Bevacizumab has been shown to improve clinical outcomes when combined with any of the 
fluoropyrimidine and oxaliplatin or irinotecan combinations (FOLFOX/XELOX, FOLFIRI) as 
well as with single-agent 5-FU or capecitabine (Strickler et al. 2012b). The results of large 
Phase 3 clinical trials of bevacizumab combined with a fluoropyrimidine and oxaliplatin or 
irinotecan as first-line treatment for mCRC are provided in Table 2. Studies of bevacizumab 
combined with a fluoropyrimidine alone include a randomised Phase 2 study of 5-FU with or 
without bevacizumab as first-line treatment for mCRC patients deemed inappropriate for 
irinotecan-based therapy (Kabbinavar et al. 2005b). In this study median PFS was 
significantly improved with the addition of bevacizumab (9.2 months versus 5.5 months; HR 
0.50; p = 0.0002). Though the difference in OS between treatment groups was not 
statistically significant, a follow-up pooled analysis of three randomised studies comparing 
5-FU with and without bevacizumab found a longer median OS time for patients receiving 
5-FU with bevacizumab than for those receiving 5-FU alone (p = 0.008) (Kabbinavar et al. 
2005a). Similarly, significantly improved PFS has been shown with the addition of 




 
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severe neutropenia (including some fatalities) have been observed in patients treated with 
some myelotoxic chemotherapy regimens plus bevacizumab in comparison to chemotherapy 
alone. 
There have been rare reports of bevacizumab treated patients developing signs and 
symptoms that are consistent with posterior reversible encephalopathy syndrome (PRES).  
Very rare cases of hypertensive encephalopathy have also been reported, some of which 
were fatal.   
Additional information regarding the safety profile of bevacizumab and details of preclinical 
and clinical studies with bevacizumab are provided in the current Bevacizumab Investigator’s 
Brochure or local labelling where applicable. 
1.2.4 
Clinical Experience with Cetuximab in CRC 
Cetuximab (Erbitux®) is an EGFR antagonist indicated for treatment of RASwt, EGFR-
expressing, mCRC: (i) in combination with FOLFIRI for first-line treatment; (ii) in combination 
with irinotecan in patients who are refractory to irinotecan-based chemotherapy; and (iii) as a 
single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or 
who are intolerant to irinotecan (Erbitux SmPC 2014).  
Cetuximab in combination with either FOLFIRI (the CRYSTAL study, Van Cutsem et al. 
2009; Van Cutsem et al. 2011) or FOLFOX (the OPUS Study, Bokemeyer et al. 2011) 
increased response rates particularly in liver-limited disease, progression-free survival (PFS) 
and overall survival (OS). Biomarker analyses from these studies have shown cetuximab 
activity is limited to patients with RASwt tumours and that BRAF mutation does not appear to 
be a predictive biomarker in this setting, but is a marker of poor prognosis (Bokemeyer et al. 
2012, Tejpar et al. 2014a).  
The main AEs associated with cetuximab are skin reactions occurring in more than 80% of 
patients treated, hypomagnesaemia occurring in more than 10% of patients treated and 
infusion-related reactions occurring with mild to moderate symptoms in more than 10% of 
patients treated and with severe symptoms in more than 1% of patients.  
In studies where cetuximab was used in combination with fluoropyrimidines to treat NSCLC, 
head and neck cancer and CRC, an increased frequency of cardiac ischaemia including 
myocardial infarction and congestive heart failure as well as the frequency of hand-foot 
syndrome (palmar-plantar erythrodysaesthesia) were increased compared to with 
fluoropyrimidines alone.  
Cetuximab may also increase the frequency of severe diarrhoea when used in combination 
with capecitabine and oxaliplatin.  
Immunogenicity including the development of human anti-chimeric antibodies (HACAs) may 
occur with any monoclonal chimeric antibody. Limited data regarding the development of 
HACAs with cetuximab treatment are available to date. Overall, measurable HACA titres 
were noted in 3.4% of the patients studied, with incidences ranging from 0% to 9.6% in the 
studies of mCRC and head and neck cancer. No conclusive data on the neutralising effect of 
HACAs on cetuximab is available to date. The appearance of HACA did not correlate with 
the occurrence of hypersensitivity reactions or any other adverse effects of cetuximab. 


 
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For additional details regarding preclinical and clinical studies with cetuximab and for further 
information on the risks associated with cetuximab, please refer to the current Erbitux SmPC. 
1.2.5 
Clinical Experience with Vemurafenib 
The protein kinase BRAF is a key component of the RAS-RAF signalling pathway, which 
plays an important role in regulating cell proliferation, differentiation, and survival. Mutations 
in BRAF at codon 600 promote catalytic activity and are associated with 8% of all human 
solid tumours, including 8 – 10% of CRC (Yang et al. 2012).  These BRAF mutations are 
usually mutually exclusive with oncogenic KRAS mutations, but imply a similar treatment-
refractory prognosis (Van Cutsem et al. 2011, Connolly et al. 2014). 
Vemurafenib (RG7204; PLX4032; RO5185426), is a first-in-class, specific small molecule 
inhibitor of BRAF (V600E).  Vemurafenib is currently authorised for the treatment of BRAFmut 
metastatic melanoma in more than 40 countries worldwide. As a single agent, vemurafenib 
shows dose-dependent inhibition of ERK and MEK phosphorylation, thereby arresting cell 
proliferation in BRAF (V600)-expressing cell lines and inhibiting tumour growth in BRAF 
(V600E) bearing xenograft models. Vemurafenib has shown limited single-agent clinical 
activity in BRAF (V600E)-mutant metastatic CRC cell lines. However, the addition of 
vemurafenib to capecitabine and/or bevacizumab, cetuximab and/or irinotecan, or erlotinib 
resulted in increased anti-tumour activity and improved survival in xenograft models, 
indicating that vemurafenib in combination with standard-of-care or novel targeted therapies 
may lead to enhanced and sustained clinical anti-tumour efficacy in CRCs harbouring the 
BRAF (V600E) mutation (Yang et al. 2012). In clinical studies, vemurafenib has been shown 
to induce dramatic responses in melanomas containing missense V600E BRAF mutations 
(Chapman et al. 2011).  
Recent laboratory studies have confirmed that de novo resistance to BRAF inhibitors in 
BRAF (V600E)-mutated CRC is caused by EGFR signalling (Corcoran et al. 2012; Prahallad 
et al. 2012), suggesting that dual blockade of the BRAF and EGFR pathways might be 
therapeutically useful (Yang et al. 2012). Lastly, a previous randomised trial of cetuximab 
combined with the non-specific RAF inhibitor sorafenib indicated a doubling of the response 
rate in patients with mCRC (Galal et al. 2011). Taken together, it is hypothesised that 
patients with mCRC may benefit from combination non-cytotoxic drug therapy 
simultaneously targeting the EGFR and BRAF signalling pathways.  
In addition to post-market experience, multiple clinical trials with vemurafenib, either alone or 
in combination with other agents, have been completed or are underway. The majority of 
these studies have been conducted in melanoma patients with BRAF mutations, where 
results have shown consistent efficacy and significant benefit in terms of OS, PFS and 
overall survival compared to chemotherapy. Preliminary results from Phase 1 and 2 
completed studies of vemurafenib BRAF mutation-positive papillary thyroid cancer indicate 
disease response and favourable PFS. Clinical efficacy data in mCRC are currently limited 
to results of Phase 1 dose escalation study (Study PLX06-02) extension cohorts wherein 1 
out of 20 evaluable patients achieved a partial response and 7 patients achieved stable 
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In clinical trials in melanoma, vemurafenib has been associated with arthralgia, fatigue, rash, 
photosensitivity reaction, nausea, alopecia and pruritus.  AEs have been predominantly mild 
in severity and transient, even with continuous dosing (over 15 months of treatment in 1 
patient).  At the recommended Phase 2 and Phase 3 dose of 960 mg b.i.d., AEs have been 
consistent with the safety profile observed in the Phase 1 setting.  Treatment-related Grade 
3 AEs and dose-limiting toxicities have been successfully managed by a temporary 
discontinuation of study drug and/or a reduction in dose.  
In mCRC in particular, vemurafenib’s safety profile has been characterised in 21 patients 
treated in the extension cohorts of a Phase 1 dose escalation study (Study PLX06-02; see 
Vemurafenib Investigator’s Brochure 2014).  AEs are similar to those observed in patients 
with metastatic melanoma. All patients experienced at least one AE, the most common 
(reported in ≥ 30% of patients) of which were fatigue (57.1%), hyperglycemia (42.9%), 
arthralgia (38.1%), diarrhoea (38.1%), hyperbilirubinemia (33.3%), nausea (33.3%), 
photosensitivity reaction (33.3%), rash (33.3%), and vomiting (33.3%). Grade 3 or greater 
study-drug-related AEs were reported in 61.9% of patients, the most common of which was 
cSCC (23.8%). Eleven (52.4%) patients had their study treatment interrupted and 4 (19.0%) 
had at least one dose reduction. AEs that led to dose interruption and/or modification for the 
CRC patients were similar to those reported for melanoma patients in the same study. No 
mCRC patients in this study experienced an AE that led to vemurafenib treatment 
discontinuation. All deaths reported during study treatment or within 28 days of the last study 
drug dose were attributed to disease progression. Seven patients (33.3%) experienced 
SAEs, the most common of these was cSCC.   
Due to its mechanism of action, vemurafenib may cause progression of cancers associated 
with RAS mutations and should be used with caution in patients with prior or concurrent 
cancers associated with RAS mutation. Notably, (K)RAS mutations are usually mutually 
exclusive to BRAF mutations (Van Cutsem et al. 2011, Connolly et al. 2014). One case of 
progression of NRAS-mutated chronic myelomonocytic leukemia occurred in a male patient 
with metastatic melanoma treated with vemurafenib for less than two weeks (Callahan et al. 
2012) and one case of progression of pancreatic adenocarcinoma in a patient with known 
(K)RAS mutation has also been reported (Vemurafenib Investigator’s Brochure 2014). More 
details of these events are provided in the Investigator’s Brochure. 
Other risks identified as important adverse drug reactions (ADRs), based on both post-
market use and clinical trial experience, include: cutaneous squamous cell carcinoma 
(cSCC; most of which are keratoacanthoma [KA] sub-type, or with some features of KA 
[incompletely expressed or with some features unusual in KA]), liver injury, photosensitivity, 
QTc prolongation, hypersensitivity and severe cutaneous reactions (including rare cases of 
Stevens-Johnson syndrome and toxic epidermal necrolysis), uveitis, VIIth nerve paralysis, 
new primary melanoma, radiation recall and radiation sensitivity. Drug reaction with 
eosinophilia and systemic symptoms (DRESS), neutropenia, panniculitis, and pancreatitis 
have also been reported with vemurafenib in the post-marketing setting. 
Vemurafenib may also be associated with the development of non-cutaneous squamous cell 
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vein occlusion. The association between these events and vemurafenib have not yet been 
fully characterised.  
Complete details of preclinical and clinical studies, all safety events and ADRs observed in 
vemurafenib clinical trials and post-market use are described in the current vemurafenib 
Investigator’s Brochure. 
1.2.6 
Clinical Experience with Atezolizumab 
Programmed death 1 (PD-1) protein, a T-cell co-inhibitory receptor, and one of its ligands, 
PD-L1, play a pivotal role in the ability of tumour cells to evade the host’s immune system. 
Atezolizumab is a non-glycosylated human immunoglobulin G1 monoclonal antibody 
produced in Chinese hamster ovary cells. The antibody is specific for human PD-L1 and 
inhibits PD-L1 interactions with PD-1 and with B7-1 (also known as CD80) that are thought 
to otherwise inhibit T-cell activation (Butte et al. 2007, current Atezolizumab Investigator’s 
Brochure). Atezolizumab has also been engineered via a single amino acid heavy chain 
substitution to eliminate Fc-effector function in order to minimise in vivo depletion of tumour 
specific T cells expressing high levels of PD-L1. The antibody exhibits minimal binding to Fc 
receptors and prevents Fc-effector function at expected concentrations in humans.  
Approximately 4% of patients with Stage IV CRC have tumours with deficiencies in the DNA 
mismatch repair system. These deficiencies are predominantly nonfamilial (sporadic) and 
lead to an accumulation of tumour mutations (hyper-mutation) particularly in repetitive 
sequences (mono-, di-, of higher-order nucleotide repeats) and microsatellites (Cancer 
Genome Atlas Network 2012). A defining molecular feature of these tumours is high 
microsatellite instability (MSI-H). Insertions or deletions in microsatellites located in coding 
regions of the genome can lead to protein truncations or the expression of frameshift 
peptides, some of which are capable of eliciting T-cell responses (Bauer et al. 2013). The 
MSI-H phenotype is also associated with mutations in specific oncogenes and tumour 
suppressors including BRAF and MRE11A (Vilar and Gruber 2010). MSI-H tumours and 
other hyper-mutated tumours may therefore exhibit higher immunogenicity in comparison to 
microsatellite-stable (MSS) tumours. One possible correlate of higher immunogenicity MSI-H 
and other hyper-mutator phenotypes is the presence of high numbers of tumour-infiltrating 
lymphocytes (Greenson et al. 2003) and a potential role of PDL-1/PD-1 signalling in 
restraining a pre-existing anti-tumour immune response in the tumour microenvironment. 
Support for these hypotheses has been borne out in a more recent study showing that 
inhibition of the PD-1 pathway with pembrolizumab (an anti-PD-1 antibody) is of clinical 
benefit in MSI-H mCRC but not in MSS cohorts (Le et al. 2015).  
Clinical data are available from multiple atezolizumab trials in patients with solid tumours 
(including CRC) and hematologic malignancies. Of these, one ongoing Phase 1a 0.03-20 
mg/kg dose ranging study of atezolizumab monotherapy (Study PCD4989g) and one 
ongoing Phase 1b combination study (GP28328: atezolizumab with bevacizumab or with 
bevacizumab plus FOLFOX) included CRC patients. Additional Phase 1, 2, and 3 studies 
are ongoing or planned. Please refer to the current atezolizumab Investigator’s Brochure for 
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Anti-tumour activity, including RECIST-based responses (i.e., RECIST 1.1 responses), have 
been observed in patients with different tumour types, including non-small cell lung cancer, 
renal cell carcinoma, melanoma, gastric cancer, and colorectal cancer, treated with 
atezolizumab in Phase I and 2 studies. Analyses of PD-L1 expression on baseline tumour 
tissue collected in these studies suggest that PD-L1 expression is likely to be associated 
with response to atezolizumab. The definition of PD-L1 positivity is still under investigation 
and appears to vary by tumour type.  
In CRC in particular, 44 evaluable patients were enrolled in Study GP28328. The overall 
response rate (ORR) ranged from 7% (1/14 patients receiving atezolizumab plus 
bevacizumab) to 40% (12/30 receiving atezolizumab plus bevacizumab and FOLFOX) with a 
PFS ranging from 10+ to 61 weeks.   
Across all patients receiving atezolizumab alone or in combination with chemotherapy in 
clinical trials, fatigue was the most frequently reported AE. The incidence of AEs in the 
treatment arms with combined use was consistent with the known safety profiles of the 
individual study drugs. Given the mechanism of action of atezolizumab, events associated 
with inflammation and/or immune-mediated AEs have been closely monitored during the 
atezolizumab clinical program. These include dermatologic, hepatic, endocrine, and 
respiratory events, as well as events of hepatitis/elevated liver function tests and influenza-
like illness that are considered ADRs associated with atezolizumab. Additional expected 
ADRs associated with atezolizumab include GI disorders, hypersensitivity/infusion-related 
reactions, nervous system disorders, pneumonitis, general and metabolic disorders, and 
vascular disorders. Currently, no maximum tolerated dose (MTD), no dose-limiting toxicities 
and no clear dose-related trends in the incidence of AEs have been determined. 
In Study GP28328 that included CRC patients receiving atezolizumab and bevacizumab with 
or without FOLFOX, a total of 141 of 144 patients (97.9%) reported at least one AE while on 
study drug. The majority of these were Grade 2 or 3 in severity. The five most commonly  
(≥ 10%) reported AEs included fatigue, nausea, diarrhea, decreased appetite, and pyrexia. 
Seven deaths were reported (6 due to disease progression, 1 due to study treatment related 
candidemia). Serious adverse events were reported in 55 patients with serious fatigue noted 
as related to atezolizumab in ≥ 2 patients. Adverse events assessed as related to study drug 
by the Investigator, and which led to discontinuation, included: neutropenia, pancytopenia, 
dehydration, proctitis and dermatitis. Immune-mediated AEs were observed in 72 patients 
and included peripheral neuropathy, rash, rash maculopapular, dermatitis, rash pruritic, rash 
vesicular, aspartate transaminase (AST) increase, alanine aminotransferase (ALT) increase, 
blood bilirubin increased, amylase increased, lipase increased, transaminase increased, 
hypothyroidism, and adrenal insufficiency. 
Anti-therapeutic antibodies to atezolizumab have been observed in some patients in Study 
PCD4989g. A relationship between antibody response and pharmacokinetics, AEs or 
therapeutic activity has not yet been determined, however, monitoring and characterization 
of this effect is ongoing in all atezolizumab clinical studies. 
Further details of preclinical and clinical studies with atezolizumab and all safety events are 
found in the current Atezolizumab Investigator’s Brochure.  


 
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1.2.7 
Clinical Experience with Trastuzumab  
Human epidermal growth factor receptor (HER) 2 (also known as c-erbB-2) is a member of 
the HER family of transmembrane receptor tyrosine kinases which includes EGFR, HER3 
and HER4. Binding of ligands to the extracellular domain of EGFR, HER3, or HER4 induces 
receptor dimerization leading to C-termini tyrosine phosphorylations and initiation of a 
downstream cascade of transforming effects mediating cell death, division, motility and 
adhesion. The receptors couple as homo and heterodimers. Though HER2 has no known 
ligand, it is the preferred dimerization partner amongst the HER family members and is 
characterised by the most potent kinase catalytic activity capable of amplifying signaling 
through HER co-receptors (Yarden et al. 2001). HER2 overexpression occurs in a wide 
variety of tumour types and has been associated with poor outcomes in the absence of 
HER2-targeted therapies (Slamon et al. 1987, Slamon et al. 1989).  
In preclinical studies, single and dual agent HER2 inhibition leads to tumour response in 
cetuximab resistant, HER2 amplified mCRC patient derived xenografts (Bertotti et al. 2011). 
HER2 overexpression has been detected by immunohistochemical (IHC) evaluation in a 
significant proportion of colorectal tumours (estimates occur between 3% and 10%) (Sartore-
Bianchi et al. 2016, Seo et al. 2014, Valtorta et al. 2015).  
Trastuzumab (Herceptin®) is a recombinant humanised anti-p185HER2 monoclonal antibody 
that binds specifically and with high affinity to the extracellular domain of HER2. 
Trastuzumab inhibits the proliferation of human tumour cells overexpressing HER2 both in 
vitro and in vivo and mediates antibody-dependent cell-mediated cytotoxicity (ADCC) in the 
presence of human effector cells. Trastuzumab administered either alone, or in combination 
with chemotherapy or an aromatase inhibitor, is indicated for treatment of HER2-
overexpressing early and metastatic breast cancer. It is also indicated in combination with a 
fluoropyrimidine (5-FU or capecitabine) for first-line treatment of HER-positive (HER2+) 
advanced carcinoma of the stomach or gastro-esophageal junction. As of 24 March 2015, 
the total estimated cumulative exposure to Herceptin since the Development International 
Birth Date (DIBD; 27 May 1992) was approximately 1,935,406 patients worldwide. 
Trastuzumab has been evaluated in advanced CRC in a phase II study in combination with 
irinotecan (Ramanathan et al. 2004). Though the study was closed prematurely due to low 
accrual attributed to the small proportion of HER2 overexpression in screening population 
(8% HER2+ by IHC), there was evidence of activity with responses observed in five of seven 
evaluable patients. More recently, trastuzumab has been combined with lapatinib, a dual 
tyrosine kinase inhibitor which interrupts the HER2 and epidermal growth factor receptor 
pathways, in a phase II study or HER2+, treatment refractory, mCRC (Sartore-Bianchi et al. 
2016). In this study, trastuzumab was administered at 4 mg/kg IV loading dose followed by 
2 mg/kg IV once per week and lapatinib was administered orally at a 1000 mg daily dose. At 
a median follow-up of 94 weeks, 30% had achieved a partial (7/27 patients) or complete 
(1/27 patients) and 44% had stable disease. Notably, exploratory analyses found that 6/7 
responses occurred in patients that were IHC3+ for HER2 (versus IHC2+) and segregated 
significantly with high gene copy number. Grade 3 adverse events (fatigue, rash, increased 
bilirubin) were observed in 22% of patients. No grade 4 or 5 adverse events were reported 
and there were no treatment related serious adverse events.  


 
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Trastuzumab has been investigated in combination with the HER2 dimerization inhibitor, 
pertuzumab (Perjeta®), in breast cancer, advanced gastric cancer and other solid tumours 
and is approved in combination with pertuzumab and chemotherapy for the treatment of 
breast cancer. These studies and clinical experience with combined trastuzumab and 
pertuzumab are described in Section 1.2.8 below.  
Complete details of preclinical and clinical studies conducted in the development of 
trastuzumab studies are provided in the current Trastuzumab Investigator’s Brochure and 
Summary of Product Characteristics.  
1.2.8 
Clinical Experience with Pertuzumab  
Pertuzumab (Perjeta®) is a recombinant, humanised monoclonal antibody specific for the 
subdomain 2 epitope of HER2’s extracellular domain. Pertuzumab inhibits HER2 
heterodimerization with other members of the HER family (EGFR, HER1, HER3 and HER4) 
thereby blocking ligand-activated downstream signalling. Pertuzumab is also capable of 
mediating ADCC in cell-based assays.  
Pertuzumab and trastuzumab bind to distinct epitopes on the HER2 receptor without 
competing with each other, and have complementary mechanisms for disrupting HER2 
signalling. Combined administration of these agents results in augmented anti-proliferative 
activity in vitro and in vivo. Pertuzumab clinical development has focussed on its 
complimentary activity with trastuzumab and is indicated for the treatment of HER+ breast 
cancer (metastatic and early) in combination with trastuzumab and chemotherapy.  
Overall, data indicate that pertuzumab is well-tolerated as monotherapy and that it can be 
given in combination with trastuzumab and a range of other therapeutic agents with 
manageable additional toxicity. No unexpected toxicities have been encountered other than 
those that are known for agents that target the HER family of receptors. Serious or severe 
infusion-related symptoms have been rarely observed in patients receiving pertuzumab. A 
low level of cardiac toxicities, predominantly asymptomatic declines in left ventricular 
ejection fraction (LVEF), has been reported. In a pivotal Phase III trial WO20698/TOC4129g, 
the rates of symptomatic and asymptomatic left ventricular systolic dysfunction (LVSD) were 
not higher in patients receiving pertuzumab combined with trastuzumab and docetaxel than 
those receiving trastuzumab and docetaxel with placebo. However, patients who have 
received prior anthracyclines or radiotherapy to the chest area may be at higher risk of 
decreased LVEF (Pertuzumab Investigator’s Brochure 2016). 
Pertuzumab has been evaluated in combination with capecitabine in a phase I trial of 19 
patients with advanced malignancies (Albanell et al. 2008). Pertuzumab was administered at 
a fixed dose of 1,050 mg IV on day 1 plus capecitabine at doses up to 1,250 mg/m2 twice 
daily orally on days 1 to 14 of each 21-day treatment cycle. The combination was well 
tolerated at all dose levels and no dose-limiting toxicities were observed. Co-administration 
of pertuzumab and capecitabine was not found to affect the pharmacokinetics of either agent.  
Combined pertuzumab and trastuzumab treatment has been included in a phase IIa study of 
advanced solid tumours that is being conducted to evaluate the safety and efficacy of 
targeted therapies in tumour types outside of their approved use (Hurwitz et al. 2016). The 
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but have not been included in comprehensive clinical development, often due to their low 
incidence. Preliminary clinical activity observed in heavily pre-treated patients with HER2+ 
CRC included in this study (overall response in 38% or 5/13 patients). Due to these results, 
the study will expand enrolment of HER2+ CRC patients.  
Combination treatment with pertuzumab, trastuzumab and capecitabine is under evaluation 
in an open-label phase III study comparing the regimen to trastuzumab and capecitabine 
alone in the treatment of metastatic breast cancer following progression after or during prior 
trastuzumab-based therapy (Urruticoechea et al. 2016). Patients in the control arm were 
treated with 8 mg/kg then 6 mg/kg trastuzumab every 3 weeks and 1250 mg/m2 capecitabine 
twice daily for 2 weeks followed by a 1 week treatment break. Patients in the experimental 
arm received the same trastuzumab dosing with 1000 mg/m2 capecitabine twice daily (same 
schedule as the control arm) and 840 mg then 420 mg pertuzumab every 3 weeks. In the 
primary study analysis, there was no significant difference in the primary study endpoint 
(PFS), however an 8-month improvement was observed in OS with the addition of 
pertuzumab (HR 0.68, 95% CI 0.51‒0.90). No new safety signals were identified in the study. 
Adverse events were reported in 214/218 patients (98.2%) treated with trastuzumab and 
capecitabine alone and 222/228 (97.4%) in patients treated with all 3 agents. Diarrhoea, 
nausea, palmar-plantar erythrodysaesthesia, rash, nasopharyngitis, neutropenia and 
insomnia occurred in 10% or more of patients in either study arm. Of these, diarrhoea, rash, 
nasopharyngitis and insomnia occurred more often in the experimental arm. Among the 
218 patient safety population treated with pertuzumab, trastuzumab and capecitabine, 
5 cases (2.2%) of symptomatic LVSD (all of which resolved) and 15 cases (6.6%) of 
asymptomatic LVSD were observed. Serious adverse events occurring in 2% or more of this 
population were diarrhoea (3.5% or 8 patients) and left ventricular dysfunction (4.4% or 
10 patients).  
Complete details of preclinical and clinical studies conducted in the development of 
pertuzumab including evaluations of pertuzumab and trastuzumab combined are provided in 
the current pertuzumab Investigator’s Brochure.  
1.2.9 
Clinical Experience with Cobimetinib 
The mitogen-activated protein kinase (MAPK) signaling cascade plays a major role in 
mediating cell growth and differentiation in response to extracellular signals. The MAPK 
pathway transduces multiple proliferative and differentiating signals within tumour cells. 
RAS-GTP activates RAF kinase, which in turn activates the MEK/ERK cascade and 
subsequent cellular proliferation (Downward et al. 2003, Roberts and Der 2007). To regulate 
cellular proliferation, activated ERKs translocate to the nucleus and regulate gene 
expression through the activation of several key transcription factors. ERK promotes cell 
survival signalling and has been implicated in angiogenesis. Abnormal regulation of the 
MAPK pathway contributes to uncontrolled proliferation, invasion, metastasis, angiogenesis, 
and diminished apoptosis.  
The RAF-MEK-ERK pathway also has been implicated in the immune resistance of tumours 
by affecting the tumour microenvironment. Inhibition of this pathway can lead to increases in 
CD8+ T-cell infiltration. Preclinical models suggest that MEK inhibition increases MHC I 
expression in tumour cells and enhances activation of dendritic cells. Furthermore, the RAF-


 
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MEK-ERK pathway has been implicated in neutrophil recruitment and activation in the 
tumour microenvironment, which may lead to overall increased inflammation and decreases 
in CD8+ T cell infiltration (Kakavand et al. 2015, Liu et al. 2015, current Cobimetinib 
Investigator’s Brochure). MEK inhibition results in increased intratumoural major 
histocompatibility complex class I expression and tumour antigen presentation, which acts to 
enhance tumour recognition by the immune system. Notably, MEK inhibition in tumours also 
increases PD-L1 expression of the checkpoint receptor PD-L1, which could counteract the 
increased presentation of tumour antigens. Lastly, the MAPK pathway is known to regulate a 
number of cytokines and chemokines, such as VEGF, interleukin-6, interleukin-8 and 
granulocyte−macrophage colony-stimulating factor, which may impact recruitment of 
vascular and other stromal cell types, including myeloid−derived suppressive cells that can 
inhibit the anti-tumour activity of T cells (Bancroft et al. 2001; Sano et al. 2001; Bancroft et al. 
2002; Phan et al. 2013). The activity of MEK inhibition outside of tumour cells may further 
contribute to the modulation of the immune microenvironment that could enable a more 
permissive immune reaction against the tumour. These effects include inhibition of tumour 
vascular maturity and integrity, tumour infiltration, activity of myeloid−derived suppressive 
cells, neutrophils, increased activity of antigen-presentation cells, such as macrophage and 
dendritic cells, and recruitment and activation status of T-cell subsets, including CD8-positive 
cytolytic and CD4−positive helper cells (Giordano et al. 2015; Liu et al. 2015; Loi et al. 2016). 
Cobimetinib is a novel and highly selective inhibitor of MEK, and consequently of the 
intracellular components of the MAPK pathway affecting tumour cell proliferation and 
survival. Cobimetinib is approved in the United States, European Union, Switzerland, and in 
multiple other countries across the world for use with vemurafenib for the treatment of 
unresectable or metastatic melanoma with BRAF mutation at codon 600 (BRAFV600). 
The combination of cobimetinib and atezolizumab is being developed for the treatment of 
locally advanced, or metastatic solid tumours for which standard therapies do not exist, have 
been proven ineffective or are intolerable. Preclinical murine studies have shown that 
combined treatment with cobimetinib and atezolizumab produces increased tumour growth 
inhibition compared to either agent alone. In addition, combined treatment results in disease 
response (partial or complete) in 30% of mice treated versus no responses in mice treated 
with either agent alone.  
Clinical data are available from one ongoing Phase Ib, open-label, multicentre, dose 
escalation/dose expansion study (study GP28363) designed to assess the safety, tolerability, 
and pharmacokinetics of cobimetinib and atezolizumab administered to patients with 
metastatic or locally advanced (unresectable) solid tumours for which no recognised 
standard therapy exists, including those that carry a KRAS or BRAFV600 mutation (Bendell et 
al. 2016). No dose limiting toxicities were observed in the dose escalation phase and 60 mg 
cobimetinib administered daily for 3 weeks followed by 1 week off (21/7 schedule) with 800 
mg atezolizumab every 2 weeks was determined as the recommended Phase II dose. 
In the dose expansion cohort for mCRC patients with KRAS−mutation (n = 23), 4 patients 
had a partial response, 5 had stable disease, and 14 had progressive disease as of 
12 October 2015. Three responses were ongoing (range 4.0 – 7.7 months) at time of data 
cutoff. Three of the 4 patients responding had MSS tumours. Notably, biomarker evaluation 


 
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from a serial tumour biopsy cohort showed a 4-fold increase of CD8−positive T-cell 
infiltration in 75% of tumours as well as increases in PD-L1 and MHC-I expression.  
Median follow-up for safety in CRC patients was 3.78 months (range 1.1 – 11.7 months). 
The most common treatment-related AEs included diarrhea (69.6%), fatigue (52.2%), 
dermatitis acneiform (43.5%), rash (34.8%), maculopapular rash (26.1%), pruritus (26.1%) 
and nausea (26.1%). The incidence of treatment-related grade 3/4 AEs was 34.8%. The only 
treatment-related grade 3/4 AE occurring in ≥ 2 patients was diarrhea (8.7%). No grade 5 
AEs were reported. 
A phase III, open-label, multicentre, 3-arm study (study GO30182) comparing cobimetinib 
(60 mg according to 21/7 schedule) plus atezolizumab (840 mg every 2 weeks) to 
atezolizumab monotherapy and to regorafenib in patients with previously treated 
unresectable locally advanced or mCRC is also underway. Data from this study are not yet 
available. 
See the current, respective Investigator’s Brochures for atezolizumab and cobimetinib for 
further details on the clinical studies conducted with each agent and descriptions of risks 
associated with each agent.  
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Advances in the treatment of mCRC have led to an improvement in survival from 12 months 
with fluorouracil monotherapy to approximately 2.5 years with current combination regimens 
(Cunningham et al. 2010, Venook and Saltz, 2013). However, there are significant molecular 
differences between tumours and between tumour microenvironments that can affect both 
prognosis and response to treatment. Many new cancer drugs target specific molecular 
aberrations or cell-signalling pathways, but these drugs are only active in a subset of 
patients due to molecular differences between tumours. Personalised medicine has made 
some major advances in CRC, with RAS testing to guide treatment with the anti-EGFR 
monoclonal antibodies cetuximab and panitumumab now being part of routine clinical 
practice (Moorcraft et al. 2013). However, not all patients who are RASwt respond to anti-
EGFR therapy and, despite extensive research into other biomarkers for anti-angiogenic 
drugs, chemotherapy and other targeted agents, these are not yet established in clinical 
practice, and a validated biomarker for anti-angiogenic therapy is still lacking. Therefore, 
there is a clear need for both molecular screening approaches to understand the disease 
better and to fully characterise tumours and identify patients who are most likely to benefit 
from targeted treatments, as well as for new biomarkers to assist with predicting response to 
both existing drugs as well as to drugs currently under investigation (Moorcraft et al. 2013).  
The current study is a randomised, multi-centre, active-controlled, open-label, parallel-group 
clinical trial of biomarker-driven maintenance treatment for first-line mCRC. All patients will 
receive induction treatment with FOLFOX and bevacizumab, a treatment regimen that is 
considered standard in many countries and that has been shown to improve outcomes 
compared to FOLFOX alone (see Section 1.2.3; Strickler et al. 2012a). Induction treatment 
will be followed by maintenance treatment with chemotherapy combined with targeted 
therapy. Administration of maintenance treatment with fewer cytotoxic drugs until 
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has become an accepted treatment approach (see Section 1.1.3.1). Only those patients who 
experience disease response or disease control during induction will proceed to further 
treatment in the Maintenance Treatment Phase of the study.    
Patients will be assigned to a maintenance treatment cohort based on their primary tumour 
biomarker results. In all maintenance treatment cohorts, the control treatment arm consists 
of a treatment regimen that has been shown to be efficacious in mCRC with a well 
characterised safety profile (see Section 1.2.3).  
The experimental regimens in each maintenance treatment cohort incorporate emerging 
therapies with or without chemotherapy background treatment.  
In Cohort 1, targeted agents delivered in conjunction with 5-FU/LV are vemurafenib and 
cetuximab. These have each been shown to be beneficial anti-cancer agents and have 
complementary mechanisms of action expected to inhibit BRAFmut disease while blocking 
compensation via EGFR pathway signalling. As shown in previous in vitro and in vivo studies 
[Corcoran et al. 2012, Prahallad et al. 2012], combined RAF and EGFR inhibition blocked 
reactivation of mitogen-activated protein kinase (MAPK) signalling in BRAFmut CRC cells, 
markedly improving anti-tumour efficacy of the combination vs RAF inhibition alone. These 
preclinical findings support the evaluation of combined RAF and EGFR inhibition in patients 
with BRAFmut CRC and two recent case reports have demonstrated the potential 
effectiveness of this approach [Connolly et al. 2014, Al-Marrawi et al. 2013]. 
The safety profiles of cetuximab in mCRC and vemurafenib in metastatic melanoma are well 
established from both clinical trial and approved-market use (see Section 1.2.4 and 
Section 1.2.5).  However, a safety review (safety run-in) is being conducted for the initial 
patients treated with the experimental combination of ‘5-FU/LV + cetuximab + vemurafenib’ 
prior to continuing treatment in these patients and prior to exposing further patients to the 
regimen. Initial iDMC reviews (February 2016, April 2016) concluded that 5-FU dose could 
be increased up to the preplanned maximum of 2400 mg/m2 with continued safety run-in 
monitoring of patients treated with 5-FU > 1600 mg/m2. The iDMC also recommended that 
patients with an Eastern Cooperative Oncology Group (ECOG) PS of 2 and low body mass 
index (BMI) must be assessed by the Investigator as adequately fit to receive treatment with 
this experimental regimen. These recommendations have been incorporated into the 
protocol guidance to the Investigator and Cohort 1 eligibility criteria.  
There are currently no international or national guidelines or recommendations regarding the 
management of BRAFmut patients, effective treatment options for BRAFmut patients are 
limited and this population is burdened with a poor prognostic outlook. For these reasons, 
this experimental regimen will also be offered to BRAFmut patients who progress during 
induction treatment even though these patients will not contribute to Cohort 1 efficacy 
analyses.   
In Cohort 2, agents delivered in conjunction with a fluoropyrimidine are atezolizumab and 
bevacizumab. Preliminary data with atezolizumab indicate it produces disease response in a 
variety of solid tumours and is generally well tolerated with a manageable AE profile (see 
Section 1.2.6). The safety and anti-cancer activity of bevacizumab have been well described 
in this setting (see Section 1.2.3).  


 
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The rationale for combining anti-PD-L1 therapy and bevacizumab is based on the knowledge 
that anti-VEGF therapy has immunomodulatory properties, including the increased trafficking 
of T cells into tumours, and a reduction of suppressive cytokines and infiltrating T regulatory 
cells and myeloid-derived suppressor cells (Manning et al. 2007, Shrimali et al. 2010, Roland 
et al. 2009). Preclinical data indicate that combining anti-PD-L1 and anti-VEGF therapy 
increases tumour suppression compared with either agent given alone in both melanoma 
and CRC tumour models (Genentech, data on file). Furthermore, a recently presented phase 
1b trial (GO28328) evaluated the combination of atezolizumab and bevacizumab ± FOLFOX 
in patients with locally advanced/metastatic solid tumours (Lieu et al. 2014). Responses 
were observed in a variety of tumour types, including CRC, and there was no evidence of an 
exacerbation of bevacizumab- or chemotherapy-associated side effects when adding 
atezolizumab. 
In Cohort 3, trastuzumab and pertuzumab are delivered with capecitabine. Preclinical 
evidence for tumouricidal activity with dual agent HER2 inhibition in HER2+ colorectal 
tumours resistant to EGFR-directed therapy have led to clinical evaluations in treatment 
refractory disease (Sartore-Bianchi et al. 2016). Trastuzumab and pertuzumab combined 
with a fluoropyrimidine has resulted in improved OS in HER2+ breast cancer patients with 
reasonable safety and no new safety signals (Urruticoechea et al. 2016; see Section 1.2.7 
and Section 1.2.8).  
HER2+ overexpression occurs in relatively few CRC patients (see Section 1.2.7). This study 
provides an opportunity for clinical evaluation of a treatment approach with a known safety 
profile and potential efficacy that targets this small subset of patients.   
In Cohort 4, patients will be treated with cobimetinib combined with atezolizumab. This novel 
combination is proposed due to the potentially synergistic effect of these agents on the 
tumour immune microenvironment (see Section 1.2.6 and Section 1.2.9).  
To summarize, increased recruitment of immune effector or antigen presenting cells 
occurring in MSI-H CRCs may at least partially explain the preferential effect of PD-1 
pathway inhibition in these tumour types (Llosa et al. 2015, Zhang et al. 2015, Smedt et al. 
2015, Le et al. 2015). The pleiotropic effects of MEK inhibition on tumour immune 
microenvironments suggested by preclinical studies includes increasing CD8−positive T-cell 
infiltration (Kakavand et al. 2015; Liu et al. 2015). Furthermore, MEK inhibition results in 
increased intratumoural major histocompatibility complex class I expression and tumour 
antigen presentation, which acts to enhance tumour recognition by the immune system and 
increases PD-L1 expression, which could counteract the increased presentation of tumour 
antigens. Activity of MEK inhibition outside of the tumour cells may further contribute to the 
modulation of the immune microenvironment that could enable a more permissive immune 
reaction against the tumour.  
These data suggest that MEK inhibition via cobimetinib could modulate the tumour immune 
microenvironment to enable better tumour recognition and killing by the immune system, 
particularly when paired with a PD-1 pathway inhibition via atezolizumab. Preliminary clinical 
data support this hypothesis and have shown reasonable safety of the regimen with no new 
safety signals observed to date.  


 
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The overall and cohort-specific study eligibility criteria have been defined to ensure a patient 
population with adequate fitness and organ function to undergo treatment and with no 
contraindications to study drugs. Study patients will be routinely monitored for disease 
progression and will undergo comprehensive general safety assessments to monitor for any 
unexpected AEs as well as cohort and treatment arm-specific safety assessments to monitor 
the known safety risks of each study drug. For example, patients randomised to the 
experimental arm of Cohort 1 will undergo regular head and neck exams, chest CTs, 
dermatology evaluations and anal and pelvis exams to check for the development of SCC 
and cSCC associated with vemurafenib treatment. All study treatments that pose a risk of 
infusion-related reactions (e.g. cetuximab) will be administered under close supervision 
according to clear instructions to minimise the likelihood of these events occurring (e.g. 
premedication and infusion rate specifications).    
Further risk mitigation measures include the use of an independent Data Monitoring 
Committee (iDMC) that is responsible for ongoing monitoring of safety outcomes and risk-
benefit balance. When necessary, a safety run-in may be included for experimental 
regimens with inadequate prior safety experience to assure appropriate dosing (e.g. as 
required for the initial patients treated with the experimental combination of ‘5-FU/LV + 
cetuximab + vemurafenib’). The iDMC will review safety data from these run-ins and make 
recommendations for subsequent dosing. The iDMC will also oversee interim evaluations of 
safety and, as necessary, response in each of the study cohorts to assure accrual to any 
cohort that does not demonstrate risk-benefit balance is terminated early.  A separate iDMC 
Charter further describes the roles and responsibilities of the iDMC and methods for cohort 
reviews. 
In summary, the study treatments offer the potential for clinical benefit in each cohort 
population. The safety profiles of each study drug have been characterised and patients will 
be closely monitored both for effects known to be associated with each individual agent as 
well as overall safety to capture any unexpected events. The study iDMC will provide an 
additional level of oversight and will ensure that cohorts are not continued if adequate safety 
and clinical benefit are not indicated throughout each cohort accrual period. Finally, this 
study represents a unique approach to establishing a signals-seeking platform for different 
compounds in mCRC.  The ability to add new treatment cohorts and/or change existing 
cohorts once the study is underway allows for future inclusion of novel biomarker findings 
and corresponding compounds or combinations of compounds thereby allowing for the 
incorporation of new scientific findings over time. Furthermore, the translational research will 
foster understanding of CRC and its heterogeneity. 
2. 
OBJECTIVES 
2.1 
EFFICACY OBJECTIVES 
The primary study objective within each cohort is to evaluate PFS.  
The secondary efficacy objectives include the evaluation of efficacy through other endpoints:  
• 
OS 
• 
ORR 


 
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• 
Disease control rate (DCR)  
• 
Time to treatment response (TTR) 
• 
Duration of response (DoR) 
• 
Change in ECOG performance status 
2.2 
SAFETY OBJECTIVES 
The safety objectives of this study are to assess the safety of each treatment including: 
• 
Incidence, nature and severity of adverse events (AEs) 
• 
Incidence and reasons for any dose reductions, interruptions or premature 
discontinuation of any component of study treatment 
• 
Clinically significant laboratory values  
AEs refer to all treatment-emergent adverse events occurring after the initiation of study 
medication (i.e. on or after Day 1, Cycle 1 of the Induction Treatment Phase).   AEs will 
continue to be collected during the Maintenance Treatment Phase and Post-Treatment 
Follow-up Phase as applicable. 
2.3 
EXPLORATORY OBJECTIVES  
The exploratory efficacy objective of this study is: 
• 
To evaluate PFS measured according to mRECIST in patients treated with atezolizumab 
The exploratory biomarker objectives of this study are as follows: 
• 
To explore whether there is differential benefit from treatment in patient subgroups 
defined by different biomarkers, e.g. but not limited to biomarker panels (mutation and 
expression profiles), immune panels etc. 
• 
If applicable, to assess correlations between biomarkers/marker panels and safety  
• 
Where possible, to investigate if changes in expression/mutation panels of biomarkers 
during treatment correlate with treatment efficacy or failure i.e. to explore potential 
resistance/escape mechanisms to (targeted) treatment 
• 
Explore prognostic and potentially predictive effects of markers/marker profiles 
• 
Explore prevalence of specific markers at Baseline and/or salvage/resistance markers to 
guide targeted therapy approaches beyond MODUL, e.g. but not limited to programmed 
cell death-1 (PD-L1) 
• 
Explore and correlate microbiome with other biomarkers, baseline characteristics and 
clinical outcome 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is a randomised, multi-centre, active-controlled, open-label, parallel-group clinical trial of 
biomarker-driven maintenance treatment for first-line mCRC. The primary study endpoint is 
PFS determined according to RECIST 1.1 in each maintenance treatment cohort.  


 
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Secondary outcomes include other efficacy measurements and safety.  In addition, 
exploratory outcomes will focus on PFS using modified response criteria in patients receiving 
immunotherapy in the study as well the correlations between biomarkers and study 
outcomes.   
Patients with mCRC are eligible for entry, and cannot have received any prior chemotherapy 
in the metastatic setting.  
Potential patients will undergo screening assessments to determine study eligibility within 28 
days prior to starting study induction treatment. Results from routine assessments conducted 
prior to informed consent signature may be used as screening assessments as long as they 
were done within 7 days prior to informed consent signature.   
The primary tumour tissue block prepared at the time of the initial diagnosis will be used for 
biomarker assessment for maintenance treatment cohort assignment (see Appendix 17).  
The sample must be shipped to the designated laboratory and receipt must be confirmed by 
the laboratory before a patient may be enrolled.  If the tumour block is not available, 
≥ 20 slides cut from the primary tumour sample will be accepted as an alternative. 
All patients enrolled in the study will be asked to give written informed consent to provide 
blood samples and to allow all available residual samples of tumour, blood and plasma 
collected for the study be used for additional exploratory biomarker research using the 
Roche Clinical Sample Repository (RCR). No additional sampling is required for RCR. Prior 
to May 2018, an optional metastatic tumour sample was collected from all study patients at 
screening. In addition, patients at selected centres were able to participate in an optional 
Supplemental Biomarker Program (described in Appendix 18). As of May 2018, collection of 
the optional baseline metastatic tumour sample has been discontinued and the 
Supplemental Biomarker Program has been closed. 
3.1.1 
Induction Treatment Phase 
Eligible patients will enter a 4-month Induction Treatment Phase.  Treatment during this 
phase, based on Investigator’s choice (see Appendix 6), will be either: 
• 
Eight 2-week cycles of 5-fluorouracil (5-FU), leucovorin (LV) and oxaliplatin (FOLFOX) in 
combination with bevacizumab 
or 
• 
Six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week 
cycles of 5-FU/LV with bevacizumab 
During the Induction Treatment Phase patients will be assessed for AEs at every cycle. 
Clinical laboratory assessments will be conducted at each cycle, however results from tests 
conducted every second treatment cycle only will be collected in the electronic case report 
form (eCRF). Physical examinations and documentation of concomitant medications will be 
done every two treatment cycles. Tumour assessments will be evaluated according to the 
Response Evaluation Criteria in Solid Tumors version 1.1 RECIST 1.1 for all study patients 
during the Induction Treatment Phase. Tumour assessments will be based on local standard 
of care, but must include an assessment at the end of the Induction Treatment Phase.  See 
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No other anti-cancer therapy is permitted during the Induction Treatment Phase except for 
radiotherapy for pain control or local ablation for liver metastases. Local ablation for liver 
metastases is allowed only if there are other non-ablated sites of measurable disease that 
have been followed from baseline tumour assessment (i.e. prior to start of induction 
treatment). 
Patients who prematurely discontinue study treatment for any reason during the Induction 
Treatment Phase, or who experience PD at any time during or at the end of the Induction 
Treatment Phase, or who refuse to proceed to the Maintenance Treatment Phase or who are 
not eligible for any study cohort will undergo a Study Treatment Discontinuation Visit within 
30 days after the last dose of study treatment and will then enter the Post-Treatment Follow-
up Phase. Prior to May 2018, patients participating in the Supplemental Biomarker Plan 
would undergo a tumour core biopsy of metastasis and provide a stool sample at the time of 
progressive disease. The Supplemental Biomarker Program is now closed (see 
Appendix 18).  All patients need to be evaluated for potential resection of metastasis at 
completion of the induction period. This is of particular importance for patients with liver 
metastases. If the patient is found to be resectable they will undergo a Study Treatment 
Discontinuation Visit within 30 days after the last dose of study treatment and will then enter 
the Post-Treatment Follow-up Phase.  
Patients who do not have progressive disease and who have completed the Induction 
Treatment Phase can then proceed to the Maintenance Treatment Phase.   
3.1.1.1 
BRAFmut Patients and Early Disease Progression 
BRAFmut patients experiencing early disease progression during induction treatment (called 
“early progressing BRAFmut patients”) will have the option of proceeding immediately to 
receive second-line treatment with 5-FU/LV, cetuximab and vemurafenib if their primary 
tumour is MSS, or with a fluoropyrimidine (5-FU/LV or capecitabine), bevacizumab, and 
atezolizumab if their primary tumour is MSI-H.   
If a patient previously indicated to have a BRAFmut primary tumour (e.g. according to local 
testing) progresses prior to the availability of results from the study primary tumour 
biomarker testing, the Investigator may request an expedited biomarker report from the 
sponsor’s Medical Monitor to confirm BRAFmut status and to obtain MS status. Such patients 
will be allocated to the appropriate second-line treatment and may begin treatment following 
approval from the Medical Monitor. 
Early progressing BRAFmut patients receiving 5-FU/LV, cetuximab and vemurafenib as 
second-line treatment will be followed for safety and efficacy in accordance with the 
Maintenance Treatment Phase Schedule of Assessments (including eligibility, biomarker 
sampling and post-treatment follow-up) for Cohort 1 (see Appendix 2) and will be managed 
according to protocol recommendations and requirements for the experimental arm of 
Cohort 1. Early progressing BRAFmut patients receiving a fluoropyrimidine (5-FU/LV or 
capecitabine), bevacizumab, and atezolizumab as second-line treatment will be followed for 
safety and efficacy in accordance with the Maintenance Treatment Phase Schedule of 
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Cohort 2 (see Appendix 3) and will be managed according to protocol recommendations and 
requirements for the experimental arm of Cohort 2. 
3.1.2 
Maintenance Treatment Phase 
Prior to May 2018, patients participating in the Supplemental Biomarker Plan would have 
had an additional tumour core biopsy of metastasis and stool sample collection upon 
completion of induction treatment prior to initiation of maintenance treatment. The 
Supplemental Biomarker Program is now closed (see Appendix 18). 
For all patients, the assessment of biomarkers for cohort assignment will be based on 
archival tumour tissue block from the primary tumour obtained at the time of initial diagnosis 
(see Appendix 17). 
Patients with an adequate tumour sample but with unknown biomarker status due to lack of 
determinant result (e.g. due to technical issues) may still be included in the study depending 
on the addition of future cohorts. 
Each cohort will consist of a cohort-specific experimental treatment arm and a standard 
control arm of fluoropyrimidine (5-FU/LV or capecitabine) and bevacizumab.  Within 3 weeks 
of completion of induction treatment, patients who have not progressed and continue to the 
biomarker-driven Maintenance Treatment Phase of the study will be randomised on a 2:1 
(experimental:control) basis to either the experimental treatment arm or the control arm of 
that cohort and will begin maintenance treatment.  Randomisation will be stratified according 
to specific biomarkers identified for each cohort, by geographical region, and/or by patient 
response after the Induction Treatment Phase. Stratification variables applicable to each 
cohort are described in Section 4.2. 
The study will follow an adaptive design, where additional cohorts can be added and/or 
existing cohorts changed over the course of the study via protocol amendment (see 
Figure 2). Refer to Section 6 for the status of cohorts following premature closure of study 
enrolment.  
Efficacy, safety and tolerability will be assessed during the entire Maintenance Treatment 
Phase. While receiving study treatment during the Maintenance Treatment Phase, patients 
will be assessed for AEs and concomitant medications at every treatment cycle. Clinical 
laboratory assessments will be conducted at every cycle. For regimens with two week 
treatment cycles, clinical laboratory results from every second treatment cycle only will be 
collected in the eCRF. For regimens with three week treatment cycles (such as Cohort 3 
experimental regimen), clinical laboratory results from every cycle will be collected in the 
eCRF. Physical examinations will be done every treatment cycle (regimens with three week 
treatment cycles) or every two treatment cycles (regimens with two week cycles). Additional 
safety reviews (safety run-ins) will be conducted by the iDMC, when necessary, for a 
prespecified number of initial patients receiving experimental combinations with inadequate 
prior safety experience to assure appropriate dosing (e.g. as required for the initial patients 
treated with the experimental combination of ‘5-FU/LV + cetuximab + vemurafenib’).  Up to 
and including May 31, 2019, disease status will be evaluated during the Maintenance 
Treatment Phase in accordance with RECIST 1.1 (see Appendix 10) for all patients, and 
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of Cohorts 2 and 4 (all patients treated with atezolizumab). Tumour assessments will be 
conducted every eight weeks. After May 31, 2019, disease status will no longer be collected 
for study analyses and will be evaluated according to local practice. Schedules of 
Assessments for each cohort are provided in Appendices 2 to 5. 
Maintenance treatment IMP dose reductions are only allowed as recommended in the 
applicable Investigator’s Brochures (see Section 5.1.3).  If any drug of any study treatment 
regimen in either the Induction or Maintenance Treatment Phase is discontinued or held for 
> 21 days, approval of the Sponsor’s Medical Monitor must be obtained prior to re-initiation 
of treatment.  Patients not approved to re-initiate treatment after > 21 day delays will come 
off all study treatment and will enter the Post-Treatment Follow-up Phase. 
No other anti-cancer therapy is permitted during the Maintenance Treatment Phase except 
for radiotherapy for pain control. 
Patients who discontinue study treatment for any reason during the Maintenance Treatment 
Phase will undergo a Study Treatment Discontinuation Visit within 30 days after the last 
dose of study treatment and will then enter the Post-Treatment Follow-up Phase. 
Patients discontinuing treatment during the Maintenance Treatment Phase, will be followed 
for new AEs for 28 days following the discontinuation of study treatment if they received 
treatment in the control arm of any cohort or the experimental arm of Cohort 1. Patients 
discontinuing from treatment in the experimental arms of Cohorts 2, 3 or 4 will be followed 
for new AEs for 90 days following the discontinuation of study treatment. At the time of 
treatment discontinuation, any ongoing AE/SAE will be followed until the event resolves, the 
Investigator assesses the event as stable or the patient is lost to follow-up, dies or withdraws 
consent.  The Sponsor should be notified if the Investigator becomes aware of any SAE or 
AEs of special interest occurring after the end of the adverse event reporting period if the 
event is believed to be related to prior study treatment (see Section 5.3.1). 
3.1.2.1 
Maintenance Treatment in Cohort 1  
Experimental Arm  
• 
5-FU/LV with cetuximab and vemurafenib 
Control Arm 
• 
fluoropyrimidine (5-FU/LV or capecitabine) and bevacizumab 
Up to and including May 31, 2019, disease status of patients in Cohort 1 will be assessed by 
the Investigator according to according to RECIST 1.1 (see Appendix 10) during the 
Maintenance Treatment Phase. After May 31, 2019, disease status will no longer be 
collected for study analyses and will be evaluated according to local practice. Maintenance 
treatment will continue in these patients until disease progression, unacceptable toxicity, 
initiation of another anti-cancer therapy, patient or physician decision to discontinue, or 
patient death, whichever occurs first. 
A safety run-in review was conducted for the first six patients treated with the experimental 
combination of ‘5-FU/LV+ cetuximab + vemurafenib’ by the iDMC in February 2016. The 
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up to 2,400 mg/m2. The iDMC will continue to monitor initial patients in this regimen treated 
with 5-FU doses ≥ 1,600 mg/m2 and have also recommended that patients with ECOG PS = 
2 and a low BMI be carefully assessed by the Investigator for physical fitness adequate for 
receipt of this regimen. Further details of the safety review are provided in the iDMC Charter. 
Prior to May 2018, all patients participating in the Supplemental Biomarker Plan would have 
undergone a tumour core biopsy of metastasis and stool sample collection at the time of 
progressive disease. The Supplemental Biomarker Program is now closed (see 
Appendix 18).   
3.1.2.2 
Maintenance Treatment in Cohort 2  
Experimental Arm 
• 
fluoropyrimidine (5-FU/LV or capecitabine) with bevacizumab and atezolizumab 
Control Arm 
• 
fluoropyrimidine (5-FU/LV or capecitabine) and bevacizumab 
Up to and including May 31, 2019, disease status of patients in the control arm of Cohort 2 
will be assessed by the Investigator according to according to RECIST 1.1 (see 
Appendix 10) during the Maintenance Treatment Phase. After May 31, 2019, disease status 
will no longer be collected for study analyses and will be evaluated according to local 
practice. Maintenance treatment will continue in these patients until disease progression, 
unacceptable toxicity, initiation of another anti-cancer therapy, patient or physician decision 
to discontinue, or patient death, whichever occurs first. 
Up to and including May 31, 2019, disease status of patients in the experimental arm of 
Cohort 2 (i.e. patients who are receiving atezolizumab), will be assessed according to both 
RECIST 1.1 (see Appendix 10) and mRECIST (see Appendix 11) during the Maintenance 
Treatment Phase. After May 31, 2019, disease status will no longer be collected for study 
analyses and will be evaluated according to local practice. Maintenance treatment may 
continue in these patients beyond the first tumour assessment showing apparent 
progression according to RECIST 1.1 as long as they meet the following criteria as assessed 
by the Investigator: 
• 
Evidence of clinical benefit  
• 
Absence of symptoms and signs (including worsening of laboratory values, e.g. new or 
worsening hypercalcemia) indicating unequivocal progression of disease 
• 
No decline in ECOG performance status that can be attributed to disease progression 
• 
Absence of tumour progression at critical anatomical sites (e.g. leptomeningeal disease) 
that cannot be managed by protocol-allowed medical interventions 
Treatment should be discontinued if the next follow-up tumour assessment continues to 
demonstrate progression per RECIST 1.1 (as compared to the assessment at the end of 
induction treatment). If the next tumour assessment does not show progression per RECIST 
1.1, the patient may continue maintenance treatment until such time as the treatment 
continuation criteria above are no longer met and/or two sequential tumour assessments 
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Atezolizumab-treated patients may be discontinued from study treatment during the 
Maintenance Phase for the following reasons other than loss of clinical benefit or persistent 
progression per RECIST 1.1: unacceptable toxicity, initiation of another anti-cancer therapy, 
patient or physician decision to discontinue, or patient death, whichever occurs first. 
Prior to May 2018, all patients participating in the Supplemental Biomarker Plan would have 
undergone a tumour core biopsy of metastasis and stool sample collection at the time of 
progressive disease. The Supplemental Biomarker Program is now closed (see 
Appendix 18).   
3.1.2.3 
Maintenance Treatment in Cohort 3 
Experimental Arm  
• 
capecitabine with trastuzumab and pertuzumab 
Control Arm 
• 
fluoropyrimidine (5-FU/LV or capecitabine) and bevacizumab 
Up to and including May 31, 2019, disease status of patients in Cohort 3 will be assessed by 
the Investigator according to according to RECIST 1.1 (see Appendix 10) during the 
Maintenance Treatment Phase. After May 31, 2019, disease status will no longer be 
collected for study analyses and will be evaluated according to local practice. Maintenance 
treatment will continue in these patients until disease progression, unacceptable toxicity, 
initiation of another anti-cancer therapy, patient or physician decision to discontinue, or 
patient death, whichever occurs first. 
Prior to May 2018, all patients participating in the Supplemental Biomarker Plan would have 
undergone a tumour core biopsy of metastasis and stool sample collection at the time of 
progressive disease. The Supplemental Biomarker Program is now closed (see 
Appendix 18).   
3.1.2.4 
Maintenance Treatment in Cohort 4 
On February 12, 2018, in accordance with iDMC recommendations following review of safety 
data, accrual into Cohort 4 was suspended. Based on their subsequent evaluation of 
additional Cohort 4 safety and efficacy data on July 3, 2018, the iDMC recommended that 
Cohort 4 accrual be closed. The basis for this recommendation was a higher number of 
deaths, the occurrence of serious toxicity, and the lack of evidence for clinical benefit (either 
response or tumour control) in the experimental arm relative to the control arm. Subsequent 
to the iDMC recommendations, additional deaths occurred in Cohort 4 including in the 
experimental arm. Even though these additional deaths were due to disease progression, 
they adversely affect the benefit-risk balance of the cobimetinib plus atezolizumab 
combination in first-line maintenance therapy for mCRC following induction with FOLFOX 
and bevacizumab. In an Urgent Safety Measure Letter dated July 25, 2018, the Sponsor 
strongly advised investigators to consider discontinuing experimental treatment in any 
ongoing patients. Investigators were advised to explore appropriate next treatment options, 
including a fluoropyrimidine (5-FU/LV or capecitabine) plus bevacizumab, with patients 
discontinuing experimental treatment.  


 
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Cohort 4 patients discontinuing experimental treatment will undergo a Study Treatment 
Discontinuation Visit and enter the Post-Treatment Follow-up Phase of the study. 
Management of these patients, including study assessments and procedures, is as 
described in this protocol for any Cohort 4 patient discontinuing treatment prior to disease 
progression.  
Following the Sponsor’s Urgent Safety Measure notification, continuation of experimental 
treatment is allowed only with written approval from the Medical Monitor following their 
review of the patient’s case with the investigator. Patients continuing experimental treatment 
will continue to be managed as described in this protocol for patients in the experimental arm 
of Cohort 4. 
Cohort 4 patients randomized to the control arm receiving standard control treatment are 
unaffected by the decisions stemming from the benefit risk evaluation of the experimental 
arm and may continue maintenance treatment in accordance with the protocol. 
Experimental Arm 
• 
cobimetinib and atezolizumab 
Control Arm 
• 
fluoropyrimidine (5-FU/LV or capecitabine) and bevacizumab 
Up to and including May 31, 2019, disease status of patients in the control arm of Cohort 4 
will be assessed by the Investigator according to according to RECIST 1.1 (see 
Appendix 10) during the Maintenance Treatment Phase. After May 31, 2019, disease status 
will no longer be collected for study analyses and will be evaluated according to local 
practice. Maintenance treatment will continue in these patients until disease progression, 
unacceptable toxicity, initiation of another anti-cancer therapy, patient or physician decision 
to discontinue, or patient death, whichever occurs first. 
Up to and including May 31, 2019, disease status of patients in the experimental arm of 
Cohort 4 (i.e. patients who are receiving atezolizumab), will be assessed according to both 
RECIST 1.1 (see Appendix 10) and mRECIST (see Appendix 11) during the Maintenance 
Treatment Phase. After May 31, 2019, disease status will no longer be collected for study 
analyses and will be evaluated according to local practice. Maintenance treatment may 
continue in these patients beyond the first tumour assessment showing apparent 
progression according to RECIST 1.1) as long as they meet the following criteria as 
assessed by the Investigator: 
• 
Evidence of clinical benefit  
• 
Absence of symptoms and signs (including worsening of laboratory values, e.g. new or 
worsening hypercalcemia) indicating unequivocal progression of disease 
• 
No decline in ECOG performance status that can be attributed to disease progression 
• 
Absence of tumour progression at critical anatomical sites (e.g. leptomeningeal disease) 
that cannot be managed by protocol-allowed medical interventions 
Treatment should be discontinued if the next follow-up tumour assessment continues to 
demonstrate progression per RECIST 1.1 (as compared to the assessment at the end of 


 
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induction treatment). If the next tumour assessment does not show progression per RECIST 
1.1, the patient may continue maintenance treatment until such time as the treatment 
continuation criteria above are no longer met and/or two sequential tumour assessments 
show progression per RECIST 1.1 
Atezolizumab-treated patients may be discontinued from study treatment during the 
Maintenance Phase for the following reasons other than loss of clinical benefit or persistent 
progression per RECIST 1.1: unacceptable toxicity, initiation of another anti-cancer therapy, 
patient or physician decision to discontinue, or patient death, whichever occurs first. 
Prior to May 2018, all study patients participating in the Supplemental Biomarker Plan would 
have undergone a tumour core biopsy of metastasis and stool sample collection at the time 
of progressive disease. The Supplemental Biomarker Program is now closed (see 
Appendix 18).   
 


 
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Figure 2: 
Study Design 
 
 


 
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3.1.3 
Post-Treatment Follow-up Phase 
All patients will undergo a Study Treatment Discontinuation visit within 30 days following 
their last study treatment and will enter the Post-Treatment Follow-up Phase of the study.   
Up to and including May 31, 2019, patients will be followed every 3 months during the Post-
Treatment Follow-up Phase for subsequent anti-cancer therapies, survival, and AEs (as 
applicable) including therapy-specific safety assessments (e.g. investigations for squamous 
cell carcinoma in patients who received vemurafenib) (see Appendices 1 to 5). After May 31, 
2019, patients in Cohorts 2 and 3 who have completed the adverse event reporting period 
and, if applicable, cohort-specific post-treatment follow-up safety assessments will be 
discontinued from the study. Cohorts 2 and 3 patients who have completed the adverse 
event reporting period (and cohort-specific post-treatment follow-up safety assessments if 
applicable) prior to May 31, 2019 will be discontinued at their Post-Treatment Follow-up visit 
within the 3 months prior to and including May 31, 2019. See Section 5.3.1 for adverse event 
reporting periods and post-treatment follow-up safety assessments. All patients in Cohorts 1 
and 4 will continue in the Post-Treatment Follow-up Phase until the end of the study. Refer 
to Appendix 19 for management of patients in each cohort based on their study status on 
May 31, 2019.  
Patients who discontinue study treatment in either the Induction or Maintenance Treatment 
Phases prior to disease progression will continue to be followed for progression during the 
Post-Treatment Follow-up Phase with disease assessments conducted according to local 
practice (patients who discontinued during the Induction Treatment Phase) or every eight 
weeks (patients who discontinued during Maintenance Treatment Phase) until progression 
or May 31, 2019, whichever comes first. After May 31, 2019, disease status will no longer be 
collected for any study patient.  Disease assessments in any patient who has not yet 
progressed as of May 31, 2019 should thereafter be conducted according to local practice.  
Second-line treatment during the Post-Treatment Follow-up Phase is at the Investigator’s 
discretion. However, patients who received atezolizumab should not receive other 
immunomodulatory agents for 10 weeks after maintenance treatment discontinuation. 
3.1.4 
Steering Committee  
The SC, composed of sponsor and external clinical representatives, will be responsible for 
overseeing the scientific validity and general conduct of the study as well as dissemination of 
the study results.  
Further details regarding the roles and responsibilities of the SC and its members are 
provided in the SC Charter. 
3.1.5 
Independent Data Monitoring Committee 
An iDMC will be responsible for evaluating the safety of the patients participating in the trial 
at regular intervals throughout the study.  The iDMC will also make recommendations as to 
whether cohort recruitment should continue based on benefit-risk evaluations that include 
efficacy as well as safety data. The efficacy data included in these reviews will be specified 
by the iDMC at a preceding iDMC meeting and will be documented in the iDMC meeting 


 
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minutes.  In addition, the iDMC will evaluate the safety data from a prespecified number of 
initial patients for experimental combinations with inadequate prior safety experience to 
assure appropriate dosing (e.g. as required for the experimental combination of ‘5-FU/LV + 
cetuximab + vemurafenib’).  
The schedule of iDMC reviews will be determined by the iDMC and described in the iDMC 
Charter. Further details regarding the roles and responsibilities of the iDMC are provided in 
the iDMC Charter.   
3.2 
END OF STUDY 
Study enrolment was suspended in February 2018 and will remain permanently closed. The 
number of patients included in each cohort is described in Section 6.2.  
The end of the study is defined as the date when all study patients have discontinued study 
treatment and completed the adverse event reporting period and, if applicable, cohort-
specific post-treatment follow-up safety assessments. See Section 5.3.1 for adverse event 
reporting periods and post-treatment follow-up safety assessments. After this, the trial will 
end and no further data will be collected in the clinical database for this study. 
Study recruitment started in April 2015. Recruitment was temporarily suspended in June 
2016 for addition of maintenance cohorts. Recruitment was suspended again beginning in 
February 2018 to accommodate closure of accrual to Cohort 4 and will not be re-opened. 
The entire study duration is estimated to be approximately 5 years.  For an individual patient, 
the study will consist of a Screening Phase (≤ 28 days), a 4-month Induction Treatment 
Phase, a Maintenance Treatment Phase, and finally follow-up during the Post-Treatment 
Follow-up Phase. 
Continued access to Roche investigational medicinal products (IMPs) used in the study will 
be in accordance with the Roche Global Policy on Continued Access to Investigational 
Medicinal Product (see Section 4.3.5). 
3.3 
RATIONALE FOR STUDY DESIGN 
In this Phase 2 study, all patients will receive an induction treatment that is considered 
standard in many countries and that has been shown to improve outcomes in the first-line 
setting. Only those patients that experience disease control or response to induction 
treatment will continue to the randomised Maintenance Treatment Phase of the study 
wherein the effects of experimental and control arms will be compared. Study treatment 
blinding is not considered necessary in this Phase 2 setting nor feasible considering the 
complexity and variation in administration methods and safety monitoring requirements with 
each regimen.   
The distribution of baseline characteristics that could contribute to variations in efficacy 
and/or safety will be controlled by randomization. Randomization will be stratified within each 
cohort according to geographic region, response to induction treatment and/or primary 
tumour biomarkers that are known or expected to affect study outcomes. In addition, 
randomization in Cohort 3 will be stratified by HER2+ IHC result since there is some 
evidence that response to HER2-targeted therapy may be dependent on the degree of 
HER2 overexpression in HER2+ patients (see Section1.2.7).  Randomization in Cohort 4 will 


 
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be stratified by microsatellite stability status due to the influence of mismatch-repair 
deficiency on tumour immune environment integral to atezolizumab’s mode of action (see 
Section 1.2.6). Cohort 4 randomization will also be stratified by RAS pathway status. The 
RAS pathway is well known to affect mCRC outcomes. 
The primary study endpoint of PFS determined according to RECIST 1.1 is an established 
measure of efficacy in the CRC setting. Secondary efficacy endpoints include OS and 
additional recognised surrogate measures of efficacy (ORR, TTR, DCR, DoR) and clinical 
benefit (change in ECOG status). Efficacy endpoints will be measured from randomization 
forward to ensure maintenance experimental and control treatment effects are evaluated 
distinctly from induction treatment effects. 
Safety endpoints will be assessed throughout all study periods (induction, maintenance, and 
study follow-up) to ensure uninterrupted monitoring of potential treatment effects that 
continue beyond last study doses, but will be summarised by study treatment phase and by 
maintenance treatment cohort.  
To assure ongoing monitoring of safety outcomes and risk-benefit balance, an iDMC will 
regularly review safety data as these become available over the course of the study. The 
efficacy data included in these reviews will be specified by the iDMC at a preceding iDMC 
meeting and will be documented in the iDMC meeting minutes. When necessary due to the 
nature of prior experience with a particular experimental regimen, a safety run-in will be 
included. The iDMC will review data from such safety run-ins and make recommendations 
for subsequent dosing. Accrual into any cohort may be terminated prior to attaining the 
planned PFS events should the iDMC find the available data do not support an adequate 
balance of benefit to risk. 
Notably, the modular study design accommodates the addition of further maintenance 
treatment cohorts consisting of regimens that include targeted therapies with potential 
efficacy in mCRC when the data to support biomarker-based assignment to such cohorts are 
established. 
3.3.1 
Rationale for mRECIST and Allowing Treatment beyond 
Progression in Atezolizumab-treated Patients 
Anti-tumour immune responses such as those associated with atezolizumab may result in 
objective responses that are delayed and that can be preceded by initial apparent 
radiological progression. This initial apparent progression may occur as a result of either 
delayed anti-tumour activity and/or robust tumour immune cell infiltration with a concomitant 
increase in tumour size. In addition, lesions that might otherwise be undetectable with 
conventional imaging may increase in size as a result of these processes and be recorded 
as new lesions (Hales et al. 2010). As a result, conventional response criteria may not 
adequately assess the activity of immunotherapeutic agents because PD determined from 
initial radiographic evaluations using these criteria may not necessarily reflect therapeutic 
failure. Because of the potential for such pseudo-progression/tumour immune infiltration, this 
study will allow patients randomised to the experimental arms of Cohort 2 and 4 to remain on 
study maintenance treatment after apparent radiographic progression, provided the benefit-
risk ratio is judged to be favourable. These patients will be discontinued for unacceptable 


 
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toxicity or symptomatic deterioration attributed to disease progression as determined by the 
Investigator after an integrated assessment of radiographic data and clinical status (see 
Section 4.6.2). 
In addition, while the primary and secondary efficacy endpoint measures will be assessed 
according to RECIST 1.1, an exploratory analysis of PFS using mRECIST (see Appendix 11) 
will be conducted for patients randomised to receive atezolizumab in this study. These 
mRECIST criteria allow the incorporation of new lesions into the calculation of total tumour 
burden after baseline. Similar to other immune-related response criteria (Wolchok et al. 
2009), it is recommended that radiological progression be confirmed at a subsequent tumour 
assessment to take into account the potential for pseudo-progression/tumour immune 
infiltration. 
3.3.2 
Rationale for Investigational Medicinal Product Maintenance 
Treatment Dosages 
3.3.2.1 
Cetuximab 
Cetuximab will be administered to patients in the experimental arm of Cohort 1 in 
combination with 5-FU/LV and vemurafenib at a dose of 500 mg/m2 via IV infusion on Day 1 
of every 2-week cycle. This dose and schedule varies from the approved weekly schedule 
(400 mg/m2 loading dose then 250 mg/m2 weekly thereafter) but has been found to exhibit 
predictable pharmacokinetics similar to the approved weekly regimen (Tabernero et al. 
2008). Findings from a phase II study of this biweekly cetuximab schedule given with 
irinotecan in patients with mCRC progressing after at least one previous line of 
chemotherapy showed similar efficacy and safety to that seen with weekly cetuximab 
(Martín-Martorell et al. 2008).  Furthermore, in a recent study of chemotherapy with or 
without cetuximab in mCRC patients with resectable liver disease, this dose and schedule 
was not associated with any new safety concerns (Primrose et al. 2014). This biweekly dose 
and schedule of cetuximab is also included in the most recent NCCN guidelines (version 2, 
2015). 
A description of the safety run-in iDMC review of patients treated with 5-FU/LV + cetuximab 
+ vemurafenib is provided in Section 3.3.2.2 below.  
3.3.2.2 
Vemurafenib 
Vemurafenib will be administered in this combination regimen at a dose of 960 mg b.i.d by 
mouth consistent with the dose and schedule approved for its use in the treatment of 
melanoma. Combined treatment with cetuximab (doses up to 400 mg/m2 loading dose then 
250 mg/m2 weekly) and vemurafenib (doses up to 960 mg b.i.d) has been found to have a 
manageable safety profile in CRC patients in an ongoing Phase 2 study (Tabernero et al. 
2014). A safety review (safety run-in) was conducted for the first six patients with the 
experimental combination of ‘5-FU/LV + cetuximab + vemurafenib’ in February 2016. The 
iDMC recommended that 5-FU dosing could be increased up to 2,400 mg/m2 with no 
changes vemurafenib or cetuximab doses. The iDMC will continue to monitor initial patients 
in this regimen treated with 5-FU doses ≥ 1,600 mg/m2. 


 
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3.3.2.3 
Atezolizumab 
Atezolizumab will be administered to patients in the experimental arm of Cohort 2 in 
combination with a fluoropyrimidine and bevacizumab at a fixed dose of 800 mg on Day 1 of 
every 2-week treatment cycle. The atezolizumab dose and schedule were determined based 
on both nonclinical studies and available clinical data as described in the current 
Investigator’s Brochure.  
Atezolizumab will be administered to patients in the experimental arm of Cohort 4 at a fixed 
dose of 840 mg on Day 1 of every 2-week treatment cycle. This dose was selected for 
further evaluation in the ongoing phase III mCRC study (GO30182) in combination with 
cobimetinib. It is expected to be pharmacologically similar to 800 mg atezolizumab every 2 
weeks recommended for phase II testing. 
As described in Section 3.3.1, due to the potential for pseudo-progression with 
immunotherapy, patients receiving atezolizumab may continue treatment beyond the first 
tumour assessment showing disease progression per RECIST 1.1 until loss of clinical 
benefit (unless the next follow-up tumour assessment also shows progression). These 
patients may also be discontinued due to unacceptable toxicity or patient or Investigator 
decision to discontinue therapy as is consistent with standard practice in the first-line 
maintenance setting.  
3.3.2.4 
Bevacizumab 
Bevacizumab will be administered in the experimental arm of Cohort 2 in combination with 
atezolizumab and a fluoropyrimidine at a dose of 5 mg/kg IV on Day 1 of every 2-week cycle. 
This dose and schedule represents the lowest dose found to be efficacious and safe in 
combination chemotherapy regimens for CRC and is approved in many countries in 
combination with 5-FU (see Section 1.2.3 and current Bevacizumab Investigator’s Brochure 
or local labelling as applicable).   
3.3.2.5 
Trastuzumab 
Trastuzumab will be administered to patients in the experimental arm of Cohort 3 on Day 1 
every 3 weeks at an initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent 
doses. This dose is indicated in the treatment of metastatic breast cancer as monotherapy 
and in combination with pertuzumab. It was administered in the phase III study evaluating 
trastuzumab in combination with pertuzumab and capecitabine with reasonable safety (see 
Section 1.2.8). 
3.3.2.6 
Pertuzumab 
Pertuzumab will be administered to patients in the experimental arm of Cohort 3 on Day 1 
every 3 weeks at an initial fixed loading dose of 840 mg followed by a fixed dose of 420 mg 
for subsequent doses. This dose is indicated in the treatment of metastatic breast cancer in 
combination with trastuzumab. This dose was administered in a phase III study evaluating 
pertuzumab in combination with trastuzumab and capecitabine with reasonable safety (see 
Section 1.2.8). 


 
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3.3.2.7 
Cobimetinib 
Cobimetinib will be administered to patients in the experimental arm of Cohort 4 at a dose of 
60 mg orally once daily for 3 weeks followed by a 1 week treatment break (21/7 schedule) in 
combination with atezolizumab. As such, cobimetinib will be administered daily every day of 
each odd numbered 2-week treatment cycle, and for the first 7 days only of each even 
numbered 2-week treatment cycle. This dose was determined as the recommended phase II 
dose in the phase I dose-escalation/dose-expansion study GP28363 of combined 
atezolizumab and cobimetinib (see Section 1.2.9). 
3.3.3 
Rationale for Patient Populations 
The study patient population was defined to ensure participants are suitable to receive the 
study mandated induction treatment in terms of both available treatment options (e.g. 
previously untreated, unresectable metastatic disease) and overall fitness (e.g. ECOG 
status ≤ 2, adequate organ function).  
Cohort populations were defined primarily upon biomarker criteria considered appropriate to 
the cohort’s experimental treatment arm regimen and to avoid contraindications to the 
experimental regimen. 
3.3.4 
Rationale for Control Group 
Each maintenance cohort will include the same control arm regimen consisting of a 
fluoropyrimidine and bevacizumab. Treatment with these agents is considered standard in 
many countries for the treatment of mCRC with or without oxaliplatin and regardless of 
biomarker status. The doses of each agent are consistent with applicable local prescribing 
information. In countries where bevacizumab is not approved in this indication, the lowest 
biweekly dose recommended for use in any jurisdiction (5 mg/kg q2w) is mandated.   
As a consequence of using the same control treatment regimens across study cohorts, study 
outcomes may be compared between the different cohorts’ control arm populations.  
3.3.5 
Rationale for Biomarker Assessments 
Overall, biomarker assessments conducted in this study are fundamental to the general 
study goal of further characterizing biomarkers in mCRC treatment. Tumour biomarker 
testing (e.g. BRAF gene analysis) for cohort assignment is required to determine which 
cohort’s experimental treatment may be appropriate to the particular patient. Importantly, 
biomarker testing for cohort assignment will be conducted on archived primary tumour 
samples already obtained as part of routine care that are available for all study patients. 
Additional biomarker assessments conducted on tumour, blood and stool samples will 
provide insight into factors which affect the efficacy and safety of specific treatments in an 
individual patient. These evaluations are critical to the development of individualised care 
including optimal treatment selection. These assessments will be conducted on tumour 
samples that have already been collected as part of routine care, on peripheral blood 
samples obtained at the same time as blood sampling for safety monitoring, or on stool 
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study purposes but these will only be obtained from patients who have provided written 
informed consent for these additional biopsies.   
3.4 
OUTCOME MEASURES  
3.4.1 
Efficacy Outcome Measures 
The primary efficacy outcome measure of PFS will be assessed within each cohort 
(experimental arm vs. control arm) during the Maintenance Treatment Phase.  PFS is 
defined as the time from randomisation into the Maintenance Treatment Phase until disease 
progression according to RECIST 1.1 per Investigator assessment or death from any cause, 
whichever occurs first. 
Secondary 
• 
OS, defined as the time from randomisation into the Maintenance Treatment Phase to 
death from any cause 
• 
ORR (defined as PR or CR) during the Maintenance Treatment Phase.  Response will 
be determined by the Investigator according to RECIST 1.1 based on comparisons to the 
tumour assessment done at the end of the Induction Treatment Phase. 
• 
DCR (defined as CR, PR or SD) during the Maintenance Treatment Phase. Response 
will be determined by the Investigator according to RECIST 1.1 based on comparisons to 
the tumour assessment done at the end of the Induction Treatment Phase. 
• 
TTR defined as the time from randomisation into the Maintenance Treatment Phase to 
the first subsequent occurrence of a documented objective response (PR or CR), as 
determined by the Investigator according to RECIST 1.1 
• 
DOR, defined as the time from the first occurrence of a documented objective response 
(PR or CR) during the Maintenance Treatment Phase to the time of progression, as 
determined by the Investigator according to RECIST 1.1, or death from any cause 
• 
ECOG performance status during and after treatment 
3.4.2 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Incidence, nature and severity of all adverse events (graded according to NCI CTCAE 
v4.0) 
• 
Incidence and nature of all Grade 3 – 5 AEs 
• 
Grade 5 AEs or AEs leading to death on study treatment 
• 
All SAEs 
• 
Incidence and reasons for any premature discontinuation of any component of study 
treatment 
• 
Incidence and reasons for any dose reductions or interruptions of any component of 
study treatment 
• 
AEs of special interest  
• 
Clinically significant changes in laboratory values  


 
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Adverse events refer to all treatment-emergent adverse events occurring after the initiation 
of study medication (i.e. on or after Day 1, Cycle 1 of the Induction Treatment Phase).   AEs 
will continue to be collected during the Maintenance Treatment Phase and Post-Treatment 
Follow-up Phase as applicable. 
3.4.3 
Exploratory Outcome Measures  
The exploratory efficacy outcome of the study is PFS in patients treated with atezolizumab 
defined as the time from randomisation into the Maintenance Treatment Phase until disease 
progression per Investigator assessment using mRECIST or death from any cause, 
whichever occurs first. 
The exploratory biomarker outcome measures of the study include molecular 
markers/marker profiles and efficacy and/or safety outcomes.  Efficacy outcomes considered 
for this analysis may include, but are not limited to, ORR, PFS and OS, as appropriate. 
Biomarkers, biomarker profiles and microbiomes may be assessed using various 
methodologies including, but not limited to, IHC (single and multiplex), RNA and DNA 
analysis (e.g. polymerase chain reaction, next generation sequencing [NGS], mutation 
expression and microsatellite instability [MSI] analyses) of tumour and/or blood samples 
collected from all study patients as well as additional tumour samples and stool samples 
collected from patients participating in the Supplemental Biomarker Program.  
Further details of biomarkers that may be assessed in the exploratory biomarker analyses 
are provided in Appendix 17.  
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
The target study population consists of patients with mCRC who have not received any prior 
chemotherapy in the metastatic setting. 
The “All Cohort” eligibility criteria are evaluated prior to initiating the first cycle of study 
treatment during the Induction Treatment Phase.  
The cohort-specific exclusion criteria must be assessed within 3 weeks of completing the 
Induction Treatment Phase.  Biomarker assessment for cohort assignment will be completed 
prior to randomisation, as the results of the biomarker assessments are required to identify 
the intended cohort in order to complete the appropriate cohort-specific eligibility 
assessments. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
All Cohorts 
Patient Status  
1. Have provided written informed consent prior to any study specific procedures 
2. Willing and able to comply with the protocol 


 
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3. ≥ 18 years of age 
4. ECOG status of ≤ 2 (see Appendix 8) 
5. At least 16 weeks of life expectancy at time of entry into the study 
Disease-related  
6. Histologically confirmed CRC with mCRC confirmed radiologically 
7. Measurable, unresectable disease according to RECIST 1.1 
8. No prior chemotherapy for CRC in the metastatic setting 
9. Archival tumour formalin-fixed paraffin-embedded tissue (FFPET) block from the primary 
tumour obtained at the time of the initial diagnosis must be shipped to the Sponsor’s 
designated laboratory with sample receipt confirmed by the laboratory. If the tumour 
block is not available, ≥ 20 slides cut from the primary tumour sample will be accepted as 
an alternative (see Appendix 17). The slides must be shipped with receipt confirmed by 
the Sponsor’s designated laboratory prior to study enrolment.  
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
All Cohorts 
Other Prior or Current Treatments  
1. Less than 6 months from completion of any prior neoadjuvant or adjuvant chemotherapy 
or radiotherapy  
2. Prior or current treatment with bevacizumab or any other anti-angiogenic drug (i.e. VEGF 
or vascular endothelial growth factor receptor [VEGFR] therapies or tyrosine kinase 
inhibitors) 
3. Current or recent (within 10 days of start of induction treatment) use of aspirin 
(> 325 mg/day), clopidogrel (> 75 mg/day), therapeutic oral or parenteral anticoagulants, 
or thrombolytic agents for therapeutic purposes  
Note: The use of full-dose oral or parenteral anticoagulants is permitted as long as the 
international normalised ratio (INR) or activated partial thromboplastin time (aPTT) is 
within therapeutic limits (according to the medical standard of the institution) and the 
patient has been on a stable dose of anticoagulants for at least two weeks prior to the 
start of study induction treatment. Prophylactic use of anticoagulants is allowed. 
4. Requirement for treatment with any medicinal product that contraindicates the use of any 
of the study medications, may interfere with the planned treatment, affects patient 
compliance or puts the patient at high risk for treatment-related complications 
5. Treatment with any other investigational agent within 28 days or 5 investigational agent 
half-lives (whichever is longer) prior to the start of study induction treatment 
Haematological, Biochemical and Organ Function 
6. Inadequate haematological function indicated by one or more of the following: 
̶ 
Absolute neutrophil count (ANC) < 1.5 x 109/L  


 
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̶ 
Platelet count < 100 x 109/L  
̶ 
Haemoglobin < 9 g/dL (patients may have transfusions and/or growth factors to attain 
adequate haemoglobin) 
7. Inadequate liver function indicated by one or more of the following:  
̶ 
Total bilirubin ≥ 1.5 x upper limit of normal (ULN)  
̶ 
Aspartate transaminase (AST) or alanine aminotransferase (ALT) ≥ 2.5 x ULN (≥ 5 x 
ULN in patients with known liver metastases) 
̶ 
Alkaline phosphatase (ALP) ≥ 2 x ULN ( ≥ 5 x ULN in patients with known liver 
metastases) 
8. Inadequate renal function indicated by one or more of the following:  
̶ 
Serum creatinine > 1.25 x ULN or calculated creatinine clearance < 50 ml/min 
̶ 
Urine dipstick for proteinuria ≥ 2+ unless a 24-hour urine protein < 1 g of protein is 
demonstrated 
9. INR > 1.5 or aPTT > 1.5 x ULN within 7 days prior to start of study induction treatment 
for patients not receiving anti-coagulation therapy. For patients, receiving anticoagulants 
INR and aPTT must be within the medical standard of enrolling institution. 
The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or 
aPTT is within therapeutic limits (according to the medical standard of the enrolling 
institution) and the patient has been on a stable dose of anticoagulants for at least two 
weeks prior to the start of study induction treatment 
General Criteria 
10. Active infection requiring intravenous antibiotics at the start of study induction treatment  
11. Previous or concurrent malignancy, except for adequately treated basal or squamous 
cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been 
disease-free for five years prior to study entry 
12. Evidence of any other disease, neurologic or metabolic dysfunction, physical 
examination finding or laboratory finding giving reasonable suspicion of a disease or 
condition that contraindicates the use of any of the study medications, puts the patient at 
higher risk for treatment-related complications or may affect the interpretation of study 
results  
13. Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg 
and/or diastolic blood pressure > 100 mmHg) 
14. Prior history of hypertensive crisis or hypertensive encephalopathy   
15. Clinically significant (i.e. active) cardiovascular disease, for example cerebrovascular 
accidents ≤ 6 months prior to start of study induction treatment, myocardial infarction 
≤ 6 months prior to study enrolment, unstable angina, New York Heart Association 
(NYHA) Functional Classification Grade 2 or greater congestive heart failure, or serious 
cardiac arrhythmia uncontrolled by medication or potentially interfering with protocol 
treatment 
16. History or evidence upon physical or neurological examination of central nervous system 
(CNS) disease (e.g. seizures) unrelated to cancer unless adequately treated with 
standard medical therapy 


 
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17. Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent 
arterial thrombosis) within 6 months of start of study induction treatment 
18. Any previous venous thromboembolism > National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) Grade 3 within the last 12 months 
prior to start of study induction treatment 
19. Active, symptomatic or untreated CNS metastases; CNS disease other than 
supratentorial or cerebellar metastases (i.e. patients with metastases to midbrain, pons, 
medulla or spinal cord are excluded); history of or known carcinomatous meningitis. 
Note:  Treatment of brain metastases, either by surgical or radiation techniques, must 
have been completed > 4 weeks prior to start of study induction treatment. Patients 
requiring anticonvulsants or corticosteroids for symptom control and patients with 
evidence of interim progression between the completion of CNS-directed therapy and 
study baseline disease assessments are excluded from the study. 
Note:  Patients without measurable disease outside the CNS are excluded from the 
study. 
20. History of haemoptysis ≥ Grade 2 (defined as ≥ 2.5 mL bright red blood per episode) 
within 1 month of start of study induction treatment 
21. History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of 
bleeding (i.e. in the absence of therapeutic anticoagulation)  
22. Surgical procedure (including open biopsy, surgical resection, wound revision, or any 
other major surgery involving entry into a body cavity) or significant traumatic injury 
within 28 days prior to start of study induction treatment, or anticipation of need for major 
surgical procedure during the course of the study.  
23. Minor surgical procedure including placement of a vascular access device, within 2 days 
of start of study induction treatment  
24. History of abdominal fistula, gastrointestinal (GI) perforation, intra-abdominal abscess or 
active GI bleeding within 6 months prior to start of study induction treatment  
25. Serious, non-healing wound, active ulcer, or untreated bone fracture 
26. Known hypersensitivity to any component of any of the study induction or maintenance 
treatment medications 
27. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanised antibodies or fusion proteins 
28. Known dihydropyrimidine dehydrogenase (DPD) deficiency 
29. Pregnancy or lactation. A serum pregnancy test is required within 7 days prior to start of 
study induction treatment, or within 14 days with a confirmatory urine pregnancy test 
within 7 days prior start of study induction treatment 
30. For women who are not post-menopausal (< 12 months of non-therapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus): refusal to use a 
highly effective contraceptive method (i.e. with a failure rate of < 1% per year such as 
sexual abstinence, hormonal implants, combined oral contraceptives, vasectomised 
partner), during both the Induction and Maintenance Treatment Phases and for at least 


 
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7 months after the last dose of study medication.  Periodic abstinence [e.g., calendar, 
ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable 
methods of contraception.  A combination of male condom with cap, diaphragm or 
sponge with spermicide (double barrier methods) is not considered highly effective, birth 
control methods. Acceptable methods of contraception may include total abstinence in 
cases where the lifestyle of the patient ensures compliance. A vasectomised partner is a 
highly effective birth control method provided that partner is the sole sexual partner of 
the MODUL trial participant and that the vasectomised partner has received medical 
assessment of the surgical success. Some of the study-related medication, such as 
vemurafenib may decrease the plasma exposure of those hormonal contraceptives 
predominantly metabolised by CYP3A4. In these cases, the use of an alternate highly 
effective method of contraception must be considered. 
31. For men: refusal to use a highly effective contraceptive method (i.e. with a failure rate of 
< 1% per year such as vasectomy, sexual abstinence or female partner use of hormonal 
implants or combined oral contraceptives) during both the Induction and Maintenance 
Treatment Phases and for a period of at least 6 months after the last dose of study 
medication.  Periodic abstinence [e.g., calendar, ovulation, symptothermal, post 
ovulation methods] and withdrawal are not acceptable methods of contraception. A 
combination of male condom with either, cap, diaphragm or sponge with spermicide 
(double barrier methods) is not considered highly effective, birth control methods. 
Acceptable methods of contraception may include total abstinence in cases where the 
lifestyle of the patient ensures compliance. A vasectomised MODUL trial participant is a 
highly effective birth control method provided that the MODUL trial participant has 
received medical assessment of the surgical success. Men must also agree not to 
donate sperm for at least 6 months after their last dose of study drug. 
Cohort-Specific Exclusion Criteria 
Cohort 1 Exclusion Criteria  
1. Have not provided informed consent to participate in Cohort 1 
Note:  At study centers where a single informed consent form is used, informed consent 
to participate in any maintenance cohort will have already been provided at study entry. 
Patients enrolled at centers using two informed consent forms must provide maintenance 
cohort-specific consent after cohort assignment and prior to cohort-specific eligibility 
assessments other than eligibility assessments already conducted as part of routine care. 
2. Inability to swallow pills 
3. Refractory nausea and vomiting, malabsorption, external biliary shunt or significant 
bowel resection that would preclude adequate absorption 
4. History or presence of clinically significant ventricular or atrial dysrhythmias ≥ NCI 
CTCAE Grade 2 
5. Corrected QT (QTc) interval ≥ 450 msec as assessed within 3 weeks prior to 
randomization, long QT syndrome, uncorrectable electrolyte abnormalities (including 
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6. For women who are not post-menopausal (< 12 months of non-therapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus): refusal to use an 
alternate highly effective contraceptive method (i.e. with a failure rate of < 1% per year 
such as sexual abstinence, vasectomised partner) other than hormonal contraceptives, 
during both the Induction and Maintenance Treatment Phases and for at least 7 months 
after the last dose of study medication. Vemurafenib may decrease the plasma exposure 
of those hormonal contraceptives predominantly metabolised by CYP3A4. 
7. ECOG PS > 2 (see Appendix 8) 
Note:  Due to the potential risks associated with treatment in the experimental arm of 
Cohort 1, patients with ECOG PS = 2 and a low body mass index (BMI) must be judged 
by the Investigator as adequately physically fit to receive treatment with 5-FU/LV + 
cetuximab + vemurafenib to be considered eligible (see Section 4.3.2.2.2). 
Cohort 2 Exclusion Criteria 
1. Have not provided informed consent to participate in Cohort 2 
Note:  At study centers where a single informed consent form is used, informed consent 
to participate in any maintenance cohort will have already been provided at study entry. 
Patients enrolled at centers using two informed consent forms must provide maintenance 
cohort-specific consent after cohort assignment and prior to cohort-specific eligibility 
assessments other than eligibility assessments already conducted as part of routine care. 
2. Known hypersensitivity or allergy to Chinese hamster ovary cell products  
3. History of autoimmune disease including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, 
Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple 
sclerosis, vasculitis, or glomerulonephritis (see Appendix 9 for a more comprehensive list 
of autoimmune diseases) 
Patients with the following are eligible: 
̶ 
a history of autoimmune-related hypothyroidism on a stable dose of thyroid 
replacement hormone 
̶ 
controlled Type 1 diabetes mellitus on a stable insulin regimen 
̶ 
eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g. patients with psoriatic arthritis would be excluded) are 
permitted provided that they meet the following conditions: 
o rash must cover less than 10% of body surface area (BSA) 
o disease is well controlled prior to randomization and only requires low potency 
topical steroids 
o no acute exacerbations of underlying condition within the previous 12 months 
(not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, high potency or oral steroids) 
4. Prior allogeneic bone marrow transplantation or prior solid organ transplantation 


 
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5. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced 
pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing 
pneumonia), or evidence of active pneumonitis on most recent chest imaging (CT scan 
or MRI) 
Note:  History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
6. Positive test for human immunodeficiency virus (HIV) 
7. Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test 
prior to randomization) or hepatitis C 
Note:  Patients with past hepatitis B virus (HBV) infection or resolved HBV infection 
(defined as having a negative HBsAg test and a positive antibody to hepatitis B core 
antigen antibody test) are eligible. 
Note:  Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction testing is negative for HCV ribonucleic acid (RNA). 
8. Active tuberculosis 
9. Severe infection within 4 weeks prior to start of maintenance treatment including, but not 
limited to, hospitalization for complications of infection, bacteremia, or severe 
pneumonia; has signs or symptoms of significant infection or has received oral or IV 
antibiotics within 2 weeks prior to start of maintenance treatment. 
Note:  Patients receiving prophylactic antibiotics (e.g. for prevention of a urinary tract 
infection or chronic obstructive pulmonary disease) are eligible. 
10. Administration of a live, attenuated vaccine within four weeks prior to start of 
maintenance treatment or anticipation that such a live attenuated vaccine will be required 
during the remainder of the study 
11. Prior treatment with CD137 agonists, anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic 
antibody or pathway-targeting agents 
12. Treatment with systemic immunostimulatory agents (including but not limited to 
interferons or interleukin-2) within four weeks or five half-lives of the drug, whichever is 
longer, prior to start of maintenance treatment  
13. Treatment with systemic corticosteroids or other systemic immunosuppressive 
medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, 
azathioprine, methotrexate, thalidomide, and anti-tumour necrosis factor agents) within 
2 weeks prior to start of maintenance treatment, or requirement for systemic 
immunosuppressive medications during the remainder of the study.  
Note:  The use of inhaled corticosteroids for chronic obstructive pulmonary disease (≤ 10 
mg oral prednisone or equivalent), mineralocorticoids (e.g., fludrocortisone) for patients 
with 
orthostatic 
hypotension, 
and 
low-dose 
supplemental 
corticosteroids 
for 
adrenocortical insufficiency are allowed. 
Note:  Patients who have received acute, low-dose (≤ 10 mg oral prednisone or 
equivalent), systemic immunosuppressant medications may be enrolled in the study after 
discussion with and approval by the Medical Monitor. 


 
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14. If receiving a RANKL inhibitor (e.g. denosumab), unwilling to adopt alternative treatment 
such as (but not limited to) bisphosphonates, while receiving atezolizumab. 
Cohort 3 Exclusion Criteria 
1. Have not provided informed consent to participate in Cohort 3 
Note:  At study centers where a single informed consent form is used, informed consent 
to participate in any maintenance cohort will have already been provided at study entry. 
Patients enrolled at centers using two informed consent forms must provide maintenance 
cohort-specific consent after cohort assignment and prior to cohort-specific eligibility 
assessments other than eligibility assessments already conducted as part of routine care. 
2. Inability to swallow pills 
3. LVEF < 50% as assessed after completion of induction treatment by either 2D 
echocardiogram (ECHO) or multiple-gated acquisition (MUGA) (ECHO is the preferred 
method). 
4. Clinically significant cardiovascular disease, including unstable angina, history of or 
active congestive heart failure of ≥ NYHA Grade 2, history of or ongoing serious cardiac 
arrhythmia requiring treatment (except for controlled atrial fibrillation and/or paroxysmal 
supraventricular tachycardia). 
5. Current uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg) 
with or without medication 
6. Current dyspnoea at rest due to complications of advanced malignancy or other disease 
requiring continuous oxygen therapy 
7. Insulin-dependent diabetes  
8. Current known infection with HIV, HBV, or HCV (active infection or carriers) 
9. Requirement for concurrent use of the antiviral agent sorivudine (antiviral) or chemically 
related analogues, such as brivudine 
10. Malabsorption syndrome, disease significantly affecting gastrointestinal function, 
resection of the stomach or small bowel, or ulcerative colitis 
11. Known hypersensitivity to murine proteins 
Cohort 4 Exclusion Criteria 
1. Have not provided informed consent to participate in Cohort 4 
Note:  At study centers where a single informed consent form is used, informed consent 
to participate in any maintenance cohort will have already been provided at study entry. 
Patients enrolled at centers using two informed consent forms must provide maintenance 
cohort-specific consent after cohort assignment and prior to cohort-specific eligibility 
assessments other than eligibility assessments already conducted as part of routine care. 
2. Inability to swallow medications 
3. Known hypersensitivity or allergy to Chinese hamster ovary cell products 
4. History of autoimmune disease including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, 


 
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Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple 
sclerosis, vasculitis, or glomerulonephritis (see Appendix 9 for a more comprehensive list 
of autoimmune diseases) 
Patients with the following are eligible: 
̶ 
a history of autoimmune-related hypothyroidism on a stable dose of thyroid 
replacement hormone 
̶ 
controlled Type 1 diabetes mellitus on a stable insulin regimen 
̶ 
eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g. patients with psoriatic arthritis would be excluded) are 
permitted provided that they meet the following conditions: 
o rash must cover less than 10% of body surface area (BSA) 
o disease is well controlled prior to randomization and only requires low potency 
topical steroids 
o no acute exacerbations of underlying condition within the previous 12 months 
(not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, high potency or oral steroids) 
5. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced 
pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing 
pneumonia), or evidence of active pneumonitis on most recent chest imaging (CT scan 
or MRI) 
Note:  History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
6. Malabsorption condition that would alter the absorption of orally administered 
medications 
7. Amylase or lipase ≥ 1.5 x ULN within 14 days prior to maintenance treatment initiation 
8. Serum albumin < 2.5 g/dL 
9. LVEF < institutional lower limit of normal or < 50%, whichever is lower. 
10. Poorly controlled hypertension, defined as a blood pressure consistently above 150/90 
mmHg despite optimal medical management. 
11. Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated drainage 
more than once every 28 days. Indwelling drainage catheters (e.g. PleurX®) are allowed. 
12. Unstable angina, new onset angina within last 3 months, myocardial infarction within last 
6 months and current congestive heart failure ≥ NYHA Grade 2. 
13. History of stroke, reversible ischemic neurological defect, or transient ischemic attack 
within 6 months prior to initiation of maintenance treatment 
14. History or evidence of intracranial hemorrhage or spinal cord hemorrhage 
15. Evidence of clinically significant vasogenic edema 
16. Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 28 days prior to 
initiation of maintenance treatment 
17. History or evidence of retinal pathology on ophthalmologic examination that is 
considered a risk factor for central serous retinopathy, retinal vein occlusion, or 
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Patients will be excluded if they currently have any of the following risk factors for retinal 
vein occlusion: 
̶ 
Uncontrolled glaucoma with intra ocular pressure ≥ 21 mmHg 
̶ 
Uncontrolled hypercholesterolemia > 300 mg/dL or 7.75 mmol/L 
̶ 
Uncontrolled hypertriglyceridemia > 300 mg/dL or 3.42 mmol/L 
̶ 
Fasting hyperglycemia > 160 mg/dL or 8.9 mmol/L 
18. Positive test for HIV  
19. Active hepatitis B (defined as having a positive HBsAg test prior to randomization) or 
hepatitis C 
Note:  Patients with past HBV infection or resolved HBV infection (defined as having a 
negative HBsAg test and a positive anti-HBc antibody test) are eligible. 
Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA. 
20. Active tuberculosis 
21. Severe infection within 4 weeks prior to start of maintenance treatment including, but not 
limited to, hospitalization for complications of infection, bacteremia, or severe 
pneumonia; has signs or symptoms of significant infection or has received oral or IV 
antibiotics within 2 weeks prior to start of maintenance treatment. 
Note:  Patients receiving prophylactic antibiotics (e.g. for prevention of a urinary tract 
infection or chronic obstructive pulmonary disease) are eligible. 
22. Prior allogeneic bone marrow transplantation or prior solid organ transplantation 
23. Administration of a live, attenuated vaccine within 4 weeks prior to start of study 
maintenance treatment or anticipation that such a live attenuated vaccine will be required 
during the study 
24. Prior treatment with CD137 agonists, anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic 
antibody or pathway-targeting agents 
25. Prior treatment with a MEK or ERK inhibitor 
26. Treatment with systemic immunostimulatory agents (including but not limited to 
interferons or interleukin-2) within 4 weeks or five half-lives of the drug, whichever is 
longer, prior to start of study maintenance treatment 
27. Treatment with systemic corticosteroids or other systemic immunosuppressive 
medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, 
azathioprine, methotrexate, thalidomide, and anti-TNF agents) within 2 weeks prior to 
start of study maintenance treatment, or requirement for systemic immunosuppressive 
medications during the trial.  
Note:  The use of inhaled corticosteroids for chronic obstructive pulmonary disease 
(≤ 10 mg oral prednisone or equivalent), and mineralocorticoids (e.g. fludrocortisone) for 
patients with orthostatic hypotension, and low-dose supplemental corticosteroids for 
adrenocortical insufficiency are allowed. 
Note:  Patients who have received acute, low-dose (≤ 10 mg oral prednisone or 
equivalent), systemic immunosuppressant medications (e.g. a one-time dose of 


 
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dexamethasone for nausea) may be enrolled in the study after discussion with and 
approval by the Medical Monitor. 
28. If receiving a RANKL inhibitor (e.g. denosumab), unwilling to adopt alternative treatment 
such as (but not limited to) bisphosphonates, while receiving atezolizumab. 
29. Consumption of foods, supplements or drugs that are potent CYP3A4 enzyme inducers 
or inhibitors ≤ 7 days before initiation of study maintenance treatment or expected 
concomitant use during maintenance treatment. These include St. John’s wort or 
hyperforin (potent CYP3A4 enzyme inducer) and grapefruit juice (potent cytochrome 
P450 CYP3A4 enzyme inhibitor). 
4.2 
METHOD OF TREATMENT ASSIGNMENT  
Within 3 weeks of completion of the Induction Treatment Phase of the study (based on the 
last day of the last cycle of induction treatment), patients who have not progressed may 
continue to the biomarker-driven Maintenance Treatment Phase.   
Patients will be randomised by an independent interactive voice or web-based response 
system (IxRS) system. At the time of enrolment to the Induction Treatment Phase, the site 
will enter demographic and Screening/Baseline patient characteristics into the IxRS. For 
patients who are eligible for enrolment, the site will obtain the patient’s identification number 
from the IxRS. 
Patients will be assigned to a cohort based on the results of biomarker assessments 
conducted on archival primary tumour tissue obtained during their initial CRC diagnosis (see 
Appendix 17).  If the primary tumour block is not available, ≥ 20 slides cut from the primary 
tumour sample will be accepted as an alternative. The determination of primary tumour 
tissue availability must be made before a potential participant undergoes any screening 
procedures and the sample (block or slides) must be shipped to the designated laboratory 
with confirmation of receipt by the laboratory before a patient may be enrolled in this study. 
Patients for whom a sufficient primary tumour sample was submitted but who do not have a 
definitive biomarker status due to indeterminate assay results (e.g. due to technical issues) 
may still be included in the study depending on the addition of future cohorts.  At the time of 
randomization to the Maintenance Treatment Phase, the site will enter the patient’s 
biomarker status.  Once assigned to a cohort, patients will be randomised on a 2:1 
(experimental:control) basis to either the experimental treatment arm or the control arm of 
that cohort.  Randomization will be stratified by specific biomarkers, geographical region 
and/or by patient response after the Induction Treatment Phase as follows: 
• 
Cohort 1: geographical region (EU, Americas, Africa or Asia), patient response after 
induction treatment (CR/PR vs. SD). 
• 
Cohort 2: geographical region (EU, Americas, Africa or Asia), patient response after 
induction treatment (CR/PR vs. SD). 
• 
Cohort 3: patient response after induction treatment (CR/PR vs. SD), HER2 IHC result 
(IHC0/IHC1+/IHC2+ vs. IHC3+)  


 
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• 
Cohort 4: geographical region (EU vs. rest of the world), patient response after induction 
treatment (CR/PR vs. SD), microsatellite stability (MSI-H vs. MSS) and RAS status (wild-
type KRAS and NRAS vs. mutant KRAS and/or NRAS) 
4.2.1 
Screening procedures 
For comparability reasons, only the archival primary tumour sample from the original 
diagnosis will be used for the biomarker assessment which determines treatment 
assignment during the Maintenance Treatment Phase, as this material will be available for 
all patients. To be eligible for the study, patients must have an archival primary tumour 
sample for biomarker assessment for cohort assignment and the sample must have been 
shipped to the Sponsor’s designated laboratory. Confirmation of sample receipt by the 
laboratory is required. The sample must be shipped to the designated laboratory with the 
corresponding pathology report. Biomarker analyses for cohort assignment will be conducted 
during the Induction Treatment Phase and these results will only be available during the 
Induction Treatment Phase and not during Screening. Patients with an adequate tumour 
sample but with unknown biomarker status due to lack of determinant result (e.g. due to 
technical issues) may still be included in the study depending on the addition of future 
cohorts. 
For enrolment into the study, patients who do not meet the study eligibility criteria (screen 
failures) may be re-screened within 7 days of the date they are determined to be screen 
failures. Re-screening of a patient > 7 days after screen failure is allowed only with prior 
approval from the Medical Monitor. Patients cannot be re-screened for the study more than 
once. 
4.3 
STUDY TREATMENT  
Study treatment includes induction treatment (FOLFOX regimens, bevacizumab) and 
maintenance treatments (5-FU/LV, capecitabine, bevacizumab, and other agents comprising 
the experimental arm regimen in each cohort).  
Investigational medicinal products 
The IMPs used in this study include: 
• 
all non-fluoropyrimidine agents comprising the experimental arms of each maintenance 
treatment cohort (i.e. cetuximab and vemurafenib in Cohort 1; bevacizumab and 
atezolizumab in Cohort 2, trastuzumab and pertuzumab in Cohort 3, cobimetinib and 
atezolizumab in Cohort 4) 
• 
bevacizumab in the Induction Treatment Phase 
• 
bevacizumab in the control arms of each maintenance treatment cohort   
• 
cetuximab, vemurafenib, bevacizumab and atezolizumab administered as optional 
second-line treatments to early progressing BRAFmut patients. 
Non-investigational medicinal products  
Non-IMPs used in this study include all fluoropyrimidine agents (i.e. 5-FU and capecitabine) 
and leucovorin administered during the Induction and Maintenance Treatment Phases and 


 
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as optional second-line treatment to early progressing BRAFmut patients. Oxaliplatin 
administered as part of induction treatment is also considered a non-IMP. 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Induction Treatment Phase  
5-FU, LV, Oxaliplatin (FOLFOX)  
5-FU, LV and oxaliplatin will be used in commercially available formulations. Refer to local 
prescribing information for details of these formulations, as well as packaging, and handling 
requirements.  
Bevacizumab 
Bevacizumab will be used in commercially available formulation. Refer to local prescribing 
information for details of the formulation as well as packaging and handling requirements. 
4.3.1.2 
Maintenance Treatment Phase  
4.3.1.2.1 
Control Arm- All Cohorts 
Fluoropyrimidine (5-FU or Capecitabine)  
The fluoropyrimidine (5-FU or capecitabine) and LV (if applicable) selected for use in the 
maintenance treatment control arms will be used in commercially available formulations. 
Refer to local prescribing information for details of these formulations as well as packaging 
and handling requirements. 
Bevacizumab 
Bevacizumab will be used in commercially available formulation. Refer to local prescribing 
information for details of the formulation as well as packaging and handling requirements. 
4.3.1.2.2 
Experimental Arm Cohort 1 
5-FU 
5-FU and LV will be used in commercially available formulations. Refer to local prescribing 
information for details of these formulations, as well as packaging, and handling 
requirements.  
Cetuximab 
Cetuximab is provided in single-use, ready-to-use, 100 mL vials containing 500 mg of 
cetuximab as a sterile, preservative-free injectable liquid.  
Chemical and physical in-use stability of cetuximab 5 mg/mL has been demonstrated for 
48 hours at 25 ºC, if the solution is prepared as described in the current cetuximab SmPC. 
Cetuximab does not contain any antimicrobial preservative or bacteriostatic agent. From a 
microbiological point of view, the product shall be used immediately after opening. If not 
used immediately, in-use storage times and conditions prior to use are the responsibility of 
the user and would normally not be longer than 24 hours at 2 – 8 ºC, unless opening has 
taken place in controlled and validated aseptic conditions. 


 
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For further details of cetuximab formulation, packaging and handling are provided in the 
cetuximab Package Insert (Appendix 14).   
Vemurafenib 
Vemurafenib is provided as 240 mg film-coated tablets for oral administration. Excipients 
include croscarmellose sodium, colloidal anhydrous silica, magnesium stearate, and 
hydroxypropylcellulose in addition to the film coat ingredients (polyvinyl alcohol, titanium 
dioxide, polyethylene glycol 3350, talc, iron oxide red). 
Vemurafenib tablets should be stored at ≤ 25 °C (77°F) and should be protected from 
excessive exposure to light. Patients will be requested to store vemurafenib at the 
recommended storage conditions noted on the label, out of reach of children or other 
vulnerable persons. Under hot weather conditions, vemurafenib may be stored in a 
refrigerator to avoid exceeding the 25 °C maximum storage temperature.  
For further details, refer to the current Vemurafenib Investigator’s Brochure. 
4.3.1.2.3 
Experimental Arm Cohort 2 
Fluoropyrimidine (5-FU/LV, Capecitabine)  
5-FU or capecitabine, and LV (if applicable) will be used in commercially available 
formulations. Refer to local prescribing information for details of these formulations, as well 
as packaging, and handling requirements. 
Bevacizumab 
Bevacizumab will be used in commercially available formulation. Refer to local prescribing 
information for details of the formulation as well as packaging and handling requirements. 
Atezolizumab 
The atezolizumab drug product is formulated as 60 mg/mL atezolizumab in 20 mM histidine 
acetate, 120 mM sucrose, 0.04% polysorbate 20, pH 5.8. It is provided in a single-use, 20-cc 
glass vial as a colourless to slightly yellow, sterile, preservative-free clear liquid solution 
intended for IV administration. The vial is designed to deliver 20.0 mL (1200 mg) of 
atezolizumab solution but may contain more than the stated volume to enable delivery of the 
entire 20.0 mL volume. 
Atezolizumab must be refrigerated at 2 °C – 8 °C (36 °F – 46 °F) upon receipt until use. 
Atezolizumab vials should not be used beyond the expiration date provided by the 
manufacturer.  No preservative is used in the atezolizumab drug product; therefore, each vial 
is intended for single use only. Vial contents should not be frozen or shaken and should be 
protected from direct sunlight. 
Atezolizumab must be administered from infusion bags with IV infusion lines with product 
contacting surfaces of polyvinylchloride or polyolefin and 0.2 µm in-line filters (filter 
membrane of polyethersulfone). No incompatibilities have been observed between 
atezolizumab and polyvinylchloride or polyolefin infusion materials (bags and infusion lines).  
For further details, refer to the Atezolizumab Pharmacy Manual and current Investigator’s 
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4.3.1.2.4 
Experimental Arm Cohort 3 
Capecitabine  
Capecitabine will be used in commercially available formulation. Refer to local prescribing 
information for details of the formulation, as well as packaging, and handling requirements. 
Trastuzumab 
Only trastuzumab (Herceptin) may be used in the study. Substitution with biosimilar drugs is 
not allowed.  
Trastuzumab for IV administration is a sterile, white to pale yellow, preservative-free 
lyophilised powder. Each vial of trastuzumab contains 150 mg of trastuzumab with L-
histidine HCl; L-histidine; α,α-trehalose dihydrate and polysorbate 20. Each vial is 
reconstituted with 7.2 mL of water for injections (not supplied). Use of other reconstitution 
solvents should be avoided. This yields a 7.4 mL solution for single-dose use, containing 
approximately 21 mg/mL trastuzumab. A volume overage of 4% ensures that the labelled 
dose of 150 mg can be withdrawn from each vial. 
Vials of trastuzumab must be stored in the closed original pack at a temperature of 
2 ºC – 8 ºC in a refrigerator. Trastuzumab reconstituted with sterile water for injection is 
stable for 48 hours at 2 ºC – 8 ºC after reconstitution and must not be frozen. 
The appropriate amount of reconstituted trastuzumab should be withdrawn from the vial and 
added to a polyvinylchloride, polyethylene or polypropylene infusion bag containing 250 mL 
of 0.9% sodium chloride solution. Do not use with glucose-containing solutions. The bag 
should be gently inverted to mix the solution in order to avoid foaming. Parenteral solutions 
should be inspected visually for particulates and discoloration prior to administration. Once 
the infusion is prepared it should be administered immediately. If diluted aseptically, it may 
be stored for 24 hours (do not store above 30 °C). 
For further details refer to the current Trastuzumab Investigator’s Brochure.  
Pertuzumab 
Pertuzumab for IV administration is provided as a single use formulation containing 
30 mg/mL pertuzumab in 20 mM L-histidine acetate (pH 6.0), 120 mM sucrose, and 0.02% 
polysorbate 20. Each 20-mL vial contains approximately 420 mg of pertuzumab 
(14.0 mL/vial). 
Vials of pertuzumab must be placed in a refrigerator 2 °C – 8 °C (36 °F – 46 °F) immediately 
upon receipt to ensure optional retention of physical and biochemical integrity and should 
remain refrigerated until immediately prior to use. DO NOT FREEZE and DO NOT SHAKE 
the pertuzumab vial. Protect from light. 
The solution of pertuzumab diluted for infusion in polyvinylchloride or non-polyvinylchloride 
polyolefin bags (including polyethylene) containing 0.9% sodium chloride injection may be 
stored at 2 °C – 8 °C (36 °F – 46 °F) for up to 24 hours prior to use. Diluted pertuzumab has 
been shown to be stable for up to 24 hours at room temperature (2 °C – 25 °C). However, 
since pertuzumab contains no preservative, the aseptically diluted solution should be stored 
refrigerated (2 °C – 8 °C) for no more than 24 hours. 


 
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For further details, see the current Pertuzumab Investigator’s Brochure. 
Note:  Trastuzumab and pertuzumab should not be administered at the same time and 
should not be mixed in the same infusion bag. 
4.3.1.2.5 
Experimental Arm Cohort 4 
Cobimetinib 
Cobimetinib is supplied as 20 mg, film-coated, white, round, immediate-release tablets 
packaged in blister packs. The inactive ingredients in cobimetinib are as follows: lactose 
monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate 
for the tablet core. The tablet coating consists of polyvinyl alcohol, part hydrolyzed, titanium 
dioxide, polyethylene glycol 3350, and talc. Cobimetinib should be stored below 30 °C 
(86 °F). 
For further details, see the current Cobimetinib Investigator’s Brochure. 
Atezolizumab 
The atezolizumab drug product is formulated as 60 mg/mL atezolizumab in 20 mM histidine 
acetate, 120 mM sucrose, 0.04% polysorbate 20, pH 5.8. It is provided in a single-use, 20-cc 
glass vial as a colourless to slightly yellow, sterile, preservative-free clear liquid solution 
intended for IV administration. The vial is designed to deliver 20.0 mL (1200 mg) of 
atezolizumab solution but may contain more than the stated volume to enable delivery of the 
entire 20.0 mL volume.  
Atezolizumab must be refrigerated at 2 °C – 8 °C (36 °F – 46 °F) upon receipt until use. 
Atezolizumab vials should not be used beyond the expiration date provided by the 
manufacturer.  No preservative is used in the atezolizumab drug product; therefore, each vial 
is intended for single use only. Vial contents should not be frozen or shaken and should be 
protected from direct sunlight. 
Atezolizumab must be administered from infusion bags with IV infusion lines with product 
contacting surfaces of polyvinylchloride or polyolefin and 0.2 µm in-line filters (filter 
membrane of polyethersulfone). No incompatibilities have been observed between 
atezolizumab and polyvinylchloride or polyolefin infusion materials (bags and infusion lines).  
For further details, refer to the Atezolizumab Pharmacy Manual and current Investigator’s 
Brochure. 
4.3.2 
Dosage and Administration 
Guidelines for dosage modification and treatment interruption or discontinuation of study 
treatment are described in Section 5.1.  Please refer to the MODUL Treatment 
Administration Guide for detailed study treatment administration instructions. 
Any overdose or incorrect administration of study drug should be noted on the Study Drug 
Administration electronic Case Report Form (eCRF).  AEs associated with an overdose or 
incorrect administration of study drug should be recorded on the Adverse Event eCRF. 


 
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4.3.2.1 
Induction Treatment Phase 
All patients will receive 4 months of study treatment in the Induction Treatment Phase.  
Treatment during this phase, based on Investigator’s choice, will be either: 
• 
eight 2-week cycles of 5-FU/LV and oxaliplatin (FOLFOX) in combination with 
bevacizumab 
or 
• 
six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week 
cycles of 5-FU/LV with bevacizumab 
The Investigator will select the FOLFOX regimen (e.g. FOLFOX-4, FOLFOX-6, modified 
FOLFOX-6, FOLFOX-7 or modified FOLFOX-7; see Appendix 6). The selected regimen 
should be administered in accordance with locally approved prescribing information including 
any recommendations for pre-treatment (i.e. antiemetic therapies).  
4.3.2.2 
Maintenance Treatment Phase  
Following cohort assignment based on biomarker status, patients will be randomised to 
receive study maintenance treatment in either the control or experimental treatment arm of 
their assigned cohort as described below. Maintenance treatment will begin within 3 weeks 
of their last dose of induction treatment. 
For patients in Cohorts 1 and 3, and the control arms of Cohorts 2 and 4 only, maintenance 
treatment will continue until disease progression (based on Investigator’s assessment 
according to RECIST 1.1), unacceptable toxicity, initiation of another anti-cancer therapy, 
patient or physician decision to discontinue, or patient death, whichever occurs first.  
Patients randomised to the experimental arms of Cohorts 2 and 4 (i.e. patients who are 
receiving atezolizumab) may continue maintenance treatment after the first tumour 
assessment showing progression per RECIST 1.1 as long as they meet the following criteria 
as assessed by the Investigator: 
• 
Evidence of clinical benefit 
• 
Absence of symptoms and signs (including worsening of laboratory values, e.g. new or 
worsening hypercalcaemia) indicating unequivocal progression of disease 
• 
No decline in ECOG performance status that can be attributed to disease progression 
• 
Absence of tumour progression at critical anatomical sites (e.g. leptomeningeal disease) 
that cannot be managed by protocol-allowed medical interventions 
Treatment should be discontinued if the next follow-up tumour assessment continues to 
demonstrate progression per RECIST 1.1 (as compared to the assessment at the end of 
induction treatment). If the next tumour assessment does not show progression per RECIST 
1.1, the patient may continue maintenance treatment until such time as the treatment 
continuation criteria above are no longer met and/or two sequential tumour assessments 
show progression per RECIST 1.1. 
Atezolizumab-treated patients may be discontinued from study treatment during the 
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progression per RECIST 1.1: unacceptable toxicity, initiation of another anti-cancer therapy, 
patient or physician decision to discontinue, or patient death, whichever occurs first. 
For all patients, dose reductions or dose delays of any IMP are only allowed as 
recommended in the applicable Investigator’s Brochure (see Section 5.1.3).  If any drug of 
any study treatment regimen in either the Induction or Maintenance Treatment Phase is 
discontinued or held for > 21 days, approval from the Medical Monitor will be required before 
treatment may be re-initiated. Patients not approved by the Medical Monitor to re-initiate 
treatment will come off all study treatment and will enter the Post-Treatment Follow-up 
Phase. 
4.3.2.2.1 
Control Arm-All Cohorts 
Control arm treatment is the same in all cohorts and should be administered as follows:  
Fluoropyrimidine (5-FU/LV or capecitabine): dose and schedule will be according to local 
label, where applicable, or otherwise will be determined per the Investigator’s discretion. 
Administration should be according to local prescribing information. 
Bevacizumab: 5 mg/kg via 15 – 30 minute IV infusion on Day 1 of every 2-week cycle. 
Bevacizumab should be prepared and administered in accordance with local prescribing 
information. Patients may be at risk of developing infusion / hypersensitivity reactions with 
bevacizumab. Close observation of the patient during and following the administration of 
bevacizumab is recommended as expected for any infusion of a therapeutic humanised 
monoclonal antibody. If a reaction occurs, the infusion should be discontinued and 
appropriate medical therapies should be administered. A systemic premedication is not 
warranted. 
Detailed treatment administration instructions are provided in the MODUL Treatment 
Administration Guide. Guidelines for dosage modification and treatment interruption or 
discontinuation of study maintenance treatment are provided in Section 5.1.3. 
4.3.2.2.2 
Experimental Arm Cohort 1 
Patients assigned to the experimental arm of Cohort 1 with an ECOG PS=2 and a low BMI 
must be carefully assessed by the Investigator for physical fitness adequate for receipt of 
this regimen prior to initiating treatment. Such patients must be closely monitored through 
the maintenance treatment period. 
Treatment in the experimental arm of Cohort 1 should be administered as follows: 
5-FU:  The first six patients in this cohort will receive 1,600 mg/m2 5-FU administered via 46-
hour IV infusion, in combination with LV 400 mg/m2 administered via 2-hour infusion, on Day 
1 of every 2-week cycle.  Subsequent patients in this cohort will receive 1,600 - 2,400 mg/m2 
5-FU administered via 46-hour IV infusion (IV bolus is not permitted), in combination with LV 
400 mg/m2 administered via 2-hour infusion, on Day 1 of every 2-week cycle.   
Cetuximab:  The dose and scheduling of cetuximab is 500 mg/m2 via IV infusion on Day 1 
of every 2-week cycle. Cetuximab must be administered in hospital under the supervision of 
a physician experienced in the use of antineoplastic medicinal products. Cetuximab must be 
administered via infusion pump or syringe pump at a rate not exceeding 5 mg/min for the 


 
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first administration and 10 mg/min for subsequent administrations. Close monitoring is 
required during the infusion and for at least 1 hour after the end of the infusion. Availability of 
resuscitation equipment must be ensured. Prior to the first infusion of cetuximab, patients 
must receive premedication with an antihistamine and a corticosteroid. This premedication is 
recommended prior to all subsequent infusions.  Refer to cetuximab Package Insert 
(Appendix 14). 
Vemurafenib: The dose and scheduling of vemurafenib is 960 mg b.i.d by mouth. 
Vemurafenib should be taken at approximately the same times each day, the first dose is to 
be taken in the morning and the second dose is to be taken approximately 12 hours later in 
the evening. Each dose should always be taken in the same manner i.e. either with or 
without a meal. Missed doses will not be made up. If a patient misses a dose (e.g., due to 
emesis), the patient should be instructed not to take or make up that dose and to resume 
dosing with the next scheduled dose.  
Note:  A safety run-in was conducted for the first six patients treated with the experimental 
combination of ‘5-FU/LV + cetuximab + vemurafenib’ in February 2016. The iDMC 
recommended that patients allocated to this regimen may now receive 5-FU at doses up to 
2,400 mg/m2. The iDMC will continue to monitor initial patients in this regimen treated with 5-
FU doses ≥ 1,600 mg/m2 and have also recommended that patients with ECOG PS = 2 and 
a low BMI be carefully assessed by the Investigator for physical fitness adequate for receipt 
of this regimen. Further details of the review are provided in the iDMC Charter.  
Detailed treatment administration instructions are provided in the MODUL Treatment 
Administration Guide. Guidelines for dosage modification and treatment interruption or 
discontinuation of study maintenance treatment are provided in Section 5.1.3. 
4.3.2.2.3 
Experimental Arm Cohort 2  
Treatment in the experimental arm of Cohort 2 should be administered as follows: 
Fluoropyrimidine (5-FU/LV or capecitabine): 1,600 – 2,400 mg/m2 5-FU administered via 
46-hour IV infusion (IV bolus is not permitted) on Day 1 of every 2-week cycle and LV 400 
mg/m2 administered via a 2-hour infusion on day 1 every 2 weeks; or 1000 mg/m2 twice-daily 
capecitabine (b.i.d.) by mouth given days 1-14 every 2 weeks followed by a one-week 
treatment break.  
Bevacizumab: The dose and schedule of bevacizumab is 5 mg/kg via 15 – 30 minute IV 
infusion on Day 1 of every 2-week cycle. Bevacizumab should be prepared and administered 
in accordance with local prescribing information. Patients may be at risk of developing 
infusion / hypersensitivity reactions with bevacizumab. Close observation of the patient 
during and following the administration of bevacizumab is recommended as expected for any 
infusion of a therapeutic humanised monoclonal antibody. If a reaction occurs, the infusion 
should be discontinued and appropriate medical therapies should be administered. A 
systematic premedication is not warranted. 
Atezolizumab:  is administered at a fixed dose of 800 mg via 60-minute IV infusion on 
Day 1 of every 2-week cycle. Atezolizumab must be administered in hospital under the 
supervision of a physician experienced in the use of antineoplastic medicinal products. For 
the first infusion, the patient’s vital signs (heart rate, respiratory rate, blood pressures, and 


 
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temperature) should be determined within 60 minutes before the infusion, every 
15 ± 5 minutes during the infusion, and 30 ± 10 minutes after the infusion. For subsequent 
infusions, vital signs will be collected within 60 minutes before the infusion and should be 
collected during or after the infusion if clinically indicated or if symptoms occurred in the prior 
infusion.  If the initial infusion is well tolerated, subsequent infusions will be done over a 30-
minute time period.  No premedication is indicated for the first dose of atezolizumab. 
Patients who experience an infusion-related reaction with Cycle 1 of atezolizumab may 
receive premedication with antihistamines or antipyretics/analgesics (e.g. acetaminophen) 
for subsequent infusions.  The rate of atezolizumab infusion should be modified in the event 
of an infusion-related reaction. Guidelines for appropriate infusion rate adjustments are 
provided in the current Atezolizumab Investigator’s Brochure. 
Detailed treatment administration instructions are provided in the MODUL Treatment 
Administration Guide. Guidelines for dosage modification and treatment interruption or 
discontinuation of study maintenance treatment are provided in Section 5.1.3. 
4.3.2.2.4 
Experimental Arm Cohort 3 
Capecitabine, trastuzumab and pertuzumab should be administered in the experimental arm 
of Cohort 3 according to the doses and schedules described below. For the first treatment 
cycle, pertuzumab should be administered on Day 1, followed by the first dose of 
trastuzumab and capecitabine on Day 2. If the administration of all three agents is well 
tolerated in the first treatment cycle, they may be given sequentially on Day 1 (pertuzumab 
and trastuzumab should not be mixed in the same infusion bag) in subsequent cycles 
thereafter. If a patient cannot tolerate all three drugs given on the same day, pertuzumab 
should continue to be delivered on Day 1, with trastuzumab and capecitabine delivered on 
Day 2 for subsequent treatment cycles. 
Capecitabine: 1000 mg/m2 twice-daily capecitabine (b.i.d.; for a total daily dose of 
2000 mg/m2) by mouth given days 1 to 14 followed by a one-week treatment break 
administered in accordance with local prescribing information. See Appendix 7 for 
capecitabine dose calculations by body surface area with corresponding tablet counts. 
Trastuzumab: Trastuzumab is administered by IV infusion on Day 1 of every 3-week 
treatment cycle at an initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent 
doses. Trastuzumab must be administered in hospital under the supervision of a physician 
experienced in the use of antineoplastic medicinal products. The first infusion should be 
delivered over 90 minutes followed by a 60 minute observation period. If the first infusion is 
well tolerated without infusion-associated AEs, the second and subsequent infusions may be 
delivered over 30 minutes with an observation period of 30 minutes. Longer infusion and/or 
observation times can be maintained if there is any doubt about tolerability. No 
premedication will be allowed for the first dose of trastuzumab. Premedication may be 
administered for subsequent cycles at the discretion of the treating physician.  The rate of 
trastuzumab infusion should be modified in the event of an infusion-related reaction. 
Pertuzumab:  Pertuzumab is administered by IV infusion on Day 1 of each 3-week 
treatment cycle at an initial fixed loading dose of 840 mg followed by 420 mg for subsequent 
doses. Pertuzumab must be administered in hospital under the supervision of a physician 


 
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experienced in the use of antineoplastic medicinal products. The first infusion should be 
delivered over 60 minutes followed by a 60 minute observation period. The observation 
period for subsequent infusions may be between 30 and 60 minutes if the first infusion is 
well tolerated without infusion-associated AEs. No premedication will be allowed for the first 
dose of pertuzumab. Premedication may be administered for subsequent cycles at the 
discretion of the treating physician.  The rate of pertuzumab infusion should be modified in 
the event of an infusion-related reaction.   
Detailed treatment administration instructions are provided in the MODUL Treatment 
Administration Guide. Guidelines for dosage modification and treatment interruption or 
discontinuation of study maintenance treatment are provided in Section 5.1.3. 
4.3.2.2.5 
Experimental Arm Cohort 4 
Treatment in the experimental arm of Cohort 4 should be administered as follows: 
Cobimetinib:  Cobimetinib is administered orally at a dose of 60 mg for 3 weeks followed by 
a 1 week treatment break (21/7 schedule). Treatment cycle length in this arm is 2 weeks. 
Cobimetinib will be administered daily every day of each odd numbered 2-week treatment 
cycle, and for the first 7 days only of each even numbered 2-week treatment cycle. 
Cobimetinib should be taken at the same time every day with or without food. If a dose is 
missed or vomiting occurs when a dose is taken, dosing should be resumed at the next 
scheduled dose.  
Atezolizumab:  Atezolizumab is administered at a fixed dose of 840 mg via 60-minute IV 
infusion on Day 1 of every 2-week cycle. Atezolizumab must be administered in hospital 
under the supervision of a physician experienced in the use of antineoplastic medicinal 
products. For anaphylaxis precautions, see Table 3 in Appendix 16. For the first infusion, the 
patient’s vital signs (heart rate, respiratory rate, blood pressures, and temperature) should 
be determined within 60 minutes before the infusion, every 15 ± 5 minutes during the 
infusion, and 30 ± 10 minutes after the infusion. For subsequent infusions, vital signs will be 
collected within 60 minutes before the infusion and should be collected during or after the 
infusion if clinically indicated or if symptoms occurred in the prior infusion.  If the initial 
infusion is well tolerated, subsequent infusions will be done over a 30-minute time period. No 
premedication is indicated for the first dose of atezolizumab. Patients who experience an 
infusion-related reaction with Cycle 1 of atezolizumab may receive premedication with 
antihistamines or antipyretics/analgesics (e.g. acetaminophen) for subsequent infusions.  
The rate of atezolizumab infusion should be modified in the event of an infusion-related 
reaction. 
Detailed treatment administration instructions are provided in the MODUL Treatment 
Administration Guide. Guidelines for dosage modification and treatment interruption or 
discontinuation of study maintenance treatment are provided in Section 5.1.3. 


 
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4.3.2.3 
Post-Treatment Follow-up Phase  
All Cohorts 
Second-line treatment during the Post-Treatment Follow-up Phase is at the Investigator’s 
discretion. However, patients who received atezolizumab should not receive other 
immunomodulatory agents for 10 weeks after maintenance treatment discontinuation. 
4.3.3 
Study Treatment Compliance 
A Drug Dispensing Log will be maintained for all study treatments and must be kept current 
with the following information: 
• 
the identification of the subject to whom the study medication was dispensed 
• 
the date(s), and quantity of study medication administered or dispensed to the subject. 
In addition, patients receiving self-administered oral study medications (i.e. capecitabine, 
vemurafenib) will be asked to record each study treatment dose in a daily drug diary which 
will be collected at regular study visits.  
4.3.4 
Investigational Medicinal Product Accountability 
The IMPs used in this study include:  
• 
all non-fluoropyrimidine agents comprising the experimental arms of each maintenance 
treatment cohort (i.e. cetuximab and vemurafenib in Cohort 1; bevacizumab and 
atezolizumab in Cohort 2, trastuzumab and pertuzumab in Cohort 3, cobimetinib and 
atezolizumab in Cohort 4) 
• 
bevacizumab in the Induction Treatment Phase 
• 
bevacizumab in the control arms of each maintenance treatment cohort  
• 
cetuximab, vemurafenib, bevacizumab and atezolizumab administered as optional 
second-line treatments to early progressing BRAFmut patients 
All IMPs required for completion of this study will be provided by the Sponsor where required 
by local health authority regulations. The study site will acknowledge receipt of IMPs and 
confirm the shipment condition and content. Any damaged shipments will be replaced.  
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate documentation. 
The site's method of IMP destruction must be agreed to by the Sponsor.  The site must 
obtain written authorization from the Sponsor before any IMP is destroyed, and IMP 
destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.5 
Continued Access to Roche Investigational Medicinal Products 
The Sponsor will offer continued access to Roche IMPs (atezolizumab, bevacizumab, 
cobimetinib, pertuzumab, trastuzumab, and vemurafenib) free of charge to eligible patients 
in accordance with the Roche Global Policy on Continued Access to Investigational 
Medicinal Product, as outlined below. 


 
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A patient will be eligible to receive Roche IMPs (atezolizumab, bevacizumab, cobimetinib, 
pertuzumab, trastuzumab, or vemurafenib) after completing the study if all of the following 
conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires continued 
Roche IMP treatment for his or her well-being  
• 
There are no appropriate alternative treatments available to the patient 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
A patient will not be eligible to receive Roche IMPs (atezolizumab, bevacizumab, cobimetinib, 
pertuzumab, trastuzumab, or vemurafenib) after completing the study if any of the following 
conditions are met: 
• 
The Roche IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't otherwise 
create a financial hardship for the patient) 
• 
The Sponsor has discontinued development of the IMP or data suggest that the IMP is 
not effective for mCRC 
• 
The Sponsor has reasonable safety concerns regarding the IMP as treatment for mCRC 
• 
Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at:  
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT THERAPY AND FOOD 
Concomitant medication includes any prescription medications or over-the-counter 
preparations used by a patient during the period between the 7 days prior to the date of 
informed consent up until the date of study discontinuation. Only concomitant medications 
used for supportive care, to alleviate symptoms of mCRC, or to treat adverse drug reactions 
should be recorded on the Concomitant Medications eCRF. At subsequent visits, only 
changes to current medications or medications used since the last documentation of 
medications will be recorded.  Concomitant medications for treatment of AEs related to study 
medication will continue to be recorded while the AE is being followed. 
4.4.1 
Permitted Therapy  
During the study, patients on allowed, ongoing therapies such as oral contraceptives, 
hormone-replacement therapy, or thyroid replacement therapy should continue their use. 
Patients should also receive full supportive care as medically warranted (including 
transfusion of blood products and antibiotics) and in accordance with local standards of 
oncology care and the Investigator’s clinical judgement. These treatment details should be 
recorded in the eCRF. 


 
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During the Induction Treatment Phase, local prescribing information for contraindicated 
medications and medications to manage study treatment-related AEs should be followed.  
Patients who require palliative radiotherapy, liver metastases ablation (during Induction 
Treatment Phase only) or initiation of bisphosphonates during therapy should be evaluated 
carefully for possible disease progression before starting these treatments and these 
treatments must be recorded in the eCRF. Irradiated or ablated lesions will thereafter be 
evaluable for progression only. See Section 4.4.2.2.2 regarding radiotherapy use in the 
experimental arm of Cohort 1. 
Patients who experience infusion-associated symptoms from study treatment may be treated 
symptomatically with antipyretics, diphenhydramine and/or other antihistamines according to 
local standard practice. Serious infusion-associated events manifested by dyspnoea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or 
respiratory distress should be managed with supportive therapies as clinically indicated (e.g. 
supplemental oxygen and β2-adrenergic agonists). 
Low-dose oral coumarin-derived anticoagulants, heparin or low-molecular weight heparins 
and/or clopidogrel (≤ 75 mg/day) are permitted during study only if treatment has started 
prior to study entry or during the Induction Treatment Phase and the patient isn’t 
experiencing any unstable cardiovascular symptoms. Prophylactic low-dose aspirin (≤ 
325 mg/day) is a recommended standard of care in patients at high-risk of an arterial 
thromboembolic event and is permitted in this study.  Patients who experience Grades 1-3 
venous thromboembolic events during study treatment are permitted to receive full dose 
anticoagulants and to remain on study medication. INR and aPTT will be assessed at 
baseline for all patients receiving anticoagulant treatment. INR and aPTT should be 
monitored during study treatment in these patients, and those initiating anticoagulant therapy 
during the study according to the local standard of care.  
Experimental Arm of Cohort 1 Only 
Photosensitivity has been reported in patients treated with vemurafenib in clinical trials. The 
majority of cases were mild or moderate in severity. All patients randomised to the 
Experimental Arm Cohort 1 (i.e. receiving vemurafenib) in this study should be advised to 
avoid sun exposure and wear protective clothing and use sun block and lip balm (minimum 
of sun protection factor (SPF) 30, re-applied every 2 to 3 hours) during vemurafenib 
treatment and for at least 5 to 10 days after study drug discontinuation. 
Should 
hypomagnesaemia 
occur 
in 
a 
patient 
receiving cetuximab, 
magnesium 
supplementation should be provided.  No dose adjustment is required, however careful 
monitoring should continue. 
4.4.2 
Therapy Permitted with Caution 
4.4.2.1 
Induction Treatment Phase 
During the Induction Treatment Phase, local prescribing information for contraindicated 
medications and medications to manage study treatment-related AEs should be followed.  


 
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4.4.2.2 
Maintenance Treatment Phase  
4.4.2.2.1 
Control Arms 
All Cohorts 
Anticoagulants 
There is no information on the safety profile of bevacizumab in patients receiving full dose of 
anticoagulants for the treatment of thromboembolism prior to starting bevacizumab treatment, 
as such patients were excluded from clinical trials (Bevacizumab Investigator’s Brochure 
2011). Therefore, caution should be exercised before initiating bevacizumab therapy in these 
patients. Notably, patients who developed venous thrombosis while receiving bevacizumab 
therapy in clinical trials did not appear to have an increased rate of ≥ Grade 3 events when 
treated with full dose of warfarin and bevacizumab concomitantly. 
Altered coagulation parameters and/or bleeding have been reported in patients taking 
capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and 
phenprocoumon. These reactions occurred within several days and up to several months 
after initiating capecitabine therapy and, in a few cases, within 1 month after stopping 
capecitabine. In a clinical pharmacokinetic interaction study, after a single 20 mg dose of 
warfarin, capecitabine treatment increased the area under the curve (AUC) of S-warfarin by 
57% with a 91% increase in INR value. Since metabolism of R-warfarin was not affected, 
these results indicate that capecitabine down-regulates isozyme 2C9, but has no effect on 
isozymes 1A2 and 3A4 (Capecitabine Summary of Product Characteristics 2010). INR and 
aPTT will be assessed at baseline for all patients receiving anticoagulant treatment. INR and 
aPTT should be monitored during study treatment in these patients, and those initiating 
anticoagulant therapy during the study according to the local standard of care. 
Phenytoin 
Increased phenytoin plasma concentrations have been reported during concomitant use of 
capecitabine with phenytoin (Capecitabine Summary of Product Characteristics 2010). 
Formal drug-drug interaction studies with phenytoin have not been conducted. Patients 
taking phenytoin concomitantly with capecitabine should be regularly monitored for 
increased phenytoin plasma concentrations and associated clinical symptoms. 
4.4.2.2.2 
Experimental Arm Cohort 1   
CYP3A4 substrates 
In a Phase I study of CYP450 metabolism conducted in melanoma patients (study NP22676; 
Vemurafenib Investigator’s Brochure 2014), vemurafenib induced CYP3A4 activity by 
approximately two-fold. Thus, medications predominantly metabolised via CYP3A4 may 
have decreased exposure when administered concomitantly with vemurafenib.  
The clinical significance of this observation depends on the therapeutic index of the specific 
CYP3A4 substrate administered concomitantly with vemurafenib.  If CYP3A4 substrates 
must be co-administered with vemurafenib, the Investigator should monitor the signs of 
reduced benefit of CYP3A4 drugs due to potential decrease in their plasma concentration. 


 
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Doses of the concomitant CYP3A4 drug, but not the dose of vemurafenib, may be adjusted 
as necessary to alleviate the impact of drug interaction. 
Appendix 13 includes a non-exhaustive list of CYP3A4 substrates. 
CYP1A2 substrates 
In CYP450 metabolism study NP22676 (Vemurafenib Investigator’s Brochure 2014), 
vemurafenib inhibited CYP1A2 in metastatic melanoma patients by approximately three-fold. 
Similarly, other pharmacokinetic assessments have demonstrated drug-drug interactions 
between vemurafenib and caffeine that are consistent with CYP1A2 inhibition. Thus, 
medications predominantly metabolised via CYP1A2 may have increased exposure when 
administered concomitantly with vemurafenib. 
The clinical significance of these observations depends on the therapeutic index of the 
specific CYP1A2 substrate administered with vemurafenib. The Investigator should assess 
the safety risk associated with a potential increase in plasma concentrations of any 
concomitantly administered CYP1A2 metabolised drug. If there is a concern, doses of the 
concomitant CYP1A2 drug, but not the dose of vemurafenib, may be adjusted as necessary 
to alleviate the impact of drug interaction. 
Appendix 13 includes a non-exhaustive list of CYP1A2 substrates. 
CYP2C9 substrates including warfarin 
Vemurafenib exhibited a strong signal for CYP2C9 inhibition in vitro studies in human 
hepatic microsomes. This in vitro inhibition did not appear to be as significant in the 
NP22676 study of CYP450 metabolism in melanoma patients where the observed increase 
in warfarin exposure was not significant. However, warfarin has a narrow therapeutic index 
and the potential increase in warfarin exposure, in addition to the in vitro evidence of 
CYP2C9 inhibition and the inherent propensity for coagulation disorders in patients with 
malignant disease, indicate the necessity for caution when vemurafenib is co-administered 
with warfarin. The same considerations are true of other medications with narrow therapeutic 
indices that are metabolised primarily by CYP2C9.  
Appendix 13 includes a non-exhaustive list of CYP2C9 substrates. 
Drugs that may cause QTc prolongation or cardiac arrhythmia 
Due to a potential preclinical signal for human Ether-à-go-go Related Gene (hERG) ion 
channel blockade by vemurafenib in vitro, as well as clinical evidence that vemurafenib may 
prolong QTc interval, caution should be taken when vemurafenib is co-administered with 
drugs that cause QTc prolongation or cardiac arrhythmia, or when there is a pre-existing 
cardiac disease or electrocardiogram (ECG) abnormality that may indicate a predisposition 
to cardiac dysrhythmia.  
Investigators should closely monitor patients who are on medications and/or supplements 
that may affect QT interval prolongation.  Such agents include, but are not limited to, 
terfenadine, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, 
risperidone, indapamide, and other drugs with potential to cause disrythmia. Alternative 
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patient prior to their inclusion into this study.  Please refer to QT Drug List by Risk Groups 
(http://www.azcert.org) for additional information and Appendix 12. 
Radiation 
Vemurafenib should be used with caution when given concomitantly or sequentially with 
radiation treatment. Cases of radiation recall and radiation sensitization have been reported 
in patients treated with radiation either prior, during, or subsequent to vemurafenib treatment. 
Refer to the current Vemurafenib Investigator’s Brochure for further details of these events. 
Radiotherapy is permitted only for pain control during the study treatment periods. 
4.4.2.2.3 
Experimental Arm Cohort 2 
Anticoagulants 
There is no information on the safety profile of bevacizumab in patients receiving full dose of 
anticoagulants for the treatment of thromboembolism prior to starting bevacizumab treatment, 
as such patients were excluded from clinical trials (Bevacizumab Investigator’s Brochure 
2011). Therefore, caution should be exercised before initiating bevacizumab therapy in these 
patients. Notably, patients who developed venous thrombosis while receiving bevacizumab 
therapy in clinical trials did not appear to have an increased rate of ≥ Grade 3 events when 
treated with full dose of warfarin and bevacizumab concomitantly. 
Altered coagulation parameters and/or bleeding have been reported in patients taking 
capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and 
phenprocoumon. These reactions occurred within several days and up to several months 
after initiating capecitabine therapy and, in a few cases, within 1 month after stopping 
capecitabine. In a clinical pharmacokinetic interaction study, after a single 20 mg dose of 
warfarin, capecitabine treatment increased the (AUC of S-warfarin by 57% with a 91% 
increase in INR value. Since metabolism of R-warfarin was not affected, these results 
indicate that capecitabine down-regulates isozyme 2C9, but has no effect on isozymes 1A2 
and 3A4 (Capecitabine Summary of Product Characteristics 2010). INR and aPTT will be 
assessed at baseline for all patients receiving anticoagulant treatment. INR and aPTT should 
be monitored during study treatment in these patients, and those initiating anticoagulant 
therapy during the study according to the local standard of care. 
Phenytoin 
Increased phenytoin plasma concentrations have been reported during concomitant use of 
capecitabine with phenytoin (Capecitabine Summary of Product Characteristics 2010). 
Formal drug-drug interaction studies with phenytoin have not been conducted. Patients 
taking phenytoin concomitantly with capecitabine should be regularly monitored for 
increased phenytoin plasma concentrations and associated clinical symptoms. 
Corticosteroids and TNF Inhibitors  
Systemic corticosteroids and TNF-α inhibitors may attenuate the potential beneficial effects 
of atezolizumab, therefore alternatives in Cohort 2 patients randomised to the experimental 
arm should be considered where feasible. If there are no feasible alternatives, systemic 
corticosteroids and TNF-α inhibitors may be administered at the discretion of the treating 
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(i.e. patients with contrast allergy or impaired renal clearance). Treatment with oral or 
parenteral steroids treatment may be warranted in the event of immune-related adverse 
effects, colitis, rash, pruritus or pulmonary toxicity occurring with atezolizumab treatment. 
See the current Atezolizumab Investigator’s Brochure further information.  The use if inhaled 
corticosteroids for chronic obstructive pulmonary disease (≤ 10 mg oral prednisone or 
equivalent), 
mineralocorticoids 
(e.g. 
fludrocortisone) 
for 
patients 
with 
orthostatic 
hypertension, and megastrol as an appetite stimulant are allowed. 
4.4.2.2.4 
Experimental Arm Cohort 3 
Anticoagulants 
Altered coagulation parameters and/or bleeding have been reported in patients taking 
capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and 
phenprocoumon. These reactions occurred within several days and up to several months 
after initiating capecitabine therapy and, in a few cases, within 1 month after stopping 
capecitabine. In a clinical pharmacokinetic interaction study, after a single 20 mg dose of 
warfarin, capecitabine treatment increased the AUC of S-warfarin by 57% with a 91% 
increase in INR value. Since metabolism of R-warfarin was not affected, these results 
indicate that capecitabine down-regulates isozyme 2C9, but has no effect on isozymes 1A2 
and 3A4 (Capecitabine Summary of Product Characteristics 2010). INR and aPTT will be 
assessed at baseline for all patients receiving anticoagulant treatment. INR and aPTT should 
be monitored during study treatment in these patients, and those initiating anticoagulant 
therapy during the study according to the local standard of care. 
Phenytoin 
Increased phenytoin plasma concentrations have been reported during concomitant use of 
capecitabine with phenytoin (Capecitabine Summary of Product Characteristics 2010). 
Formal drug-drug interaction studies with phenytoin have not been conducted. Patients 
taking phenytoin concomitantly with capecitabine should be regularly monitored for 
increased phenytoin plasma concentrations and associated clinical symptoms. 
4.4.2.2.5 
Experimental Arm Cohort 4 
Corticosteroids and TNF Inhibitors  
Systemic corticosteroids and TNF-α inhibitors may attenuate the potential beneficial effects 
of atezolizumab, therefore alternatives in Cohort 4 patients randomised to the experimental 
arm should be considered where feasible. If there are no feasible alternatives, systemic 
corticosteroids and TNF-α inhibitors may be administered at the discretion of the treating 
physician except in the case of patients for whom CT scans with contrast are contraindicated 
(i.e. patients with contrast allergy or impaired renal clearance). Treatment with oral or 
parenteral steroids treatment may be warranted in the event of immune-related adverse 
effects, colitis, rash, pruritus or pulmonary toxicity occurring with atezolizumab treatment. 
See the current Atezolizumab Investigator’s Brochure further information. The use if inhaled 
corticosteroids for chronic obstructive pulmonary disease (≤ 10 mg oral prednisone or 
equivalent), mineralocorticoids (e.g. fludrocortisone) and megastrol as an appetite stimulant 
are allowed. 


 
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4.4.3 
Prohibited Therapy 
The use of any other experimental medications during the study is prohibited. 
4.4.3.1 
Induction Treatment Phase 
No anti-cancer therapy other than the protocol specified induction regimen is permitted 
during the study with the following exceptions: 
• 
local ablation for liver metastases only if there are other non-ablated sites of measurable 
disease that have been followed from baseline tumour assessment (i.e. prior to start of 
induction treatment)   
• 
radiotherapy for pain control  
Patients who require local ablation or radiotherapy for pain control should be assessed for 
evidence of progression first.  
During the Induction Treatment Phase, local prescribing information for contraindicated 
medications and medications to manage study treatment-related AEs should be followed.  
4.4.3.2 
Maintenance Treatment Phase  
4.4.3.2.1 
All Cohorts 
With the exception of radiotherapy for pain control, no anti-cancer treatments other than the 
protocol-specified maintenance regimens are allowed during the Maintenance Treatment 
Phase. Patients who require radiotherapy for pain control should be assessed for evidence 
of progression first. 
Low-dose oral coumarin-derived anticoagulants, heparin or low-molecular weight heparins 
and/or clopidogrel (≤ 75 mg/day) are prohibited during the Maintenance Treatment Phase 
unless treatment started prior to maintenance treatment (i.e. prior to study entry or during the 
Induction Treatment Phase) and the patient is not experiencing any unstable cardiovascular 
symptoms. 
During treatment with 5-FU/LV, capecitabine and/or bevacizumab, local prescribing 
information for contraindicated medications should be followed.  
Allopurinol 
Interactions with allopurinol have been observed for 5-FU with possible decreased efficacy 
of 5-FU. Concomitant use of allopurinol with capecitabine or 5-FU should be avoided. 
Antivirals and Antiprotozoals 
Capecitabine or 5-FU should not be administered together with the antiviral drug sorivudine 
or its chemically-related analogues, such as brivudine. A clinically significant drug-drug 
interaction between sorivudine and 5-FU, resulting from the inhibition of dihydropyrimidine 
dehydrogenase by sorivudine, has been described in the literature. This interaction, which 
leads to increased fluoropyrimidine toxicity, is potentially fatal. 
Laxatives 
The use of drugs with laxative properties should be avoided. 


 
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4.4.3.2.2 
Experimental Arm Cohort 1 
There are no additional therapies specifically prohibited during treatment in the experimental 
arm of Cohort 1. 
4.4.3.2.3 
Experimental Arm Cohort 2 
Patients receiving atezolizumab should not receive any of the following during the study 
Maintenance Phase: 
• 
traditional herbal medicines; herbal therapies intended for the treatment of cancer are 
prohibited. Herbal therapies are not fully studied and their pharmacokinetics, safety 
profiles, and potential drug-drug interactions are generally unknown therefore their 
concomitant use is not recommended. However, herbal therapies not intended for the 
treatment of cancer may allowed at the discretion of the Investigator, provided that there 
are no known interactions with any study treatment.   
• 
RANKL inhibitor (denosumab)  
• 
immunomodulatory agents, including but not limited to interferons or interleukin-2; these 
agents could potentially increase the risk for autoimmune conditions when received in 
combination with atezolizumab treatment 
• 
Steroids for premedication of patients for whom CT scans with contrast are 
contraindicated (i.e. patients with contrast allergy or impaired renal clearance). In such 
patients, non-contrast CT of the chest and non-contrast CT or MRIs of the abdomen and 
pelvis should be performed. 
• 
live, attenuated vaccines (e.g. live attenuated influenza virus [FluMist®]) including for 5 
months after last atezolizumab dose. Inactivated influenza vaccines are allowed. 
Initiation or increased dose of granulocyte colony-stimulating factors (e.g., granulocyte 
colony-stimulating 
factor, 
granulocyte/macrophage 
colony-stimulating 
factor, 
and/or 
pegfilgrastim) is prohibited.  
In addition, patients treated with atezolizumab should not receive other immunomodulatory 
agents for 10 weeks after study treatment discontinuation. 
4.4.3.2.4 
Experimental Arm Cohort 3 
Folinic Acid 
Folinic acid has an effect on the pharmacodynamics of capecitabine, and its toxicity may be 
enhanced by folinic acid and should be avoided. 
Allopurinol 
Interactions with allopurinol have been observed for 5-FU with possible decreased efficacy 
of 5-FU. Concomitant use of allopurinol with capecitabine should be avoided. 
Antivirals and Antiprotozoals 
Capecitabine should not be administered together with the antiviral drug sorivudine or its 
chemically-related analogues, such as brivudine. A clinically significant drug-drug interaction 
between sorivudine and 5-FU, resulting from the inhibition of dihydropyrimidine 


 
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dehydrogenase by sorivudine, has been described in the literature. This interaction, which 
leads to increased fluoropyrimidine toxicity, is potentially fatal. 
4.4.3.2.5 
Experimental Arm Cohort 4  
Patients receiving atezolizumab should not receive any of the following during the study 
Maintenance Phase: 
• 
traditional herbal medicines; herbal therapies intended for the treatment of cancer are 
prohibited. Herbal therapies are not fully studied and their pharmacokinetics, safety 
profiles, and potential drug-drug interactions are generally unknown therefore their 
concomitant use is not recommended. However, herbal therapies not intended for the 
treatment of cancer may allowed at the discretion of the Investigator, provided that there 
are no known interactions with any study treatment.   
• 
RANKL inhibitor (denosumab)  
• 
immunomodulatory agents, including but not limited to interferons or interleukin-2; these 
agents could potentially increase the risk for autoimmune conditions when received in 
combination with atezolizumab treatment 
• 
Steroids for premedication of patients for whom CT scans with contrast are 
contraindicated (i.e. patients with contrast allergy or impaired renal clearance). In such 
patients, non-contrast CT of the chest and non-contrast CT or MRIs of the abdomen and 
pelvis should be performed. 
• 
live, attenuated vaccines (e.g. live attenuated influenza virus [FluMist®]) including for 5 
months after last atezolizumab dose. Inactivated influenza vaccines are allowed.   
Initiation or increased dose of granulocyte colony-stimulating factors (e.g., granulocyte 
colony-stimulating 
factor, 
granulocyte/macrophage 
colony-stimulating 
factor, 
and/or 
pegfilgrastim) is prohibited.  
In addition, patients treated with atezolizumab should not receive other immunomodulatory 
agents for 10 weeks after study treatment discontinuation. 
Patients receiving cobimetinib should not receive any of the following during the 
Maintenance Treatment Phase:  
• 
strong and moderate inhibitors of CYP3A (e.g. clarithromycin, grapefruit juice, 
itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole) should be 
avoided as cobimetinib is a sensitive substrate of CYP3A and exposures will be 
increased in presence of these agents (approximately 7-fold increase in presence of 
itraconazole in healthy subjects).  
• 
strong and moderate CYP3A inducers (e.g. rifampin, phenytoin, carbamazepine, 
phenobarbital, and St. John’s wort) as they increase the metabolism of cobimetinib. 
Strong inducers of CYP3A4 should be avoided, or selection of an alternate concomitant 
medicinal product, with no or minimal potential to induce CYP3A4 should be considered. 
4.4.4 
Food 
Other than the two exceptions listed below, there are no other food-related study 
requirements or recommendations (including no prohibited foods). 


 
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Capecitabine 
All patients receiving capecitabine as part of their maintenance treatment regimen in any 
cohort should take each dose no later than 30 minutes after meals. Administration of 
capecitabine with food decreases the rate of capecitabine absorption. All current safety and 
efficacy data for capecitabine are based upon administration with food.  
Vemurafenib 
All patients receiving vemurafenib as part of their maintenance treatment regimen should 
take each dose in the same manner with respect to meals i.e. all doses with a meal or all 
doses without a meal. 
4.5 
STUDY ASSESSMENTS  
Please see Appendices 1 to 5 for the Schedule of Assessments performed during the study. 
4.5.1 
Induction Treatment Phase 
4.5.1.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before performing 
any study-specific screening tests or evaluations. However, results from routine 
assessments conducted prior to informed consent signature may be used as screening 
assessments as long as they were done within 7 days prior to informed consent signature. 
Informed Consent Forms for enrolled patients and for patients who are not subsequently 
enrolled will be maintained at the study site. 
The “All Cohort” eligibility criteria are evaluated prior to initiating the first cycle of study 
treatment during the Induction Treatment Phase. Patients who do not have archival primary 
tumour tissue available for shipping to the Sponsor’s designated laboratory during the 
Screening Phase should not undergo any screening procedures. Informed consent must be 
obtained prior to shipping the tumour sample to the designated laboratory. The Investigator 
will maintain a screening log to record details of all patients screened and to confirm 
eligibility or record reasons for screening failure, as applicable. 
4.5.1.2 
Demographic Data and Medical History  
Medical history includes clinically significant diseases, surgeries, cancer history (including 
prior cancer therapies and procedures), reproductive status, smoking history, use of alcohol 
and drugs of abuse, and all medications (e.g. prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by the patient within 7 days 
prior to the Screening visit. 
The location of the primary tumour defined as either right colon (up to the splenic flexure) or 
left colon (below the splenic flexure including the rectum) will also be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity (where permitted by 
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4.5.1.3 
Vital Signs 
Vital signs will include measurements of systolic and diastolic blood pressure while the 
patient is in a seated position, and temperature. 
4.5.1.4 
Physical Examinations 
A complete physical examination should include an evaluation of the head, eyes, ears, nose, 
and 
throat, 
and 
the 
cardiovascular, 
dermatological, 
musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems. Abnormalities identified at 
Screening/Baseline will be recorded as baseline conditions. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline, with new or worsened clinically 
significant abnormalities should be recorded as AEs is appropriate. 
4.5.1.5 
ECOG Performance Status 
See Appendix 8. 
4.5.1.6 
Concomitant Medications 
Concomitant medication includes any prescription medications or over-the-counter 
preparations used by a patient between the 7 days prior to the date of informed consent up 
until the study discontinuation.  Only concomitant medications used for supportive care, to 
alleviate symptoms of mCRC, or to treat adverse drug reactions should be recorded on the 
Concomitant Medications eCRF. At subsequent visits, only changes to current medications 
or medications used since the last documentation of medications will be recorded.   
Concomitant medications for treatment of AEs related to study medication will continue to be 
recorded while the AE is being followed. For permitted and prohibited concomitant 
medications, see Section 4.4. 
4.5.1.7 
Laboratory Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory for 
analysis: 
• 
Haematology (haemoglobin, haematocrit, platelet count, red blood cell count, white blood 
cell count, and differential) 
• 
Blood chemistry (ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin, 
blood urea nitrogen or urea, lactate dehydrogenase (LDH), creatinine, glucose, calcium, 
phosphorus, sodium, potassium, chloride and bicarbonate) 
• 
Pregnancy Test (urine or blood pregnancy test; only for women of childbearing potential 
(i.e. not post-menopausal as indicated by < 12 months of non-therapy-induced 
amenorrhea, nor surgically sterile [absence of ovaries and/or uterus]), including those 
who have had a tubal ligation).  If a urine pregnancy test is positive, it must be confirmed 
by a serum pregnancy test 
• 
Coagulation (INR and aPTT; only for patients receiving anticoagulants while on protocol-
specified treatment) 


 
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• 
Urinalysis must be performed by dipstick within 48 hours prior to every cycle.  A 24-hour 
urine collection is needed in the event of proteinuria ≥ ± 2 by dipstick test 
Test results must be available to the Investigator prior to start of each treatment cycle.  
Clinical laboratory results constituting a clinically significant AE should be recorded as such.  
4.5.1.8 
Whole Blood and Plasma Samples 
Whole blood and plasma samples will be collected from all study patients for exploratory 
biomarker analyses. If genomic (inheritable) analysis is not allowed per local regulations, 
only plasma testing (non-inheritable) will be conducted. All samples will be sent to a Central 
Laboratory.  Samples during treatment should be taken within 48 hours before study 
treatment administration on Day 1 of cycle, unless otherwise specified (see Appendix 17 and 
the Laboratory Manual). 
Data arising from clinical genotyping (inheritable) conducted on whole blood samples will be 
subject to the confidentiality standards described in Section 4.5.3.4. 
4.5.1.9 
Tumour and Response Evaluations 
Tumour assessments will include radiology, chest and abdominal computed tomography 
(CT) or magnetic resonance imaging (MRI), and other scans to document all sites of disease. 
Upper abdomen imaging should be included at Baseline. If there is a clinical suspicion of 
CNS metastases during screening, at Baseline or at any time during the study, a CT or MRI 
scan of the brain must be conducted. Subsequent tumour assessments will be done 
according to standard of care at each study centre, with the exception that all patients must 
have a tumour assessment at the end of the Induction Treatment Phase.   
Response will be determined by the Investigator according to RECIST 1.1.  
Patients who discontinue study treatment during the Induction Treatment Phase prior to 
disease progression will also continue to be followed for progressive disease, with disease 
status followed according to local practice until progression or May 31, 2019, whichever 
comes first. 
4.5.1.10 
Archival Tumour Tissue 
For all patients, the assessment of biomarkers for cohort assignment will be based on 
archival tumour FFPET block from the primary tumour obtained at the time of initial 
diagnosis (see Appendix 17).  If the tumour block is not available, ≥ 20 slides cut from the 
primary tumour sample will be accepted as an alternative. After the patient has provided 
informed consent to participate in the study but before they are enrolled, their sample (block 
or slides) must be shipped to the designated laboratory with receipt of shipment confirmed 
by the laboratory.  An associated pathology report must also be sent with all samples.  
The remainder of the block will be returned to the study site. 
Only biomarker results from the designated laboratory which will be available during the 
Induction Treatment Phase will guide treatment allocation for the Maintenance Treatment 
Phase. For testing details please refer to Appendix 17. 


 
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4.5.1.11 
Optional Metastatic Tumour Sample 
Prior to May 2018, a core biopsy of metastatic tumour was collected from all patients who 
provided specific consent to provide this optional sample. Biopsies already done as part of 
routine practice within two months of the 28-day Screening Phase were acceptable. These 
samples will be included in the exploratory biomarker analyses as described in Appendix 17. 
4.5.1.12 
Stool Sample-Supplemental Biomarker Program Participants Only 
Prior to May 2018, stool samples were collected from Supplemental Biomarker Program 
participants for exploratory biomarker analyses as described in Appendix 17. The 
Supplemental Biomarker Program was closed in May 2018. 
4.5.2 
Maintenance Treatment Phase 
4.5.2.1 
Cohort-Specific Informed Consent 
Patients enrolled at centers using two informed consent forms must provide maintenance 
cohort-specific consent after cohort assignment and prior to cohort-specific eligibility 
assessments other than eligibility assessments already conducted as part of routine care. 
At study centers where a single informed consent form is used, informed consent to 
participate in any maintenance cohort will have already been provided at study entry.  
4.5.2.2 
Confirmation of Cohort-Specific Eligibility 
All Cohorts 
The cohort-specific exclusion criteria must be assessed prior to randomization to study 
maintenance treatment but assessment of cohort-specific eligibility can only be completed 
after the biomarker analysis results from the patient’s archival primary tumour tissue from 
initial diagnosis are known.  Biomarker results will be available during the Induction 
Treatment Phase. Patients with an adequate tumour sample but with unknown biomarker 
status due to lack of determinant result (e.g. due to technical issues) may still be included in 
the study depending on the addition of future cohorts. Patients should start the Maintenance 
Treatment Phase within 3 weeks of completing induction treatment (based on the last day of 
the last cycle of induction treatment). 
4.5.2.3 
Screening Log 
The Investigator will update the screening log to record details of all patients who complete 
the Induction Treatment Phase and to confirm continued eligibility according to the cohort-
specific exclusion criteria or record reasons for ineligibility, as applicable. 
4.5.2.4 
Randomization 
All Cohorts 
Each cohort will consist of an experimental treatment arm and a control arm.  Randomization 
will be on a 2:1 (experimental:control) basis to either the experimental or control arm within 
each cohort (see Section 4.2). 


 
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4.5.2.5 
Vital Signs 
All Cohorts 
Vital signs will include measurements of systolic and diastolic blood pressure while the 
patient is in a seated position, and temperature. 
4.5.2.6 
Physical Examinations 
All Cohorts 
Physical examinations will be symptom-directed, and will include changes from Baseline 
(pre-induction).  New or worsened clinically significant abnormalities should be recorded as 
AEs on the Adverse Event eCRF. 
4.5.2.7 
ECOG Performance Status 
All Cohorts 
See Appendix 8. 
4.5.2.8 
Concomitant Medications 
All Cohorts 
Concomitant medication includes any prescription medications or over-the-counter 
preparations used by a patient between the 7 days prior to the date of informed consent up 
until the Study Treatment Discontinuation visit. Only concomitant medications used for 
supportive care, to alleviate symptoms of mCRC, or to treat adverse drug reactions should 
be recorded on the Concomitant Medications eCRF. At subsequent visits, only changes to 
current medications or medications used since the last documentation of medications will be 
recorded. Concomitant medications for treatment of AEs related to study medication will 
continue to be recorded while the AE is being followed. For permitted and prohibited 
concomitant medications, see Section 4.4. 
4.5.2.9 
Laboratory Samples 
All Cohorts 
Samples for the following laboratory tests will be sent to the study site's local laboratory for 
analysis: 
• 
Haematology (haemoglobin, haematocrit, platelet count, red blood cell count, white blood 
cell count, and differential) 
• 
Blood chemistry (ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin, 
blood urea nitrogen or urea, LDH, creatinine, glucose, calcium, phosphorus, sodium, 
potassium, chloride, and bicarbonate).  
• 
Pregnancy Test (urine or blood pregnancy test; only for women of childbearing potential 
(i.e. not post-menopausal as indicated by < 12 months of non-therapy-induced 
amenorrhea, nor surgically sterile [absence of ovaries and/or uterus]), including those 
who have had a tubal ligation). If a urine pregnancy test is positive, it must be confirmed 
by a serum pregnancy test 


 
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• 
Coagulation (INR and aPTT; only for patients receiving anticoagulants while on protocol-
specified treatment) 
• 
Urinalysis must be performed by dipstick within 48 hours prior to every cycle.  A 24-hour 
urine collection is needed in the event of proteinuria ≥ ± 2 by dipstick test 
Test results must be available to the Investigator prior to start of each treatment cycle.  
Laboratory results constituting a clinically significant AE should be recorded as such.  
4.5.2.9.1 
Experimental Treatment Arm Cohort 1 
• 
Magnesium, amylase and lipase (experimental treatment arm only) 
4.5.2.9.2 
Cohort 2 
The following tuberculosis (TB) and virology laboratory tests are required for assessment of 
eligibility for Cohort 2 and will be sent to the study site's local laboratory for analysis: 
• 
TB test 
• 
HIV testing (performed in accordance with national and/or institutional guidelines) 
• 
HBV serology (HBsAg, anti-HBc) 
• 
HCV serology (anti-HCV) 
4.5.2.9.3 
Experimental Treatment Arm Cohort 2 
Thyroid function testing will be conducted at the study site’s local laboratory. 
• 
Thyroid function testing (thyroid-stimulating hormone [TSH], free or total triiodothyronine 
[T3], free or total thyroxine [T4]) (experimental treatment arm only) 
4.5.2.9.4 
Cohort 3 
The following virology laboratory tests are required for assessment of eligibility for Cohort 3 
and will be sent to the study site's local laboratory for analysis: 
• 
HIV testing (performed in accordance with national and/or institutional guidelines) 
• 
HBV serology (HBsAg, anti-HBc) 
• 
HCV serology (anti-HCV) 
4.5.2.9.5 
Cohort 4 
The following TB and virology laboratory tests are required for assessment of eligibility for 
Cohort 4 and will be sent to the study site's local laboratory for analysis: 
• 
TB test 
• 
HIV testing (performed in accordance with national and/or institutional guidelines) 
• 
HBV serology (HBsAg, anti-HBc) 
• 
HCV serology (anti-HCV) 


 
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4.5.2.9.6 
Experimental Treatment Arm Cohort 4 
• 
Thyroid function testing including TSH, free or total T3, and free or total T4 conducted at 
the study site’s local laboratory (experimental treatment arm only) 
• 
Magnesium, amylase, creatine phosphokinase (CPK), lipase (experimental treatment 
arm only) 
4.5.2.10 
Plasma Samples 
All Cohorts 
Plasma samples will be collected from all study patients for exploratory biomarker analyses. 
All samples will be sent to a Central Laboratory.  Samples during treatment should be taken 
within 48 hours before study treatment administration on Day 1 of cycle, unless otherwise 
specified (see Appendix 17 and the Laboratory Manual). 
4.5.2.11 
Tumour and Stool Samples- Supplemental Biomarker Program 
Participants Only 
Prior to May 2018, metastatic tumour samples (if clinically feasible) and stool samples were 
collected from all Supplemental Biomarker Program participants for exploratory analyses as 
described in Appendix 17. Since May 2018, the Supplemental Biomarker Program is closed 
and no further samples are being collected. 
4.5.2.12 
Tumour and Response Evaluations 
All Cohorts 
Up to and including May 31, 2019, tumour assessments will include radiology, chest and 
abdominal CT or MRI, and other scans to document all sites of disease. A CT or MRI scan of 
the brain must be conducted at any time there is a clinical suspicion of CNS metastases. 
Tumour assessments will be conducted every eight weeks with disease status during 
maintenance treatment determined based on comparison with the tumour assessment done 
at the end of induction treatment according to RECIST 1.1 (all treatment arms in all cohorts) 
and mRECIST (experimental arms of Cohorts 2 and 4 only) as described below.  
After May 31, 2019, disease status will not be documented for the study and tumour 
assessments may be conducted according to local practice.  
Patients who discontinue study treatment during the Maintenance Treatment Phase prior to 
disease progression will also continue to be followed for progressive disease, with disease 
assessments conducted every eight weeks until progression, or May 31, 2019, whichever 
comes first. 
4.5.2.12.1 
Cohorts 1 and 3 
For patients in Cohorts 1 and 3 disease status will be assessed by the Investigator according 
to RECIST 1.1 (see Appendix 10) based on comparison with the tumour assessment 
conducted at the end of induction treatment.  
Target lesions identified at start of induction treatment will be considered target lesions for 
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RECIST 1.1 (e.g. < 10 mm by CT scan) during or following induction treatment. As such, all 
target lesions, including those that decrease below the minimum measurable size, will 
continue to be followed through the Maintenance Treatment Phase and until disease 
progression. An increase in size of any target lesion that had previously decreased to below 
measurability (per RECIST 1.1) to the minimum measurable size or greater will be 
considered indicative of disease progression.   
4.5.2.12.2 
Cohorts 2 and 4 
For all patients in Cohorts 2 and 4, disease status will be assessed by the Investigator 
according to RECIST 1.1 (see Appendix 10) based on comparison with the tumour 
assessments done at the end of induction treatment.   
For patients in the experimental arms of Cohorts 2 and 4, disease status will additionally be 
assessed for the purpose of treatment management and exploratory efficacy analysis by the 
Investigator according to mRECIST (see Appendix 11) based on comparison with the tumour 
assessment done at the end of induction treatment. 
Target lesions identified at start of induction treatment will be considered target lesions for 
the entire study period regardless of decreases below sizes considered measurable by 
RECIST 1.1 (e.g. < 10 mm by CT scan) during or following induction treatment. As such, all 
target lesions, including those that decrease below the minimum measurable size, will 
continue to be followed through the Maintenance Treatment Phase and until disease 
progression. An increase in size of any target lesion that had previously decreased to below 
measurability (per RECIST 1.1) to the minimum measurable size or greater will be 
considered indicative of disease progression. 
4.5.2.13 
Additional Assessments for Cohort 1 
All patients will require a 12-lead ECG to determine cohort eligibility. Cohort 1 experimental 
arm patients only will require subsequent ECGs. ECGs will include measurements includes 
heart rate, PR interval, QRS duration, and QT and QTc intervals. 
4.5.2.14 
Additional Assessments for Experimental Arm Cohort 1 
The following assessments only apply to patients randomised to the experimental treatment 
arm of Cohort 1. 
Head and neck assessment for SCC 
To be performed by the Investigator or other qualified physician as part of the evaluation for 
SCC. The head and neck examination will consist of at least a visual inspection of the oral 
mucosa and lymph node palpation. Any suspicious findings will be referred to an appropriate 
specialist. 
Chest CT assessment for SCC 
The routinely scheduled radiographic assessment for tumour burden may be used (if 
available) as the chest CT for the evaluation of non-cutaneous SCC. MRI may be used if a 
CT scan is contra-indicated for the patient.   


 
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Dermatology evaluation 
Evaluation to be performed by a dermatologist, the Investigator or other qualified physician.  
Anal and pelvic exam 
Pelvic examinations for women (with special attention to cervix) and anal examinations for all 
patients will be performed by the Investigator or other qualified physician prior to start of 
experimental therapy and at the Study Treatment Discontinuation Visit for the evaluation of 
SCC. The pelvic examination should include a complete external and internal examination 
(internal examination of uterine cervix may include a Pap smear, which would be a decision 
of the Investigator). The anal examination should include external examination, digital 
anorectal examination and anoscopy or proctoscopy. However, if in opinion of the 
Investigator the presence of “abnormal lesions including SCC” can be excluded by the 
external inspection and the manual examination, this is acceptable. However, if the presence 
of a lesion is suspected, an anoscopy or proctoscopy are recommended.  
12-lead Electrocardiograms 
See Section 4.5.2.13. 
4.5.2.15 
Additional Assessment for Experimental Arm Cohort 2  
Blood oxygen saturation will be measured only in patients randomised to the experimental 
treatment arm of Cohort 2. Blood oxygen saturation will be measured by pulse oximetry. 
4.5.2.16 
Additional Assessment for Cohort 3 
Left ventricular ejection fraction 
All Cohort 3 patients will require evaluation of LVEF to determine cohort eligibility. Cohort 3 
experimental arm patients only will require subsequent LVEF evaluations. 
Evaluation of LVEF must be performed by the same method (ECHO or MUGA) for each 
patient. It is strongly encouraged that the same laboratory and operator perform 
ECHO/MUGA scans for each individual patient. Investigators must be aware of local 
institution regulations regarding repeat MUGA scans. The repeat administration of 
radioisotopes is limited in some nuclear medicine laboratories, and some patients in this 
study could require monitoring on four or more occasions.  
4.5.2.17 
Additional Assessments for Cohort 4 
Left ventricular ejection fraction 
All Cohort 4 patients will require evaluation of LVEF to determine cohort eligibility. Cohort 4 
experimental arm patients only will require subsequent LVEF evaluations. 
Evaluation of LVEF must be performed by the same method (ECHO or MUGA) for each 
patient. It is strongly encouraged that the same laboratory and operator perform 
ECHO/MUGA scans for each individual patient. Investigators must be aware of local 
institution regulations regarding repeat MUGA scans. The repeat administration of 
radioisotopes is limited in some nuclear medicine laboratories, and some patients in this 
study could require monitoring on four or more occasions.   


 
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Ophthalmology Examination 
All Cohort 4 patients will require an ophthalmology exam to determine cohort eligibility. 
Cohort 4 experimental arm patients only will require subsequent ophthalmology exams. 
Ophthalmologic examination must be performed by a qualified ophthalmologist to evaluate 
potential risk factors for, or evidence of, central serous retinopathy or retinal vein occlusion. 
The exam will include visual acuity testing, intraocular pressure measurements by tonometry, 
slit-lamp ophthalmoscopy, indirect ophthalmoscopy and spectral−domain optical coherence 
tomography. Spectral domain optical coherence tomography, if not available, may be 
substituted with time-domain optical coherence tomography. 
4.5.2.18 
Additional Assessment for Experimental Arm Cohort 4 
Blood oxygen saturation will be measured only in patients randomised to the experimental 
treatment arm of Cohort 4. Blood oxygen saturation will be measured by pulse oximetry. 
4.5.3 
Samples for Roche Clinical Repository  
4.5.3.1 
Overview of the Roche Clinical Repository 
The Roche Clinical Repository (RCR) is a centrally administered group of facilities used for 
the long-term storage of human biologic specimens, including body fluids, solid tissues, and 
derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection and analysis of RCR 
specimens will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualised drug therapy for patients 
in the future. 
RCR specimens will be used to achieve the following objectives: 
• 
To further study the association of biomarkers with efficacy, adverse events, or disease 
progression 
• 
To increase knowledge and understanding of disease biology 
• 
To study drug response, including drug effects and the processes of drug absorption and 
disposition 
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
4.5.3.2 
Approval by the Institutional Review Board or Ethics Committee 
Collection and submission of biological samples to the RCR is contingent upon the review 
and approval of the exploratory research and the RCR portion of the Informed Consent Form 
by each site's Institutional Review Board or Ethics Committee (IRB/EC) and, if applicable, an 
appropriate regulatory body.  If a site has not been granted approval for RCR sampling, this 
section of the protocol (Section 4.5.3) will not be applicable at that site. 
4.5.3.3 
Sample Collection 
All blood, tissue and stool samples collected in this study and derivatives thereof will be 
destroyed no later than 5 years after the date of final closure of the clinical study database. 
However, patients who enrol in this study will have the option, at the time of enrolment, to 


 
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consent to RCR sampling to allow the remainder of these samples and derivatives thereof to 
be stored and used for exploratory research. If the patient provides consent for this optional 
exploratory research, these samples will be sent to and stored in the RCR and will be 
destroyed no later than 15 years after the date of final closure of the clinical study database. 
These specimens will be used for research purposes to identify biomarkers that are 
predictive of response to study treatment (in terms of dose, safety, and tolerability) and will 
help to better understand the pathogenesis, course, and outcome of CRC. Specimens for 
non-inherited biomarker discovery will be single coded like any other clinical sample 
(labelled and tracked using the patient’s study identification number (see Section 8.4). 
Genetic specimens will undergo additional processes to maintain confidentiality upon receipt 
by the RCR (see Section 4.5.3.4). 
Residual tumour tissue, whole blood, plasma and stool samples and derivatives thereof 
collected throughout the study for purposes of biomarker assessment (see Section 2.3 and 
Schedule of Assessments listed in Appendices 1 to 5 and Appendix 17) will be collected and 
stored for research purposes, including: 
• 
Tissue slides and blocks. These include core biopsies of metastases (including those 
collected at Baseline from all patients and those collected at completion of induction and 
at disease progression from patients participating in the Supplemental Biomarker 
Program). Archival tumour tissue blocks from the initial diagnosis will be returned to the 
site.  
• 
Whole blood samples collected at Baseline (unless genomic analysis not allowed per 
federal regulations) 
• 
Plasma samples taken during the Induction Treatment Phase, Maintenance Treatment 
Phase, at time of progressive disease and during post-study follow-up 
• 
Stool samples taken at baseline, post-induction (but prior to start of maintenance 
treatment) and at study discontinuation from patients participating in the Supplemental 
Biomarker Program 
The specimens in the RCR will be made available for future biomarker research toward 
further understanding of study treatment, CRC and related diseases, adverse events and 
toward development of potential associated diagnostic assays. The implementation and use 
of the RCR specimens is governed by the RCR policy to ensure the appropriate use of the 
RCR specimens. 
For all samples, dates of consent and specimen collection should be recorded on the 
associated RCR page of the eCRF. For sampling procedures, storage conditions, and 
shipment instructions, see the Laboratory Manual.   
4.5.3.4 
Confidentiality 
The dynamic biomarker specimens will be subject to the confidentiality standards described 
in Section 8.4.  The genetic biomarker specimens will undergo additional processes to 
ensure confidentiality, as described in the section below. 
Given the sensitive nature of genetic data, Roche has implemented additional processes to 
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receipt by the RCR, specimens for genetic research are "double-coded" by replacing the 
patient identification number with a new independent number.  Data generated from the use 
of these specimens and all clinical data transferred from the clinical database and 
considered relevant are also labelled with this same independent number.  A "linking key" 
between the patient identification number and this new independent number is stored in a 
secure database system. Access to the linking key is restricted to authorised individuals and 
is monitored by audit trail. Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee and 
Roche's Legal Department, as applicable. 
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, representatives, 
and collaborators, as appropriate. 
Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient (or 
where applicable, their legally authorised representative) unless permitted or required by law. 
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study Investigators unless a request for research use is granted. The aggregate 
results of any research conducted using RCR specimens will be available in accordance with 
the effective Roche policy on study data publication. 
Any inventions and resulting patents, improvements, and/or know-how originating from the 
use of the RCR data will become and remain the exclusive and unburdened property of 
Roche, except where agreed otherwise. 
4.5.3.5 
Consent to Participate in the Roche Clinical Repository 
The Informed Consent Form administered at study enrolment will contain a separate section 
that addresses participation in the RCR.  The Investigator or authorised designee will explain 
to each patient the objectives, methods, and potential hazards of participation in the RCR.  
Patients will be told that they are free to refuse to participate and may withdraw their 
specimens at any time and for any reason during the storage period. A separate, specific 
signature will be required to document a patient's agreement to participate in the optional 
RCR research.  Patients who decline to participate will not provide a separate signature. 
The Investigator should document whether or not the patient has given consent to participate 
by completing the RCR Research Sample Informed Consent eCRF. 
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research. 
4.5.3.6 
Withdrawal from the Roche Clinical Repository 
Patients who give consent to RCR research have the right to withdraw their specimens from 
the RCR at any time for any reason. However, if RCR samples have been tested prior to 
withdrawal of consent, results from those tests will remain as part of the overall research 


 
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data. If a patient wishes to withdraw consent to the testing of his or her specimens, the 
Investigator must inform the Medical Monitor in writing of the patient's wishes through use of 
the RCR Subject Withdrawal Form and, if the trial is ongoing, must enter the date of 
withdrawal on the RCR Research Sample Withdrawal of Informed Consent eCRF. If a 
patient wishes to withdraw consent to the testing of his or her RCR samples after closure of 
the study site, the investigator must inform the Sponsor by emailing the study number and 
patient number to the following email address: 
global_rcr-withdrawal@roche.com. 
A patient's withdrawal from Study MO29112 does not, by itself, constitute withdrawal of 
specimens from the RCR. Likewise, a patient's withdrawal from the RCR does not constitute 
withdrawal from Study MO29112. 
4.5.3.7 
Monitoring and Oversight 
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information management 
system, to ensure compliance with data confidentiality as well as adherence to authorised 
use of specimens as specified in this protocol and in the Informed Consent Form. Roche 
monitors and auditors will have direct access to appropriate parts of records relating to 
patient participation in the RCR for the purposes of verifying the data provided to Roche. The 
site will permit monitoring, audits, IRB/EC review, and health authority inspections by 
providing direct access to source data and documents related to the RCR samples. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  In 
addition, the Investigator has the right to withdraw a patient from the study at any time. 
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the Investigator or Sponsor determines may jeopardise the 
patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
Every effort should be made to obtain information on patients who withdraw from the study. 
The primary reason for withdrawal from the study should be documented on the appropriate 
eCRF. However, patients will not be followed for any reason after consent has been 
withdrawn. Patients who withdraw from the study will not be replaced. 
4.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
• 
Pregnancy 
• 
Progressive disease per RECIST 1.1 with the following exception: 


 
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Patients randomised to the experimental arms of Cohort 2 and 4 (i.e. patients who are 
receiving atezolizumab), may continue maintenance treatment after the first tumour 
assessment showing progression according to RECIST 1.1 if they meet the following 
criteria as assessed by the Investigator: 
̶ 
Evidence of clinical benefit  
̶ 
Absence of symptoms and signs (including worsening of laboratory values, e.g. new 
or worsening hypercalcaemia) indicating unequivocal progression of disease 
̶ 
No decline in ECOG performance status that can be attributed to disease 
progression 
̶ 
Absence of tumour progression at critical anatomical sites (e.g. leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions 
Treatment will be discontinued if the next follow-up tumour assessment continues to 
demonstrate progression per RECIST 1.1 (as compared to the assessment at the end of 
induction treatment). If the next tumour assessment does not show progression per 
RECIST 1.1, maintenance treatment may be continued until such time as the treatment 
continuation criteria above are no longer met and/or two sequential tumour assessments 
show progression per RECIST 1.1 
• 
Any medical condition that the Investigator or Sponsor determines may jeopardise the 
patient’s safety if he or she continues on study treatment 
• 
Hold in administration of any drug in any study treatment regimen for > 21 days without 
Medical Monitor approval to re-initiate treatment and continue in the study 
• 
Initiation of treatment with any other anti-cancer medication 
• 
Are not eligible for any maintenance treatment cohort 
• 
Found to be resectable at the end of the Induction Treatment Phase 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. Patients who discontinue study treatment prematurely will not be 
replaced. 
4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time. Reasons for terminating the 
study may include, but are not limited to, the following: 
• 
The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients. 
• 
Patient enrolment is unsatisfactory. 
The Sponsor will notify the Investigator if the Sponsor decides to discontinue the study. 
The Sponsor has the right to close a site at any time. Reasons for closing a site may include, 
but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 


 
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• 
Non-compliance with the International Conference on Harmonisation (ICH) guideline for 
Good Clinical Practice 
• 
No study activity (i.e., all patients have completed and all obligations have been fulfilled) 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Study medications, or the combination of study medications may not be approved and may 
be currently in clinical development. Thus, the entire safety profile of all study medications 
(or their combinations) are not known at this time. The safety plan for this study is designed 
to ensure patient safety and will include specific eligibility criteria and monitoring 
assessments as detailed below. 
Patients will be assessed by prior medical history, vital signs, weight, physical examination, 
AEs and concomitant medications. A complete medical history (including prior treatments for 
cancer) will be documented at Screening. A complete physical exam will be performed at 
Screening, with symptom-directed physical exams performed throughout study treatment. 
Changes in concomitant medication will be recorded at each study visit.  Concomitant 
medications for treatment of AEs related to study medication will continue to be recorded 
while the AE is being followed. 
Additional safety-related tests and procedures will be performed as required for patients who 
are receiving specific study medications during the Maintenance Treatment Phase (see 
Schedule of Assessments, Appendices 2 to 5). When necessary, preplanned safety run-ins 
will be conducted for experimental combinations (e.g. as required for initial patients treated 
with the experimental combination of ‘5-FU/LV + cetuximab + vemurafenib’). Safety data 
from safety run-in patients will be reviewed by the iDMC to ensure acceptable safety prior to 
continuing treatment in these patients and prior to exposing further patients to the regimen. 
Safety run-ins will be indicated in the study protocol. Further details of the safety run-in 
procedures are provided in the iDMC Charter.  
AEs will be monitored and documented continuously during the study and SAEs will also be 
documented and reported (see Section 5.4.2). All AEs will be graded according to NCI 
CTCAE version 4.0.  
Patients who discontinue study treatment prior to start of maintenance treatment or were 
treated in the control arm of any maintenance cohort or the experimental arm of Cohort 1 will 
be followed for new AEs for 28 days following the discontinuation of study treatment. 
Patients who discontinue maintenance treatment in the experimental arm of Cohorts 2, 3 or 
4 will continue be followed for new AEs for 90 days following the discontinuation of study 
treatment. At the time of treatment discontinuation, any ongoing AE/SAE will be followed 
until the event resolves, the Investigator assesses the event as stable, or the patient is lost 
to follow-up, dies or withdraws consent. Death related to disease progression is not 
considered to be an SAE. The Sponsor should be notified if the Investigator becomes aware 
of any SAE or AEs of special interest occurring after the end of the adverse event reporting 
period if the event is believed to be related to prior study treatment. 


 
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5.1.1 
Management of Specific Adverse Events 
For each IMP administered in the study, guidelines for management of AEs including dose 
reductions and treatment interruptions are described in the applicable, current Investigator’s 
Brochures and SmPCs and this protocol. Please refer to Section 5.1.2 and Section 5.1.3 
where the appropriate resources for AE management guidelines for induction treatment and 
each maintenance treatment cohort are indicated. It is important to note that any revisions or 
additions to AE management and dosing recommendations introduced with an Investigator’s 
Brochure update are indicated in the summary of changes at the front of the document. 
For each non-IMP administered in the study, guidelines for the management of specific AEs 
including dose reductions and treatment interruptions are described in the Summary of 
Product Characteristics. 
5.1.2 
Induction Treatment Phase 
Dose reductions and treatment interruptions of the selected FOLFOX regimen should be 
based on standard clinical practice and the Investigator’s discretion. Please refer to the 
Summary of Product Characteristics for each FOLFOX treatment component. 
If any drug of any study treatment regimen is delayed > 21 days, approval must be obtained 
from the Medical Monitor prior to re-initiation of treatment. Patients not approved to continue 
treatment in the study will be discontinued from study treatment and enter the Post-
Treatment Follow-up Phase. 
Bevacizumab 
No dose reduction of bevacizumab is foreseen for an individual patient. Skipped doses or 
termination of treatment will be based on the observed toxicities specified in the current 
Investigator’s Brochure for bevacizumab. No dose adjustments are allowed except for body 
weight changes of more than 10%. Missed doses will not be made up for.   
5.1.3 
Maintenance Treatment Phase 
As described in this section, dose modifications or delays may be allowed for certain agents 
in the maintenance treatment regimens.   
If any drug of any study treatment regimen is delayed > 21 days, approval must be obtained 
from the Medical Monitor prior to re-initiation of treatment. Patients not approved to continue 
treatment in the study will be discontinued from study treatment and enter the Post-
Treatment Follow-up Phase. 
5.1.3.1 
Control Arms 
Fluoropyrimidine (5-FU/LV or capecitabine) 
Dose reductions and treatment interruptions of the fluoropyrimidine should be based on 
standard clinical practice and the Investigator’s discretion. Please refer to the Summary of 
Product Characteristics. 
Bevacizumab 
Refer to Induction Treatment Section 5.1.2 above. 


 
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5.1.3.2 
Experimental Arm Cohort 1  
5-FU/LV 
Dose reductions and treatment interruptions of 5-FU/LV should be based on standard clinical 
practice and the Investigator’s discretion. Please refer to the 5-FU/LV Summary of Product 
Characteristics (SmPC). 
Cetuximab 
Cetuximab dose modifications or interruptions may be required due to toxicity. Please refer 
to the Erbitux SmPC (see Appendix 14). 
Vemurafenib 
Vemurafenib dose modifications or interruptions may be required due to toxicity. Please refer 
to the current Vemurafenib Investigator’s Brochure.   
5.1.3.3 
Experimental Arm Cohort 2 
Fluoropyrimidine (5-FU/LV or capecitabine) 
Dose reductions and treatment interruptions of the fluoropyrimidine should be based on 
standard clinical practice and the Investigator’s discretion. Please refer to the capecitabine 
or 5-FU/LV Summary of Product Characteristics (SmPC) as applicable. 
Bevacizumab 
Refer to Induction Treatment Section 5.1.2 above. 
Atezolizumab 
There will be no dose reductions of atezolizumab however atezolizumab may be delayed for 
toxicity as described in the current Atezolizumab Investigator’s Brochure.  
Atezolizumab has been associated with risks such as the following:  infusion-related 
reactions and immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, 
hyperthyroidism, 
adrenal 
insufficiency, 
hypophysitis, 
Guillain-Barré 
syndrome, myasthenic syndrome or myasthenia gravis, meningoencephalitis, myocarditis, 
nephritis, and myositis. Refer to the Investigator’s Brochure for further details of risks 
associated with atezolizumab and the management of these events. 
If a patient must be tapered off steroids used to treat AEs, atezolizumab may be withheld for 
additional time from the last dose until steroids are discontinued or reduced to prednisone 
dose (or dose equivalent) ≤ 10 mg/day. Patients must be discontinued from study treatment 
for delays > 21 days unless approval to continue is obtained from the Medical Monitor.  
Immune-mediated reactions with atezolizumab may involve any organ system and may lead 
to hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). 
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of the 
following eight criteria are met: 
• 
Fever ≥ 38.5°C 
• 
Splenomegaly 


 
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• 
Peripheral blood cytopenia consisting of at least two of the following: 
̶ 
Haemoglobin < 90 g/L (9 g/dL) (< 100 g/L [10 g/dL] for infants < 4 weeks old) 
̶ 
Platelet count < 100 x 109/L (100,000/µL) 
̶ 
ANC < 1.0 x 109/L (1000/µL) 
• 
Fasting triglycerides > 2.992 mmol/L (265 mg/dL) and/or fibrinogen < 1.5 g/L (150 
mg/dL) 
• 
Haemophagocytosis in bone marrow, spleen, lymph node, or liver 
• 
Low or absent natural killer cell activity 
• 
Ferritin > 500 mg/L (500 ng/mL) 
• 
Soluble interleukin-2 (IL-2) receptor (soluble CD25) elevated ≥ 2 standard deviations 
above age-adjusted laboratory-specific norms 
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016). A febrile patient should be 
classified as having MAS if the following criteria are met: 
• 
Ferritin > 684 mg/L (684 ng/mL) 
• 
At least two of the following: 
̶ 
Platelet count ≤ 181 x 109/L (181,000/µL) 
̶ 
AST ≥ 48 U/L 
̶ 
Triglycerides > 1.761 mmol/L (156 mg/dL) 
̶ 
Fibrinogen ≤ 3.6 g/L (360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the following guidelines: 
• 
Permanently discontinue atezolizumab and contact Medical Monitor. 
• 
Consider patient referral to haematologist. 
• 
Initiate supportive care, including intensive care monitoring if indicated per institutional 
guidelines. 
• 
Consider initiation of IV corticosteroids and/or an immunosuppressive agent. 
• 
If event does not improve within 48 hours after initiating corticosteroids, consider adding 
an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
5.1.3.4 
Experimental Arm Cohort 3  
Capecitabine 
Capecitabine dose reductions and treatment interruptions should be based on standard 
clinical practice and the Investigator’s discretion. Capecitabine dose calculations by body 
surface area with corresponding tablet counts are provided in Appendix 7. Please refer to 
the current capecitabine SmPC as applicable. 


 
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Trastuzumab and Pertuzumab 
Trastuzumab and pertuzumab dose reductions are not allowed. The dose of trastuzumab 
should be recalculated if the patient’s body weight has changed by more than 10% from start 
of trastuzumab treatment.  
If a delay in either trastuzumab or pertuzumab is required for toxicity, both drugs should be 
held.  
If a trastuzumab dose is delayed by > 7 days, a re-loading dose (8 mg/kg) should be given. If 
re-loading is required for a given cycle the three study drugs should be given on the same 
schedule as Cycle 1 (i.e. pertuzumab on Day 1 and trastuzumab and capecitabine on Day 2). 
If a pertuzumab dose is delayed for < 21 days, re-loading is not required (the next dose 
should be 420 mg). If a pertuzumab dose is delayed for ≥ 21 days, a re-loading dose (840 
mg) should be given. If re-loading is required for a given cycle, the three study drugs should 
be given on the same schedule as Cycle 1 (i.e. pertuzumab on Day 1 and trastuzumab and 
capecitabine on Day 2). Note: If treatment is delayed for > 21 days, approval must be 
obtained from the Medical Monitor before study treatment can be re-initiated.  
For dose delays of trastuzumab and pertuzumab, please refer to the current trastuzumab 
and pertuzumab Investigator’s Brochures. Appropriate management of safety events other 
than left ventricular dysfunction (see below) associated with combined trastuzumab and 
pertuzumab treatment is described in the current Pertuzumab Investigator’s Brochure.   
Guidelines for the management and reporting of cardiac toxicity in patients treated with 
trastuzumab and pertuzumab are provided in Appendix 15.  
5.1.3.5 
Experimental Arm Cohort 4 
Cobimetinib and Atezolizumab 
Cobimetinib dose modifications or interruptions may be required due to toxicity. There will be 
no dose reductions of atezolizumab, however, atezolizumab may delayed for toxicity. With 
the exception of guidelines for infusion-related reactions to atezolizumab, guidelines for 
management of toxicities and specific AEs in patients treated with cobimetinib and 
atezolizumab are provided in Appendix 16.  
Guidelines for infusion-related reactions to atezolizumab are provided in the current 
Atezolizumab Investigator’s Brochure. Anaphylaxis precautions are provided in Appendix 16. 
Immune-mediated reactions with atezolizumab may involve any organ system and may lead 
to HLH and MAS. Refer to Section 5.1.3.3 for initial evaluation and management of possible 
cases of HLH or MAS. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording AEs, including serious adverse 
events (SAEs) and AEs of special interest; measurement of protocol-specified safety 
laboratory assessments; measurement of protocol-specified vital signs; and other protocol-
specified tests that are deemed critical to the safety evaluation of the study. 


 
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Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an AE is any untoward medical 
occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution.  An AE can therefore be any of the following: 
• 
Any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition), except as described in Section 5.3.5.10 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
AEs that are related to a protocol-mandated intervention, including those that occur prior 
to assignment of study treatment (e.g., screening invasive procedures such as biopsies) 
5.2.2 
Serious Adverse Events (Immediately Reportable to the Sponsor) 
An SAE is any AE that meets any of the following criteria: 
• 
Fatal (i.e., the AE actually causes or leads to death). 
• 
Life threatening (i.e., the AE, in the view of the Investigator, places the patient at 
immediate risk of death). 
• 
This does not include any AE that had it occurred in a more severe form or was allowed 
to continue might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11) 
• 
Results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the patient’s ability to conduct normal life functions) 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study 
drug 
• 
Significant medical event in the Investigator's judgment (e.g., may jeopardise the patient 
or may require medical/surgical intervention to prevent one of the outcomes listed above) 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of an 
AE (e.g., rated according to NCI CTCAE criteria; see Section 5.3.3); the event itself may be 
of relatively minor medical significance (such as severe headache without any further 
findings). 
Severity and seriousness need to be independently assessed for each AE recorded on the 
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SAEs are required to be reported by the Investigator to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2 for reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to the 
Sponsor) 
Adverse events of special interest are required to be reported by the Investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).   
These events may or may not be SAEs and they may or may not be considered related to 
study medication. Regardless of relationship or severity, these events will be recorded if they 
start from the time of the first dose of study treatment and will be followed until resolution.  
After the end of the adverse event reporting period, the Sponsor should be notified if the 
Investigator becomes aware of any AEs of special interest that are believed to be related to 
prior study treatment. 
5.2.3.1 
Adverse Events of Special Interest in Both Induction and 
Maintenance Treatment Phases 
AEs of special interest for all patients in both the Induction and Maintenance Treatment 
Phases of the study include the following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s law 
(see Section 5.3.5.7) 
• 
Suspected transmission of an infectious agent by a study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent.  A transmission of an infectious agent may be suspected from clinical symptoms 
or laboratory findings that indicate an infection in a patient exposed to a medicinal 
product.  This term applies only when a contamination of the study drug is suspected. 
5.2.3.2 
Adverse Events of Special Interest in the Induction Treatment 
Phase 
There are no additional AEs of special interest for induction treatment. 
5.2.3.3 
Adverse Events of Special Interest in the Maintenance Treatment 
Phase 
5.2.3.3.1 
Control Arms 
Bevacizumab 
For patients receiving bevacizumab, the following are considered additional AEs of special 
interest: 
• 
Hypertension ≥ Grade 3 
• 
Proteinuria ≥ Grade 3 


 
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• 
GI perforation, abscesses and fistulae (any grade) 
• 
Wound healing complications ≥ Grade 3 
• 
Haemorrhage ≥ Grade 3 (any grade CNS bleeding; ≥ Grade 2 haemoptysis) 
• 
Arterial thromboembolic events (any grade) 
• 
Venous thromboembolic events ≥ Grade 3 
• 
PRES (or RPLS; any grade) 
• 
CHF ≥ Grade 3 
• 
Non-GI fistula or abscess ≥ Grade 2 
5.2.3.3.2 
Experimental Arm Cohort 1 
Cetuximab 
No additional AEs of special interest. 
Vemurafenib 
For patients receiving vemurafenib, the following are considered additional AEs of special 
interest: 
• 
Cutaneous SCC 
• 
Keratoacanthoma (KA) 
• 
GI polyps 
• 
Photosensitivity 
• 
Adverse events potentially associated with prolongation of cardiac repolarization or 
arrhythmia ("cardiac events") 
• 
Potentiation of radiation toxicity 
Any lesion at baseline or during treatment clinically suspected of representing cutaneous, 
basal cell carcinoma, actinic keratosis, KA or other skin conditions identified should be 
treated as per local standard of care. 
If more than one SCC lesion occurs in more than one location on the skin, and the multiple 
lesions are detected during the same observation period (i.e. clinic visit), then these SCC 
lesions should be reported together as one AE.  Locations of each lesion can be listed in the 
event term and narrative. 
If more than one SCC lesion occurs in more than one location on the skin and the lesions 
are detected during separate observation periods (i.e., separate clinic visits), then these 
SCC lesions should be reported as separate AEs. 
Cases in which patients rapidly develop multiple lesions within a limited time-frame (e.g., 5–
10 lesions over a 2-week period) will be handled on a case by case basis in terms of 
reporting.  Please contact the Medical Monitor when these cases occur, for additional 
discussion. 


 
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Skin biopsies should be performed by a dermatologist, as necessary, with histopathologic 
interpretation of suspected lesions. Biopsy-proven non-melanoma skin cancers should be 
excised.   
When completing the AE and SAE forms in the eCRF, the following guidelines should be 
followed: 
• 
Cutaneous SCC events should be reported using the event term of “Squamous Cell 
Carcinoma of the skin” or “Cutaneous Squamous Cell Carcinoma”. The event should be 
designated as Grade 3 severity. 
• 
The term “Squamous Cell Carcinoma” should only be used if there is a confirmed non-
cutaneous squamous cell carcinoma. 
• 
If SCC is confirmed to be cutaneous the term “Cutaneous Squamous Cell Carcinoma” or 
“Squamous Cell Carcinoma of the skin” should be used.  Do not report the event term of 
“treatment-related secondary malignancy” or “Squamous Cell Carcinoma”. 
• 
If cSCC or SCC is suspected, an SAE with the event term “suspected cutaneous SCC” 
or “suspected non-cutaneous of <insert organ site>”and onset date of admission has to 
be submitted to the Sponsor within 24 hours.  
For all SCC cases, the tick box medically significant must be ticked. The onset date for an 
SCC SAE is always the date of when the suspicion of an SCC occurred regardless of when 
and if the suspected diagnosis was confirmed. 
5.2.3.3.3 
Experimental Arm Cohort 2  
Bevacizumab 
See Section 5.2.3.3.1. 
Atezolizumab 
For patients receiving atezolizumab in Cohort 2, the following are considered additional AEs 
of special interest: 
• 
Confirmed treatment-emergent immune related conditions including the following: 
̶ 
Pneumonitis 
̶ 
Colitis 
̶ 
Endocrinopathies: 
diabetes 
mellitus, 
pancreatitis, 
adrenal 
insufficiency, 
hypothyroidism or hyperthyroidism 
̶ 
Vasculitis 
̶ 
Hepatitis 
̶ 
Transaminitis: AST/ALT > 10 x ULN 
̶ 
Systemic lupus erythematosus 
̶ 
Neurologic: Guillain-Barré syndrome, myasthenia gravis, meningoencephalitis 
̶ 
Nephritis 
• 
Events suggestive of hypersensitivity, cytokine release syndrome, influenza like illness, 
systemic inflammatory response system (SIRS), systemic immune activation (SIA) or 
infusion reaction syndromes 


 
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5.2.3.3.4 
Experimental Arm Cohort 3 
For patients in the experimental arm of Cohort 3, the following are considered additional AEs 
of special interest: 
• 
Asymptomatic decline in LVEF requiring treatment or leading to discontinuation of 
trastuzumab or pertuzumab 
5.2.3.3.5 
Experimental Arm Cohort 4 
For patients in the experimental arm of Cohort 4, the following are considered additional AEs 
of special interest: 
• 
Pneumonitis 
• 
Colitis 
• 
Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency, hypothyroidism 
or hyperthyroidism 
• 
Systemic lupus erythematosus 
• 
Neurologic: Guillain-Barré syndrome, myasthenia gravis, meningoencephalitis 
• 
Nephritis 
• 
Events suggestive of hypersensitivity, cytokine release, influenza-like illness, systemic 
inflammatory response system, or infusion-reaction syndromes 
• 
Retinal vein occlusion 
• 
Serous retinopathy, including events of retinal detachment, retinal pigment epithelium 
detachment, neurosensory retinal detachment, and central serous chorioretinopathy 
• 
Rhabdomyolysis or Grade ≥ 3 CPK elevation 
• 
Grade ≥ 3 hemorrhage or any grade cerebral hemorrhage 
• 
Grade ≥ 3 rash 
• 
Grade ≥ 3 diarrhea 
• 
Significant liver toxicity 
• 
AST and/or ALT > 10 × ULN 
• 
Symptomatic heart failure or Grade ≥ 3 LVEF reduction 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The Investigator is responsible for ensuring that all AEs (see Section 5.2.1 for definition) are 
recorded on the Adverse Event eCRF and reported to the Sponsor in accordance with 
instructions provided in this section and in Sections 5.4−5.6. 
For each AE recorded on the Adverse Event eCRF, the Investigator will make an 
assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   


 
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5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on AEs at each patient contact.  All AEs, whether reported 
by the patient or noted by study personnel, will be recorded in the patient’s medical record 
and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
SAEs caused by a protocol-mandated intervention (e.g., invasive procedures such as 
biopsies, discontinuation of medications) should be reported (see Section 5.4.2 for 
instructions for reporting SAEs). 
After initiation of study drug, all AEs, regardless of relationship to study drug, will be 
documented at every cycle during treatment.  All AEs, regardless of relationship to study 
drug, will continue to be reported for all patients who discontinue study treatment prior to the 
start of maintenance treatment, all patients treated in the control arm of any maintenance 
cohort and all patients treated in the experimental arm of Cohort 1 until 28 days after their 
last dose of study drug.  Patients treated in the experimental arm of Cohorts 2, 3 or 4 will 
continue to be followed until 90 days after their last dose of study drug.  
After the 28 or 90 day post-treatment period as described above, the Investigator is not 
required to actively monitor patients for AEs; however, the Sponsor should be notified if the 
Investigator becomes aware of any death, other SAE or AEs of special interest if the event is 
believed to be related to prior study treatment (see Section 5.6).  
Note that patients in the experimental arm of Cohort 1 must complete assessments for SCC 
and cuSCC six months after their last study treatment (see Appendix 2) and all female 
patients of childbearing potential in the experimental arm of Cohort 3 must have a final 
pregnancy test 7 months after their last trastuzumab/pertuzumab dose (see Appendix 4). 
The study will not be considered to have ended until all patients in the experimental arm of 
Cohort 1 and all female patients of childbearing potential in the experimental arm of Cohort 3 
have completed these follow-up safety assessments. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all patient evaluation timepoints.  Examples of non-directive questions include 
the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
5.3.3 
Assessment of Severity of Adverse Events 
The AE severity grading scale for the NCI CTCAE (v4.0) will be used for assessing AE 
severity.  Table 3 will be used for assessing severity for AEs that are not specifically listed in 
the NCI CTCAE. 




 
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Table 4: 
Causal Attribution Guidance 
Is the AE suspected to be caused by the study drug on the basis of facts, evidence, science-based 
rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the AE and administration of 
the study drug, and the AE cannot be readily explained by the patient's clinical state, 
intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of 
response to the study drug; and/or the AE abates or resolves upon discontinuation of the 
study drug or dose reduction and, if applicable, reappears upon re-challenge. 
NO 
An AE will be considered related, unless it fulfils the criteria specified below. 
Evidence exists that the AE has an etiology other than the study drug (e.g., pre-existing 
medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or 
the AE has no plausible temporal relationship to administration of the study drug (e.g., cancer 
diagnosed 2 days after first dose of study drug). 
For patients receiving combination therapy, causality will be assessed individually for each 
protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording AEs on the 
Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one AE term should be recorded in the event field on the Adverse Event eCRF. 
5.3.5.1 
Infusion-Related Reactions 
AEs that occur during or within 24 hours after study drug administration and are judged to be 
related to study drug infusion should be captured as a diagnosis (e.g., "infusion-related 
reaction" or "anaphylactic reaction") on the Adverse Event eCRF.  If possible, avoid 
ambiguous terms such as "systemic reaction."  Associated signs and symptoms should be 
recorded on the dedicated Infusion-Related Reaction eCRF.  If a patient experiences both a 
local and systemic reaction to the same dose of study drug, each reaction should be 
recorded separately on the Adverse Event eCRF, with signs and symptoms also recorded 
separately on the dedicated Infusion-Related Reaction eCRF. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
Reactions Temporally Associated with Infusions 
AEs that occur during or within 24 hours after study drug infusion should be captured as 
individual signs and symptoms unless assessed as secondary to an allergic reaction or 
infusion reaction. 
Other Adverse Events 
For AEs other than infusion-related or injection reactions (see Section 5.3.5.1), a diagnosis 
(if known) should be recorded on the Adverse Event eCRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases).  However, if a constellation of signs and/or symptoms cannot be 
medically characterised as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded on the Adverse Event eCRF.  If a diagnosis is 


 
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subsequently established, all previously reported AEs based on signs and symptoms should 
be nullified and replaced by one AE report based on the single diagnosis, with a starting date 
that corresponds to the starting date of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, AEs that are secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or serious 
secondary events.  A medically significant secondary AE that is separated in time from the 
initiating event should be recorded as an independent event on the Adverse Event eCRF.  
For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, only 
vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately on 
the eCRF. 
• 
If a severe gastrointestinal haemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be reported 
separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported separately 
on the eCRF. 
All AEs should be recorded separately on the Adverse Event eCRF if it is unclear as to 
whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
 A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation time points.  Such events should only be recorded once on the Adverse 
Event eCRF.  The initial severity (intensity or grade) of the event will be recorded at the time 
the event is first reported.  If a persistent adverse event becomes more severe, the most 
extreme severity should also be recorded on the Adverse Event eCRF.  If the event 
becomes serious, it should be reported to the Sponsor immediately (i.e., no more than 24 
hours after learning that the event became serious; see Section 5.4.2 for reporting 
instructions).  The Adverse Event eCRF should be updated by changing the event from 
"non-serious" to "serious," providing the date that the event became serious, and completing 
all data fields related to serious adverse events. A recurrent AE is one that resolves between 
patient evaluation time points and subsequently recurs.  Each recurrence of an AE should be 
recorded as a separate event on the Adverse Event eCRF. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an AE.  A laboratory test result must be 
reported as an AE if it meets any of the following criteria: 
• 
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• 
Results in a change in study treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) or a 
change in concomitant therapy 
• 
Clinically significant in the Investigator’s judgment  
It is the Investigator’s responsibility to review all laboratory findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should 
be classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5  ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded on the Adverse Event eCRF, along with a descriptor 
indicating if the test result is above or below the normal range (e.g., "elevated potassium," as 
opposed to "abnormal potassium").  If the laboratory abnormality can be characterised by a 
precise clinical term per standard definitions, the clinical term should be recorded as the AE.  
For example, an elevated serum potassium level of 7.0 mEq/L should be recorded as 
"hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded on the Adverse Event eCRF, unless the etiology changes.  The 
initial severity of the event should be recorded, and the severity or seriousness should be 
updated any time the event worsens. 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an AE.  A vital sign result must be reported as 
an AE if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Clinically significant in the Investigator’s judgment  
It is the Investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality should 
be classified as an AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high 
blood pressure), only the diagnosis (i.e., hypertension) should be recorded on the Adverse 
Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit should 
not be repeatedly recorded on the Adverse Event eCRF, unless the etiology changes.  The 


 
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initial severity of the event should be recorded, and the severity or seriousness should be 
updated any time the event worsens. 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3  baseline value) in combination with either an 
elevated total bilirubin (> 2  ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy’s Law).  Therefore, Investigators must report as an AE the occurrence of 
either of the following: 
• 
Treatment-emergent ALT or AST  3  baseline value in combination with total bilirubin 
 2 ULN (of which ≥ 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST  3  baseline value in combination with clinical 
jaundice 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.5) and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the event), 
either as a SAE or an AE of special interest (see Section 5.4.2). 
5.3.5.8 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the protocol-
specified adverse event reporting period (see Section 5.3.1) that are attributed by the 
Investigator solely to progression of mCRC should be recorded only on the Study 
Completion/Early Discontinuation eCRF.  All other on-study deaths, regardless of 
relationship to study drug, must be recorded on the Adverse Event eCRF and immediately 
reported to the Sponsor (see Section 5.4.2). The iDMC will monitor the frequency of deaths 
from all causes. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be reported. 
The term "sudden death" should be used only for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a patient with or without pre-existing 
heart disease, within 1 hour after the onset of acute symptoms or, in the case of an 
unwitnessed death, within 24 hours after the patient was last seen alive and stable.  If the 
cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF.  If the cause of 
death later becomes available (e.g., after autopsy), "unexplained death" should be replaced 
by the established cause of death. 
During survival follow-up, deaths attributed to progression of mCRC should be recorded only 
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5.3.5.9 
Pre-existing Medical Conditions 
A pre-existing medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline Conditions 
eCRF. 
A pre-existing medical condition should be recorded as an AE only if the frequency, severity, 
or character of the condition worsens during the study.  When recording such events on 
the Adverse Event eCRF, it is important to convey the concept that the pre-existing condition 
has changed by including applicable descriptors (e.g., "more frequent headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of mCRC 
Events that are clearly consistent with the expected pattern of progression of the underlying 
disease should not be recorded as AEs.  These data will be captured as efficacy 
assessment data only.  In most cases, the expected pattern of progression will be based on 
RECIST 1.1 or mRECIST.  In rare cases, the determination of clinical progression will be 
based on symptomatic deterioration.  However, every effort should be made to document 
progression through use of objective criteria.  If there is any uncertainty as to whether an 
event is due to disease progression, it should be reported as an AE. 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any AE that results in hospitalization (i.e., in-patient admission to a hospital) or prolonged 
hospitalization should be documented and reported as a SAE (per the definition of SAE in 
Section 5.2.2), except as outlined below.   
The following hospitalization scenarios are not considered to be AEs: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., for study drug administration or 
insertion of access device for study drug administration) 
• 
Hospitalization for a pre-existing condition, provided that all of the following criteria are 
met: 
̶ 
The hospitalization was planned prior to the study or was scheduled during the study 
when elective surgery became necessary because of the expected normal 
progression of the disease 
̶ 
The patient has not experienced an AE 
• 
Hospitalization due solely to progression of the underlying cancer 
5.3.5.12 
Adverse Events Associated with an Overdose 
An overdose is the accidental or intentional use of a drug in an amount higher than the dose 
being studied.  An overdose or incorrect administration of study treatment is not itself an AE, 
but it may result in an AE.  All AEs associated with an overdose or incorrect administration of 
study drug should be recorded on the Adverse Event eCRF.  If the associated AE fulfils 
serious criteria, the event should be reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event; see Section 5.4.2). 


 
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5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM INVESTIGATOR 
TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The Investigator must report such 
events to the Sponsor immediately; under no circumstances should reporting take place 
more than 24 hours after the Investigator learns of the event.  The following is a list of events 
that the Investigator must report to the Sponsor within 24 hours after learning of the event, 
regardless of relationship to study drug: 
• 
SAEs 
• 
AEs of special interest 
• 
Pregnancies 
The Investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the information).  
New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
Investigators must also comply with local requirements for reporting SAEs to the local health 
authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
To ensure the safety of study patients, an Emergency Medical Call Centre Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the Investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Centre Help Desk will be available 
24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk and Medical 
Monitor contact information will be distributed to all Investigators (see "Protocol 
Administrative and Contact Information & List of Investigators").  
5.4.2 
Reporting Requirements for SAEs and AEs of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention should be reported.  A paper Serious Adverse 
Event Reporting Form and fax cover sheet should be completed and faxed to Roche Safety 
Risk Management or its designee immediately (i.e., no more than 24 hours after learning of 
the event), using the fax numbers provided to Investigators (see "Protocol Administrative 
and Contact Information & List of Investigators"). 


 
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5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, SAEs and AEs of special interest will be reported. After the end 
of the adverse event reporting period, the Sponsor should be notified if the Investigator 
becomes aware of any SAE or AEs of special interest if the event is believed to be related to 
prior study treatment. Investigators should record all case details that can be gathered 
immediately (i.e., within 24 hours after learning of the event) on the Adverse Event eCRF 
and submit the report via the electronic data capture (EDC) system.  A report will be 
generated and sent to Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, a paper Serious Adverse Event Reporting 
Form and fax cover sheet should be completed and faxed to Roche Safety Risk 
Management or its designee immediately (i.e., no more than 24 hours after learning of the 
event), using the fax numbers provided to Investigators (see "Protocol Administrative and 
Contact Information & List of Investigators"). Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system.   
Instructions for reporting post-study AEs are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential (i.e. not post-menopausal as indicated by 
< 12 months of non-therapy-induced amenorrhea, nor surgically sterile [absence of ovaries 
and/or uterus]) will be instructed to immediately inform the Investigator if they become 
pregnant during the study or within 7 months after the last dose of study drug. A Clinical Trial 
Pregnancy Reporting Form provided to investigators should be completed and submitted to 
Roche or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to Investigators. 
Pregnancy should not be recorded on the Adverse Event eCRF. The Investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy and 
the possible effects on the fetus. 
Monitoring of the patient should continue until conclusion of the pregnancy.  Any SAEs 
associated with the pregnancy (e.g., an event in the fetus, an event in the mother during or 
after the pregnancy, or a congenital anomaly/birth defect in the child) should be reported on 
the Adverse Event eCRF. In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available. 
Additional information on any pertuzumab and trastuzumab-exposed pregnancy and infant 
will be requested by Roche Drug Safety at specific time points (i.e. after having received the 
initial report during the first trimester, at the end of the second trimester, 2 weeks after the 
expected date of delivery and at 3, 6, and 12 months of the infant’s life). In case of a report 
of a congenital abnormality, a guided questionnaire will be sent out by Roche Drug Safety. 


 
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5.4.3.2 
Pregnancies in Female Partners of Male Patients  
Male patients will be instructed through the Informed Consent Form to immediately inform 
the Investigator if their partner becomes pregnant during the study or within 6 months after 
the last dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed 
and submitted to the Roche or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy) either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators. Attempts should be made to collect 
and report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study drug.  The pregnant partner will need to sign an Authorization for 
Use and Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
Once the authorization has been signed, the Investigator will submit a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available.  An Investigator who is contacted by the male patient or his 
pregnant partner may provide information on the risks of the pregnancy and the possible 
effects on the fetus, to support an informed decision in cooperation with the treating 
physician and/or obstetrician. 
5.4.3.3 
Abortions 
Any abortion should be classified as an SAE (as the Sponsor considers abortions to be 
medically significant), recorded on the Adverse Event eCRF, and reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study drug 
or the female partner of a male patient exposed to study drug should be classified as an 
SAE, recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., 
no more than 24 hours after learning of the event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The Investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the Investigator, the patient is lost to follow-up, or 
the patient withdraws consent.  Every effort should be made to follow all SAEs considered to 
be related to study drug or trial-related procedures until a final outcome can be reported. 
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the patient’s medical record to facilitate source data verification.  
If, after follow-up, return to baseline status or stabilization cannot be established, an 
explanation should be recorded on the Adverse Event eCRF.  
All pregnancies reported during the study should be followed until pregnancy outcome.   
5.5.2 
Sponsor Follow-Up 
For SAEs, AEs of special interest, and pregnancies, the Sponsor or a designee may 
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details and outcome information (e.g., from hospital discharge summaries, consultant reports, 
autopsy reports) in order to perform an independent medical assessment of the reported 
case. 
5.6 
POST-STUDY ADVERSE EVENTS 
At the time of study completion or study discontinuation, the Investigator should instruct each 
patient to report to the Investigator any subsequent AEs that the patient’s personal physician 
believes could be related to prior study drug treatment or study procedures.   
The Investigator is not required to actively monitor patients for AEs after the end of the 
adverse event reporting period (defined as either 28 or 90 days after the last dose of study 
drug).  However, the Sponsor should be notified if the Investigator becomes aware of any 
death, other SAE, or AE of special interest occurring after the end of the adverse event 
reporting period if the event is believed to be related to prior study treatment.  The Sponsor 
should also be notified if the Investigator becomes aware of the development of cancer or a 
congenital anomaly/birth defect in a subsequently conceived offspring of a female patient 
exposed to study drug or the female partner of a male patient exposed to study drug. 
The Investigator should report these events directly to Roche Safety Risk Management via 
telephone or via fax machine using the Serious Adverse Event Reporting Form and fax 
cover sheet (see "Protocol Administrative and Contact Information & List of Investigators"). 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all SAEs and AEs of special interest against cumulative 
product experience to identify and expeditiously communicate possible new safety findings 
to Investigators, IRBs, ECs, and applicable health authorities based on applicable legislation. 
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the following Investigator's Brochures, local prescribing 
information or Core Data sheets as reference documents, as described below. 
• 
Refer to European Medicines Agency (EMA) website for Summary of Product 
Characteristics (SmPC): 
̶ 
cetuximab 
• 
Investigator’s Brochure  
̶ 
bevacizumab 
̶ 
vemurafenib 
̶ 
atezolizumab 
̶ 
trastuzumab 
̶ 
pertuzumab 
̶ 
cobimetinib 
The Sponsor will compare the severity of each event and the cumulative event frequency 
reported for the study with the severity and frequency reported in the applicable reference 
document. 


 
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Reporting requirements will also be based on the Investigator's assessment of causality and 
seriousness, with allowance for upgrading by the Sponsor as needed. 
Certain AEs are anticipated to occur in the study population at some frequency independent 
of study drug exposure and will be excluded from expedited reporting.  These anticipated 
events include, but are not limited to, the following: 
• 
Death due to progressive disease 
• 
Disease progression 
An iDMC will monitor the incidence of the above-listed anticipated events during the study.  
An aggregate report of any clinically relevant imbalances that do not favour the test products 
will be submitted to health authorities. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
Update on Statistical Analysis Plans and Cohort Status Following Premature Closure 
of Study Enrolment   
Study enrolment and accrual into Cohort 4 were suspended in February 2018 as a result of 
an unfavourable benefit-risk evaluation of Cohort 4 by the iDMC. Accrual to Cohort 4 was not 
re-opened after February 2018 due to iDMC recommendations. No new or modified cohorts 
with broad biomarker eligibility have been identified for addition to the study. In the absence 
of a cohort with broad biomarker eligibility to replace Cohort 4, the majority of patients 
eligible for study entry would not be eligible for maintenance cohort assignment. For this 
reason, study enrolment will not be re-opened following the February 2018 suspension. 
Accrual to Cohort 2 was completed in November 2016 after reaching its target sample size. 
Accrual to Cohort 4 was closed in February 2018, prior to reaching its target sample size. 
Cohort assignment and randomization of any patients who were already enrolled and eligible 
for Cohorts 1 and 3 were continued following the February 2018 suspension of study 
enrolment; however, Cohorts 1 and 3 did not reach their target sample size.  
The clinical cut-off for the primary analysis of Cohort 2 occurred on May 31, 2017. The 
primary analyses for Cohorts 1, 3 and 4 will be conducted based on the same clinical cut-off 
as the update analysis of Cohort 2 occurring on May 31, 2019 (24 months from Cohort 2 
primary analysis clinical cut-off date). Following May 31, 2019, disease status data will not 
be collected for any cohort. Since survival follow-up at 24 months after the primary analysis 
clinical cut-off date will have been reported in Cohort 2, and only five patients were accrued 
in Cohort 3 (see Section 6.2), no further survival (other than during the adverse event 
reporting period) or subsequent anti-cancer therapy data will be collected for patients in 
Cohorts 2 and 3 after May 31, 2019. Survival and subsequent anti-cancer therapy will 
continue to be collected for Cohorts 1 and 4 until the end of the study. 
6.1 
OVERVIEW 
The cohorts will be based on different biomarkers (see Appendix 17), with each cohort 
consisting of an experimental treatment arm and a control arm. The inclusion of a control 
group allows discrimination of patient outcomes caused by the experimental treatment from 
outcomes caused by other factors. Randomisation avoids systematic differences (bias) 


 
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between the groups with respect to known or unknown baseline variables that could affect 
outcome. The treatment for patients in the control arms represents standard of care. 
The primary objective of the study is to evaluate PFS within each cohort. 
Provided the iDMC does not recommend discontinuation of enrolment to a cohort or 
enrolment is not otherwise discontinued prior to a cohort reaching its target sample size, the 
primary analysis for the cohort will occur when the target number of PFS events has been 
reached. Secondary endpoints will also be summarised at this time. An updated analysis of 
time-to-event and safety endpoints will be conducted for such cohorts once 24 months of 
survival follow-up has been completed.  
The final study analysis will be conducted after all patients in the study have discontinued 
study treatment and completed the adverse event reporting period and any applicable post-
treatment follow-up safety assessments.   
Data will be summarised using appropriate summary statistics: mean, standard deviation, 
median, quartiles and range (minimum and maximum) for continuous variables, and number 
and percentage for categorical variables. 
The following is an outline of the statistical methodology that will be used to analyse this 
study. More detailed descriptions will be provided in statistical analysis plans (SAPs) 
applicable to each cohort which may also include additional exploratory analyses not 
explicitly mentioned in the following sections. The timing and methods of analyses for any 
cohort closed to accrual before its target sample size is reached may differ from descriptions 
provided below. These will be described in the SAP applicable to the cohort and will depend 
on accrual at the time of early closure. The SAPs will be finalised before closure of the study 
database.  Deviations from the SAPs will be reported and justified in the clinical study 
reports. 
6.1.1 
Analysis Populations 
For each cohort, the Intent-To-Treat (ITT) Population will include patients entered into the 
Maintenance Treatment Phase of the study, irrespective of whether or not they received 
study medication. In this population, patients will be allocated to the study maintenance 
treatment into which they were randomised. The ITT Population will be used for all efficacy 
analyses. 
The Per Protocol Population will not be defined for this study but major protocol violations 
will be listed. 
The Safety Population will include all patients who received at least one dose of study 
medication during the Induction or Maintenance Treatment Phases. Patients will be allocated 
to the treatment regimen that they actually received. The Safety Population will be used for 
all safety analyses. 
6.1.2 
Statistical Hypotheses 
Cohorts 1 and 3 
The null and alternative hypotheses when comparing PFS between the two randomised 
treatments in Cohort 1 (Arm A: 5-FU/LV with cetuximab and vemurafenib vs. Arm B: 


 
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fluoropyrimidine and bevacizumab) and in Cohort 3 (Arm A: capecitabine with trastuzumab 
and pertuzumab vs. Arm B: fluoropyrimidine and bevacizumab) are: 
H0:  
the distribution of the PFS time is the same in the two treatment groups 
PFS (Arm A) = PFS (Arm B) 
H1:  
the distribution of the PFS time is different in the two treatment groups 
specifically PFS (Arm A) > PFS (Arm B) 
If the hazard ratio (HR) of Arm A compared to Arm B is assumed to be constant over time, 
then the null and alternative hypotheses are: 
H0: 
HR = 1 vs. H1: HR < 1 
Due to the relatively low prevalence of mCRC patients with HER2+ or BRAFmut disease, the 
formal statistical tests for Cohorts 1 and 3 will be one-sided and performed at an alpha level 
(type I error rate) of 10%. 
Cohorts 2 and 4 
The null and alternative hypotheses when comparing PFS (evaluated per RECIST v1.1) 
between the two randomised treatments in Cohort 2 (Arm A: fluoropyrimidine with 
bevacizumab and atezolizumab vs. Arm B: fluoropyrimidine and bevacizumab) and in Cohort 
4 (Arm A: cobimetinib with atezolizumab vs. Arm B: fluoropyrimidine and bevacizumab) are: 
H0:  
the distribution of the PFS time is the same in the two treatment groups 
PFS (Arm A) = PFS (Arm B) 
H1:  
the distribution of the PFS time is different in the two treatment groups 
PFS (Arm A) ≠ PFS (Arm B) 
If the HR of Arm A compared to Arm B is assumed to be constant over time, then the null 
and alternative hypotheses are: 
H0: 
HR = 1 vs. H1: HR ≠ 1 
The formal statistical tests for Cohorts 2 and 4 will be two-sided and performed at an alpha 
level (type I error rate) of 5%. 
6.2 
DETERMINATION OF SAMPLE SIZE 
Before study enrolment was closed prematurely, approximately 1,820 patients were 
expected to be screened and approximately 1,400 patients were expected to be enrolled in 
the Induction Treatment Phase of the study in order to randomise the target sample size in 
each maintenance cohort. The target sample size was reached in Cohort 2 (final n=445). 
Target sample sizes were not reached in Cohort 1 (final n=60), Cohort 3 (final n=5), or 
Cohort 4 (final n=99) due to premature closure of study enrolment.  
The calculated sample size for each study cohort has been based on an estimated 
recruitment period for 11 months for Cohorts 2 and 4 and on the comparison between PFS 
in the experimental and control arms of that cohort. Estimated proportions of the patients 
enrolled into the study that are eligible for each cohort are based on published reports 




 
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6.4 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic and baseline characteristics (e.g. age, sex, ethnicity) and baseline disease 
characteristics (e.g. prior treatment, sites of metastatic disease, ECOG performance status) 
for experimental and control arms of each cohort will be summarised.  
6.5 
EFFICACY ANALYSES 
Efficacy analyses will be conducted separately for each study cohort. 
No adjustment will be made for multiplicity of endpoints or subgroup analyses. 
6.5.1 
Primary Efficacy Endpoints 
All Cohorts 
The primary study endpoint within each cohort is PFS evaluated according to RECIST 1.1. 
PFS is defined as the time from randomisation into the Maintenance Treatment Phase until 
disease progression evaluated according to RECIST 1.1 or death from any cause, whichever 
occurs first.  Tumour size will be calculated using the sum of the longest diameters of all 
target lesions, and reduction will be based on comparisons to the tumour assessment done 
at the end of the Induction Treatment Phase. Patients without an event will be censored at 
the date of their last evaluable tumour assessment or, if this is not available, at the date of 
randomisation. For each cohort, the primary analysis of PFS will occur when the target 
number of PFS events has been reached. 
Within each cohort, PFS will be presented graphically for each treatment group using the 
Kaplan-Meier method. Estimates and the corresponding 95% confidence interval will be 
reported by treatment group for median survival time, and for the 4-, 6- and 12-month PFS 
rates. 
Within each cohort, the comparison of PFS between the treatment groups will be performed 
using an unstratified log-rank test. In addition, a Cox regression will be performed with 
treatment and applicable stratification variables (biomarkers, geographic region and/or 
response after induction treatment) as terms in the model. The estimated hazard ratio and its 
corresponding 95% confidence interval will be presented.  
6.5.2 
Secondary Efficacy Endpoints 
All Cohorts 
The secondary efficacy endpoints for each cohort are OS, ORR, DCR, TTR, DoR and ECOG 
performance status. 
OS is defined as the time from randomisation until death from any cause.  Patients who are 
still alive at the time of analysis (clinical cut-off) and patients who are lost to follow-up will be 
censored at their last clinical assessment date. 
Best overall response will be assessed for all patients after randomisation until disease 
progression. ORR will be calculated as the proportion of patients with a best overall 
response of CR or PR. ORR will be summarised and presented along with the 95% Clopper-
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DCR will be calculated as the proportion of patients with a best overall response of CR, PR 
or SD. DCR will be summarised and presented along with the 95% Clopper-Pearson 
confidence interval. 
TTR will be calculated as the time from randomisation to the first occurrence of a 
documented objective response (CR or PR). 
DoR will be assessed for all patients after randomisation until PD. Only patients with a best 
overall response of CR or PR are considered responders. The duration of response is the 
time from the first assessment of CR or PR until disease progression or death from any 
cause, whichever occurs first. 
The secondary time-to-event endpoints will be analysed by the same methods and at the 
same time as the primary endpoint. 
The above efficacy outcomes will be evaluated using RECIST 1.1. 
ECOG performance status will be summarised over time. 
6.5.3 
Exploratory Efficacy Endpoints 
Cohorts 2 and 4 
PFS defined as the time from randomisation into the Maintenance Treatment Phase until 
disease progression evaluated according to mRECIST or death from any cause (whichever 
occurs first) will be evaluated as an exploratory endpoint.  This endpoint will only be 
assessed in patients treated with atezolizumab. Patients without an event will be censored at 
the date of their last evaluable tumour assessment or, if this is not available, at the date of 
randomisation. PFS may be presented graphically using the Kaplan-Meier method. 
Estimates and the corresponding 95% confidence interval may be reported for the 4-, 6- and 
12-month PFS rates. 
6.6 
SAFETY ANALYSES 
All Cohorts 
Verbatim adverse event (AE) data will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms. 
All treatment-emergent AEs occurring during or after the first dose (including partial doses) 
of study medication will be summarised by treatment group in frequency tables, as follows: 
• 
By preferred term and system organ class 
• 
By severity of all adverse events (graded according to NCI CTCAE v4.0) 
• 
Grade 3 – 5 AEs 
• 
Grade 5 AEs or AEs leading to death on study treatment 
• 
All SAEs 
• 
AEs leading to premature discontinuation of any component of study treatment 
• 
AEs leading to dose reduction or interruption of any component of study treatment 
• 
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The above safety data will be summarised separately for the Induction and Maintenance 
Treatment Phases overall and by individual maintenance treatment cohort. 
Deaths reported during the Study Treatment Phase and those reported during follow-up after 
treatment completion/discontinuation will be summarised by treatment group.  
Study medication exposure will be separately summarised by number of cycles, duration, 
dose and dose intensity. 
Vital signs data, clinical laboratory parameters, concomitant medication and subsequent 
anti-cancer therapy will also be summarised. 
6.7 
EXPLORATORY BIOMARKER ANALYSES 
All Cohorts 
Biomarker and microbiome analyses will be of exploratory nature only, utilizing all available 
data obtained from archival tumour samples from the initial diagnosis and all other tumour, 
blood and stool samples from all study patients including Supplemental Biomarker Program 
participants.  These analyses will be of exploratory nature only, using descriptive methods 
with no fixed hypotheses testing. 
With the ongoing analyses of the study’s various biomarker-based cohorts, more information 
on the concordance of different biomarkers will be collected and summarised.  Relevant 
findings will be discussed with the study’s SC in order to conduct further exploratory 
biomarker analyses accordingly. 
6.8 
INTERIM ANALYSES 
All Cohorts 
The iDMC will evaluate accumulating safety and efficacy data within each cohort to assure 
these data continue to support an early positive benefit-risk ratio and to confirm that 
continued enrolment into each cohort is appropriate. The amount of efficacy data to be 
assessed in a given cohort will be determined by the iDMC at the preceding iDMC meeting. 
Details of this process are described in the iDMC charter. Decisions on what efficacy data 
have to be evaluated for each cohort will be documented in the iDMC meeting minutes.  In 
addition, the iDMC will review data from any safety run-in patients required for an 
experimental regimen (e.g. as conducted for the initial patients treated with the experimental 
combination of ‘5-FU/LV + cetuximab + vemurafenib’). These safety run-ins will be specified 
in the protocol.  
6.9 
SUBGROUP ANALYSES 
Subgroup analysis will be defined in the SAP. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will supply eCRF specifications for this study.  A contract research organization 
(CRO) will be responsible for data management of this study, including quality checking of 


 
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the data.  Data entered manually will be collected via EDC using eCRFs.  Sites will be 
responsible for data entry into the EDC system.  In the event of discrepant data, the CRO 
will request data clarification from the sites, which the sites will resolve electronically in the 
EDC system. 
The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data.  Central laboratory data will be sent directly to the CRO using the 
CRO's standard procedures to handle and process the electronic transfer of these data. 
The Sponsor will perform oversight of the data management of this study, including approval 
of the CRO’s data management plans and specifications.  Data will be periodically 
transferred electronically from the CRO to the Sponsor, and the Sponsor’s standard 
procedures will be used to handle and process the electronic transfer of these data.   
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored at the CRO and records retention for the study data will be 
consistent with the CRO’s standard procedures.  
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites will 
receive training and have access to a manual for appropriate eCRF completion.  eCRFs will 
be submitted electronically to the Sponsor and should be handled in accordance with 
instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be reviewed 
and electronically signed and dated by the Investigator or a designee. 
At the end of the study, the Investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical protocol 
data (i.e., source data) entered into the eCRFs by authorised site personnel are accurate, 
complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded and 
documented for the first time.  They include, but are not limited to, hospital records, clinical 
and office charts, laboratory notes, memoranda, patient-reported outcomes, evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies of transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, and 
records kept at pharmacies, laboratories, and medico-technical departments involved in a 
clinical trial. 
Before study initiation, the types of source documents that are to be generated will be clearly 
defined in the Trial Monitoring Plan.  This includes any protocol data to be entered directly 
into the eCRFs (i.e., no prior written or electronic record of the data) and considered source 
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Source documents that are required to verify the validity and completeness of data entered 
into the eCRFs must not be obliterated or destroyed and must be retained per the policy for 
retention of records described in Section 7.5. 
To facilitate source data verification, the Investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow inspection 
by applicable health authorities. 
7.4 
USE OF COMPUTERISED SYSTEMS 
When clinical observations are entered directly into a study site’s computerised medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve as 
the source document if the system has been validated in accordance with health authority 
requirements pertaining to computerised systems used in clinical research.  An acceptable 
computerised data collection system allows preservation of the original entry of data.  If 
original data are modified, the system should maintain a viewable audit trail that shows the 
original data as well as the reason for the change, name of the person making the change, 
and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of IMP, 
including eCRFs, Informed Consent Forms, laboratory test results, and medication inventory 
records, must be retained by the Principal Investigator for at least 15 years after completion 
or discontinuation of the study, or for the length of time required by relevant national or local 
health authorities, whichever is longer.  After that period of time, the documents may be 
destroyed, subject to local regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to another 
party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good Clinical 
Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the 
country in which the research is conducted, whichever affords the greater protection to the 
individual.  The study will comply with the requirements of the ICH E2A guideline (Clinical 
Safety Data Management:  Definitions and Standards for Expedited Reporting).  Studies 
conducted in the EU or European Economic Area will comply with the EU Clinical Trial 
Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
Due to the complexity of the study and the number of different maintenance regimens a 
patient could potentially receive, the informed consent process including signing of the 
informed consent form, may be conducted twice unless the individual study center chooses 


 
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to obtain informed consent including all potential regimens in a single process (i.e. provide 
all induction and maintenance treatment information prior to study entry). Sites conducting 
two informed consent procedures will obtain the first informed consent prior to study 
screening and enrolment into the Induction Treatment Phase. The second informed consent 
will be obtained prior to cohort-specific eligibility assessments and randomization into the 
Maintenance Treatment Phase. The informed consent just prior to Maintenance Treatment 
Phase will be based on only those regimens in the assigned maintenance cohort. Patients 
will have the option of reviewing informed consent information for all maintenance treatment 
cohorts before entry into the study. 
The Sponsor’s sample Informed Consent Forms will be provided to each site.  If applicable, 
they will be provided in a certified translation of the local language.  The Sponsor or its 
designee must review and approve any proposed deviations from the Sponsor's sample 
Informed Consent Forms or any alternate consent forms proposed by the site (collectively, 
the "Consent Forms") before IRB/EC submission.  The final IRB/EC−approved Consent 
Forms must be provided to the Sponsor for health authority submission purposes according 
to local requirements. 
The Informed Consent Form signed before entry into the study will contain a separate 
section that addresses the use of remaining samples for optional exploratory research.  The 
Investigator or authorised designee will explain to each patient the objectives of the 
exploratory research.  Patients will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the storage period.  A 
separate, specific signature will be required to document a patient's agreement to allow any 
remaining specimens to be used for exploratory research.  Patients who decline to 
participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient, or, where applicable, their 
legally authorised representative, before his or her initial participation in the study and again 
prior to entry into the Maintenance Phase.  The case history or clinical records for each 
patient shall document the informed consent processes and that written informed consents 
were obtained prior to participation in the study and entry into the Maintenance Treatment 
Phase. 
The Consent Forms should be revised whenever there are changes to study procedures or 
when new information becomes available that may affect the willingness of the patient to 
participate.  The final revised IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised Consent 
Forms, the case history or clinical records for each patient shall document the informed 
consent process and that written informed consent was obtained using the updated/revised 
Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient, or, where applicable, 
their legally authorised representative. All signed and dated Consent Forms must remain in 


 
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each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
An additional consent form will be provided to patients who agree to also participate in the 
Supplemental Biomarker Program outlined in Appendix 18. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, and 
relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of the 
study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible for 
promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all AEs to the Sponsor, Investigators must 
comply with requirements for reporting SAEs to the local health authority and IRB/EC.  
Investigators may receive written Investigational New Drug (IND) safety reports or other 
safety-related communications from the Sponsor.  Investigators are responsible for ensuring 
that such reports are reviewed and processed in accordance with health authority 
requirements and the policies and procedures established by their IRB/EC, and archived in 
the site’s study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the study 
through assignment of a unique patient identification number.  This means that patient 
names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed to 
third parties only as permitted by the Informed Consent Form (or separate authorization for 
use and disclosure of personal health information) signed by the patient (or where applicable, 
their legally authorised representative) unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. Food and Drug Administration (FDA) and other national and local 
health authorities, Sponsor monitors, representatives, and collaborators, and the IRB/EC for 
each study site, as appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities. 


 
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Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
9. 
STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented, including but not limited to the protocol, protocol amendments, 
Informed Consent Forms, and documentation of IRB / EC and governmental approval.  In 
addition, at the end of the study, the Investigator will receive the patient data, including an 
audit trail containing a complete record of all changes to data. 
9.2 
PROTOCOL DEVIATIONS 
The Investigator should document and explain any protocol deviations.  The Investigator 
should promptly report any deviations that might have an impact on patient safety and data 
integrity to the Sponsor and to the IRB / EC in accordance with established IRB / EC policies 
and procedures. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorised representative for inspection of 
study data, patients’ medical records, and eCRFs.  The Investigator will permit national and 
local health authorities, Sponsor monitors, representatives, and collaborators, and the 
IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This study is sponsored by Roche, who has overall responsibility for this study. 
A CRO will be responsible for clinical operations oversight, data management support, and 
medical monitoring. 
A SC will be responsible for overseeing the general conduct of the study. 
An iDMC will be responsible for evaluating the safety of the patients participating in the trial 
at regular intervals throughout the study, providing recommendations regarding continued 
enrolment in each study cohort, and conducting pre-planned safety run-in reviews. 
Tumour tissue and exploratory blood / plasma samples will be sent to a Roche-approved 
designated laboratory for analysis of biomarker status. 
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor prior 
to submission. This allows the Sponsor to protect proprietary information and to provide 
comments based on information from other studies that may not yet be available to the 
Investigator. 


 
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The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multi-centre trials only in their entirety and not as individual centre data.  In this 
case, a coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.  Any formal publication of the study in 
which contribution of Sponsor personnel exceeded that of conventional monitoring will be 
considered as a joint publication by the Investigator and the appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from the 
use of data from this study will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will be 
submitted to the IRB/EC and to regulatory authorities in accordance with local regulatory 
requirements. 
Approval must be obtained from the IRB / EC and regulatory authorities (as locally required) 
before implementation of any changes, except for changes necessary to eliminate an 
immediate hazard to patients or changes that involve logistical or administrative aspects only 
(e.g., change in Medical Monitor or contact information). 


 
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10. 
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APPENDICES 
 








 
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f. 
Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive status, 
smoking history, use of alcohol and drugs of abuse, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, 
nutritional supplements) used by the patient within 7 days prior to the Screening visit.  Demographic data will include age, sex, and self-reported 
race/ethnicity (where permitted by federal regulations). 
g. Vital signs include measurements of systolic and diastolic blood pressure while the patient is in a seated position, and temperature.  During Screening, 
weight only required ≤ 7 days. 
h. Baseline assessment requires a complete physical exam. A complete physical examination should include an evaluation of the head, eyes, ears, nose, 
and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems. Abnormalities 
identified at Screening / Baseline will be recorded as baseline conditions.  At subsequent visits (or as clinically indicated), limited, symptom-directed 
physical examinations should be performed. Changes from Baseline, with new or worsened clinically significant abnormalities, should be reported as AEs 
if appropriate.  
i. 
ECOG status assessed within 7 days prior to Day 1 of Cycle 1 (Induction Treatment Phase) for eligibility determination.  See Appendix 8. 
j. 
Concomitant medication includes any prescription medications or over-the-counter preparations used by a patient between the 7 days prior to the date of 
informed consent up until the date of study discontinuation.  Only concomitant medications used for supportive care, to alleviate symptoms of mCRC, or 
to treat adverse drug reactions should be recorded on the Concomitant Medications eCRF. At subsequent visits, only changes to current medications or 
medications used since the last documentation of medications will be recorded.  Concomitant medications for treatment of AEs related to study 
medication will continue to be recorded while the AE is being followed. For permitted and prohibited concomitant medications, see Section 4.4. 
k. Haematology includes haemoglobin, haematocrit, platelet count, red blood cell count, white blood cell count, and differential. Blood chemistry includes 
ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin, blood urea nitrogen or urea, LDH, creatinine, glucose, calcium, phosphorus, sodium, 
potassium, chloride, and bicarbonate. Hematology and blood chemistry tests must be conducted prior to each treatment cycle, with the results available 
for review prior to start of treatment according to local standards for treatment management. However, only tests conducted every second treatment cycle 
will be recorded in the eCRF. Clinical laboratory results constituting a clinically significant AE should be recorded as such.  
l. 
INR and aPTT are required for all patients at screening but only for patients receiving anticoagulants while on protocol-specified treatment. 
m. Urinalysis must be performed by dipstick at Baseline and within 48 hours prior to every cycle.  A 24-hour urine collection is needed in the event of 
proteinuria ≥ ± 2 by dipstick test. 
n. Urine or blood pregnancy test, only for women of childbearing potential (i.e. not post-menopausal as indicated by < 12 months of non-therapy-induced 
amenorrhea, nor surgically sterile [absence of ovaries and/or uterus]), including those who have had a tubal ligation.  A serum pregnancy test is required 
within 7 days prior to start of study induction treatment, or within 14 days with a confirmatory urine pregnancy test within 7 days prior start of study 
induction treatment 
o. Will include radiology, chest and abdominal CT or MRI, and other scans to document all sites of disease. Include upper abdomen at Baseline.  A CT or 
MRI scan of the brain is required if there is clinical suspicion of CNS metastases at screening/Baseline or at any time during the Induction Treatment 
Phase. Subsequent tumour assessments will be done according to standard of care at each study centre, with the exception that all patients must have a 
tumour assessment at the end of the Induction Treatment Phase. Tumour assessments are not required for study purposes after disease progression has 
been documented. Patients who discontinue study treatment during the Induction Treatment Phase prior to disease progression will also continue to be 
followed for progressive disease, with disease status followed according to local practice until progression or May 31, 2019, whichever comes first. After 
May 31, 2019, disease status will not be collected for the study. 


 
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p. Archival tumour tissue (FFPET) block from the primary tumour obtained at the time of the initial diagnosis. If the tumour block is not available, ≥ 20 slides 
cut from the primary tumour sample will be accepted as an alternative.  Before a patient can be enrolled, the sample (block or slides) must be shipped to 
the designated laboratory with the corresponding pathology report and receipt of the shipment must be confirmed by the laboratory.  See Appendix 17. 
q. Collection of the optional core biopsy of metastatic tumours was discontinued as of May 2018. (See Appendix 18). 
r. 
Whole blood and plasma samples will be collected from all study patients for exploratory biomarker analyses unless genomic analysis is not allowed per 
local regulations. In such instances, only plasma samples will be collected.  All samples will be sent to a designated laboratory.  Samples during treatment 
should be taken within 48 hours prior to study treatment Day 1 of each cycle indicated, unless otherwise specified (see Appendix 17 and Laboratory 
Manual). 
s. After the signing of the informed consent form, and prior to Day 1 of Cycle 1 (Induction Treatment Phase), any SAEs thought to be related to a protocol-
mandated intervention should be reported.  Adverse events will be documented at every cycle during treatment. All patients will be followed for new AEs 
for 28 days following the discontinuation of study treatment. At the time of treatment discontinuation, any ongoing AE/SAE will be followed until the event 
resolves, the Investigator assesses the event as stable, the patient is lost to follow-up, dies or withdraws consent. Death related to disease progression is 
not considered to be an SAE. The Sponsor should be notified if the Investigator becomes aware of any SAE or AEs of special interest occurring after the 
end of the adverse event reporting period if the event is believed to be related to prior study treatment. 
t. 
Eligible patients will enter a 4-month Induction Treatment Phase.  Treatment during this phase, based on Investigator’s choice, will be either eight 2-week 
cycles of 5-FU, LV and oxaliplatin (FOLFOX) in combination with bevacizumab or six 2-week cycles of FOLFOX in combination with bevacizumab, 
followed by two 2-week cycles of 5-FU/LV with bevacizumab. 








 
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k. Evaluation to be performed by a dermatologist, the Investigator or other qualified physician.  
l. 
Pelvic examinations for women (with special attention to cervix) and anal examinations for all patients will be performed by the Investigator or other 
qualified physician prior to start of Experimental Therapy and at the Study Treatment Discontinuation Visit for the evaluation of SCC. The pelvic 
examination should include a complete external and internal examination (internal examination of uterine cervix may include a Pap smear, which would 
be a decision of the Investigator). The anal examination should include external examination, digital anorectal examination and anoscopy or proctoscopy. 
However, if in opinion of the Investigator the presence of “abnormal lesions including SCC” can be excluded by the external inspection and the manual 
examination, this is acceptable.  However, if the presence of a lesion is suspected, an anoscopy or proctoscopy are recommended.  
m. See Appendix 8. 
n. ECG to determine Cohort 1 eligibility must conducted within 3 weeks of randomization. During maintenance treatment, ECGs will be required in 
experimental arm patients only. Measurements include heart rate, PR interval, QRS duration, and QT and QTc intervals. 
o. Concomitant medication includes any prescription medications or over-the-counter preparations used by a patient between the 7 days prior to the date of 
informed consent up until the Study Treatment Discontinuation visit.  Only concomitant medications used for supportive care, to alleviate symptoms of 
mCRC, or to treat adverse drug reactions should be recorded on the Concomitant Medications eCRF. At subsequent visits, only changes to current 
medications or medications used since the last documentation of medications will be recorded.  Concomitant medications for treatment of AEs related to 
study medication will continue to be recorded while the AE is being followed.  For permitted and prohibited concomitant medications, see Section 4.4. 
p. Haematology includes haemoglobin, haematocrit, platelet count, red blood cell count, white blood cell count, and differential. Blood chemistry includes 
ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin, blood urea nitrogen or urea, LDH, creatinine, glucose, calcium, phosphorus, sodium, 
potassium, chloride and bicarbonate. Patients in the experimental arm will also have magnesium, amylase and lipase tested. Haematology and blood 
chemistry tests must be conducted prior to each treatment cycle, with the results available for review prior to start of treatment according to local 
standards for treatment management. However, only tests conducted every second treatment cycle will be recorded in the eCRF. Clinical laboratory 
results constituting a clinically significant AE should be recorded as such.  
q. INR and aPTT only for patients receiving anticoagulants while on protocol-specified treatment. 
r. 
Urinalysis must be performed by dipstick within 48 hours prior to every cycle.  A 24-hour urine collection is needed in the event of proteinuria ≥ ± 2 by 
dipstick test. Urinalysis results from every second cycle only will be recorded in the CRF. 
s. Urine or blood pregnancy test, only for women of childbearing potential (i.e. not post-menopausal as indicated by < 12 months of non-therapy-induced 
amenorrhea, nor surgically sterile [absence of ovaries and/or uterus]), including those who have had a tubal ligation.  If urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test. 
t. 
Up to and including May 31, 2019, tumour assessments will be conducted according to RECIST 1.1 for Cohort 1 with disease status during maintenance 
treatment determined based on comparison with the tumour assessment done at the end of induction treatment. Assessments will include radiology, 
chest and abdominal CT or MRI, and other scans to document all sites of disease. A CT or MRI scan of the brain is required if there is a clinical suspicion 
of CNS metastases. Up to and including May 31, 2019, tumour assessments will be conducted every eight weeks from the start of maintenance treatment 
regardless of treatment delays. After May 31, 2019, disease status will not be collected for the study and tumour assessments may be conducted per 
local practice. Patients who discontinue study treatment during the Maintenance Treatment Phase prior to disease progression will also continue to be 
followed for progressive disease, with disease assessments per RECIST 1.1 conducted every eight weeks until progression or May 31, 2019, whichever 
comes first. 
u. Supplemental Biomarker Program closed as of May 2018. Collection of these samples has been discontinued (see Appendix 18). 


 
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v. Plasma samples will be collected from all patients for exploratory biomarker analyses. These samples will be sent to a designated laboratory.  Samples 
during treatment should be taken within 48 hours prior to study treatment Day 1 of each cycle indicated, unless otherwise specified (see Appendix 17 and 
the Laboratory Manual). 
w. Adverse events will be documented at every cycle during treatment. All patients will be followed for new AEs for 28 days following the discontinuation of 
study treatment. At the time of treatment discontinuation, any ongoing AE/SAE will be followed until the event resolves, the Investigator assesses the 
event as stable, the patient is lost to follow-up, dies or withdraws consent. Death related to disease progression is not considered to be an SAE.  The 
Sponsor should be notified if the Investigator becomes aware of any SAE or AEs of special interest occurring after the end of the adverse event reporting 
period if the event is believed to be related to prior study treatment. 
x. Patients in the Experimental Arm will receive:  The first six patients in this cohort received 1,600 mg/m2 5-FU administered via 46-hour IV infusion, in 
combination with LV 400 mg/m2 administered via 2-hour infusion, on Day 1 of every 2-week cycle.  Based on results of February 2016 iDMC 
recommendations, subsequent patients in this cohort will receive 1,600 - 2,400 mg/m2 5-FU administered via 46-hour IV infusion (IV bolus is not 
permitted), in combination with LV 400 mg/m2 administered via 2-hour infusion, on Day 1 of every 2-week cycle.  In addition, patients will receive 
cetuximab 500 mg/m2 via IV infusion on Day 1 of every 2-week cycle and vemurafenib 960 mg b.i.d. orally.  Patients in the Control arm will receive: 5-FU 
or capecitabine, dose and schedule will be according to local label, where applicable, or otherwise will be determined per the Investigator’s discretion, 
with bevacizumab 5 mg/kg via 15 – 30 minute IV infusion on Day 1 of every 2-week cycle. If a control arm patient receives capecitabine administered 
according to a 3- week cycle, timing of all study procedures and assessments scheduled according to 2-week treatment cycles (e.g. ECOG performance 
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f. 
Each cohort will consist of an experimental treatment arm and a control arm.  Randomised on a 2:1 (experimental:control) basis to either the experimental 
treatment arm or the control arm of that cohort.  See Section 4.2. 
g. Vital signs include measurements of systolic and diastolic blood pressure while the patient is in a seated position, and temperature. Experimental arm 
only: For the first atezolizumab infusion, the patient’s vital signs (heart rate, respiratory rate, blood pressures, and temperature) should be determined 
within 60 minutes before the infusion, every 15 ± 5 minutes during the infusion, and 30 ± 10 minutes after the infusion. For subsequent infusions, vital 
signs will be collected within 60 minutes before the infusion and should be collected during or after the infusion if clinically indicated or if symptoms 
occurred in the prior infusion. Vital sign measurements from every second treatment cycle only will be recorded in the CRF.  
h. Physical examinations will be symptom-directed, and will include changes from Baseline (pre-Induction) with new or worsened clinically significant 
abnormalities being reported as AEs if appropriate.  
i. 
See Appendix 8. 
j. 
Concomitant medication includes any prescription medications or over-the-counter preparations used by a patient between the 7 days prior to the date of 
informed consent up until the Study Treatment Discontinuation visit.  Only concomitant medications used for supportive care, to alleviate symptoms of 
mCRC, or to treat adverse drug reactions should be recorded on the Concomitant Medications eCRF. At subsequent visits, only changes to current 
medications or medications used since the last documentation of medications will be recorded. Concomitant medications for treatment of AEs related to 
study medication will continue to be recorded while the AE is being followed.   For permitted and prohibited concomitant medications, see Section 4.4. 
k. Haematology includes haemoglobin, haematocrit, platelet count, red blood cell count, white blood cell count, and differential. Blood chemistry includes 
ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin, blood urea nitrogen or urea, LDH, creatinine, glucose, calcium, phosphorus, sodium, 
potassium, chloride, and bicarbonate. Hematology and blood chemistry tests must be conducted prior to each treatment cycle, with the results available 
for review prior to start of treatment according to local standards for treatment management. However, only tests conducted every second treatment cycle 
will be recorded in the eCRF. Clinical laboratory results constituting a clinically significant AE should be recorded as such.  
l. 
INR and aPTT only for patients receiving anticoagulants while on protocol-specified treatment. 
m. Urinalysis must be performed by dipstick within 48 hours prior to every cycle.  A 24-hour urine collection is needed in the event of proteinuria ≥ ± 2 by 
dipstick test. Results from every second cycle only will be recorded in the CRF. 
n. Urine or blood pregnancy test, only for women of childbearing potential (i.e. not post-menopausal as indicated by < 12 months of non-therapy-induced 
amenorrhea, nor surgically sterile [absence of ovaries and/or uterus]), including those who have had a tubal ligation.  If urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test. 
o. Patients with active tuberculosis are not eligible for Cohort 2 and will be excluded from entering the Maintenance Phase of the study. Investigators must 
confirm absence of active disease in patients with a positive test.  
p. HIV testing performed in accordance with national and/or institutional guidelines.  HBV serology includes HBsAg and anti-HBc.  HCV serology includes 
anti-HCV. Results required to determine eligibility for Cohort 2. 
q. Up to and including May 31, 2019, tumour assessments will be conducted according to RECIST1.1 for Cohort 2, and additionally according to mRECIST 
for the experimental arm of Cohort 2. Assessments will include radiology, chest and abdominal CT or MRI, and other scans to document all sites of 
disease. A CT or MRI scan of the brain is required if there is a clinical suspicion of CNS metastases. Disease status during maintenance treatment will be 
determined based on comparison with the tumour assessment done at the end of induction treatment. Up to and including May 31, 2019, tumour 
assessments will be conducted every 8 weeks from the start of maintenance treatment regardless of treatment cycle delays. After May 31, 2019, disease 
status will not be collected for the study and tumour assessments may be conducting per local practice. Tumour assessments for Cohort 2 control arm 


 
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patients will not be collected for study purposes after disease progression per RECIST 1.1 has been documented or May 31, 2019, whichever occurs first. 
Tumour assessments for Cohort 2 experimental arm patients will not be collected for study purposes after disease progression per mRECIST has been 
documented or May 31, 2019, whichever occurs first. Patients who discontinue study treatment during the Maintenance Treatment Phase prior to disease 
progression will also continue to be followed for progressive disease, with disease assessments per RECIST 1.1 or mRECIST (as described above) 
conducted every 8 weeks until progression or May 31, 2019, whichever comes first. 
r. 
Supplemental Biomarker Program closed as of May 2018. Collection of these samples has been discontinued (see Appendix 18). 
s. Plasma samples will be collected from all patients for exploratory biomarker analyses. These samples will be sent to a designated laboratory.  Samples 
during treatment should be taken within 48 hours prior to study treatment Day 1 of each cycle indicated, unless otherwise specified (see Appendix 17 and 
the Laboratory Manual). 
t. 
Adverse events will be documented at every cycle during treatment. Patients in the experimental arm of Cohort 2 will be followed for new AEs for 90 days 
following the discontinuation of study treatment. Patients in the control arm will be followed for new AEs for 28 days following the discontinuation of study 
treatment. At the time of treatment discontinuation, any ongoing AE/SAE will be followed until the event resolves, the Investigator assesses the event as 
stable, the patient is lost to follow-up, dies or withdraws consent. Death related to disease progression is not considered to be an SAE.  The Sponsor 
should be notified if the Investigator becomes aware of any SAE or AEs of special interest occurring after the end of the adverse event reporting period if 
the event is believed to be related to prior study treatment. 
u. Patients in the Experimental Arm will receive 5-FU or capecitabine 1,600 – 2,400 mg/m2 5-FU administered via 46-hour IV infusion (IV bolus is not 
permitted) and LV 400 mg/m2 administered via a 2-hour infusion given day 1 every 2 weeks; or 1000 mg/m2 b.i.d. capecitabine given days 1-14 every 2 
weeks followed by a one-week treatment break. Atezolizumab at a fixed dose of 800 mg administered via 60-minute IV infusion on Day 1 of every 2-week 
cycle (if initial infusion is well tolerated, subsequent infusions will be done over a 30-minute time period) and bevacizumab 5 mg/kg via 15 – 30 minute IV 
infusion on Day 1 of every 2-week cycle.  Patients in the Control arm will receive: 5-FU or capecitabine, dose and schedule will be according to local label, 
where applicable, or otherwise will be determined per the Investigator’s discretion, with bevacizumab 5 mg/kg via 15 – 30 minute IV infusion on Day 1 of 
every 2-week cycle. If a patient receives capecitabine administered according to a 3-week cycle, timing of all study procedures and assessments 
scheduled according to 2-week treatment cycles (e.g. ECOG performance status) will be defined by the treatment cycles of concurrently administered 
bevacizumab (control arm) or concurrently administered bevacizumab and atezolizumab (experimental arm). 






 
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a. With the exception of Cycle 1, all other study visits and assessments should be performed within ± 7 days of the scheduled date. If a control arm patient 
receives capecitabine administered according to a 3- week cycle, timing of all study procedures and assessments scheduled according to 2-week control 
arm treatment cycles (e.g. ECOG performance status) will be defined by the treatment cycles of concurrently administered bevacizumab.  
b. Patients who experience PD at any time during the Maintenance Treatment Phase, or who need to permanently discontinue study medication for any 
reason, will undergo a Study Treatment Discontinuation Visit within 30 days after the last dose of study medication.  These patients will then enter the 
Post-Treatment Follow-up. 
c. After discontinuation of study treatment and the Study Treatment Discontinuation Visit, patients will enter the Post-Treatment Follow-up Phase. Beginning 
after the Study Treatment Discontinuation Visit, patients will be followed up every 3 months. Up to and including May 31, 2019, follow-up will include 
recording subsequent anti-cancer therapies, disease status (until progression as applicable), survival and safety evaluations. Patients who have 
completed the adverse event reporting period and, if applicable, 7 month post-treatment pregnancy test will be discontinued from the study at the post-
treatment follow-up visit within the 3 months prior to and including May 31, 2019 (i.e. at the visit on/after March 1, 2019). After May 31, 2019, patients who 
have not yet completed the adverse event reporting period (and 7 month pregnancy test as applicable) will be discontinued from the study after 
completion of the adverse event reporting period (and 7 month pregnancy test as applicable). Refer to Appendix 19 for the management of patients based 
on their study status as of May 31, 2019. Treatment during the Post-Treatment Follow-up Phase is at the Investigator’s discretion. Patients who 
discontinue study treatment prior to disease progression will be followed for PFS, with disease status followed every 8 weeks until progression or May 31, 
2019, whichever comes first. 
d. Patients completing the Induction Treatment Phase, and who have not experienced PD can then proceed to the Maintenance Treatment Phase.  
Depending on the patient’s biomarker status (based on the archival sample from initial diagnosis), these patients will be assigned to a maintenance 
treatment cohort.  Cohorts 2 and 4 are closed to further accrual.  Patients with an adequate tumour sample but with unknown biomarker status due to lack 
of determinant result (e.g. due to technical issues) may still be included in the study depending on the addition of future cohorts. 
e. The cohort-specific exclusion criteria must be assessed prior to randomization to study maintenance treatment but assessment of cohort-specific eligibility 
can only be completed after the biomarker analysis results from the patient’s archival tumour tissue from initial diagnosis are known. Patients found 
ineligible for any cohort will undergo a Study Treatment Discontinuation Visit and enter the Post-Treatment Follow-up Phase. 
f. 
Each cohort will consist of an experimental treatment arm and a control arm.  Randomised on a 2:1 (experimental:control) basis to either the experimental 
treatment arm or the control arm of that cohort.  See Section 4.2. 
g. Vital signs include measurements of systolic and diastolic blood pressure while the patient is in a seated position, and temperature. For the control arm 
only, vitals conducted every second treatment cycle only will be recorded in the eCRF. 
h. Physical examinations will be symptom-directed, and will include changes from Baseline (pre-Induction) with new or worsened clinically significant 
abnormalities being reported as AEs if appropriate.  
i. 
See Appendix 8. 
j. 
Concomitant medication includes any prescription medications or over-the-counter preparations used by a patient between the 7 days prior to the date of 
informed consent up until the Study Treatment Discontinuation visit.  Only concomitant medications used for supportive care, to alleviate symptoms of 
mCRC, or to treat adverse drug reactions should be recorded on the Concomitant Medications eCRF. At subsequent visits, only changes to current 
medications or medications used since the last documentation of medications will be recorded. Concomitant medications for treatment of AEs related to 
study medication will continue to be recorded while the AE is being followed.   For permitted and prohibited concomitant medications, see Section 4.4. 


 
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k. Haematology includes haemoglobin, haematocrit, platelet count, red blood cell count, white blood cell count, and differential. Blood chemistry includes 
ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin, blood urea nitrogen or urea, LDH, creatinine, glucose, calcium, phosphorus, sodium, 
potassium, chloride, and bicarbonate. Haematology and blood chemistry tests must be conducted prior to each treatment cycle, with the results available 
for review prior to start of treatment according to local standards for treatment management. For the control arm only, tests conducted every second 
treatment cycle only will be recorded in the eCRF. Clinical laboratory results constituting a clinically significant AE should be recorded as such.  
l. 
INR and aPTT only for patients receiving anticoagulants while on protocol-specified treatment. 
m. Urinalysis must be performed by dipstick within 48 hours prior to every cycle.  A 24-hour urine collection is needed in the event of proteinuria ≥ ± 2 by 
dipstick test. For the control arm only, tests conducted every second treatment cycle only will be recorded in the eCRF. 
n. Urine or blood pregnancy test, only for women of childbearing potential (i.e. not post-menopausal as indicated by < 12 months of non-therapy-induced 
amenorrhea, nor surgically sterile [absence of ovaries and/or uterus]), including those who have had a tubal ligation.  If a urine pregnancy test is positive, 
it must be confirmed by a serum pregnancy test. In the experimental arm, a serum pregnancy test must be done ≤ 7 days from maintenance treatment 
start. Urine pregnancy tests must also be done every 3 cycles during treatment (with result available prior to Day 1 dose of the next cycle), and every 3 
months until 7 months after the last doses of trastuzumab and pertuzumab.  
o. HIV testing performed in accordance with national and/or institutional guidelines.  HBV serology includes HBsAg and anti-HBc.  HCV serology includes 
anti-HCV. Results required to determine eligibility for Cohort 3. 
p. LVEF must be assessed in all Cohort 3 patients prior to randomization. Only experimental arm patients require subsequent LVEF monitoring. Subsequent 
LVEF measurements (using the same method as at baseline) will be conducted every third cycle until Cycle 6 and then every fourth cycle until termination 
of study treatment (i.e., during Cycles 3, 6, 10, 14, etc.), with the results made available prior to administration of the subsequent treatment cycle (i.e., 
prior to Cycles 4, 7, 11, 15, etc.). For patients who stop study drug(s) because of a decrease in LVEF, LVEF should be assessed at least every 6 weeks 
to determine recovery/stabilization (until LVEF recovers to ≥ 50% or 2 years, whichever occurs first). In patients who required a repeat LVEF assessment 
to ensure an acceptable LVEF before continuing trastuzumab/pertuzumab treatment, an additional LVEF assessment is to be performed at the next 
treatment cycle. Note: approval of the Medical Monitor must be obtained before continuation of study treatment after delays > 21 days. 
q. Up to and including May 31, 2019, tumour assessments will be conducted according to RECIST1.1 and will include radiology, chest and abdominal CT or 
MRI, and other scans to document all sites of disease. A CT or MRI scan of the brain is required if there is a clinical suspicion of CNS metastases. 
Disease status during maintenance treatment will be determined based on comparison with the tumour assessment done at the end of induction 
treatment. Up to and including May 31, 2019, tumour assessments will be conducted every 8 weeks from the start of maintenance treatment regardless of 
treatment delays. After May 31, 2019, disease status will not be collected for the study and tumour assessments may be conducting per local practice. 
Patients who discontinue study treatment during the Maintenance Treatment Phase prior to disease progression will also continue to be followed for 
progressive disease, with disease assessments per RECIST 1.1 conducted every 8 weeks until progression or May 31, 2019, whichever comes first. 
r. 
Supplemental Biomarker Program closed as of May 2018. Collection of these samples has been discontinued (see Appendix 18). 
s. Plasma samples will be collected from all patients for exploratory biomarker analyses. These samples will be sent to a designated laboratory.  Samples 
during treatment should be taken within 48 hours prior to study treatment Day 1 of each cycle indicated, unless otherwise specified (see Appendix 17 and 
the Laboratory Manual). 
t. 
Adverse events will be documented at every cycle during treatment. Patients in the experimental arm of Cohort 3 will be followed for new AEs for 90 days 
following the discontinuation of study treatment. Patients in the control arm will be followed for new AEs for 28 days following the discontinuation of study 
treatment. At the time of treatment discontinuation, any ongoing AE/SAE will be followed until the event resolves, the Investigator assesses the event as 


 
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stable, the patient is lost to follow-up, dies or withdraws consent. Death related to disease progression is not considered to be an SAE.  The Sponsor 
should be notified if the Investigator becomes aware of any SAE or AEs of special interest occurring after the end of the adverse event reporting period if 
the event is believed to be related to prior study treatment. 
u. Patients in the experimental arm will receive capecitabine 1000 mg/m2 b.i.d. Days 1-14 followed by a one-week treatment break for every 3-week 
treatment cycle. Capecitabine dose calculations by body surface area with corresponding tablet counts are provided in Appendix 7. Trastuzumab will be 
administered by IV infusion on Day 1 of every 3-week treatment cycle at an initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent doses. 
Pertuzumab will be administered by IV infusion on Day 1 of each 3-week treatment cycle at an initial fixed loading dose of 840 mg followed by 420 mg for 
subsequent doses. Patients in the control arm will receive: 5-FU or capecitabine, dose and schedule will be according to local label, where applicable, or 
otherwise will be determined per the Investigator’s discretion, with bevacizumab 5 mg/kg via 15 – 30 minute IV infusion on Day 1 of every 2-week cycle. If 
a control arm patient receives capecitabine administered according to a 3- week cycle, timing of all study procedures and assessments scheduled 
according to 2-week control arm treatment cycles (e.g. ECOG performance status) will be defined by the treatment cycles of concurrently administered 
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signs will be collected within 60 minutes before the infusion and should be collected during or after the infusion if clinically indicated or if symptoms 
occurred in the prior infusion. Vital sign measurements from every second treatment cycle only will be recorded in the eCRF. 
h. Physical examinations will be symptom-directed, and will include changes from Baseline (pre-Induction) with new or worsened clinically significant 
abnormalities being reported as AEs if appropriate.  
i. 
See Appendix 8. 
j. 
Concomitant medication includes any prescription medications or over-the-counter preparations used by a patient between the 7 days prior to the date of 
informed consent up until the Study Treatment Discontinuation visit.  Only concomitant medications used for supportive care, to alleviate symptoms of 
mCRC, or to treat adverse drug reactions should be recorded on the Concomitant Medications eCRF. At subsequent visits, only changes to current 
medications or medications used since the last documentation of medications will be recorded. Concomitant medications for treatment of AEs related to 
study medication will continue to be recorded while the AE is being followed.   For permitted and prohibited concomitant medications, see Section 4.4. 
k. Haematology includes haemoglobin, haematocrit, platelet count, red blood cell count, white blood cell count, and differential. Blood chemistry includes 
ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin, blood urea nitrogen or urea, LDH, creatinine, glucose, calcium, phosphorus, sodium, 
potassium, chloride, bicarbonate. For experimental arm only patients, blood chemistry will also include magnesium, creatine phosphokinase, lipase and 
amylase. Haematology and blood chemistry tests must be conducted prior to treatment administration on Day 1 of each treatment cycle with the results 
available for review prior to start of treatment according to local standards for treatment management. Clinical laboratory results from every second cycle 
only will be recorded in the CRF. Clinical laboratory results constituting a clinically significant AE should be recorded as such.  
l. 
INR and aPTT only for patients receiving anticoagulants while on protocol-specified treatment. 
m. Urinalysis must be performed by dipstick within 48 hours prior to every treatment cycle.  A 24-hour urine collection is needed in the event of proteinuria ≥ 
± 2 by dipstick test. Urinalysis results from every second cycle only will be recorded in the CRF. 
n. Urine or blood pregnancy test, only for women of childbearing potential (i.e. not post-menopausal as indicated by < 12 months of non-therapy-induced 
amenorrhea, nor surgically sterile [absence of ovaries and/or uterus]), including those who have had a tubal ligation.  If urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test. 
o. Patients with active tuberculosis are not eligible for Cohort 4 and will be excluded from entering the Maintenance Phase of the study. Investigators must 
confirm absence of active disease in patients with a positive test.  
p. HIV testing performed in accordance with national and/or institutional guidelines.  HBV serology includes HBsAg and anti-HBc.  HCV serology includes 
anti-HCV.  Results required to determine eligibility for Cohort 4. 
q. LVEF must be assessed in all Cohort 4 patients prior to randomization. Only experimental arm patients require subsequent LVEF monitoring which 
should be conducted every 6 cycles after Cycle 4. In addition, if any experimental arm patient develops clinical signs or symptoms suspicious of cardiac 
failure they should undergo an LVEF assessment without delaying until the next scheduled assessment (i.e. if indicated prior to the next scheduled 
assessment). For experimental arm patients who restart cobimetinib following a delay due to asymptomatic or symptomatic LVEF decrease, LVEF must 
be assessed at 2, 4, 10, and 16 weeks, then every 6 cycles after restarting treatment (see Appendix 16). Evaluation of LVEF must be performed by the 
same method (ECHO or MUGA) for each patient. It is strongly encouraged that the same laboratory and operator perform ECHO/MUGA scans for each 
individual patient. The treatment discontinuation visit evaluation of LVEF does not need to be performed at the treatment discontinuation visit if an 
evaluation has been performed within the last 12 weeks and there are no clinically significant findings and/or changes from baseline. 
r. 
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s. Up to and including May 31, 2019, tumour assessments will be conducted according to RECIST1.1, and additionally according to mRECIST for patients in 
the experimental arm. Assessments will include radiology, chest and abdominal CT or MRI, and other scans to document all sites of disease. A CT or 
MRI scan of the brain is required if there is a clinical suspicion of CNS metastases. Disease status during maintenance treatment will be determined 
based on comparison with the tumour assessment done at the end of induction treatment. Up to and including May 31, 2019, tumour assessments will be 
conducted every 8 weeks from the start of maintenance treatment regardless of treatment cycle delays. After May 31, 2019, disease status will not be 
collected for the study and tumour assessments may be conducting per local practice. Tumour assessments for control arm patients will not be collected 
for study purposes after disease progression per RECIST 1.1 has been documented or May 31, 2019, whichever occurs first. Tumour assessments for 
experimental arm patients will not be collected for study purposes after disease progression per mRECIST has been documented or May 31, 2019, 
whichever occurs first. Patients who discontinue study treatment during the Maintenance Treatment Phase prior to disease progression will also continue 
to be followed for progressive disease, with disease assessments per RECIST 1.1 or mRECIST (as described above) conducted every 8 weeks until 
progression or May 31, 2019, whichever comes first. 
t. 
Supplemental Biomarker Program closed as of May 2018. Collection of these samples has been discontinued (see Appendix 18).   
u. Plasma samples will be collected from all patients for exploratory biomarker analyses. These samples will be sent to a designated laboratory.  Samples 
during treatment should be taken within 48 hours prior to study treatment on the days indicated, unless otherwise specified (see Appendix 17 and the 
Laboratory Manual). 
v. 
Patients in the experimental arm of Cohort 4 will be followed for new AEs for 90 days following the discontinuation of study treatment. Patients in the 
control arm will be followed for new AEs for 28 days following the discontinuation of study treatment. At the time of treatment discontinuation, any ongoing 
AE/SAE will be followed until the event resolves, the Investigator assesses the event as stable, the patient is lost to follow-up, dies or withdraws consent. 
Death related to disease progression is not considered to be an SAE.  The Sponsor should be notified if the Investigator becomes aware of any SAE or 
AEs of special interest occurring after the end of the adverse event reporting period if the event is believed to be related to prior study treatment. 
w. Patients in the experimental arm will receive cobimetinib 60 mg orally once daily for 3 weeks followed by a 1 week treatment break (21/7 schedule). 
Treatment cycle length in this arm is 2 weeks. Cobimetinib will be administered daily every day of each odd numbered 2-week treatment cycle, and for the 
first 7 days only of each even numbered 2-week treatment cycle. Atezolizumab will be administered at a fixed dose of 840 mg administered via 60-minute 
IV infusion on Day 1 of every 2-week cycle (if initial infusion is well tolerated, subsequent infusions will be done over a 30-minute time period).  Patients in 
the control arm will receive: 5-FU or capecitabine, dose and schedule will be according to local label, where applicable, or otherwise will be determined 
per the Investigator’s discretion, with bevacizumab 5 mg/kg via 15 – 30 minute IV infusion on Day 1 of every 2-week cycle. If a control arm patient 
receives capecitabine administered according to a 3- week cycle, timing of all study procedures and assessments scheduled according to 2-week 
treatment cycles (e.g. ECOG performance status) will be defined by the treatment cycles of concurrently administered bevacizumab. 
 


 
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11.6 
APPENDIX 6  FOLFOX REGIMENS: INDUCTION TREATMENT 
PHASE 
The choice of FOLFOX regimen administered with bevacizumab in the Induction Treatment 
Phase is according to the Investigator’s discretion. Typical FOLFOX regimens are described 
below.   
FOLFOX-4 
• 
Oxaliplatin: 85 mg/m2 by 2-hour IV infusion, Day 1 of every 2 week cycle 
• 
Leucovorin: 200 mg/m2 by 2-hour IV infusion, Day 1 and Day 2 of every 2 week cycle 
• 
5-FU: 400 mg/m2 IV bolus loading dose on Day 1 then 600 mg/m2 by 22-hour IV infusion, 
Day 1 and Day 2 of every 2 week cycle. 
FOLFOX-6 
• 
Oxaliplatin: 100 mg/m2 by 2-hour IV infusion, Day 1 of every 2 week cycle 
• 
Leucovorin: 400 mg/m2 by 2-hour IV infusion, Day 1 of every 2 week cycle 
• 
5-FU: 400 mg/m2 IV bolus loading dose then 3,000 mg/m2 by 46-hour IV infusion, Day 1 
of every 2 week cycle 
modified FOLFOX-6 
• 
Oxaliplatin: 85 mg/m2 by 2-hour IV infusion on Day 1 of every 2 week cycle 
• 
Leucovorin: 400 mg/m2 by 2-hour IV infusion on Day 1 of every 2 week cycle 
• 
5-FU: 400 mg/m2 IV bolus loading dose on Day 1 then 2,400 by 46-hour IV infusion 
starting Day 1 of every 2 week cycle 
FOLFOX-7 
• 
Oxaliplatin: 130 mg/m2 by 2-hour IV infusion, Day 1 of every 2 week cycle 
• 
Leucovorin: 400 mg/m2 by 2-hour IV infusion, Day 1 of every 2 week cycle 
• 
5-FU: 2,400 mg/m2 by 46-hour IV infusion, Day 2 of every 2 week cycle. 
modified FOLFOX-7 
• 
Oxaliplatin: 85 mg/m2 by 2-hour IV infusion, Day 1 of every 2 week cycle 
• 
Leucovorin: 200 mg/m2 by 2-hour IV infusion, Day 1 of every 2 week cycle 
• 
5-FU: 2,400 mg/m2 by 46-hour IV infusion, Day 2 of every 2 week cycle. 






 
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11.9 
APPENDIX 9  PRE-EXISTING AUTOIMMUNE DISEASES 
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune 
deficiencies or autoimmune disease are excluded from participating in the study.  Possible 
exceptions to this exclusion could be patients with a medical history of such entities as 
atopic disease or childhood arthralgias where the clinical suspicion of autoimmune disease 
is low.  Patients with a history of autoimmune-related hypothyroidism on a stable dose of 
thyroid replacement hormone may be eligible for this study.  In addition, transient 
autoimmune manifestations of an acute infectious disease that resolved upon treatment of 
the infectious agent are not excluded (e.g., acute Lyme arthritis).  Please contact the Medical 
Monitor regarding any uncertainty over autoimmune exclusions. 
 


 
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11.10 
APPENDIX 10  RECIST 1.1 
1. 
MEASURABILITY OF TUMOUR AT BASELINE 
1.1 
Definitions 
At baseline, tumour lesions/lymph nodes will be categorized measurable or non-measurable 
as follows: 
1.1.1 
Measurable 
Tumour lesions: Must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of: 
• 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
• 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
• 
20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed. 
1.1.2 
Non-measurable 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions.  Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
1.1.3 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment: 
Bone lesions: 
• 
Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence 
or disappearance of bone lesions. 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• 
Blastic bone lesions are non-measurable. 


 
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Cystic lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
• 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
noncystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment: 
• 
Tumour lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
1.2 
Specifications by methods of measurements 
1.2.1 
Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed.  
All baseline evaluations should be performed as close as possible to the treatment start and 
never more than 4 weeks before the beginning of the treatment. 
1.2.2 
Method of assessment 
The same method of assessment and the same technique should be used to characterise 
each identified and reported lesion at baseline and during follow-up. Imaging based 
evaluation should always be done rather than clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and ≥ 10 mm diameter as assessed using calipers (e.g. skin nodules).  For the case of skin 
lesions, documentation by colour photography including a ruler to estimate the size of the 
lesion is suggested.  As noted above, when lesions can be evaluated by both clinical exam 
and imaging, imaging evaluation should be undertaken since it is more objective and may 
also be reviewed at the end of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions.  However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less.  When CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as 
a method of measurement.  Ultrasound examinations cannot be reproduced in their entirety 


 
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for independent review at a later date and, because they are operator dependent, it cannot 
be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT or MRI is advised.  If there is concern about radiation exposure at CT, 
MRI may be used instead of CT in selected instances. 
Endoscopy, laparoscopy: The utilisation of these techniques for objective tumour evaluation 
is not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following CR or 
surgical resection is an endpoint. 
Tumour markers: Tumour markers alone cannot be used to assess objective tumour 
response. If markers are initially above the upper normal limit, however, they must normalise 
for a patient to be considered in CR.  Because tumour markers are disease specific, 
instructions for their measurement should be incorporated into protocols on a disease 
specific basis. 
Cytology, histology: These techniques can be used to differentiate between PR and CR in 
rare cases if required by protocol (for example, residual lesions in tumour types such as 
germ cell tumours, where known residual benign tumours can remain).  When effusions are 
known to be a potential adverse effect of treatment (e.g. with certain taxane compounds or 
angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any effusion 
that appears or worsens during treatment can be considered if the measurable tumour has 
met criteria for response or stable disease in order to differentiate between response (or 
stable disease) and progressive disease. 
2. 
TUMOUR RESPONSE EVALUATION 
2.1 
Assessment of overall tumour burden and measurable disease 
To assess objective response or future progression, it is necessary to estimate the overall 
tumour burden at baseline and use this as a comparator for subsequent measurements.  
Only patients with measurable disease at baseline should be included in protocols where 
objective tumour response is the primary endpoint.  Measurable disease is defined by the 
presence of at least one measurable lesion. In studies where the primary endpoint is tumour 
progression (either time to progression or proportion with progression at a fixed date), the 
protocol must specify if entry is restricted to those with measurable disease or whether 
patients having non-measurable disease only are also eligible. 
2.2 
Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum 
of five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline 
(this means in instances where patients have only one or two organ sites involved a 
maximum of two and four lesions respectively will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that lend 


 
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themselves to reproducible repeated measurements.  It may be the case that, on occasion, 
the largest lesion does not lend itself to reproducible measurement in which circumstance 
the next largest lesion which can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may 
be visible by imaging even if not involved by tumour. Pathological nodes which are defined 
as measurable and may be identified as target lesions must meet the criterion of a short axis 
of ≥ 15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline 
sum.  The short axis of the node is the diameter normally used by radiologists to judge if a 
node is involved by solid tumour. Nodal size is normally reported as two dimensions in the 
plane in which the image is obtained (for CT scan this is almost always the axial plane; for 
MRI the plane of acquisition may be axial, saggital or coronal). The smaller of these 
measures is the short axis. For example, an abdominal node which is reported as being 
20 mm × 30 mm has a short axis of 20 mm and qualifies as a malignant, measurable node.  
In this example, 20 mm should be recorded as the node measurement.  All other 
pathological nodes (those with short axis ≥ 10 mm but < 15 mm) should be considered non-
target lesions. Nodes that have a short axis < 10 mm are considered non-pathological and 
should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes 
are to be included in the sum, then as noted above, only the short axis is added into the sum.  
The baseline sum diameters will be used as reference to further characterise any objective 
tumour regression in the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline.  Measurements are not 
required and these lesions should be followed as ‘present’, ‘absent’, or in rare cases 
‘unequivocal progression’.  In addition, it is possible to record multiple non-target lesions 
involving the same organ as a single item on the case record form (e.g. ‘multiple enlarged 
pelvic lymph nodes’ or ‘multiple liver metastases’). 
2.3 
Response criteria 
This section provides the definitions of the criteria used to determine objective tumour 
response for target lesions. 
2.3.1 
Evaluation of target lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note:  the appearance of one or more 
new lesions is also considered progression). 


 
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Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
2.3.2 
Special notes on the assessment of target lesions 
Lymph nodes.  Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study.  This means that when 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if CR 
criteria are met, since a normal lymph node is defined as having a short axis of < 10 mm.  
Case report forms or other data collection methods may therefore be designed to have 
target nodal lesions recorded in a separate section where, in order to qualify for CR, each 
node must achieve a short axis < 10 mm.  For PR, SD and PD, the actual short axis 
measurement of the nodes is to be included in the sum of target lesions. 
Target lesions that become ‘too small to measure’.  While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g. 2 mm).  However, sometimes lesions or 
lymph nodes which are recorded as target lesions at baseline become so faint on CT scan 
that the radiologist may not feel comfortable assigning an exact measure and may report the 
mass being ‘too small to measure’.  When this occurs it is important that a value be recorded 
on the case report form. If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm.  If the lesion is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned (Note:  It is less likely that this rule will be used for lymph nodes since they usually 
have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but 
too small to measure, a default value of 5 mm should be assigned in this circumstance as 
well).  This default value is derived from the 5 mm CT slice thickness (but should not be 
changed with varying CT slice thickness).  The measurement of these lesions is potentially 
non-reproducible, therefore providing this default value will prevent false responses or 
progressions based upon measurement error.  To reiterate, however, if the radiologist is able 
to provide an actual measure, that should be recorded, even if it is below 5 mm. 
Lesions that split or coalesce on treatment.  When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion 
sum.  Similarly, as lesions coalesce, a plane between them may be maintained that would 
aid in obtaining maximal diameter measurements of each individual lesion.  If the lesions 
have truly coalesced such that they are no longer separable, the vector of the longest 
diameter in this instance should be the maximal longest diameter for the ‘coalesced lesion’. 
2.3.3 
Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumour response 
for the group of non-target lesions.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only qualitatively 
at the time points specified in the protocol. 
CR: Disappearance of all non-target lesions and normalisation of tumour marker level. All 
lymph nodes must be non-pathological in size (< 10 mm short axis). 


 
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Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumour marker level above the normal limits. 
PD: Unequivocal progression of existing non-target lesions. (Note:  the appearance of one or 
more new lesions is also considered progression). 
2.3.4 
Special notes on assessment of progression of nontarget disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When the patient also has measurable disease.  In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in 
target disease, the overall tumour burden has increased sufficiently to merit discontinuation 
of therapy.  A modest ‘increase’ in the size of one or more non-target lesions is usually not 
sufficient to quality for unequivocal progression status. The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of 
target disease will therefore be extremely rare. 
When the patient has only non-measurable disease.  This circumstance arises in some 
Phase III trials when it is not a criterion of study entry to have measurable disease.  The 
same general concepts apply here as noted above, however, in this instance there is no 
measurable disease assessment to factor into the interpretation of an increase in non-
measurable disease burden.  Because worsening in non-target disease cannot be easily 
quantified (by definition: if all lesions are truly non-measurable) a useful test that can be 
applied when assessing patients for unequivocal progression is to consider if the increase in 
overall disease burden based on the change in non-measurable disease is comparable in 
magnitude to the increase that would be required to declare PD for measurable disease: i.e. 
an increase in tumour burden representing an additional 73% increase in ‘volume’ (which is 
equivalent to a 20% increase diameter in a measurable lesion).  Examples include an 
increase in a pleural effusion from ‘trace’ to ‘large’, an increase in lymphangitic disease from 
localised to widespread, or may be described in protocols as ‘sufficient to require a change 
in therapy’.  If ‘unequivocal progression’ is seen, the patient should be considered to have 
had overall PD at that point.  While it would be ideal to have objective criteria to apply to 
non-measurable disease, the very nature of that disease makes it impossible to do so, 
therefore the increase must be substantial. 
2.3.5 
New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e. not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumour (for example, some 
‘new’ bone lesions may be simply healing or flare of pre-existing lesions). This is particularly 
important when the patient’s baseline lesions show partial or complete response. For 
example, necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic 
lesion, which it is not. 


 
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A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of 
this is the patient who has visceral disease at baseline and while on study has a CT or MRI 
brain ordered which reveals metastases. The patient’s brain metastases are considered to 
be evidence of PD even if he/she did not have brain imaging at baseline. If a new lesion is 
equivocal, for example because of its small size, continued therapy and follow-up evaluation 
will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible ‘new’ disease). New lesions on the basis of FDG-PET 
imaging can be identified according to the following algorithm: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: 
̶ 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed 
by CT, this is PD. 
̶ 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). 
̶ 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on 
CT that is not progressing on the basis of the anatomic images, this is not PD. 
2.4 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment taking into account any requirement for confirmation.  On 
occasion a response may not be documented until after the end of therapy so protocols 
should be clear if post-treatment assessments are to be considered in determination of best 
overall response.  Protocols must specify how any new therapy introduced before 
progression will affect best response designation.  The patient’s best overall response 
assignment will depend on the findings of both target and non-target disease and will also 
take into consideration the appearance of new lesions.  Furthermore, depending on the 
nature of the study and the protocol requirements, it may also require confirmatory 
measurement.  Specifically, in non-randomised trials where response is the primary endpoint, 
confirmation of PR or CR is needed to deem either one the ‘best overall response’.  This is 
described further below. 
2.4.1 
Time point response 
It is assumed that at each protocol specified time point, a response assessment occurs.  
Table A provides a summary of the overall response status calculation at each time point for 
patients who have measurable disease at baseline. 






 
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In trials where confirmation of response is required, repeated ‘NE’ time point assessments 
may complicate best response determination. The analysis plan for the trial must address 
how missing data/assessments will be addressed in determination of response and 
progression.  For example, in most trials it is reasonable to consider a patient with time point 
responses of PR-NE-PR as a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. The objective response status 
of such patients is to be determined by evaluation of target and non-target disease as shown 
in Table A, Table B, and Table C. 
Conditions that define ‘early progression, early death and inevaluability’ are study specific 
and should be clearly described in each protocol (depending on treatment duration, 
treatment periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
assigning a status of complete response. FDG-PET may be used to upgrade a response to a 
CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is 
thought to represent fibrosis or scarring. The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease specific medical literature 
for the indication. However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
2.5 
Frequency of tumour re-evaluation 
Frequency of tumour re-evaluation while on treatment should be protocol specific and 
adapted to the type and schedule of treatment. However, in the context of Phase II studies 
where the beneficial effect of therapy is not known, follow-up every 6–8 weeks (timed to 
coincide with the end of a cycle) is reasonable. Smaller or greater time intervals than these 
could be justified in specific regimens or circumstances. The protocol should specify which 
organ sites are to be evaluated at baseline (usually those most likely to be involved with 
metastatic disease for the tumour type under study) and how often evaluations are repeated.  
Normally, all target and non-target sites are evaluated at each assessment. In selected 
circumstances certain non-target organs may be evaluated less frequently. For example, 
bone scans may need to be repeated only when complete response is identified in target 
disease or when progression in bone is suspected. 
After the end of the treatment, the need for repetitive tumour evaluations depends on 
whether the trial has as a goal the response rate or the time to an event (progression/death). 


 
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If ‘time to an event’ (e.g. time to progression, disease-free survival, progression-free survival) 
is the main endpoint of the study, then routine scheduled re-evaluation of protocol specified 
sites of disease is warranted. In randomised comparative trials in particular, the scheduled 
assessments should be performed as identified on a calendar schedule (for example: every 
6–8 weeks on treatment or every 3–4 months after treatment) and should not be affected by 
delays in therapy, drug holidays or any other events that might lead to imbalance in a 
treatment arm in the timing of disease assessment. 
2.6 
Confirmatory measurement/duration of response 
2.6.1 
Confirmation 
In non-randomised trials where response is the primary endpoint, confirmation of PR and CR 
is required to ensure responses identified are not the result of measurement error. This will 
also permit appropriate interpretation of results in the context of historical data where 
response has traditionally required confirmation in such trials. However, in all other 
circumstances, i.e. in randomised trials (Phase II or III) or studies where stable disease or 
progression are the primary endpoints, confirmation of response is not required since it will 
not add value to the interpretation of trial results. However, elimination of the requirement for 
response confirmation may increase the importance of central review to protect against bias, 
in particular in studies which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after study 
entry at a minimum interval (in general not less than 6–8 weeks) that is defined in the study 
protocol. 
2.6.2 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first 
met for CR/PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded on study). 
The duration of overall complete response is measured from the time measurement criteria 
are first met for CR until the first date that recurrent disease is objectively documented. 
2.6.3 
Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomised trials, from date of 
randomisation) until the criteria for progression are met, taking as reference the smallest 
sum on study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of stable disease varies in different studies and 
diseases. If the proportion of patients achieving stable disease for a minimum period of time 
is an endpoint of importance in a particular trial, the protocol should specify the minimal time 
interval required between two measurements for determination of stable disease. 
REFERENCES: 
Eisenhauer EA, et al.  New response evaluation criteria in solid tumours:  Revised RECIST 
guideline (version 1.1).  Eur J Cancer.  2009 Jan;45(2):228-47. 




 
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thickness recommended to be no greater than 5 mm). At baseline and follow-up, only the 
short axis will be measured and followed. 
1.2 
Non-measurable lesions 
Non-measurable tumour lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with short axis ≥ 10 but < 15 mm), as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin 
or lung, peritoneal spread, and abdominal mass/abdominal organomegaly identified by 
physical examination that is not measurable by reproducible imaging techniques. 
2 
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
2.1 
Bone lesions 
Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques for measuring bone lesions. However, these techniques can 
be used to confirm the presence or disappearance of bone lesions. 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
Blastic bone lesions are non-measurable. 
2.2 
Cystic lesions 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
2.3 
Lesions with prior local treatment 
Tumour lesions situated in a previously irradiated area or in an area subjected to other loco-
regional therapy are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions under 
which such lesions would be considered measurable. 


 
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3 
TUMOUR RESPONSE EVALUATION 
3.1 
Definitions of target/non-target lesions 
3.1.1 
Target Lesions 
When more than one measurable lesion is present at baseline, all lesions up to a maximum 
of five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline. 
This means that, for instances in which patients have only one or two organ sites involved, a 
maximum of two lesions (one site) and four lesions (two sites), respectively, will be recorded. 
Other lesions (albeit measurable) in those organs will be recorded as non-measurable 
lesions (even if the size is > 10 mm by CT scan). 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition, should lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, 
the largest lesion does not lend itself to reproducible measurement, in which circumstance, 
the next largest lesion that can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures that may be 
visible by imaging even if not involved by tumour. As noted above, pathological nodes that 
are defined as measurable and may be identified as target lesions must meet the criterion of 
a short axis of ≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to the 
baseline sum. The short axis of the node is the diameter normally used by radiologists to 
judge if a node is involved by solid tumour. Nodal size is normally reported as two 
dimensions in the plane in which the image is obtained (for CT, this is almost always the 
axial plane; for MRI, the plane of acquisition may be axial, sagittal, or coronal). The smaller 
of these measures is the short axis. For example, an abdominal node that is reported as 
being 20 mm x 30 mm has a short axis of 20 mm and qualifies as a malignant, measurable 
node. In this example, 20 mm should be recorded as the node measurement. All other 
pathological nodes (those with short axis ≥ 10 mm but <15 mm) should be considered non-
target lesions. Nodes that have a short axis of < 10 mm are considered non-pathological and 
should not be recorded or followed. 
Lesions irradiated within 3 weeks prior to Cycle 1, Day 1 may not be counted as target 
lesions. 
3.1.2 
Non-Target Lesions 
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline. Measurements are 
not required. 
It is possible to record multiple non-target lesions involving the same organ as a single item 
on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph nodes” or “multiple 
liver metastases”). 
After baseline, changes in non-target lesions will contribute only in the assessment of 
complete response (i.e., a complete response is attained only with the complete 


 
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disappearance of all tumour lesions, including non-target lesions) and will not be used to 
assess progressive disease. 
3.2 
Calculation of sum of the diameters 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated as a measure of tumour burden. 
The sum of the diameters is calculated at baseline and at each tumour assessment for the 
purpose of classification of tumour responses. 
Sum of the Diameters at Baseline: The sum of the diameters for all target lesions identified 
at baseline prior to treatment on Day 1. 
Sum of the Diameters at Tumour Assessment: For every on-study tumour assessment 
collected per protocol or as clinically indicated, the sum of the diameters at tumour 
assessment will be calculated using tumour imaging scans. All target lesions and all new 
measurable lesions that have emerged after baseline will contribute to the sum of the 
diameters at tumour assessment. Hence, each net percentage change in tumour burden per 
assessment with use of modified RECIST accounts for the size and growth kinetics of both 
old and new lesions as they appear. 
3.3 
Response criteria 
3.3.1 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Lymph nodes that shrink to 
< 10 mm short axis are considered normal. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of all target 
and all new measurable lesions, taking as reference the baseline sum of diameters, in the 
absence of CR. 
Note:  The appearance of new measurable lesions is factored into the overall tumour burden 
but does not automatically qualify as progressive disease until the sum of the diameters 
increases by ≥ 20% when compared with the sum of the diameters at nadir. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of the diameters while on study. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of all target 
and all new measurable lesions, taking as reference the smallest sum on study (this includes 
the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, 
the sum must also demonstrate an absolute increase of at least 5 mm. 
3.3.2 
Impact of New Lesions on Modified RECIST 
New lesions alone do not qualify as progressive disease. However, their contribution to total 
tumour burden is included in the sum of the diameters, which is used to determine the 
overall modified RECIST tumour response. 




 
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b. PR: Decrease in the sum of the diameters of all target and all new measurable lesions 
≥ 30% relative to baseline, in the absence of CR, confirmed by a consecutive 
assessment ≥ 4 weeks from the date first documented. 
c. SD: Criteria for CR, PR, and PD are not met. 
d. PD: Increase in the sum of the diameters of all target and all new measurable lesions 
≥ 20% relative to the nadir, which may be confirmed by a consecutive assessment 
≥ 4 weeks from the date first documented as follows: 
The confirmatory assessment shows an additional measurable increase in tumour 
burden as measured by the sum of the diameters of all target and all new measurable 
lesions. 
This protocol allows patients to continue to receive study treatment even after confirmed 
radiographic PD per modified RECIST, and patients may achieve a best overall response of 
PR or CR based on tumour regression achieved at any time prior to study treatment 
discontinuation. 
REFERENCES: 
1. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228−47. 
2. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy 
activity 
in 
solid 
tumors: 
immune-related 
response 
criteria. 
Clin 
Can 
Res 
2009;15:7412−20. 
3. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of 
anti−PD-1 antibody in cancer. N Engl J Med 2012;366:2443−54. 








 
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11.14 
APPENDIX 14  CETUXIMAB PACKAGE INSERT 
Please refer to the below European Medicines Agency hyperlink: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000558/WC500029119.pdf 


 
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11.15 
APPENDIX 15  CARDIAC TOXICITY MANAGEMENT AND 
REPORTING CONVENTIONS WITH TRASTUZUMAB AND 
PERTUZUMAB 
Pertuzumab and trastuzumab should be discontinued in any Cohort 3 experimental arm 
patient who develops clinical signs and symptoms suggesting CHF, with the diagnosis 
confirmed by a suggestive chest X-ray and a drop in LVEF by ECHO or MUGA. CHF should 
be treated and monitored according to standard medical practice. At the present time, there 
are inadequate data available to assess the prognostic significance of asymptomatic drops 
of LVEF. However, to ensure patient safety, pertuzumab and trastuzumab must be 
discontinued in all patients for whom a drop of LVEF to a value lower than 40% is 
documented and confirmed with a repeat assessment within 3 weeks of the first assessment, 
using the same assessment method. 
For Cohort 3 experimental arm patients whose LVEF drops to values lower than 45%, the 
decision to stop or continue study treatment is based on the algorithm shown in Figure 3. In 
patients who required a repeat LVEF assessment to ensure an acceptable LVEF before 
continuing trastuzumab/pertuzumab treatment, an additional LVEF assessment is to be 
performed at the next treatment cycle. Note approval of the Medical Monitor must be 
obtained before continuation of study treatment after delays > 21 days. 
Cohort 3 experimental arm patients for whom study treatment was permanently discontinued 
because of a drop in LVEF should continue to have LVEF assessments repeated as 
clinically indicated, with a maximum interval between LVEF assessments of 6 weeks, until 
the LVEF values return to ≥ 50% or for 2 years, whichever occurs first. 
All patient management decisions will be made by the investigator based on local LVEF 
assessments. LVEF assessment results must be available before or on the day of the next 
scheduled trastuzumab administration, and a decision to give or hold that dose must be 
made based on the algorithm in Figure 3. In addition, any patient who develops clinical signs 
or symptoms suspicious of cardiac failure at any time during the study should undergo an 
LVEF assessment immediately. 
Note:  Anemia can occur in patients receiving treatment with capecitabine. Because anemia 
might place a strain on the myocardium, transfusion should be considered for Cohort 3 
experimental arm patients whose hemoglobin levels fall during study treatment, particularly if 
the anemia is symptomatic. Transfusion of packed red blood cells is preferred over 
transfusion of whole blood so as to minimise the fluid load. 
Appropriate methods for AE and AE of special interest reporting of left ventricular systolic 
dysfunction/heart failure in Cohort 3 experimental arm patients are shown in Table 1 of this 
appendix.  


 
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Figure 3: 
Trastuzumab/Pertuzumab Dose Management for Left Ventricular 
Dysfunction 
 


































 
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11.17 
APPENDIX 17  BIOMARKER ASSESSMENTS 
11.17.1 
Archival Primary Tumour Block from Initial Diagnosis 
For all patients (including those enrolled in the Supplemental Biomarker Program), 
biomarker assessments determining cohort assignment and stratification will be conducted 
on archival tumour tissue (FFPET) block from primary tumour used for their initial CRC 
diagnoses that was obtained as part of standard clinical practice. The primary tumour 
specimen was selected for biomarker assessment for consistency and comparability reasons, 
as they are the only samples collected for all study patients. If the tumour block is not 
available, ≥ 20 slides cut from the primary tumour sample will be accepted as an alternative. 
After a patient has provided informed consent to participate in the study, but before they can 
be enrolled in the study, their sample must be shipped to the designated laboratory with the 
corresponding pathology report and receipt of shipment must be confirmed by the 
designated laboratory. Patients without confirmed receipt of their primary tumour sample 
(either the block or ≥ 20 slides) at the designated laboratory are not eligible for the study. 
Tumour blocks from patients who are not enrolled in the study and remainders of tumour 
blocks from patients who are enrolled in the study will be returned to the study site. 
Biomarker results to determine cohort assignment (see Figure 4) will be available to IxRS 
during the Induction Treatment Phase.  
Next generation sequencing may be performed by Foundation Medicine.  If performed by 
Foundation Medicine, the Investigator can obtain results from the samples collected at the 
time of disease progression in the form of an NGS report, which is available upon request 
directly from Foundation Medicine.  The Investigator may share and discuss the results with 
the patient, unless the patient chooses otherwise.  The Foundation Medicine NGS assay has 
not been cleared or approved by health authorities.  The NGS report is generated for 
research purposes and is not provided for the purposes of guiding future treatment decisions. 
11.17.2 
Biomarker Testing for Cohort Assignment 
Tumour (non-inherited) DNA will be isolated from archival tumour blocks for NGS on tumour 
related genes. Results from this analysis on the following biomarkers only will guide 
maintenance treatment cohort assignment (shown in Figure 4):  
a. HER2: gene copy numbers ≥ 5 will be considered as amplified and HER2+ for the 
purposes of cohort assignment. Amplified samples will be reflex tested by HER2 
IHC/FISH. HER2 overexpression by IHC is a stratification variable in Cohort 3 
randomization (IHC0/IHC1+/IHC2+ vs. IHC3+). 
b. MSI: microsatellite stability determined as stable (MSS) or unstable (MSI-H)   
c. BRAF: determined as either mutated (BRAFmut) or wild-type (BRAFwt) 
d. KRAS and NRAS: activating RAS gene mutations. 


 
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Figure 4: 
Biomarker-based Cohort Assignment Decision Tree 
 
Patients with an adequate tumour sample but without biomarker results available for cohort 
assignment due to lack of determinant test outcome (e.g. due to technical issues) may still 
be included in the study depending on the addition of future cohorts. Patients who are not 
eligible for their assigned cohort will undergo a Study Treatment Discontinuation Visit and 
enter the Post-Treatment Follow-up Phase.   
11.17.3 
Biomarker Stratification Variables 
Randomisation in Cohorts 3 and 4 will be stratified by biomarkers.  


 
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Randomisation in Cohort 3 will be stratified by IHC result (IHC0/IHC1+/IHC2+ vs. IHC3+) in 
addition to patient response after induction treatment (CR/PR vs. SD). 
Randomisation in Cohort 4 will be stratified by microsatellite stability (MSI-H vs. MSS) and 
RAS status (wild-type KRAS and NRAS vs. mutant KRAS and/or NRAS) in addition to region 
(EU vs. rest of world) and patient response after induction treatment (CR/PR vs. SD). 
11.17.4 
Core Biopsy of Metastases  
Prior to May 2018, a core tumour biopsy of metastases at baseline was optional for all 
patients. Since May 2018, these samples are not being collected.  
Additional core tumour biopsies of metastases were required from patients participating in 
the Supplemental Biomarker Program (see Appendix 18) post-induction (but before start of 
maintenance) and at progression. The Supplemental Biomarker Program was closed in May 
2018 and no further samples are being collected.  
Baseline metastatic tumour samples and Supplemental Biomarker Program samples 
obtained prior to the May 2018 discontinuation of collection may still be used for exploratory 
biomarker analyses. 
11.17.5 
Stool Sample 
Stool samples were collected from all Supplemental Biomarker Program Participants at 
screening (prior to start of induction treatment), at completion of induction treatment (prior to 
start of maintenance treatment) and at disease progression (see Appendix 18). The 
Supplemental Biomarker Program was closed in May 2018 and no further samples are being 
collected. Sample collected up to this timepoint may still be used for exploratory biomarker 
analyses. 
11.17.6 
Exploratory Biomarker Outcome Measures 
The exploratory biomarker outcome measures for this study include molecular markers, 
marker profiles, microbiome results and efficacy and/or safety outcomes.  Efficacy outcomes 
considered for this analysis may include ORR, PFS and OS, as appropriate. 
Non-inherited (somatic) biomarkers and biomarker profiles will be assessed using multiple 
technologies including but not limited to IHC and RNA/DNA sequencing methods (e.g. 
polymerase chain reaction, NGS). These tests will be conducted on material that includes 
proteins, DNA and RNA obtained from tumour tissue, peripheral blood and stool.  
Profiling of inherited (germline) markers obtained from peripheral blood may be performed in 
countries where allowed by federal law. 
 


 
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11.17.7 
Whole Blood and Plasma Biomarker Assessments 
Figure 5: 
Blood Biomarker Sample Collections 
 
Whole blood (unless genomic analysis not allowed per federal regulations) and plasma testing will be performed for all study patients.  All 
samples during treatment should be taken within 48 hours before study treatment administration on Day 1 of cycle, unless otherwise specified.  
Please refer to the study’s Laboratory Manual for further information including sample quality requirements, sample preparation methods, 
shipping and handling. 
 


 
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11.18 
APPENDIX 18  SUPPLEMENTAL BIOMARKER PROGRAM  
 
As of May 2018, the Supplemental Biomarker Program is closed (no further samples 
collected) and collection of the optional baseline tumour sample has ended. Baseline 
metastatic tumour samples and Supplemental Biomarker Program samples collected up to 
this time point may still be used for exploratory biomarker analyses. 
Prior to May 2018, selected study sites participating in the Supplemental Biomarker Program 
collected samples from patients enrolled at these sites who had provided separate informed 
consent to participate in the program.  
Participation in the program involved obtaining additional metastatic tumour tissue biopsies 
and stool samples at the following time points as shown in Figure 6: 
a. Stool: mandatory at screening (prior to initiation of induction treatment) 
b. Metastatic tumour tissue: mandatory if clinically feasible at completion of study induction 
treatment, prior to initiation of study maintenance treatment  
c. Stool: mandatory at completion of study induction treatment, prior to initiation of study 
maintenance treatment 
d. Metastatic tumour tissue: mandatory if clinically feasible at disease progression during 
the Induction or Maintenance Treatment Phases 
e. Stool: mandatory at disease progression during induction or maintenance treatment 
study phases. Sample may be collected at the time of the Study Treatment 
Discontinuation Visit. 
Samples were submitted to the designated laboratory for inclusion in the exploratory 
biomarker analyses described in Appendix 17. 
Please refer to the study’s Laboratory Manual for further information including sample 
quality requirements, sample preparation methods, shipping and handling.  
 


 
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Figure 6: 
Mandatory and Supplemental Biomarker Program Tumour and Stool Sampling 
Optional Baseline Tumour and Supplemental Biomarker Program- Discontinued May 2018 
 
Archival Tumour Sample: Mandatory for all patients:  Assessment of biomarkers for cohort assignment will be based on archival primary tumour samples for all patients. 
Prior to performing any screening procedures, the Investigator must ensure that adequate archival tissue from a potential participant’s primary tumour is 
available. The sample must be shipped to the Sponsor’s designated laboratory and sample receipt confirmed by the laboratory before study enrolment.  If the 
tumour block is not available, ≥ 20 slides cut from the primary tumour sample will be accepted as an alternative. 
Tumour Biopsy 1: Collection of the optional sample discontinued May 2018.  
Tumour Biopsy 2: Supplemental Biomarker Program sample collection discontinued May 2018.  
Tumour Biopsy 3: Supplemental Biomarker Program sample collection discontinued May 2018.  
Stool Samples: 
Supplemental Biomarker Program sample collection discontinued May 2018. 
 





SAP_001.pdf: 
 
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(s): 
Cohort 1 SAP Version 1.1: 06-Jun-2019 
Cohort 2 SAP Addendum Version 2.0: 02-Aug-2018 
Cohort 2 SAP Version 2.0: 15-Sep-2017 
Cohort 3 SAP Version 1.0: 09-May-2019 
Cohort 4 SAP Version 1.0: 09-May-2019 
 
 


CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
Bevacizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29112 Cohort 1 (Version 1.1) 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A MULTI-CENTRE RANDOMISED CLINICAL TRIAL OF 
BIOMARKER-DRIVEN MAINTENANCE TREATMENT FOR 
FIRST-LINE METASTATIC COLORECTAL CANCER (MODUL) 
COHORT 1 
PROTOCOL NUMBER: 
MO29112 
COHORT 1 STUDY 
DRUGS: 
 
bevacizumab (RO4876646) 
vemurafenib (RO5185426) 
cetuximab 
VERSION NUMBER: 
1.1 
IND NUMBER: 
N/A  
EUDRACT NUMBER: 
2014-001017-61 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
, Cytel, Inc 
DATE FINAL: 
6th June 2019 
 
 


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Statistical Analysis Plan MO29112 Cohort 1 (Version 1.1) 
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TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 9 
2. 
STUDY DESIGN ........................................................................................... 9 
2.1 
Protocol Synopsis .................................................................. 12 
2.2 
Outcome Measures ............................................................... 12 
2.2.1 
Primary Efficacy Outcome Measures .................................... 12 
2.2.2 
Secondary Efficacy Outcome Measures ................................ 12 
2.2.2.1 Overall Survival (OS) ............................................................ 12 
2.2.2.2 Best Overall Response (BOR) ............................................. 13 
2.2.2.3 Objective Response Rate (ORR) ......................................... 13 
2.2.2.4 Disease Control Rate (DCR) ................................................ 13 
2.2.2.5 Time to Treatment Response (TTR) ..................................... 13 
2.2.2.6 Duration of Response (DoR) ................................................ 13 
2.2.2.7 Other .................................................................................... 13 
2.2.3 
Exploratory Efficacy Outcome Measures ............................... 14 
2.2.3.1 Progression Free Survival (PFS) Sensitivity 
Analysis 14 
2.2.3.2 Best Overall Response (BOR) Sensitivity 
Analysis 14 
2.2.4 
Safety Outcome Measures .................................................... 14 
2.2.5 
Pharmacokinetic (PK) Outcome Measures ............................ 15 
2.2.6 
Exploratory Biomarker Outcome Measures ........................... 15 
2.3 
Determination of Sample Size ............................................... 15 
2.4 
Analysis Timing ..................................................................... 16 
3. 
STUDY CONDUCT ..................................................................................... 16 
3.1 
Randomization Issues ........................................................... 16 
3.2 
Independent Review Facility .................................................. 16 
3.3 
Data Monitoring ..................................................................... 17 
4. 
STATISTICAL METHODS .......................................................................... 17 
4.1 
General Descriptive methods ................................................ 17 
4.2 
Definition of Treatment Phase ............................................... 18 
4.2.1 
Induction Treatment Phase (ITP) ........................................... 18 


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4.2.2 
Maintenance Treatment Phase (MTP) ................................... 19 
4.2.3 
Post-Treatment Follow-up Phase .......................................... 19 
4.3 
Data Convention .................................................................... 19 
4.4 
Computing Environment ........................................................ 20 
4.5 
Grading and Coding of Adverse Events, 
Laboratory Parameters and Medications ............................... 20 
4.6 
Adustments for Covariates .................................................... 21 
4.7 
Subgroup Analysis ................................................................. 21 
4.8 
Analysis Populations ............................................................. 22 
4.8.1 
All Population ......................................................................... 22 
4.8.2 
Randomized Population......................................................... 22 
4.8.3 
Safety Population .................................................................. 22 
4.8.4 
Per Protocol (PP) Population ................................................. 23 
4.8.5 
Pharmacokinetic-Evaluable Population ................................. 23 
4.8.6 
Biomarker-Evaluable Population ........................................... 23 
4.9 
Analysis of Study Conduct ..................................................... 23 
4.9.1 
Patient Disposition ................................................................. 23 
4.9.2 
Protocol Deviations ................................................................ 24 
4.10 
Analysis of Treatment Group Comparability .......................... 24 
4.10.1 
Demographics and Baseline Disease 
Characteristics ......................................................................................... 24 
4.10.2 
Medical History ...................................................................... 27 
4.10.3 
Prior and Concomitant Medications ....................................... 27 
4.10.3.1 Prior Anti-Cancer Treatment/Procedure ............................. 27 
4.10.3.2 Non Anti-Cancer Treatment/Procedure .............................. 28 
4.10.4 
Subsequent Anti-Cancer Therapy ......................................... 29 
4.11 
Efficacy Analysis .................................................................... 29 
4.11.1 
Primary Efficacy Endpoint ...................................................... 29 
4.11.2 
Secondary Efficacy Endpoints ............................................... 30 
4.11.2.1 Overall Survival .................................................................. 30 
4.11.2.2 Overall Response Rate (based on Primary 
Definition of BOR)............................................................................... 30 
4.11.2.3 Overall Response Rate (based on Secondary 
Definition of BOR)............................................................................... 31 


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4.11.2.4 Disease Control Rate ......................................................... 31 
4.11.2.5 Time to Treatment Response ............................................. 31 
4.11.2.6 Duration of Response ......................................................... 31 
4.11.2.7 Eastern Cooperative Oncology Group (ECOG) 
Performance Status ............................................................................ 32 
4.11.2.8 Additional Tumor Assessments .......................................... 32 
4.11.3 
Exploratory Efficacy Endpoints .............................................. 32 
4.11.4 
Sensitivity Analyses ............................................................... 32 
4.11.5 
Subgroup Analyses ............................................................... 33 
4.12 
Pharmacokinetic and Pharmacodynamic 
Analyses ................................................................................ 34 
4.13 
Safety Analyses ..................................................................... 34 
4.13.1 
Exposure of Study Medication ............................................... 34 
4.13.1.1 Treatment Duration and Dose Exposure ............................ 34 
4.13.1.2 Cycle Delay ........................................................................ 39 
4.13.2 
Adverse Events ..................................................................... 40 
4.13.3 
Death ..................................................................................... 45 
4.13.4 
Laboratory Data ..................................................................... 45 
4.13.5 
Vital Signs .............................................................................. 47 
4.13.6 
Other Safety Assessment - Applicable only for 
the experimental group ............................................................................ 48 
4.13.7 
Other Safety Assessment ...................................................... 48 
4.14 
Missing Data .......................................................................... 49 
4.15 
Interim Analyses .................................................................... 51 
5. 
REFERENCES ........................................................................................... 52 
 
 
 


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LIST OF TABLES 
Table 1: Biomarker Profile by Cohort .................................................................. 10 
Table 2: Sample Size Determination per Cohort ................................................ 15 
Table 3: Exposure Definitions for Induction Treatments ..................................... 36 
Table 4: Exposure Definitions for Maintenance .................................................. 37 
Table 5: Adverse Events Definitions ................................................................... 40 
 
 
 
LIST OF APPENDICES 
Appendix 1: Protocol Synopsis ........................................................................... 53 
Appendix 2: Schedule of Assessments for All Patients (Screening / Baseline 
and Induction Treatment Phase) ................................................. 81 
Appendix 3: Schedule of Assessments During Maintenance Phase (Cohort 
1) ................................................................................................. 86 
Appendix 4: SAS code ........................................................................................ 91 
Appendix 5 : List of Outputs ............................................................................... 93 


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HISTORY CHANGE 
Version 
Date 
Changes 
Final 1.0 
04-Apr-2019 
N/A 
Final 1.1 
06-Jun-2019 
Update in sample size section to add some scenarios in 
order to provide power calculation considering the actual 
number of patients. 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse events of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase  
ANC 
absolute neutrophils count 
aPTT 
activated partial thromboplastin time  
AST 
aspartate aminotransferase  
BMI 
body mass index 
BOR 
best overall response 
BRAFmut 
BRAF mutation 
BSA 
body surface area 
CI 
confidence interval 
CR 
complete response 
cSCC 
cutaneous squamous cell carcinoma 
CSR 
clinical study report 
DCR 
disease control ate 
DoR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
electronic Case Report Form  
EU 
European Union 
FP 
fluoropyrimidine 
Hb 
haemoglobin 
HER2 
human epidermal growth factor receptor 2 
HER2+ 
human epidermal growth factor receptor 2 positive 
HR 
hazard ratio 
IC 
informed consent 
ICH 
International Conference on Harmonization 
iDMC 
Independent Data Monitoring Committee 
IHC 
immunohistochemistry 
INR 
international normalized ratio  
ITP 
Induction Treatment Phase 
IxRS 
interactive voice or web-based response system  
KM 
Kaplan Meier 
LDH 
lactate dehydrogenase 
mCRC 
metastatic Colorectal Cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 


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Abbreviation 
Definition 
mRECIST 
modified Response Evalution Criteria in Solid Tumors 
MSI-H 
high microsatellite instability 
MSS 
microsatellite stable 
MTP 
Maintenance Treatment Phase 
NCI CTCAE  
National Cancer Institute Common Terminology  
Criteria for Adverse Events  
NE 
not evaluable 
NGS 
next generation sequencing 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PDMS 
protocol deviation management system 
PFS 
progression free survival 
PK 
pharmacokinetic  
PP 
Per protocol 
PR 
partial response 
PS 
performance status 
PT 
preferred term 
PTFUP 
Post-treatment follow-up phase 
RBC 
red blood cell 
RDI 
relative dose intensity 
RECIST 
Response Evaluation Criteria in Solid Tumors  
SAE 
serious adverse event 
SAF 
safety population 
SAP 
statistical analysis plan 
SC 
Steering Committee 
SCC 
squamous cell carcinoma 
SD 
stable disease 
SI 
Système International  
SOC 
System Organ Class 
SOD 
sum of target lesions diameter 
TEAE 
treatment emergent adverse event 
TSH 
thyroid-stimulating hormone 
TTR 
time to treatment response 
WBC 
white blood cells counts or leukocytes 
 


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1. 
BACKGROUND 
The study is a randomized, multi-center, active-controlled, open-label, parallel-group clinical 
study of biomarker-driven maintenance treatment for first-line metastatic colorectal cancer 
(mCRC) patients.  All patients will receive induction treatment with FOLFOX and bevacizumab. 
Induction treatment will be followed by maintenance treatment with chemotherapy combined with 
targeted therapy within one of several maintenance treatment cohorts. Only those patients who 
experience disease response or disease control during induction and who are not assessed as 
resectable at completion of induction will proceed to further treatment in the Maintenance 
Treatment Phase (MTP) of the study. Patients will be assigned to a maintenance treatment cohort 
based on their primary tumour biomarker results. The primary study objective within each cohort 
is to evaluate progression-free survival (PFS).   
Maintenance treatment cohorts may be added or modified over the course of the study. This SAP 
describes planned analyses of patients who were assigned, or would have been assigned, to 
maintenance treatment Cohort 1 based on their primary tumour biomarker profile. Analyses of 
patients assigned to all other MODUL cohorts will be described in SAPs applicable to each 
specific cohort. 
A Steering Committee (SC) is responsible for overseeing the general conduct of the study.  
In addition, an independent Data Monitoring Committee (iDMC) is responsible for evaluating the 
safety of the patients participating in the trial at regular intervals throughout the study. The iDMC 
makes recommendations as to whether cohort recruitment should continue based on benefit-risk 
evaluations that include efficacy as well as safety data. To minimize the impact of such reviews 
on efficacy endpoint analyses, efficacy data included in these reviews has to be specified by the 
iDMC at a preceding iDMC meeting and has to be documented in the iDMC meeting minutes. In 
addition, the iDMC evaluates the safety data from a prespecified number of initial patients for 
experimental combinations with inadequate prior safety experience to assure appropriate dosing 
(e.g. as required for the initial patients treated with the Cohort 1 experimental combination of ‘5-
FU/LV + cetuximab + vemurafenib’).  
 
2. 
STUDY DESIGN 
Patients continuing from the Induction Treatment Phase (ITP) to the Maintenance Treatment 
Phase are assigned to a maintenance treatment cohort based on their primary tumour biomarker 
status. Following eligibility assessment for their assigned cohort, eligible patients are randomized 
to the experimental or control arm within their cohort. 
The study was initiated with 2 maintenance treatment cohorts, Cohorts 1 and 2. Two additional 
cohorts, Cohorts 3 and 4, were added with protocol amendment 5 (protocol version 6). With the 
addition of these new cohorts, primary tumour biomarker criteria for assignment to Cohort 1 were 
revised as shown in Table 1. 
In this open-label study, all patients will receive 8 cycles induction treatment that is considered 
standard in many countries and that has been shown to improve outcomes in the first-line setting. 
Treatment during the ITP, based on investigator’s choice, will be either: 
 


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 
Eight 2-week cycles of 5-fluorouracil (5-FU), leucovorin (LV) and oxaliplatin (FOLFOX) in 
combination with bevacizumab 
or 
 
Six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week 
cycles of 5-FU/LV with bevacizumab  
 
Patients who prematurely discontinue study treatment for any reason during the ITP, who 
experience progressive disease (PD) at any time during or at the end of the ITP, who are 
evaluated as resectable at the end of ITP, who refuse to proceed to the MTP or who are not 
eligible for any maintenance cohort will undergo a study treatment discontinuation visit and enter 
post-treatment follow-up. Patients who experience disease control or tumor response to induction 
treatment will continue to the randomized MTP of the study wherein the effects of experimental 
and control groups will be compared. Patients in study screening prior to June 28, 2016 were 
assigned to Cohort 1 if their primary tumour was BRAFmut. Patients in screening after June 28, 
2016, were were assigned to Cohort 1 if their primary tumour was HER2-/MSS/BRAFmut/RASwt. 
Treatment in each cohort is shown in Figure 1.  
Table 1: Biomarker Profile by Cohort 
 
 
Biomarker profile 
 
Patients in Screening Prior June 
28, 2016 
Patients in Screening After June 28, 2016 
Cohort 1 
BRAFmut 
HER2-/MSS/BRAFmut/RASwt 
Cohort 2 
BRAFwt 
or 
biomarker 
status 
unknown 
Closed to patients screened after June 28, 
2016 
Cohort 3 
Not applicable 
HER2+ 
Cohort 4 
 Not applicable 
HER2-/MSI-H; HER2-/MSS/BRAFwt; HER2-
/MSS/BRAFmut/RASmut 
 
 
 


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Figure 1: Study Design as of protocol version 6 
 
 


 
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Primary objective of this study: 
The primary study objective within each cohort is to evaluate PFS.  
An iDMC is responsible for regularly reviewing safety data. 
 
2.1 
PROTOCOL SYNOPSIS 
The Protocol version 8 synopsis is provided in Appendix 1. For additional details, see the 
Schedule of Assessments in Appendix 2. 
 
2.2 
OUTCOME MEASURES 
As mentioned in the protocol, each cohort will be analysed separately and therefore this SAP 
focuses on the description of the analysis required for cohort 1 data only, i.e. applicable to 
enrolled patients eligible for cohort 1 based on primary tumour biomarker status.  
 
2.2.1 
Primary Efficacy Outcome Measures 
PFS is defined as the time from randomization into the MTP until documented disease 
progression as per investigator assessment using Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 or death from any cause, whichever occurs first. If no progression / 
death is observed at the time of clinical cut-off or by the date of any on-study colorectal anti-
cancer surgery with palliative or curative intent, patients will be censored at the date of the 
last evaluable tumor assessment or date of randomization, whichever comes last. 
(Of note: (i) Progressive disease are identified by the Overalll Response=’PD’, even if solely 
based on symptomatic deterioration, (ii) Only surgery occurring between baseline tumor 
assessment for MTP and PFS events are considered for censoring PFS) 
 
2.2.2 
Secondary Efficacy Outcome Measures 
2.2.2.1 
Overall Survival (OS) 
OS is defined as the time from randomization into the MTP to time of death from any cause. 
Patients still alive at time of clinical cut-off will be censored at their last date known to be alive 
as defined in section 4.3. For imputation of “Partial Death Date”, please refer to section 4.14. 
 
 
 


 
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2.2.2.2 
Best Overall Response (BOR)  
Main definition 
BOR (e.g. complete response [CR], partial response [PR], stable disease [SD], progressive 
disease [PD], not evaluable [NE]) for the MTP will be defined as the best response recorded 
from the randomization date until progressive disease (taking as reference for progressive 
disease the smallest measurements recorded since randomization date). For patients under 
maintenance treatment at the time of primary analysis, the BOR will be defined based on 
available tumor assessments at time of clinical cut-off. The overall response per time point 
reported on the electronic Case Report Form (eCRF) by the investigator (as per RECIST v1.1) 
will be used for the derivation of the BOR. No confirmation of response is required as per 
protocol. 
A minimum interval of 28 days will be considered for SD to be assigned as best overall 
response, i.e. in the case the single response is SD, SD must have been assessed no less 
than 28 days after randomization date of the MTP, otherwise the best overall response will 
be NE. 
If the patient has missing baseline tumor assessment, best overall response will be NE. 
Patients without tumor assessment after randomization will be assigned a tumor response of 
NA (Not applicable). 
Patients with only non-target lesions classified as having an eCRF tumor response status of 
"Non-CR/Non-PD" are classified as SD. 
 
2.2.2.3 
Objective Response Rate (ORR)  
ORR is defined as the number of patients with a BOR of CR or PR during the MTP phase 
divided by the number of patients in the studied population.  
 
2.2.2.4 
Disease Control Rate (DCR)  
DCR is defined as the number of patients with a BOR during the MTP of CR, PR or SD divided 
by the number of patients in the studied population.  
 
2.2.2.5 
Time to Treatment Response (TTR)  
TTR will be calculated for responders (i.e. patients with a MTP BOR of CR or PR) only. It will 
be defined as the time from randomisation to the first occurrence of a documented objective 
response (CR or PR). 
 
2.2.2.6 
Duration of Response (DoR)  
DoR will be calculated for responders only. It will be defined as the time from the first 
assessment of CR or PR until disease progression or death from any cause, whichever 
occurs first. Patients who do not progress or die after they have had a response are censored 
at the date of their last tumor measurement. 
 
2.2.2.7 
Other 
 
Change from baseline in tumor size during MTP 
The change from baseline in tumor size at a specific assessment occurring during the 
maintenance treatment phase will be defined as: 
100*((SOD at visit x– baseline SOD) / baseline SOD) 


 
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with: 
 
SOD at visit x corresponding to the Sum Of target lesions Diameter (SOD) at visit  
 
Baseline SOD is the last SOD recorded on or prior to the randomization date in the 
MTP. This baseline assessment should correspond to the tumor assessment 
performed at the end of ITP as defined in section 4.10.1.  
 
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) during and after 
MTP 
 
 
2.2.3 
Exploratory Efficacy Outcome Measures 
 
2.2.3.1 
Progression Free Survival (PFS) Sensitivity Analysis 
PFS is defined as the time from randomization into the MTP until documented disease 
progression as per investigator assessment using Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 or death from any cause, whichever occurs first. If no progression / 
death is observed at the time of clinical cut-off, patients will be censored at the date of the 
last evaluable tumor assessment or date of randomization, whichever comes last. 
 
2.2.3.2 
Best Overall Response (BOR) Sensitivity Analysis 
BOR (e.g. CR, PR, SD, PD, NE) for the MTP will defined as the best response recorded from 
the randomization date until end of maintenance treatment or progressive disease whichever 
comes first (taking as reference for progressive disease the smallest measurements recorded 
since randomization date).  
The derivation of the BOR will be the same as for the main definition (section 2.2.2.2), the 
only change being the time window during which the best overall response is observed. In 
other words, the main definition for BOR considers all tumor assessments collected on study 
(i.e. including post-treatment tumor assessments phase for patients withdrawing 
maintenance treatment for other reason than PD) whereas the secondary/sensitivity definition 
considers only tumor assessments collected on maintenance treatment phase (i.e within 30 
days from last day of treatment of MTP, up to the day before the start of further anti-cancer 
therapy, whichever comes first). Therefore, the secondary/sensitivity analysis regarding BOR 
is an on-treatment analysis.  
 
2.2.4 
Safety Outcome Measures 
The safety outcome measures for this study are as follows 
 
Incidence, nature and severity of all adverse events (graded according to National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
v4.0)  
 
Incidence and nature of all Grade 3- 5 AEs 
 
Grade 5 AEs or AEs leading to death on study treatment 
 
All serious adverse events (SAEs)  
 
Incidence and reasons for any dose reductions, interruptions or premature 
discontinuation of any component of study treatment  
 
Adverse events of special interest (AESI)  






 
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3.3 
DATA MONITORING 
An iDMC is responsible for:  
 
evaluating the safety of the patients participating in the trial at regular intervals 
throughout the study, 
 
making recommendations as to whether cohort recruitment should continue based on 
benefit-risk evaluations that include efficacy as well as safety data. To minimize the 
impact of such reviews on efficacy endpoint analyses, efficacy data included in these 
reviews has to be specified by the iDMC at a preceding iDMC meeting and has to be 
documented in the iDMC meeting minutes, 
 
performing a review of the safety data from a prespecified number of initial patients 
for experimental combinations with inadequate prior safety experience to assure 
appropriate dosing (e.g. as required for the Cohort 1 experimental combination of ‘5-
FU/LV + cetuximab + vemurafenib’). 
 
4. 
STATISTICAL METHODS 
4.1 
GENERAL DESCRIPTIVE METHODS 
Categorical variables 
For categorical variables, summary tabulations of the number and missing observations as 
well as the number and percentage within each category of the parameter will be presented. 
Missing will not be considered as a separate category and thus missing observations will not 
be part of the denominator to compute the percentages. Percentages will be rounded to one 
decimal place. Therefore, there may be cases where for instance the total of the percentages 
does not exactly equal 100%. If number of patients is ‘0’ then 0 will be reported instead of ‘0 
(0.0%)’  
Continuous variables 
For continuous variables, N, the mean, median, standard deviation, 25th and 75th percentile, 
minimum and maximum values will be presented.  
Time-to-event efficacy variables 
Time-to-event efficacy variables (e.g. PFS and OS) summaries will include number of patients 
in the population (N), number of patients with the event of interest, number of patients 
censored, median and two-sided 95% confidence interval (CI) computed according to 
Brookmeyer and Crowley (1982) method. Kaplan-Meier (KM) estimates and median survival 
times are calculated with the PROC LIFETEST procedure in SAS. KM curves (product-limit 
method) will be presented as well as the event rates at certain time points with the relevant 
CIs calculated via log-log transformation method (default option CONFTYPE=LOGLOG in 
SAS) based on standard errors computed using the Greenwood’s formula.  
Cox proportional hazards models 
Cox proportional hazards model will be implemented using PHREG procedure with option 
TIES=EXACT. It assumes that there is a true but unknown ordering for the tied event times 
as contrasted to option TIES=DISCRETE which assumes that the events occurred at exactly 
the same time. 


 
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Missing values 
For categorical variables, summary tabulations of the number and missing observations as 
well as the number and percentage within each category of the parameter will be presented. 
For continuous variable, number of missing is displayed between brackets next to ‘n’, unless 
otherwise specified.  
Decimals 
Mean, standard deviation, and median (Q1 and Q3 if applicable) will be presented with one 
more decimal place compared to the raw data, minimum and maximum will be presented with 
same number of decimal places as the raw data. Hazard ratio, odds ratio will be provided with 
two decimals. P-value will be provided with three decimals. If <0.001, then ‘<0.001’ will be 
displayed. 
 
4.2 
DEFINITION OF TREATMENT PHASE 
In this study, there are 3 treatment phases:  
1. Patients are treated first in the Induction Treatment Phase (ITP) for a planned duration 
of 8 cycles, i.e. 16 weeks.  
2. If they do not experience any progressive disease before or at the end of the ITP, are 
not considered resectable at the end of the ITP and do not withdraw from the study and 
are still eligible for any cohort, they are randomized and treated in the Maintenance 
Treatment Phase (MTP). 
3. If they discontinue study treatment for any reason during the Induction or Maintenance 
Treatment Phases, do not withdraw from the study and are still alive, they enter the Post-
Treatment Follow-up Phase. 
 
4.2.1 
Induction Treatment Phase (ITP) 
ITP is defined as the time from first study drug administration until  
 
the day before the randomization for patients continuing treatment in the MTP   
 
the last assessment date otherwise 
 
The first day of treatment in the ITP is defined as the earliest day of a non-null 
administration of any induction phase treatment. 
The last day of treatment in the ITP is defined as the last day of the last initiated cycle of 
the induction phase, or as the death day if the patient died in between. A two-week cycle 
duration is assumed. 
Baseline evaluations for the ITP will be those performed not earlier than 28 days prior to 
the first day of treatment in the induction phase, unless otherwise stated. The latest available 
assessment up to start of the first day of treatment in the induction phase will be considered 
as baseline. For laboratory examinations, weight, vital signs and ECOG PS, assessments 
performed on the first day of treatment of the ITP will be assumed to have been performed 
before drug was given and, thus, will be considered as baseline evaluations. 
On-treatment evaluations for the ITP will be post baseline evaluations performed until 
 
the day before the randomization for patients continuing treatment in the MTP   


 
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 
(including) the study treatment discontinuation visit within 30 days after last day of 
treatment of the ITP (as defined above), for patients not randomized in the MTP. 
 
4.2.2 
Maintenance Treatment Phase (MTP) 
MTP is defined as the time from randomization into MTP until (including) the study treatment 
discontinuation visit in the MTP. 
The first day of treatment in the MTP is defined as the earliest day of a non-null 
administration of any maintenance phase treatments. 
The last day of treatment in the MTP is defined as the last day of the last initiated cycle of 
the maintenance phase, or as the death day if the patient died in between. A two-week cycle 
duration is assumed. 
Baseline evaluations for the MTP will be those performed prior to the first day of treatment 
in the maintenance, unless otherwise stated. The latest available assessment prior to the first 
day of treatment in the maintenance phase will be considered as baseline for safety 
assessments. For laboratory examinations, weight and vital signs, assessments performed 
on the first day of treatment of the MTP will be assumed to have been performed before drug 
was given and, thus, will be considered as baseline evaluations. For subjects randomized but 
not treated in the MTP, the latest available assessment before or on randomization date 
(including assessments from ITP) will be considered as baseline for the MTP.  
For efficacy assessments, the latest available assessment prior or on the randomization date 
will be considered as baseline. 
On-Treatment evaluations for the MTP will be evaluations performed on or after the first 
day of treatment in the MTP within 30 days from last day of treatment in the maintenance 
phase. On-treatment laboratory will be all values collected after the first day of treatment in 
the maintenance phase and within 30 days from last day of treatment in the maintenance 
phase (as defined above). For adverse events, treatment emergent adverse events (TEAEs) 
will be events occurring on or after the first day of treatment in the MTP within 30 days from 
last day of treatment in the maintenance phase (as defined above). 
 
4.2.3 
Post-Treatment Follow-up Phase 
Post treatment Follow-up Phase is defined as the time from (excluding) the study treatment 
discontinuation visit until the last available assessment date before clinical cut-off date. For 
patients who discontinue study treatment but without any study treatment discontinuation visit 
date, please refer to 4.14 for imputation of this missing visit date. 
Post-Treatment Follow-up evaluations will be evaluations performed according to the 
protocol after the study treatment discontinuation visit.  
 
4.3 
DATA CONVENTION 
All data will be listed (e.g. pre-treatment serious adverse events), whereas only baseline and 
on-treatment assessments will be considered for summary tables. 
Baseline and on-treatment data will be flagged in the data listings as well as the different 
phases of the study. 
The overall column will not be displayed in any summary tables.  


 
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The following conversion factors will be used to convert days to months or years, where 
applicable:  
 
1 week= 7 days 
 
1 month = 30.4375 days  
 
1 year = 365.25 days 
Age at informed consent (IC) {in years} = (date of informed consent – date of birth) / 365.25 
To calculate duration / time between two dates the following convention will be used: 
[later date] – [earlier date] + 1 day 
Durations and times between two dates will be calculated only when both start and end dates 
are available (imputed dates cannot be used for computation), apart for overall survival when 
date of death has only day as missing). 
Body surface area (BSA) will be recalculated based on the height and weight of the patient 
using the following formula: 
 BSA (m2) = ([Height {cm} x Weight {kg}] / 3600)½ 
Body mass index (BMI) will be calculated using the following formula: 
BMI (kg/m2) = Weight {kg} / Height2 {m} 
The last known date to be alive will be the latest date among all dates specified in the eCRF 
except the following:  
 
Survival Follow-up date when status is either dead (in this case the date of death is 
specified on the Adverse events or Study Completion/Early Discontinuation or SAE 
reporting summary form) or lost to follow-up (in this case last date known to be alive 
is specified on the Survival follow-up form)  
 
Study Completion/Early Discontinuation date when reason is either death or lost to 
follow-up. 
 
A sample / record with test ‘Not Done’.  
4.4 
COMPUTING ENVIRONMENT 
All statistical analyses will be performed using SAS statistical software (Version 9.2 or newer 
version), unless otherwise noted.   
 
4.5 
GRADING AND CODING OF ADVERSE EVENTS, LABORATORY 
PARAMETERS AND MEDICATIONS 
Laboratory results, adverse events, and other symptoms will be graded using the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE), version 
4.0, except where CTC grades are not available. 
Adverse events and relevant Medical History data fields (i.e. prior symptoms / AEs) will be 
coded using the most recent version of Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary available at the time of analysis.  


 
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Prior and concomitant anti-cancer therapy / other medications will be coded using the most 
up-to-date version of the in house Genentech Drug Thesaurus Dictionary. 
Dictionary versions used will be displayed in analysis outputs. 
 
4.6 
ADUSTMENTS FOR COVARIATES 
When indicated, efficacy analysis will be adjusted i.e. the covariates will be incorporated in 
the model used to assess the treatment effect upon the efficacy endpoints. The covariate 
below will be considered:  
 
Patient response after induction treatment as per eCRF data: CR/PR vs. SD. For 
inferential analysis, “SD” will be used as reference, unless otherwise specified.  
(Of note: no adjustment will be made for region since most of patients are in Europe.) 
 
4.7 
SUBGROUP ANALYSIS 
The following subgroups will be considered to repeat PFS and OS analysis by subgroup: 
 
Demographic characteristics: 
o Age (<65 years, >= 65 years) 
o Gender (male vs female) 
o Tumor response at end of ITP (SD vs. CR/PR) as per eCRF 
o Baseline ECOG performance status (0 vs. 1/2), 
 
Baseline disease characteristics: 
o Initial AJCC/UICC stage (stage I/II/III vs. stage IV) 
o Prior systemic adjuvant therapy (yes vs no) 
o Number of metastatic sites at screening (<2 x vs. >= 2) 
o Liver metastatic site at baseline (yes vs no) 
o Cancer type (colon vs rectal) 
o Tumor colon location (right vs left) 
o Initial diagnosis (synchronous vs metachronous) 
 
The subset tumor colon location (left, right) will be derived based on the primary tumor 
location information collected on the colorectal cancer history eCRF page. Right colon is 
defined as patients with ceacum, appendix, ascending colon or right hepatic flexture or 
transverse colon as primary tumor location. Left colon is defined as patients with left splenic 
flexture or descending colon or sigmoid or rectum as primary tumor location. 
The subset cancer type (colon, rectal) will be derived based on the primary tumor location 
collected on the colorectal cancer history eCRF page. Colon cancer type is defined as 
patients with ceacum, appendix, ascending colon or right hepatic flexure or transverse colon 
or left splenic flexure or descending colon or sigmoid as primary tumor location. Rectal cancer 
type is defined as patients with rectum as primary tumor location.  
The subset initial diagnosis (synchronous, metachronous) will be derived based on the time 
from initial histological diagnosis to first diagnosis of metastatic disease. If this time is longer 
than 6 months then the initial diagnosis of the corresponding patient will be considered 
metachronous, or as synchronous otherwise. In case date of first diagnosis of metastatic 
disease is missing, this one will be replaced by the date of first diagnosis of locally recurrent 
disease. In case both are missing, the corresponding patients will be excluded from the 
corresponding subgroup analysis. In case one of the dates (i.e. date of initial histological 


 
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diagnosis or date of first diagnosis of metastatic disease or date of first diagnosis of locally 
recurrent disease) is partially missing, it will be imputed as described in section 4.14.  
 
4.8 
ANALYSIS POPULATIONS 
The following patient populations will be evaluated and used for presentation and analysis of 
the data. 
 
4.8.1 
All Population 
ALL Population: The ALL population consists of all enrolled patients with BRAFmut primary 
tumor if in study screening prior to June 28, 2016 and all enrolled patients with HER2-
/MSS/BRAFmut/RASwt biomarker profile if in study screening after June 28, 2016).  
Induction Treatment Phase (ITP) Population: all patients included in the ALL Population 
and who are treated in the ITP, i.e. who received at least one non-null dose of any study 
medications during the ITP. The ITP population is the main population to be used to 
summarize ITP data and Post Induction Treatment data. The 2 following groups will be 
considered when tabulating ITP data:  patients randomized into MTP versus patients not 
randomized into MTP. Post Induction Treatment data will be summarized using one single 
group, i.e. patients not randomized into MTP. ITP population will be the main population for 
the data listings, unless otherwise specified; the 3 following groups will be displayed in listings: 
patients randomized in the experimental group of MTP, patients randomized in the control 
group of MTP, patients not randomized into MTP. 
 
4.8.2 
Randomized Population 
Maintenance Treatment Phase (MTP) Population is defined as all patients randomized into 
the Cohort 1 MTP of the study, irrespective of whether or not they received study medication. 
Patients will be allocated to the treatment group into which they were randomized (as per 
interactive voice or web-based response system [IxRS]). The MTP population is the primary 
population for the analysis of efficacy parameters and baseline characteristics for the MTP. 
The MTP population will be used as well to report the Post Maintenance Treatment data. 
 
4.8.3 
Safety Population 
Safety (SAF) Population: all patients randomized in Cohort 1 who have been treated, i.e. 
who received at least one non-null dose of any study medications during the MTP. 
Patients will be allocated to the treatment group they actually received using the following 
rule: 
 
Patients receiving at least one dose (non-null) of cetuximab or vemurafenib, while on 
treatment 
will 
be 
allocated 
to 
the 
experimental 
group 
5-
FU/LV+cetuximab+vemurafenib. Even if a patient was allocated to the control group 
and received by mistake a dose of cetuximab or vemurafenib, then this patient will be 
reallocated to the experimental group. 
 
Patients who did not receive any dose of cetuximab or vemurafenib will be allocated 
to the control group FP+bevacizumab.  
The SAF population is the primary population for the analysis of MTP safety parameters. 
 


 
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4.8.4 
Per Protocol (PP) Population 
As stated in the protocol, the PP Population will not be defined for this study but major protocol 
violations will be listed.  
 
4.8.5 
Pharmacokinetic-Evaluable Population 
Not applicable. 
 
4.8.6 
Biomarker-Evaluable Population 
Not applicable. 
 
4.9 
ANALYSIS OF STUDY CONDUCT 
This SAP focuses only on the description of the analysis required for cohort 1 data. All MTP 
data will be reported. ITP data for BRAF mutant patients (if in screening prior to June 28, 
2016) and HER2-/MSS/BRAFmut/RASwt patients (if in screening after June 28, 2016) 
randomized and not randomized into the MTP will be tabulated in 2 separate columns. Post-
treatment data will be reported separately for induction and maintenance treatments. This 
Post-treatment data includes adverse events, deaths, subsequent anti-cancer therapies and 
tumor assessments (until PD if PD not experienced before study treatment discontinuation 
visit), but this last one applies only for Post Maintenance treatment.  
 
4.9.1 
Patient Disposition 
The patient disposition table for ITP will be based on the ALL population and will include the 
following information: 
 Number of patients enrolled (ALL) 
 Number of patients not treated in ITP who discontinued trial without being treated and 
associated reason 
 Number of patients treated with induction treatment (ITP population)  
 Number of patients who completed the ITP  
 Number of patients treated in induction who discontinued early ITP and reason for early 
discontinuation  
 Number of patients treated in induction and not randomized who went to post-treatment 
follow-up phase post induction 
 Number of patients being treated in induction who discontinued study prior to MTP and 
associated reason 
 
The patient disposition table for MTP will include the following information: 
 Number of randomized patients (MTP population) (percentage based on MTP) 
 Number of randomized patients without being treated in MTP still on-trial  
 Number of randomized patients who discontinued trial without being treated in MTP and 
the corresponding reason for trial discontinuation (percentages based on MTP) 


 
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 Number of treated patients with maintenance treatment (SAF) (percentages based on 
MTP) 
 Number of patients treated who discontinued all treatments received in MTP and the 
reason for discontinuation from each maintenance treatment (percentage based on MTP). 
All reasons for treatment discontinuation will be displayed and will be taken from the 
individual treatment completion/Early discontinuation eCRF pages. 
 Number of patients treated in MTP who discontinued trial during MTP and the 
corresponding reason for trial discontinuation (percentages based on MTP) 
 Number of patients who entered in the follow-up post-MTP 
 Number of patients being treated in MTP who discontinued trial during follow-up and the 
corresponding reason for trial discontinuation (percentages based on MTP) 
 
A consort flow diagram will be provided to show progress of screened patients and especially 
for BRAF mutant patients (if in screening prior to June 28, 2016) and HER2-
/MSS/BRAFmut/RASwt patients (if in screening after June 28, 2016).  Another diagram for 
patients randomized in Cohort 1 will be provided.  
 
The following supportive listings will be provided: 
 
Patient disposition (including the tumor response status at the end of ITP) and study 
termination information based on ITP 
 
Patients who discontinue treatment due to AE (based on ITP) 
 
4.9.2 
Protocol Deviations 
All major protocol deviations from Protocol Deviation Management System (PDMS) will be 
reported for each phase separately and will be summarized by group. The ITP population will 
be used for ITP data and the MTP population for the MTP data. 
The following will be displayed 
 
Number of patients having at least one major protocol deviation 
 
Number of patients by major protocol deviations category  
Listings for protocol deviations will be provided based on ITP population. Listing for analysis 
population will be provided on ALL population. 
 
4.10 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
4.10.1 
Demographics and Baseline Disease Characteristics 
Baseline and demographic characteristics will be summarized using descriptive statistics.  No 
formal statistical comparisons will be performed.  
Summaries of Patient Demographics will be provided based on the ITP and MTP population 
and will present the following information: 
 
Age at informed consent (yrs) 
 
Age categories (yrs): < 18, 18-64, 65-84, 85 and over 
 
Sex 
 
Ethnicity: Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown  


 
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 
Race  
 
Region: Europe, Americas, Africa, Asia (derived based on country information from 
the clinical database) 
 
Smoking status: Never, Current, Previous 
 
Alcohol use history: Never, Current, Previous 
 
Drug Use: Never, Current, Previous 
 
ECOG Performance Status at baseline: 0,1,> 1,  
 
Baseline Weight (kg) 
 
BMI (see definition in section 4.3) 
 
BSA (see definition in section 4.3) 
 
Baseline Height (cm) 
 
Female reproductive status (for female participants only. Percentage will be based 
on the total number of female patients)  
 
The summary of patient’s characteristics based on MTP will be included. For the summary 
based on MTP only, ECOG and weight collected just prior to or on the first day of MTP will 
be used as baseline. Please refer to sections 4.2.1 and 4.2.2 for further details related to 
definition of baseline evaluations. 
All the biomarker outcomes of interest as per section 4.7 will be summarized using descriptive 
statistics by treatment group on ITP and MTP population: 
Given that the end of the induction phase is the same timepoint as the baseline tumor 
response for the MTP, two summary tables presenting the information as mentioned below 
will be produced. One for the tumor response status at the end of the induction phase based 
on ITP population and as per data collected on the eCRF and will present the following 
information. 
 
Number of patients with CR or PR at end of ITP   
 
Number of patients with SD at end of ITP   
 
Number of patients with PD at end of ITP 
 
Number of patients with NE at end of ITP 
 
Number of patients with NA at end of ITP (i.e. no tumor response during ITP)  
 
Another table will be generated for baseline tumor response for the MTP based on MTP 
population and as per data collected on the eCRF and will present the following information. 
 
Number of patients with CR or PR at end of ITP   
 
Number of patients with SD at end of ITP 
 
Number of patients with tumor response other than CR, PR or SD at end of ITP    
 
The number of patients in MTP population will be summarized by country and study center 
(as per clinical database) and by treatment group based on the MTP population.  
In addition, the number of patients will be summarized by the following stratification factors 
as per IxRS, by treatment group on the MTP: 
 
Region 
o European Union 
o Americas  
o Africa 
o Asia 
 
Tumor response at the end of ITP 


 
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o CR/PR 
o SD 
 
A table will show the concordance between the tumor response status at the end of ITP as 
per IxRS and the tumor response status at the end of ITP as per data collected on the eCRF. 
This table will be based on the MTP population and will display the following categories:  
 
CR/PR, SD, Total for the IxRS tumor response 
 
CR, PR, CR/PR, SD for eCRF tumor response 
 
eCRF Tumor response status (CR, PR, SD, PD, NE) at the end of ITP is defined as the last 
tumor response observed during the ITP. Patients without tumor assessment after first day 
of induction treatment will be assigned a tumor response of NA (Not available).  
Patients with only non-target lesions classified as having an eCRF tumor response status at 
the end of the ITP of "Non-CR/Non-PD" are classified as SD for the 2 summary tables 
mentioned above.    
 
Summary of colorectal cancer history will be provided based on the ITP and MTP population 
and will present the following information: 
 
Histological grade at diagnosis 
 
Location of primary tumor 
 
Colon Location: left, right 
 
Cancer type: colon, rectal 
 
Initial AJCC/UICC stage 
 
Initial diagnosis: synchronous, metachronous 
 
Locally recurrent disease: yes, no 
 
Metastatic disease: yes, no 
 
Sites of metastatic disease at time of study enrolment (adrenal gland, ascites, bone, 
liver, lung, mediastinum, skin, other) 
 
Liver as metastatic site: yes, no 
 
Extent of disease by number of sites at time of study enrolment: 0, 1, > 1  
 
Time from initial diagnosis to first dose of ITP (in years) 
 
Time from first diagnosis of locally recurrent disease to first dose of ITP (in years) 
 
Time from first diagnosis of metastatic disease to first dose of ITP (in years)  
 
Number of target lesions at baseline 
 
Of note, if start and/or end dates are incomplete or missing the corresponding time between 
the start and the end date cannot be derived. In this case, time from initial diagnosis to first 
dose of ITP or time for first diagnosis of locally recurrent disease to first dose of ITP or time 
from first diagnosis of metastatic disease to first dose of ITP cannot be derived and will be 
missing.  
 
Summary of RECIST tumor-specific characteristics at baseline will be generated on the MTP 
population and will provide the following information: 
 
Number of site/organs involved; 1, 2, >2 
 
Site/organ type involved:  colon, rectum, liver, lung, lymph nodes, peritoneum, brain, 
other   


 
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 
Type of lesions: target only, non-target only, target and non-target lesions 
Of note for the above summary table, tumor-specific characteristics at baseline refer to the 
tumor assessment prior to randomization in MTP, i.e. last tumor assessment from the 
induction treatment phase.  
 
The following listings will be provided: 
 
Patient Demographics based on ITP population 
 
Biomarker status based on MTP population 
 
Patients by randomization stratification factors as per IxRS and eCRF (based on 
MTP) 
 
Colorectal cancer history based on ITP population 
 
4.10.2 
Medical History 
Medical history, as collected on the “General Medical History and Baseline Conditions” eCRF 
page will be summarized using the ITP and MTP populations. These summary tables will 
include the number and percentage of patients with at least one medical history by Primary 
System Organ Class (SOC) sorted in a descending order of the total frequency count and by 
preferred term [PT] (sorted in a descending order of the total frequency count within each 
SOC).  
A patient with more than one occurrence of the same medical history in a particular SOC/PT 
will be counted only once in the total of those experiencing events in that particular system 
organ class/preferred term. 
Medical history data will be listed based on ITP population. 
 
4.10.3 
Prior and Concomitant Medications 
4.10.3.1 
Prior Anti-Cancer Treatment/Procedure 
Prior anti-cancer treatments/procedures summaries based on the ITP and MTP populations 
will present the following information: 
 
Number of patients with prior colorectal cancer surgery: Yes, No 
 
Number of patients by site of prior colorectal cancer surgery: Colon, Rectum, Colon 
and Rectum, Other.  
 
Number of patients with prior radiotherapy: yes, no 
 
Number of patients with prior anti-cancer therapies: yes, no  
 
Number of patients by setting of prior systemic therapy 
 
Number of patients with prior systemic adjuvant therapy: yes, no  
 
Number of regimens for prior systemic therapy: 0, 1, 2, >=3.  
The following listings will be provided based on the ITP population: 
 
Prior anti-cancer therapy 
 
Prior and on-study cancer radiotherapy 
 
Prior and on-study cancer colorectal surgery 
 
 
 


 
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4.10.3.2 
Non Anti-Cancer Treatment/Procedure 
 
A prior medication/therapy is defined as any medication/therapy with an end date prior to the 
start of the induction treatment. 
Concomitant medication for ITP 
Concomitant medication includes both medication concomitant at baseline and concomitant 
medication initiated post-baseline. It is defined as any medication/therapy with 
 
 start date before or on: 
o the randomization date for patients randomized in the MTP  
o last dosing date of ITP+30 days for patients not randomized in the MTP  
 
and end-date on or after first dosing date of the ITP or with a missing (ongoing) end-
date 
 
Concomitant medication for MTP 
It is defined as any medication/therapy with 
 
start date before or on last dosing date in the MTP+30 days  
 
and end-date on or after first dosing date of the MTP or with a missing (ongoing) 
end-date. 
Post-treatment Medication 
It is defined as any medication/therapy with a start date more than 30 days after the last 
dosing date. 
In case a medication has an incomplete or missing start date/end date, please refer to section 
4.14 for the rules to be applied in order to identify prior, concomitant or post-treatment 
medications.  
Prior and Concomitant Medications/therapies will be summarized. Summary tables will 
present number and percentage of patients with any medication overall and by Drug 
Thesaurus Class and Generic Name. At each level of summation (overall, Drug Thesaurus 
Class, Generic Name), patients reporting more than one medication are counted only once. 
Drug Thesaurus Class will be sorted in a descending order of the total frequency count and 
the generic names with the highest frequency will be displayed first within each Drug 
Thesaurus class, unless otherwise indicated. The analysis population will be the ITP 
population and the MTP population for ITP data and MTP data, respectively. 
The following tables will be provided: 
 
Prior medications based on ITP population 
 
Concomitant medications for the ITP based on ITP population 
 
Concomitant medications for the MTP based on SAF population 
 
Concomitant radiotherapy performed during the ITP based on ITP population (as 
collected on the On-Study Cancer Radiotherapy eCRF page): Number of patients 
with radiotherapy, site (colon, other)  and setting (neo-adjuvant, adjuvant, palliative. 
other) of therapy 
 
Concomitant radiotherapy performed during the MTP based on SAF population (as 
collected on the On-Study Cancer Radiotherapy eCRF page): Number of patients 
with radiotherapy, site (colon, other)  and setting (neo-adjuvant, adjuvant, palliative, 
other) of therapy 


 
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 
Concomitant colorectal cancer surgery during ITP based on ITP population: Number 
of patients with at least one surgery, site of surgery, surgical procedure and intent 
 
Concomitant colorectal cancer surgery during MTP based on SAF population: 
Number of patients with at least one surgery, site of surgery, surgical procedure and 
intent 
 
Corresponding listings will be provided using the ITP population. 
 
4.10.4 
Subsequent Anti-Cancer Therapy 
Post Induction Treatment and Post Maintenance Treatment anti-cancer therapies will be 
listed using the ITP population patients who have a study treatment discontinuation visit date.  
 
4.11 
EFFICACY ANALYSIS 
Efficacy analysis will be conducted on the data collected during the MTP/Post maintenance 
treatment (when applicable) and using the MTP population. Analysis will be performed by 
randomized treatment group. Tumor assessments collected during the ITP will be listed only 
but will not be part of the efficacy analysis and will be listed on the ITP population. ITP and 
MTP tumor assessments will be flagged, as appropriate for patients randomized in the MTP.  
As Cohort 1 will not reach its target sample size, the analysis is not event driven as described 
in the study protocol, but is time driven instead. As a consequence, all p-values will be 
reported descriptively only, due to low power. All formal statistical tests will be two-sided and 
performed at an alpha of 5%, therefore 95% two sided CI will be presented. No adjustment 
will be made for multiplicity of testing secondary endpoints or subgroups for single efficacy 
endpoints. 
4.11.1 
Primary Efficacy Endpoint 
The primary efficacy objective of this study is to evaluate PFS. 
To answer the primary objective, the following null and alternative hypotheses will be tested  
 
H0: the distribution of the PFS time is the same in the two treatment groups, i.e.   
PFS (Experimental group) = PFS (Control group) 
 
H1: the distribution of the PFS time is different in the two treatment groups, i.e. PFS 
(Experimental group) ≠ PFS (Control group) 
The primary analysis of PFS will be a comparison between the experimental and the control 
group using an unstratified log-rank test. Please refer to Appendix 4 for the SAS code to be 
used. 
PFS for each treatment group will be estimated using KM product-limit method estimates. 
PFS will be summarized by treatment group and will display the following information: 
 
Number of patients in the population (N) 
 
Number of patients with PFS event  
 
Number of patients censored 
 
Median and two-sided 95% CI computed according to Brookmeyer and Crowley 
method,  
 
25th and 75th quantile, and the corresponding two-sided 95% CI computed 
according to Brookmeyer and Crowley method,  
 
Minimum and maximum 
 
The PFS rates (with the two-sided 95% CI) at 3, 6, 9, 12, 15 and 18 months 


 
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 
Unstratified log-rank test p-value 
KM plot of PFS by treatment group will be generated. 
PFS time will be listed on MTP population in a dedicated time to event listing.  
Model checking 
Sensitivity analyses concerning proportional hazards assumption will consist of log-log-
Survival plots (log(-log(S(t))) vs log(time) by treatment group (plots=(lls) in PROC LIFETEST). 
 
4.11.2 
Secondary Efficacy Endpoints 
4.11.2.1 
Overall Survival 
This study is not powered for OS, so adequately powered statistical testing for this endpoint 
will not be possible. However, the results of an unstratified log-rank test will be provided in an 
exploratory manner to assess the difference between treatment groups for OS. 
The same analysis as those described for the primary endpoint will be repeated for OS on 
MTP population The survival rate will be displayed at the following time points: 6, 9, 12 and 
higher (every 3 months) if appropriate. 
OS time will be listed on MTP population in a dedicated time to event listing.  
 
4.11.2.2 
Overall Response Rate (based on Primary Definition of BOR) 
The Best Overall Response for MTP as per main definition will be tabulated on MTP by 
treatment group. 
ORR for the MTP will be summarized in each treatment group of the MTP population and will 
present the number and percentage of patients with objective response (CR or PR) as best 
response along with the two-sided 95% Clopper-Pearson confidence interval. The difference 
in ORR among treatment groups will be estimated with associated two-sided 95% CI using 
the Hauck-Anderson approach. The treatment difference will be tested using a Chi-square 
test at a two-sided alpha level of 5%. 
A logistic regression analysis, using treatment and tumor response at end of induction as per 
eCRF data (SD vs CR/PR) as covariates will be performed. An estimate of the odds ratio with 
an associated two-sided 95 % confidence interval and a p-value for the coefficient will be 
presented for each covariate, including treatment. Please refer to Appendix 4 for the SAS 
code to be used.  
Note: SD will be used as reference. The region stratification factor won’t be used as a 
covariate as almost all the patients are in Europe (only 5 patients from other regions).  
Forest plots displaying ORR odds ratio from the logistic regression by subgroups will be 
generated, for further details please refer to section 4.11.5. 
Waterfall plots (both treatment groups one the same plot) of the best percentage change from 
baseline in sum of diameter collected during the MTP will be provided.  
 
A listing of tumor assessments per timepoint will be provided based on the ITP. It will include: 
 
MTP/ITP/Post-treatment flag 
 
visit 
 
imaging date  


 
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 
lesions number 
 
location, site/organ, assessment method and type of lesion   
 
diameter (mm) for target lesion, status for non-target lesion 
 
sum of diameter of target lesions (mm)  
 
response per timepoint for target lesion and non-target lesion, presence/absence of  
new lesion(s) 
 
overall Response per timepoint 
Information will be collected from the “RECIST 1.1 Target Lesions”, “RECIST 1.1 Non-Target 
Lesions”, “RECIST 1.1 New Lesions” and "RECIST 1.1 - Overall Response Assessment" 
eCRF pages.  
Another listing based on the MTP population will provide the best overall response (main and 
secondary definitions), time to response and the duration of response. Censored patients for 
the duration of response will be flagged as per section 2.2.2.6. 
 
4.11.2.3 
Overall Response Rate (based on Secondary Definition of BOR) 
The analyses performed for Overall Response Rate for MTP based on main definition of BOR 
will be repeated using secondary definition of BOR (refer to section 2.2.3.2). 
 
4.11.2.4 
Disease Control Rate  
The same analysis as described for ORR for MTP will be provided for the following endpoints: 
 
DCR for MTP based on main definition of BOR using the MTP population 
 
DCR for MTP based on secondary definition of BOR using the MTP population 
All corresponding information will be listed on the MTP population. 
 
4.11.2.5 
Time to Treatment Response 
Time to objective response (CR and PR) for each treatment group will be summarized 
separately based on the main and secondary definition of BOR using descriptive statistics 
(median, minimum and maximum) which will be calculated using PROC UNIVARIATE and 
are based on MTP population restricted to responders. 
Two separate summary tables will be created: one for the time to response by considering all 
tumor assessments as in the main definition of BOR and another one by considering on-
treatment tumor assessment as in the secondary definition of BOR. No formal statistical 
comparisons between the treatment groups are planned.  
Time to response will be listed on MTP. 
 
4.11.2.6 
Duration of Response   
The duration of response (DoR) for each treatment group will be estimated using KM product-
limit method estimates. Summary table for duration of response based on MTP population 
restricted to responders will display, by treatment group, the number of patients with best 
overall response CR or PR (N), number of patients with progression or death, number of 
patients censored, min, max, 25th quantile, 75th quantile and median with the associated 
two-sided 95% CIs computed according to Brookmeyer and Crowley method.  
Two separate summary tables will be created: one for duration of response by considering all 
tumor assessments as in the main definition of BOR and another one by considering on-
treatment assessments as in the secondary definition of BOR. 


 
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The duration of response will be compared between the experimental and the control group 
using an unstratified log-rank test. 
Duration of response will be listed on MTP. 
 
4.11.2.7 
Eastern Cooperative Oncology Group (ECOG) Performance 
Status 
Summary table presenting the number of patients and percentage by ECOG performance 
status will be displayed by visit occurring during the MTP. In addition, a shift table of MTP 
baseline ECOG PS versus ECOG PS at the end of MTP will be provided. Supportive listing 
will be provided for the MTP.  
ECOG PS data will be listed based on the ITP population. ITP and MTP evaluations will be 
flagged.  
 
4.11.2.8 
Additional Tumor Assessments 
Listing for each specific assessments to Cohort 1 (head and neck assessment for SCC, Chest 
CT assessment for SCC, dermatology evaluation, anal and pelvic exam) will be provided.  
 
4.11.3 
Exploratory Efficacy Endpoints 
Not Applicable. 
4.11.4 
Sensitivity Analyses 
In addition, the following sensitivity analyses will be performed on PFS, the primary efficacy 
endpoint: 
 
The PFS hazard ratio, and its 95% two-sided confidence interval, of experimental 
group versus control group, will be estimated using a Cox proportional hazards model 
with treatment as the single covariate. Please refer to Appendix 4 for the SAS code to 
be used. 
 
The PFS hazard ratio, and its 95% two-sided confidence interval, of experimental 
group versus control group, will be estimated using different adjusted Cox proportional 
hazards models, using as covariates the treatment and one of the stratification factors, 
i.e. response at the end of induction treatment as mentioned below 
o cov1 (SD vs CR/PR as per eCRF) 
o cov1 (SD vs CR/PR as per IxRS) 
Note: No adjustment on the region will be performed as almost all the patients are in 
Europe. 
 
A sensitivity analysis will be performed for PFS by considering all PFS events reported 
in MTP regardless of the surgery.   
An unstratified log-rank test will be performed to compare PFS between the 
experimental and the control group. PFS will be estimated for each treatment group 
using KM product-limit method estimates. PFS will be summarized by treatment group 
and will display the information as mentioned in section 4.11.1. The PFS hazard ratio, 
and its 95% two-sided confidence interval, of experimental group versus control group, 
will be estimated using a Cox proportional hazards model with treatment as the single 
covariate. 


 
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 
The OS hazard ratio, and its 95% two-sided confidence interval, of experimental group 
versus control group, will be estimated using a Cox proportional hazards model with 
treatment as the single covariate. Please refer to Appendix 4 for the SAS code to be 
used. 
 
For ORR and DCR, a logistic regression analysis, using treatment as single covariates 
will be performed. An estimate of the odds ratio with an associated two-sided 95 % 
confidence interval and a p-value for the coefficient will be presented for treatment. 
Please refer to Appendix 4 for the SAS code to be used. 
 
To assess any bias regarding the completeness of the follow up to capture PFS events, 
KM curve with reverse censoring will be produced by treatment group. In this analysis, 
censored patients in the primary analysis will be considered as having an event, for 
these patients the event date will be the date of last evaluable tumor assessment or 
date of randomization, whichever comes last. Patients with a PFS event in the primary 
analysis will be censored in this analysis, for these patients the censor date will be the 
earliest date between PD date and death date. 
 
4.11.5 
Subgroup Analyses 
Subgroup analyses of PFS and OS will be conducted based on: 
 
Stratification factor (reponse at the end of ITP)   
 
Tumor colon location 
 
The following information will be provided/computed within each subset: 
 
Number of patients in the subgroup 
 
Number of patients with PFS or OS event  
 
Number of patients censored 
 
Median and two-sided 95% CI computed according to Brookmeyer and Crowley 
method, 
 
25th and 75th quantile, and the corresponding two-sided 95% CI computed 
according to Brookmeyer and Crowley method, 
 
PFS HR of experimental versus control group and its two-sided 95% CI computed 
by means of an un-stratified Cox proportional hazards model with treatment as the 
single covariate. 
Forest plots presenting the PFS HR of experimental group versus control group and 
corresponding 95% CI obtained from adjusted Cox model for each subset as defined in 
section 4.7 will be generated.  
Forest plots presenting the OS HR of experimental group versus control group and 
corresponding 95% CI obtained from adjusted Cox model for each subset as defined in 
section 4.7 will be generated.   
    
The Best Overall Response for MTP as per main and secondary definition (see section 
2.2.2.2 and 2.2.3.2) will be tabulated on MTP by treatment group on reponse at the end of 
ITP and tumor colon location  
For each of these subsets, ORR for the MTP will be summarized in each treatment group on 
MTP and will present the number and percentage of patients with objective response (CR or 
PR) as best response along with the two-sided 95% Clopper-Pearson confidence interval. 


 
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The difference in ORR among treatment groups will be estimated with associated two-sided 
95% CI using the Hauck-Anderson approach. 
For each of these  subsets, a logistic regression analysis, using treatment as single covariate 
will be performed. An estimate of the odds ratio (experimental vs control group) with an 
associated two-sided 95 % confidence interval will be provided. 
Forest plots displaying the ORR odds ratio of experimental group compared to control group 
and corresponding 95% CI from the logistic regression with treatment as unique covariate for 
each subset as defined in section 4.7 will be provided. One forest plot will be generated for 
each subgroup. 
No formal statistical comparisons will be conducted within subsets. 
 
4.12 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Not applicable 
4.13 
SAFETY ANALYSES 
Separate safety summaries will be produced for ITP, MTP, Post Induction Treatment and 
Post Maintenance Treatment.   
For ITP data, outputs will be generated on the ITP displaying randomized vs. non randomized 
patients in MTP. MTP outputs will be based on the SAF population and will be presented by 
treatment group. For Post Induction Treatment data, outputs will be generated on ITP for 
patients who completed study treatment discontinuation visit, whereas for Post Maintenance 
Treatment data, outputs will be generated on MTP for patients who completed study 
treatment discontinuation visit. 
No inferential statistical analyses are planned. 
 
4.13.1 
Exposure of Study Medication 
4.13.1.1 
Treatment Duration and Dose Exposure 
A patient will be considered as having initiated a cycle in the ITP if at least one (non-null) 
dose of any study drugs of the ITP has been administered in the corresponding cycle. 
The overall number of cycles initiated during the ITP is defined as the sum of all initiated 
cycles (as defined above) in the ITP. 
For the MTP, the overall number of cycles initiated (i.e. for drug combination) will be computed 
as the sum of all initiated cycles as defined below: 
 
Day 1 of a cycle is defined as the first day in the considered cycle when treatment is 
administered. 
 
The cycle length is assumed to be 2 weeks 
 
For experimental group: 
o a cycle will be assumed to be initiated if cetuximab, vemurafenib and 5-FU and 
LV or any LV substitute  are  administered at any time during the same cycle 
 
For control group: 


 
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o  If capecitabine is administered: a cycle will be assumed to be initiated if 
capecitabine and bevacizumab are administered at any time during the same 
cycle  
o If 5-FU/LV or LV substitute is administered: a cycle will be assumed to be 
initiated if bevacizumab and 5-FU and LV or any LV substitute are 
administered at any time during the same cycle 
 
The overall duration (in weeks) for all components of maintenance treatment is defined as 
follows:  
 
Experimental group:  
 [MAX(min(last dosing date of 5-FU/LV+13, death), min(last dosing date of cetuximab+13, 
death date), min(last dosing date of vemurafenib, death date)) – MIN (first dosing date of 
FP, first dosing date of cetuximab, first dosing date of vemurafenib) + 1]/7  
  with last dosing date of 5-FU/LV = max(last dosing date of 5-FU, last dosing date of LV) 
and first dosing date of 5-FU/LV = min(first dosing date of 5-FU, first dosing date of LV) 
 
Control group:  
o If capecitabine is administered in the last cycle:  
[MAX(min(last dosing date of capecitabine+6, min(last doing date of bevacizumab+13, 
death date)) – MIN (first dosing date FP, first dosing date of bevacizumab) + 1]/7. 
o If 5-FU/LV is administered in the last cycle: 
 [MAX(min(last dosing date of 5-FU/LV+13, death), min(last dosing date of 
bevacizumab+13, death date)) – MIN (first dosing date of FP, first dosing date of 
bevacizumab) + 1]/7  
  with first dosing date of FP = min(fist dosing date of 5-FU, first dosing date of LV or any 
LV substitute, first dosing date of capecitabine) and last dosing date of 5-FU/LV = 
max(first dosing date of last administration of 5-FU, first dosing date of last administration 
of LV or any LV substitute)  
 
The number of cycles administered, duration of dosing, cumulative dose, dose intensity and 
relative dose intensity (RDI) definitions are provided for each drug individually in Table 3 and 
Table 4 for induction and maintenance, respectively. 
 
According to protocol, the cycle length is 2 weeks, excepted for capecitabine in the control 
arm for which each cycle length is as per local practise. A 2-week cycle schedule will be 
considered for drugs other than capecitabine and for the drug combinations. For capecitabine, 
a cycle is defined as any continuous administration separated by a rest period, regardless of 
the duration of the continuous administration and the duration of the rest period. A patient will 
be considered as having initiated a cycle in the MTP for a specific drug if at least one (non-
null) dose of this study drug has been administered in the corresponding cycle. 


 
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Table 3: Exposure Definitions for Induction Treatments 
 
FOLFOX 
5-FU/LV 
bevacizumab 
Number of cycles 
sum of all cycles in which at 
least one non-null dose of 
FOLFOX  has been 
administered 
sum of all cycles in which at least 
one non-null dose of 5-FU and LV 
has been administered. Of note, 
consider only cycles where 
oxaliplatin is not administered 
concomitantly with 5-FU/LV.  
sum of all cycles in which at least 
one non-null dose of bevacizumab 
has been administered 
Duration of dosing 
(weeks) (1) 
 
[min (last  date of FOLFOX+13, 
death date) – first FOLFOX 
dosing date+1] / 7 or 
If FOLFOX-4 or FOLFOX-7 or 
modified FOLFOX-7 is 
administered in the last cycle 
initiated  
 [min (last  date of FOLFOX 
+12, death date) – first 
FOLFOX dosing date+1] / 7 
 
max (min(last date of 5-FU+13, 
death date), min(last date of LV+13, 
death date)) – min (first date of 5-
FU, first  date of LV) +1] / 7 
Of note, consider only 
records/cycles where oxaliplatin is 
not administered concomitantly with 
5-FU/LV. 
[min (last date of bevacizumab +13, 
death date)) – (first bevacizumab 
dosing date in the induction) +1]  / 7 
(1) According to the proposed formula, the duration of dosing may be overestimated in case patients discontinued treatment prior to the end of 
the last cycle. 


 
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Table 4: Exposure Definitions for Maintenance 
 
capecitabine 
5-FU or LV or cetuximab 
bevacizumab 
vemurafenib 
Number of 
cycles 
The sum of all cycles in which at least one non-null dose of <treatment> has been administered 
NA  
Duration of 
dosing (weeks) 
(1) 
[min (last dosing date of <treatment> + x, death date)) – (first <treatment> dosing date in the maintenance) +1] / 7 
Where x=6 for capecitabine  
      x=13 for 5FU, LV, cetuximab, bevacizumab 
      x=0 for vemurafenib 
For 5-FU and LV, last dosing date of treatment will be replaced by the first dosing date of the last administration 
Actual dose  
<treatment> dose administered (in mg) as collected on the dosing eCRF page  
Unit: mg 
Planned dose  
<treatment> planned dose (in mg) as collected on the dosing eCRF page   
Unit: mg 
Normalized 
dose 
dose / recalculated BSA(2) 
Unit: mg/m2 
dose / weight(3) 
Unit: mg/kg 
NA 
Cumulative 
dose  
The cumulative dose will be derived 
for each records as below: (end date 
of administration - start date of 
administration +1) * normalized actual 
dose for the record * 2  
Cumulative dose= sum of cumulative 
dose across all records  
Unit: mg/m2  
sum of the all <treatment > 
normalized actual doses (in 
mg/m2) administered in all 
cycles 
 
 
sum of the all bevacizumab 
normalized actual doses (in 
mg/kg)  administered in all 
cycles 
The cumulative dose will be 
derived for each records as 
below: (end date of 
administration - start date of 
administration +1) * actual dose 
for the record  
Cumulative dose= sum of 
cumulative dose across all 
records  
Unit: mg 
 
 


 
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capecitabine 
5-FU or LV or cetuximab 
bevacizumab 
vemurafenib 
Dose intensity 
Cumulative dose / (duration of dosing 
*7) 
Unit: mg/m2/day 
Cumulative dose / duration 
of dosing  
Unit: mg/m2/week 
Cumulative dose / duration 
of dosing  
Unit: mg/kg/week 
Cumulative dose / (duration of 
dosing * 7)  
Unit: mg/day 
Cumulative 
planned dose 
(CPD) 
Sum of all normalized planned dose 
(in mg/m2) in all cycles    
Sum of all normalized 
planned dose (in mg/m2) in 
all cycles  
Sum of all normalized 
planned dose (in mg/kg) in 
all cycles  
Sum of the all planned doses (in 
mg) reported in all cycles 
Planned dose 
intensity  
CPD / (duration of dosing *7) 
Unit: mg/m2/day  
CPD / duration of dosing 
Unit: mg/m2/week 
CPD / duration of dosing  
Unit: mg/kg/week 
CPD / (duration of dosing*7) 
Unit: mg/ day 
Relative dose 
intensity (RDI) 
(%) 
100 * (dose intensity) / (planned dose intensity) 
(1) According to the proposed formula, the duration of dosing may be overestimated in case patients discontinued treatment prior to the end of the 
last cycle. 
(2) The BSA will be recalculated based on the height and weight (see point 3 for identification of weight) of the patient using the formula as mentioned 
in section 4.3. 
(3) The baseline weight will be used as reference. If the last available weight of the patient prior to or on the cycle start has changed by 10% or 
greater (i.e. patient has gained or lost more than 10% of their body weight since baseline) the patient new weight will be set as the baseline 
weight and will be used at the patient current and subsequent cycles. If a patient weight has changed by 10% or greater at a later cycle, then 
this new weight will be set as the base weight as aforementioned. 


 
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The following information will be tabulated for the ITP using the ITP population: 
 
Summary of total number of cycles initiated per patient 
o Total number of cycles initiated (1,2,3,4,5,6,7,8)  
o Summary statistics of total number of cycles initiated 
 
Summary of drug exposure 
o The number of cycles administered and treatment duration (in weeks) for 
bevacizumab, FOLFOX and 5-FU/LV alone 
 
The following information will be tabulated for the MTP using the SAF population:  
 
Summary of overall duration of treatment and overall number of cycles initiated 
o Overall duration of maintenance treatment (in weeks) 
o Overall number of cycles initiated: 1,2,3,4,5,6,7,8,9,10, 10-15, >=15  
o Summary statistics of overall number of cycles initiated per patient 
 
Summary of drug exposure  
o Total number of cycles administered (tabulated separately for each drug) 
o Duration of dosing (in weeks) (tabulated separately for each drug) 
o Cumulative dose (tabulated separately for each drug according to definition 
provided in table 3) 
o Dose intensity (tabulated separately for each drug according to definition provided 
in table 3) 
o Relative dose intensity: ≤90%, >90%-≤100%, >100% (tabulated separately for 
each drug according to definition provided in table 3) Note: Number and 
percentage will be based on the patients who received the corresponding drug. 
 
Supportive listings presenting the study drug administration as well as the exposure information 
will be provided separately based on ITP population and SAF population for the induction and 
for the maintenance, respectively.  
 
4.13.1.2 
Cycle Delay  
Cycle delay is applicable to the following treatments: FP (5-FU, LV or capecitabine), 
bevacizumab and cetuximab. 
Cycle delay is defined as follow:  
 
For 5-FU, LV, cetuximab, bevazicumab, which have planned cycle of 2 weeks: 
A cycle delay for <treatment> will be defined as the number of days in excess of the expected 
days between two consecutive doses of <treatment> (14 days) and will be calculated as D1Cn+1 
- D1Cn where D1Cn+1 and D1Cn  correspond to date of administration of <treatment> in cycle 
n+1 and cycle n, respectively.  An excess of more than 3 days will qualified cycle Cn+1 as delayed 
for <treatment>. Of note, the first cycle (C1) cannot be identified as cycle delay.  
 
For capecitabine: 
Cycle delay will be defined as the number of days in excess of the expected days between two 
non-zero administrations (21 days, i.e. 14 days of administration and a rest period of 7 days) and 
will be calculated as D1Cn+1 - D1Cn where D1Cn+1 and D1Cn correspond to the start date of 
the first administration of capecitabine in cycle n+1 and cycle n, respectively.  An excess of more 
than 3 days will qualify cycle Cn+1 as delayed for capecitabine. Of note, the first cycle (C1) 
cannot be identified as cycle delay.  


 
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The following information will be tabulated for the MTP on the SAF population:  
 
Summary of <treatment> cycle delay (for 5-FU, LV, capecitabine, bevazicumab and 
cetuximab) at the patient level 
o Number of patients with at least one cycle delayed for <treatment>,  
o Number of patients with 1, 2, 3, ≥3 cycles delayed for <treatment> 
 
Summary of <treatment> cycle delay (for 5-FU, LV, capecitabine, bevazicumab and 
cetuximab) at the cycle level 
o Number of cycles delayed 
o Length of cycle delayed (>3 -7 days, >7-14, >14-21, >21)  
 
4.13.2 
Adverse Events 
Adverse events variables are defined in Table 5. 
Table 5: Adverse Events Definitions 
Variable 
Definition 
Treatment 
Emergent 
Adverse Events 
(TEAEs) for the 
induction 
treatment phase 
(1) 
 
Any adverse events (serious and non-serious) with an onset date on (only if the 
“Event occurred prior to first study drug administration” from the AE eCRF page is 
not checked) or after the first day of treatment of the ITP and up to the:  
 
first day of treatment of the MTP (excluding) if it occurs within the 30 days 
from last day of treatment of induction treatment for patients treated with 
maintenance treatment 
 
within 30 days from last day of treatment of induction treatment (as defined 
in section 4.2.1), for patients not treated with maintenance treatment or for 
patients treated with maintenance treatment but with first day of treatment of 
MTP being more than 30 days after last day of treatment of ITP.  
TEAEs for the 
maintenance 
treatment 
phase(1) 
 
Any adverse events (serious and non-serious) with an onset date on (only if the 
“Event occurred prior to first study drug administration” from the AE eCRF page is 
not checked)  or after the first day of treatment of the MTP and up to 30 days from 
the last day of treatment of MTP (as defined in section 4.2.2) 
Post induction 
treatment 
Adverse Events  
Any adverse events (serious and non-serious): 
 
with an onset date more than 30 days after the last day of treatment of the 
ITP (as defined in section 4.2.1) for patients not treated with maintenance 
treatment. 
 
with an onset date more than 30 days after the last day of treatment of the 
ITP and prior the first day of treatment of the MTP, for patients treated with 
maintenance treatment with first day of treatment of MTP being more than 
30 days after last day of treatment of ITP.. 


 
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Post maintenance 
treatment 
Adverse events  
Any adverse events (serious and non-serious) with an onset date more than 30 
days after the last day of treatment of the MTP (as defined in section 4.2.2) (as 
defined in section 4.2.2). 
Adverse Events 
NCI CTCAE 
grade 
The adverse events grade will be the one with tick box checked for "AE most 
extreme NCI CTCAE grade" 
Serious Adverse 
Events (SAEs) 
Any adverse events qualified as “serious” by the investigator.  
Adverse Events 
with fatal 
outcome 
Any adverse events with outcome of “Fatal”. 
Adverse events 
related to 
<FOLFOX, 
bevacizumab, FP, 
cetuximab, 
vemurafenib>  
Any adverse events with an “AE suspected to be caused by study drug <FOLFOX, 
bevacizumab, FP, cetuximab, vemurafenib >  as ‘Yes’. 
For AE suspected to be caused by FOLFOX while starting in the maintenance 
phase, the unique text ‘“AE considered related to Folfox”‘ has been reported in the 
comment field ‘ 
Adverse events 
leading to 
<FOLFOX, 
bevacizumab, FP, 
cetuximab, 
vemurafenib > 
discontinuation 
Any adverse events with an “Action taken with <FOLFOX, bevacizumab, FP, 
cetuximab, vemurafenib> due to SAE/AE” of “drug withdrawn” 
Adverse events of 
Special Interest 
(AESI) as 
reported on eCRF  
AESIs will be selected based on the tick box from the eCRF.  
<Bevacizumab, 
Vemurafenib> 
AESIs based on 
pre-defined terms 
AESIs will be selected from AEs based on the <bevacizumab, vemurafenib> list of 
pre-defined terms.  
(1) Of note, in case an event has an incomplete or missing start date, which consequently prevents its 
allocation to only one treatment phase of the study, the event will be allocated to both the induction 
and maintenance phase. Refer to section 4.14 for further details. 
Safety summaries will be produced for the ITP on the ITP population and for the MTP on the SAF 
population, unless otherwise specified. ITP summaries will display patients randomized vs. 
patients not randomized in MTP. MTP summaries will be done by actual maintenance treatment 


 
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group as defined for the SAF. Descriptive statistics will be generated as appropriate. No 
inferential statistical analyses are planned. 
Summaries of adverse events for ITP and MTP will be generated for those events that are 
considered treatment emergent. The AE tables will include the number and percentage of 
patients with at least one AE, by MedDRA primary System Organ Classes (SOC) (sorted in a 
descending order of the total frequency count) and MedDRA Preferred Terms (PT) (sorted by 
descending order of the overall frequency count within each SOC) unless otherwise indicated. A 
patient with more than one occurrence of the same adverse event in a particular system organ 
class/preferred term will be counted only once in the total of those experiencing adverse events 
in that particular system organ class/preferred term. For the overall summary tables, information 
presented by grade will not be restricted to the worst grade per patient i.e. all events will be 
presented.  Any AEs with a missing CTC grade will be reported in the “missing” category grade.  
 
An overview table will be produced for the ITP based on the ITP population and will present: 
 
Number of TEAEs 
 
Number of patients with at least one TEAE 
 
Number of patients with at least one TEAE by CTC grade: 1, 2, 3, 4, 5, ≥3, missing 
 
Number of patients with at least one related TEAE 
o Any study drug  
o FOLFOX 
o 5-FU/LV 
o bevacizumab 
 
Number of patients with at least one serious TEAE 
 
Number of patients with at least one related serious TEAE  
o Any study drug  
o FOLFOX 
o 5-FU/LV 
o bevacizumab 
 
Number of patients with at least one TEAE with fatal outcome 
 
Number of patients with at least one TEAEs leading to treatment discontinuation of: 
o Any study drug  
o FOLFOX 
o 5-FU/LV 
o bevacizumab 
 
An overview table will be produced for the Post Induction Treatment AEs, i.e. occurring more 
than 30 days after last day of treatment during the Induction Phase (as defined in section 4.2.1), 
based on patients from the ITP population who has a study treatment discontinuation visit date. 
This table will present the following information for the non-randomized patients to MTP only: 
 
Number of AEs 
 
Number of patients with at least one AE 
 
Number of patients with at least one AE by CTC grade: 1, 2, 3, 4, 5, ≥3, missing 
 
Number of patients with at least one related AE  
 
Number of patients with at least one serious AE 
 
Number of patients with at least one related serious AE  
 
Number of patients with at least one AE with fatal outcome 


 
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An overview table will be produced for the maintenance phase based on the SAF and will present: 
 
Number of TEAEs 
 
Number of patients with at least one TEAE 
 
Number of patients with at least one TEAE by CTC grade: 1, 2, 3, 4, 5, ≥3, missing 
 
Number of patients with at least one related TEAE  
o Any study drug  
o Fluoropyrimidines 
o bevacizumab  
o cetuximab,  
o vemurafenib 
o  FOLFOX 
 
Number of patients with at least one serious TEAE 
 
Number of patients with at least one related serious TEAE  
o Any study drug  
o Fluoropyrimidines 
o bevacizumab  
o cetuximab,  
o vemurafenib 
o  FOLFOX 
 
Number of patients with at least one TEAE with fatal outcome 
 
Number of patients with at least one TEAEs leading to treatment discontinuation of: 
o Any study drug  
o bevacizumab  
o cetuximab,  
o vemurafenib  
 
Number of patients with at least one treatment emegent AESI (as reported on eCRF) 
 
Number of patients with at least one treatment emegent AESI (based on list of pre-
defined terms) 
o bevacizumab, 
o vemurafenib 
 
Number of patients with at least one serious treatment emergent AESI (as reported on 
eCRF) 
 
An overview table will be produced for the Post Maintenance Treatment AEs, i.e. AEs occurring 
more than 30 days after the last day of treatment during the Maintenance Phase (as defined in 
section 4.2.2), based on patients from the MTP population who have a study treatment 
discontinuation visit date. This table will present the following information: 
 
Number of AEs 
 
Number of patients with at least one AE 
 
Number of patients with at least one AE by CTC grade: 1, 2, 3, 4, 5, ≥3, missing 
 
Number of patients with at least one related AE  
 
Number of patients with at least one serious AE 
 
Number of patients with at least one related serious AE  
 
Number of patients with at least one AE with fatal outcome 
 


 
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In addition, the following tables (number and percentage of patients) will be presented for the 
ITP based on the ITP population and will display the number of patients (and corresponding 
number of TEAEs) and percentage with any: 
 
TEAEs by SOC and PT  
 
TEAEs by SOC and PT and by Worst Intensity 
 
Grade 3-5 TEAEs by SOC and PT 
 
Related TEAEs by SOC and PT: to any study drugs, FOLFOX, 5 FU/LV, bevacizumab 
 
Serious TEAEs by SOC and PT  
 
Related serious TEAEs by SOC and PT: to any study drugs, bevacizumab 
 
TEAEs leading to treatment discontinuation by SOC and PT: any study drug,   
 
TEAEs leading to dose reduction or interruption by SOC: any study drugs, bevacizumab  
 
Grade 5 TEAEs or TEAEs with fatal outcome by SOC and PT 
 
Treatment emergent AESI by AESI eCRF categories, SOC and PT   
 
Bevacizumab treatment emergent AESI based on pre-defined categories  
 
The following tables will be presented for the MTP only and will display the number and 
percentage of patients (and corresponding number of TEAEs) with any: 
 
TEAEs by SOC and PT  
 
TEAEs by SOC and PT and by Worst Intensity  
 
Grade 3-5 TEAEs by SOC and PT 
 
Related TEAEs by SOC and PT: any study drugs, 5-FU/LV, FOLFOX, bevacizumab, 
cetuximab, vemurafenib,  
 
Serious TEAEs by SOC and PT  
 
Related Serious TEAEs by SOC and PT: any study drugs, 5-FU/LV, cetuximab, 
vemurafenib, bevacizumab, FOLFOX 
 
Grade 5 TEAEs or TEAEs with fatal outcome by SOC and PT  
 
TEAEs leading to treatment discontinuation by SOC and PT: any study drugs,  
 
TEAEs leading to dose reduction or interruption by SOC and PT: any study drugs, 5-
FU/LV, cetuximab, vemurafenib, bevacizumab  
 
Treatment emergent AESI by AESI eCRF categories, SOC and PT and by Worst 
Intensity   
 
Serious Treatment emergent AESI by AESI eCRF categories, SOC and PT and by 
Worst Intensity 
 
Treatment emergent AESI by AESI eCRF categories, SOC and PT   
 
Serious Treatment emergent by AESI eCRF categories, SOC and PT  
 
Bevacizumab treatment emergent AESI based on pre-defined categories  
 
Vemurafenib treatment emergent AESI based on pre-defined categories  
  
By-patient listings will be provided for AEs; they will include Post-treatment adverse events. 
Appropriate flagging of study phase (ITP/MTP) as well as TEAEs/Post-treatment AEs will be 
done. The following listings will be provided based on ITP population 
 
All adverse events  
 
All Grade 5 adverse events or any adverse events with fatal outcome  
 
All adverse events leading to treatment discontinuation  
 
All AESI (as reported on eCRF)   
 


 
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4.13.3 
Death 
The following summary tables will be provided and will present: 
 
The number of patients who died within 30 days from last day of treatment of the ITP 
(as defined in section 4.2.1) and the corresponding reason of death based on ITP 
population 
 
The number of patients who died more than 30 days from last day of treatment of 
ITP (as defined in section 4.2.1) and the corresponding reason of death based on 
ITP population who has a study treatment discontinuation visit date 
 
The number of patients who died within 30 days from last day of treatment of MTP 
for treated patients or within 30 days from randomization with the corresponding 
cause of death based on MTP population 
 
The number of patients who died within 30 days from last day of treatment of MTP 
(as defined in section 4.2.1) with the corresponding death reason using the SAF 
population 
 
The number of patients who died more than 30 days from last day of treatment of 
maintenance treatment and the corresponding reason of death based on patients 
from the MTP population who has a study treatment discontinuation visit date 
One listing will be generated for deaths based on the ITP population and including appropriate 
flagging of study phase (ITP and MTP) and on-treatment/post-treatment deaths (i.e. within 30 
days from last day of treatment/more than 30 days from last day of treatment).  
All deaths information (including reason and date) will be retrieved from the Study 
Completion/Early Discontinuation eCRF page.  
 
4.13.4 
Laboratory Data 
The following laboratory parameters will be considered as CTC gradable parameters. 
 
Haematology 
 
Absolute Neutrophils Count (ANC)  
 
Hemoglobin (Hb) 
 
Leukocytes/White Blood Cells counts (WBC) 
 
Platelet Count 
 
Blood chemistry 
 
Albumin  
 
Alkaline Phosphatase (ALP)  
 
Calcium 
 
Creatinine  
 
Glucose 
 
Potassium  
 
SGPT or alanine aminotransferase (ALT)  
 
SGOT or aspartate aminotransferase (AST)  
 
Sodium 
 
Total Bilirubin 


 
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 
Magnesium 
 
Amylase 
 
Lipase 
 
Coagulation  
 
international normalized ratio (INR)  
 
activated partial thromboplastin time (aPTT) 
 
The following parameters will be considered as non CTC gradable parameters. 
 
Hematology  
 
Red blood Cell (RBC) 
 
Hematocrit 
 
Lymphocytes 
 
Neutrophils 
 
Eosinophils 
 
Basophils 
 
Monocytes 
 
Blood Chemistry 
 
Blood Urea Nitrogen 
 
Bicarbonate 
 
Chloride Lactate dehydrogenase (LDH) 
 
Phosphorus 
 
Total Protein 
 
Urinalysis 
 
Urine Protein Dipstick 
 
24-hour urine protein 
 
All laboratory parameter information will be summarized for each phase separately. Laboratory 
information reported in tables will be restricted to the baseline and on-treatment measurements. 
The analysis population will be the ITP and the SAF population for the ITP and MTP, respectively.  
Clinical laboratory values will be expressed using Système International (SI) units.  
When applicable, laboratory tables will display their High (hyper)/Low (hypo) values of a specific 
parameter (e.g. calcium (high) and calcium (low) in separate tables. 
In case of missing normal ranges for parameters that are not differential and have only grade 1 
defined from normal ranges (e.g. Neutrophils, WBC, Albumin…) the worst case scenario will be 
applied, i.e. grade 1. 
A “Missing” category will be reported for patients with missing grades or missing reference range 
indicators at baseline and/or on-treatment and patients with no laboratory assessments.  
For hematology, blood chemistry and coagulation parameters which can be graded per CTCAE, 
the information will be summarized by means of a shift table summarizing the baseline grade 
versus the worst CTC grade per patient defined as the highest CTC grade among the on-


 
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treatment evaluations. If there is no on-treatment evaluation, then the worst grade will be set to 
‘Missing’. 
Hematology and blood chemistry parameters which cannot be graded per CTCAE, the 
information will be summarized by means of a shift table from baseline category to worst on-
treatment category. The following categories will be used: 
 
Baseline: Low/Normal/High/Missing/Overall 
 
Worst on-treatment: Low/Normal/High/Missing/Overall 
Patient with “High” and “Low” for the same laboratory test (at different visits) is counted for each 
direction in summary tables. 
For urinalysis protein dipstick, all non-missing assessments excepted “0-absent” assessment will 
be considered “Present”. A shift table presenting baseline category versus worst on-treatment 
category will be produced with the following categories: 
 
Baseline: Absent/Present/Missing/Overall 
 
Worst on-treatment: Absent/Present/Missing/Overall 
For urinalysis, 24-hour urine protein values will not be tabulated but listed only. 
All laboratory values will be listed along with CTC grade/category.  Separate listings will be 
generated to include all abnormal laboratory values.  
 
4.13.5 
Vital Signs 
Vital signs parameters include: 
 
Temperature (°C) 
 
Systolic blood pressure (SBP seated position) (mmHg) 
 
Diastolic blood pressure (DBP seated position) (mmHg) 
 
Weight (kg) 
 
BSA (m2) 
 
Heart rate (beats/min) 
 
Respiratory rate (breaths/min) 
 
Vital signs information will be summarized for each phase separately and by treatment group 
when applicable. Vital signs information reported in tables will be restricted to non-missing 
baseline and non-missing on-treatment measurements. The analysis population will be the ITP 
population for the ITP and the SAF population for the MTP.  
Actual value and change from baseline for heart rate and systolic and diastolic blood pressure 
will be summarized by treatment group for each visit using descriptive statistics.  
All vital signs data including change from baseline (and data reported at timepoints not included 
in the summary table) will be listed. 
 
 
 


 
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4.13.6 
Other Safety Assessment - Applicable only for the experimental 
group 
ECG data will be summarized on the SAF population for the MTP as follow: 
 
Summary of Qualitative ECG results over time presenting the number of patients by 
categories: 
Normal/Abnormal, 
not 
clinically 
significant/Abnormal, 
clinically 
significant/unable to Evaluate/Missing 
 
Summary of QTcF (in categories) over time presenting the number of patients with QTcF 
in categories: <=450 ms/ >450 ms - <=480 ms/>480 ms - <= 500 ms / >500 ms. 
All ECG data will be listed on ITP population. 
4.13.7 
Other Safety Assessment  
Pregnancy test data will be listed on the ITP population, ITP and MTP data will be flagged. 
 
 


 
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4.14 
MISSING DATA 
Imputation of partial/missing death date will be done as follows:  
 
If the date is completely missing, then the day of “Last known to be alive” +1 will be used  
 
If only day is missing and year and month are same as “Last known to be alive”, then the 
day of “Last known to be alive”+1 will be used otherwise the 1st day of the month will be 
used 
 
If day and month are missing and year is same as “Last known to be alive”, then the “Last 
known to be alive”+1 will be used, otherwise 1st of January will be used 
 
Partially missing dates for adverse events (AEs) will be imputed as follows. Of note, imputation 
of missing/partial AE date will be done only to identify treatment emergent AEs. 
AE onset dates 
 Partially missing onset dates will be imputed as follows 
 
When only Day is missing:  
o If Month & Year of the onset date are the same as Month & Year of the 
first day of treatment of the induction/maintenance treatment phase, the 
imputed onset date will be imputed as the minimum of the first day of 
treatment of the induction/maintenance treatment phase and the AE 
resolution date (imputed if needed). 
o Otherwise, the missing day will be replaced by “1”. 
 
When Day & Month are missing:  
o If Year of the onset date is the same as Year of the induction/maintenance 
treatment phase, the imputed onset date will be imputed as the minimum 
of the first day of treatment of the induction/maintenance treatment phase 
and the AE resolution date (imputed if needed). 
o Otherwise, the missing Day & Month will be replaced by “01JAN”. 
 
 Complete missing onset dates for AEs will be imputed by first day of treatment of the 
induction/maintenance treatment phase and the AE will be considered as treatment 
emergent, unless the end date of the AE (imputed if needed) or the end year of the 
AE (if day and month are missing) is entered and is before the year of the first 
treatment administration of the induction/maintenance treatment phase. 
 
AE resolution dates 
 Incomplete resolution dates will be replaced by the last day of the month (if day is 
missing only), if not resulting in a date later than the date of patient's death. In the 
latter case the date of death will be used to impute the incomplete resolution date 
 In all other cases the incomplete resolution date will not be imputed 
Of note, the above rules may allow allocation of an event to both the ITP and MTP treatment 
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Partially missing dates for medications/therapies will be imputed as follows. Of note, imputation 
of missing/partial medicationstherapies date will be done only to identify concomitant 
medications/therapies. 
Partial dates will be imputed as follow: 
 
Start dates 
o When only Day is missing: the missing day will be replaced by “1” 
o When Day & Month are missing: the missing Day & Month will be replaced by 
“01JAN”. 
 
End dates 
o When only Day is missing: the missing day will be replaced by the last day of the 
month 
o When Day & Month are missing: the missing Day & Month will be replaced by 
“31DEC”. 
And rules described in section 4.10.3.2 and below will be applied using imputed dates. 
 
In case of complete missing dates, the following will be applied: 
 
If the start date of the medication/therapy is unknown (i.e. complete missing date) and 
there is no end date, medication/therapy is flagged as taken prior to study but not as 
ongoing then the medication/therapy will be considered as a prior medication.  
 
If both the start date and end date of the medication/therapy is unknown (i.e. complete 
missing date), then the medication/therapy will be considered as a concomitant 
medication/therapy for both the induction and maintenance phase if the patient is treated 
in the phase of interest. 
 
If the start date of the medicationtherapy is unknown (i.e. complete missing date), but the 
end date is known and is prior to the first dosing date of the considered phase, then the 
medicationtherapy will not be considered as concomitant for the corresponding phase. 
 
If the start date of the medication/therapy is available and the end date is unknown, then 
the medication/therapy will not be considered as prior. Concomitance to ITP/MTP will be 
assessed using the available start date.  
Partially missing dates for surgery will be imputed as follows. Of note, imputation of 
missing/partial surgeries date will be done only to identify concomitant surgeries. 
Partial dates will be compared as follow: 
 
When only Day is missing: Month & Year of the surgery will be compared to Month & 
Year of the first dosing date of interest (either ITP or MTP). If on or after, the surgery will 
be considered as concomitant to the period of interest. If on or before the first doing date 
of ITP, the surgery will be considered as prior. 
 
When Day & Month are missing: Year of the surgery will be compared to Year of the 
dosing date of interest (either ITP or MTP). If on or after, the surgery will be considered 
as concomitant to the period of interest. If on or before the first doing date of ITP, the 
surgery will be considered as prior. 
Of note, the above rules may allow a medication/procedure to be concomitant to both the ITP 
and MTP treatment phase. 
 
 


 
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For patients who discontinued study treatment but without any study treatment discontinuation 
visit date, this visit will be imputed as follows: 
 
If patient was treated in the MTP, the last dose will be retrieved from the treatment drug 
completion/early discontinuation page from the eCRF in the maintenance phase. The 
maximum date among the date mentioned for each treatment during MTP + 30 days will 
be considered.  
 
If patient was treated in the ITP, the last dose will be retrieved from the treatment drug 
completion/early discontinuation page from the eCRF in the induction phase. The 
maximum date among the date mentioned for each treatment during ITP + 30 days will 
be considered  
with the following exception: 
o If a patient died within 30 days from last dose, the follow up phase does not exist 
for this patient 
Partially missing dates for date of initial histological diagnosis or date of first diagnosis of 
metastatic disease or date of first diagnosis of locally recurrent disease will be imputed as follows: 
Imputation of these partial dates will be done only to determine if the initial diagnosis is 
synchronous or metachronous and only in case the date day is missing. The imputation will 
consist in replacing the missing day by “1”. In case month and/or year are missing, no imputation 
will be done. 
 
No other dates will be imputed, unless otherwise specified. The original incomplete, missing or 
partial dates will be presented in the listings, not the imputed dates. 
 
4.15 
INTERIM ANALYSES 
 
No formal interim analyses on PFS or OS are planned. 


 
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5. 
REFERENCES 
Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response to 
panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008 Dec 
10;26(35):5705-12. doi: 10.1200/JCO.2008.18.0786. Epub 2008 Nov 10. 
 
Ron Brookmeyer and John Crowley, A Confidence Interval for the Median Survival Time. 
Biometrics  Vol. 38, No. 1 (Mar., 1982), 29-41 
 


 
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Appendix 1: Protocol Synopsis 
  


 
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prior to informed consent signature may be used as screening assessments as long as they were done within 7 days prior to informed consent 
signature. 
e. The “All Cohort” eligibility criteria are evaluated prior to initiating the first cycle of study treatment during the Induction Treatment Phase.  
f. 
Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, smoking history, use of alcohol and drugs of abuse, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 7 days prior to the Screening visit.  Demographic data will include 
age, sex, and self-reported race/ethnicity (where permitted by federal regulations). 
g. Vital signs include measurements of systolic and diastolic blood pressure while the patient is in a seated position, and temperature.  During 
Screening, weight only required ≤ 7 days. 
h. Baseline assessment requires a complete physical exam. A complete physical examination should include an evaluation of the head, eyes, 
ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological 
systems. Abnormalities identified at Screening / Baseline will be recorded as baseline conditions.  At subsequent visits (or as clinically 
indicated), limited, symptom-directed physical examinations should be performed. Changes from Baseline, with new or worsened clinically 
significant abnormalities, should be reported as AEs if appropriate.  
i. 
ECOG status assessed within 7 days prior to Day 1 of Cycle 1 (Induction Treatment Phase) for eligibility determination.  See Appendix 8. 
j. 
Concomitant medication includes any prescription medications or over-the-counter preparations used by a patient between the 7 days prior to 
the date of informed consent up until the date of study discontinuation.  Only concomitant medications used for supportive care, to alleviate 
symptoms of mCRC, or to treat adverse drug reactions should be recorded on the Concomitant Medications eCRF. At subsequent visits, only 
changes to current medications or medications used since the last documentation of medications will be recorded.  Concomitant medications 
for treatment of AEs related to study medication will continue to be recorded while the AE is being followed. For permitted and prohibited 
concomitant medications, see Section 4.4. 
k. Haematology includes haemoglobin, haematocrit, platelet count, red blood cell count, white blood cell count, and differential. Blood chemistry 
includes ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin, blood urea nitrogen or urea, LDH, creatinine, glucose, calcium, 
phosphorus, sodium, potassium, chloride, and bicarbonate. Hematology and blood chemistry tests must be conducted prior to each treatment 
cycle, with the results available for review prior to start of treatment according to local standards for treatment management. However, only 
tests conducted every second treatment cycle will be recorded in the eCRF. Clinical laboratory results constituting a clinically significant AE 
should be recorded as such.  
l. 
INR and aPTT are required for all patients at screening but only for patients receiving anticoagulants while on protocol-specified treatment. 
m. Urinalysis must be performed by dipstick at Baseline and within 48 hours prior to every cycle.  A 24-hour urine collection is needed in the event 
of proteinuria ≥ ± 2 by dipstick test. 
n. Urine or blood pregnancy test, only for women of childbearing potential (i.e. not post-menopausal as indicated by < 12 months of non-therapy-
induced amenorrhea, nor surgically sterile [absence of ovaries and/or uterus]), including those who have had a tubal ligation.  A serum 
pregnancy test is required within 7 days prior to start of study induction treatment, or within 14 days with a confirmatory urine pregnancy test 
within 7 days prior start of study induction treatment 


 
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o. Will include radiology, chest and abdominal CT or MRI, and other scans to document all sites of disease. Include upper abdomen at Baseline.  
A CT or MRI scan of the brain is required if there is clinical suspicion of CNS metastases at screening/Baseline or at any time during the 
Induction Treatment Phase. Subsequent tumour assessments will be done according to standard of care at each study centre, with the 
exception that all patients must have a tumour assessment at the end of the Induction Treatment Phase. Tumour assessments are not required 
for study purposes after disease progression has been documented. Patients who discontinue study treatment during the Induction Treatment 
Phase prior to disease progression will also continue to be followed for progressive disease, with disease status followed according to local 
practice until progression or May 31, 2019, whichever comes first. After May 31, 2019, disease status will not be collected for the study.    
p. Archival tumour tissue (FFPET) block from the primary tumour obtained at the time of the initial diagnosis. If the tumour block is not available, ≥ 
20 slides cut from the primary tumour sample will be accepted as an alternative.  Before a patient can be enrolled, the sample (block or slides) 
must be shipped to the designated laboratory with the corresponding pathology report and receipt of the shipment must be confirmed by the 
laboratory.  See Appendix 17. 
q. Collection of the optional core biopsy of metastatic tumours was discontinued as of May 2018 (See Appendix 18).  
r. 
Whole blood and plasma samples will be collected from all study patients for exploratory biomarker analyses unless genomic analysis is not 
allowed per local regulations. In such instances, only plasma samples will be collected.  All samples will be sent to a designated laboratory.  
Samples during treatment should be taken within 48 hours prior to study treatment Day 1 of each cycle indicated, unless otherwise specified 
(see Appendix 17 and Laboratory Manual). 
s. After the signing of the informed consent form, and prior to Day 1 of Cycle 1 (Induction Treatment Phase), any SAEs thought to be related to a 
protocol-mandated intervention should be reported.  Adverse events will be documented at every cycle during treatment. All patients will be 
followed for new AEs for 28 days following the discontinuation of study treatment. At the time of treatment discontinuation, any ongoing AE/SAE 
will be followed until the event resolves, the Investigator assesses the event as stable, the patient is lost to follow-up, dies or withdraws 
consent. Death related to disease progression is not considered to be an SAE. The Sponsor should be notified if the Investigator becomes 
aware of any SAE or AEs of special interest occurring after the end of the adverse event reporting period if the event is believed to be related to 
prior study treatment. 
t. 
Eligible patients will enter a 4-month Induction Treatment Phase.  Treatment during this phase, based on Investigator’s choice, will be either 
eight 2-week cycles of 5-FU, LV and oxaliplatin (FOLFOX) in combination with bevacizumab or six 2-week cycles of FOLFOX in combination 
with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab. 
 
 








 
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f. 
Each cohort will consist of an experimental treatment arm and a control arm.  Randomised on a 2:1 (experimental:control) basis to either the 
experimental treatment arm or the control arm of that cohort.  See Section 4.2. 
g. Vital signs include measurements of systolic and diastolic blood pressure while the patient is in a seated position, and temperature.  
h. Physical examinations will be symptom-directed, and will include changes from Baseline (pre-Induction) with new or worsened clinically 
significant abnormalities being reported as AEs if appropriate.  
i. 
To be performed by the Investigator or other qualified physician as part of the evaluation for SCC. The head and neck examination will consist 
of at least a visual inspection of the oral mucosa and lymph node palpation. Any suspicious findings will be referred to an appropriate 
specialist.  
j. 
The routinely scheduled radiographic assessment for tumour burden may be used (if available) as the chest CT for the evaluation of non-
cutaneous SCC. MRI may be used if a CT scan is contra-indicated for the patient. 
k. Evaluation to be performed by a dermatologist, the Investigator or other qualified physician.  
l. 
Pelvic examinations for women (with special attention to cervix) and anal examinations for all patients will be performed by the Investigator or 
other qualified physician prior to start of Experimental Therapy and at the Study Treatment Discontinuation Visit for the evaluation of SCC. The 
pelvic examination should include a complete external and internal examination (internal examination of uterine cervix may include a Pap 
smear, which would be a decision of the Investigator). The anal examination should include external examination, digital anorectal examination 
and anoscopy or proctoscopy. However, if in opinion of the Investigator the presence of “abnormal lesions including SCC” can be excluded by 
the external inspection and the manual examination, this is acceptable.  However, if the presence of a lesion is suspected, an anoscopy or 
proctoscopy are recommended.  
m. See Appendix 8. 
n. ECG to determine Cohort 1 eligibility must conducted within 3 weeks of randomization. During maintenance treatment, ECGs will be required 
in experimental arm patients only. Measurements include heart rate, PR interval, QRS duration, and QT and QTc intervals. 
o. Concomitant medication includes any prescription medications or over-the-counter preparations used by a patient between the 7 days prior to 
the date of informed consent up until the Study Treatment Discontinuation visit.  Only concomitant medications used for supportive care, to 
alleviate symptoms of mCRC, or to treat adverse drug reactions should be recorded on the Concomitant Medications eCRF. At subsequent 
visits, only changes to current medications or medications used since the last documentation of medications will be recorded.  Concomitant 
medications for treatment of AEs related to study medication will continue to be recorded while the AE is being followed.  For permitted and 
prohibited concomitant medications, see Section 4.4. 
p. Haematology includes haemoglobin, haematocrit, platelet count, red blood cell count, white blood cell count, and differential. Blood chemistry 
includes ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin, blood urea nitrogen or urea, LDH, creatinine, glucose, calcium, 
phosphorus, sodium, potassium, chloride and bicarbonate. Patients in the experimental arm will also have magnesium, amylase and lipase 
tested. Haematology and blood chemistry tests must be conducted prior to each treatment cycle, with the results available for review prior to 
start of treatment according to local standards for treatment management. However, only tests conducted every second treatment cycle will be 
recorded in the eCRF. Clinical laboratory results constituting a clinically significant AE should be recorded as such.  
q. INR and aPTT only for patients receiving anticoagulants while on protocol-specified treatment. 


 
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r. 
Urinalysis must be performed by dipstick within 48 hours prior to every cycle.  A 24-hour urine collection is needed in the event of proteinuria ≥ 
± 2 by dipstick test. Urinalysis results from every second cycle only will be recorded in the CRF. 
s. Urine or blood pregnancy test, only for women of childbearing potential (i.e. not post-menopausal as indicated by < 12 months of non-therapy-
induced amenorrhea, nor surgically sterile [absence of ovaries and/or uterus]), including those who have had a tubal ligation.  If urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
t. 
Up to and including May 31, 2019, tumour assessments will be conducted according to RECIST 1.1 for Cohort 1 with disease status during 
maintenance treatment determined based on comparison with the tumour assessment done at the end of induction treatment. Assessments 
will include radiology, chest and abdominal CT or MRI, and other scans to document all sites of disease. A CT or MRI scan of the brain is 
required if there is a clinical suspicion of CNS metastases. Up to and including May 31, 2019, tumour assessments will be conducted every 
eight weeks from the start of maintenance treatment regardless of treatment delays. After May 31, 2019, disease status will not be collected 
for the study and tumour assessments may be conducted per local practice. Patients who discontinue study treatment during the Maintenance 
Treatment Phase prior to disease progression will also continue to be followed for progressive disease, with disease assessments per RECIST 
1.1 conducted every eight weeks until progression or May 31, 2019, whichever comes first. 
u. Supplemental Biomarker Program closed as of May 2018. Collection of these samples has been discontinued (see Appendix 18). 
v. Plasma samples will be collected from all patients for exploratory biomarker analyses. These samples will be sent to a designated laboratory.  
Samples during treatment should be taken within 48 hours prior to study treatment Day 1 of each cycle indicated, unless otherwise specified 
(see Appendix 17 and the Laboratory Manual). 
w. Adverse events will be documented at every cycle during treatment. All patients will be followed for new AEs for 28 days following the 
discontinuation of study treatment. At the time of treatment discontinuation, any ongoing AE/SAE will be followed until the event resolves, the 
Investigator assesses the event as stable, the patient is lost to follow-up, dies or withdraws consent. Death related to disease progression is 
not considered to be an SAE.  The Sponsor should be notified if the Investigator becomes aware of any SAE or AEs of special interest 
occurring after the end of the adverse event reporting period if the event is believed to be related to prior study treatment. 
 


 
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Appendix 4: SAS code 
 
The following SAS code will be used to obtain the log-rank p-value from the unstratified 
log-rank test mentioned in section 4.11.1:  
PROC LIFETEST data=dataset METHOD=KM CONFTYPE=LOGLOG;  
TIME pfstime*censor(1);  
STRATA treat / test=logrank; 
RUN;  
* pfstime represents variable containing event/censor times;  
* censor represents censoring variable (1=censored, 0=event);  
* treat represents treatment group variable;  
Further options to control the output may be added. 
 
 
The following SAS code will be used for the logistic regression mentioned in section 
4.11.2.2:  
PROC LOGISTIC DATA= dataset;  
CLASS treat (ref=’FP+Bev’)strate1 / param=ref;  
MODEL response (event=’1’) = treat strate1 / alpha=0.05;  
RUN;  
* response represents the response variable;  
* treat represents the treatment group; 
* strate1 represents the categorical covariate related to stratification 
factors as per eCRF data for tumor response;  
Further options to control the output may be added. 
 
The following SAS code will be used to obtain the hazard ratio and corresponding 
confidence interval from the Cox Model with treatment as single covariate mentioned in 
section 4.11.4: 
PROC PHREG data=dataset;  
CLASS treat; 
MODEL pfstime*censor(1)=treat /RL TIES=EXACT;  
RUN;  
* pfstime represents variable containing event/censor times;  
* censor represents censoring variable (1=censored, 0=event);  
* treat represents treatment group variable;  
Further options to control the output may be added.  
 
 
The following SAS code will be used to obtain the hazard ratio and corresponding 
confidence interval from the adjusted Cox Model mentioned in section 4.11.4:  
PROC PHREG data=dataset;  
CLASS treat strate1; 
MODEL pfstime*censor(1)=treat stratum1 /RL TIES=EXACT;  
RUN;  
* pfstime represents variable containing event/censor times;  
* censor represents censoring variable (1=censored, 0=event);  
* treat represents treatment group variable;  
* strate1 represents the categorical covariates related to stratification 
factors;  
Further options to control the output may be added.  
 
 


 
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The following SAS code will be used for the logistic regression with treatment as single 
covariate mentioned in section 4.11.4:  
PROC LOGISTIC DATA= dataset;  
CLASS treat (ref=’FP+Bev’) / param=ref;  
MODEL response (event=’1’) = treat / alpha=0.05;  
RUN;  
* response represents the response variable;  
* treat represents the treatment group; 
Further options to control the output may be added. 
 
 


 
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Appendix 5 : List of Outputs 
List of Outputs: Tables 
 
Table 
Number 
Table Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
 
Patient Disposition 
 
 
 
 
14.1.1.1 
Patient Disposition For Induction Treatment Phase 
ITP 
ALL 
X 
  
14.1.1.2 
Patient Disposition For Maintenance Treatment Phase 
MTP 
MTP 
X 
X 
14.1.1.3 
Duration of Follow-up 
MTP 
MTP 
X 
X 
14.1.2.1 
Major Protocol Deviations For Induction Treatment Phase 
ITP 
ITP 
X 
  
14.1.2.2 
Major Protocol Deviations For Maintenance Treatment Phase 
MTP 
MTP 
X 
X 
 
Demographics and Baseline Characteristics 
 
 
 
 
14.1.3.1 
Summary of Baseline and Demographic Characteristics  
ITP 
ITP 
X 
  
14.1.3.2 
Summary of Baseline and Demographic Characteristics  
MTP 
MTP 
X 
  
14.1.3.3 
Summary of Baseline Biomarker Status 
MTP 
MTP 
X 
  
14.1.3.4 
Summary of Baseline Biomarker Status 
ITP 
ITP 
X 
  
14.1.4.1 
Tumor Response Status (RECIST 1.1) at End of Induction (eCRF data)  
ITP 
ITP 
X 
  
14.1.5 
Randomization by Country and Study Center  
MTP 
MTP 
X 
  
14.1.6 
Stratification Factors as per IxRS 
MTP 
MTP 
X 
  
14.1.7.1 
Tumor Response Status (RECIST 1.1) at End of Induction (eCRF data)  
MTP 
MTP 
X 
  
14.1.7.2 
Tumor Response (RECIST 1.1) at End of Induction as per IxRS versus eCRF Data 
MTP 
MTP 
X 
  
14.1.8.1 
Summary of Colorectal Cancer History 
ITP 
ITP 
X 
  
14.1.8.2 
Summary of Colorectal Cancer History 
ITP 
MTP 
X 
  
14.1.9 
RECIST Tumor-Specific Characteristics at Baseline 
MTP 
MTP 
X 
  
14.1.10.1 
Medical History  
ITP 
ITP 
X 
  
14.1.10.2 
Medical History  
ITP 
MTP 
X 
  
14.1.11.1 
Summary of Prior Anti-Cancer Treatments/Procedures  
ITP 
ITP 
X 
  
14.1.11.2 
Summary of Prior Anti-Cancer Treatments/Procedures  
ITP 
MTP 
X 
  
14.1.12 
Prior Medications  
ITP 
ITP 
X 
  


 
Bevacizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29112 Cohort 1 (version 1.1) 
94 
Table 
Number 
Table Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
14.1.13.1 
Concomitant Medications during the Induction Phase 
ITP 
ITP 
X 
  
14.1.13.2 
Concomitant Medications during the Maintenance Phase 
MTP 
SAF 
X 
 
14.1.14.1 
Concomitant Radiotherapy during the Induction Phase 
ITP 
ITP 
X 
 
14.1.14.2 
Concomitant Radiotherapy during the Maintenance Phase 
MTP 
SAF 
X 
 
14.1.15.1 
Concomitant Colorectal Cancer Surgery during the Induction Phase 
ITP 
ITP 
X 
 
14.1.15.2 
Concomitant Colorectal Cancer Surgery during the Maintenance Phase 
MTP 
SAF 
X 
 
 
Exposure 
 
 
 
 
14.1.16.1 
Summary of Total Number of Cycles Initiated during ITP 
ITP 
ITP 
X 
  
14.1.16.2 
Summary of Drug Exposure during ITP 
ITP 
ITP 
X 
  
14.1.17.1 
Summary of Overall Duration of Treatment and Number of Cycles Initiated during MTP 
MTP 
SAF 
X 
X 
14.1.17.2 
Summary of Drug Exposure during MTP 
MTP 
SAF 
X 
X 
14.1.17.3 
Summary of Cycles Delayed during MTP 
MTP 
SAF 
X 
X 
14.1.17.4 
Summary of Cycles Delayed (at the Cycle Level) during MTP 
MTP 
SAF 
X 
X 
 
Efficacy 
 
 
 
 
14.2.1.1 
Summary of Progression Free Survival - Primary Analysis (Surgery Censored)  
MTP 
MTP 
X 
 
14.2.1.2 
Progression Free Survival: Hazard Ratio 
MTP 
MTP 
X 
  
14.2.1.3.2 
Summary of Progression Free Survival by Tumor Response at end of ITP (based on 
eCRF data) 
MTP 
MTP 
X 
  
14.2.1.3.3 
Summary of Progression Free Survival by Tumor Colon Location 
MTP 
MTP 
X 
  
14.2.2.1 
Summary of Progression Free Survival - Sensitivity Analyses (Surgery not Censored) 
MTP 
MTP 
X 
  
14.2.2.2 
Progression Free Survival: Hazard Ratio - Sensitivity Analyses (Surgery not Censored) 
MTP 
MTP 
X 
  
14.2.7.1 
Summary of Overall Survival 
MTP 
MTP 
X 
X 
14.2.7.2 
Overall Survival: Hazard Ratio 
MTP 
MTP 
X 
X 
14.2.7.3.2 
Summary of Overall Survival by Tumor Response at end of ITP (based on eCRF data) 
MTP 
MTP 
X 
X 
14.2.7.3.3 
Summary of Overall Survival by Tumor Colon Location 
MTP 
MTP 
X 
X 
14.2.8.1 
Summary of Overall Response Rate (Main Definition) 
MTP 
MTP 
X 
  


 
Bevacizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29112 Cohort 1 (version 1.1) 
95 
Table 
Number 
Table Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
14.2.8.2.2 
Summary of Overall Response Rate (Main Definition) by Tumor Response at End of 
ITP (Based on eCRF Data) 
MTP 
MTP 
X 
  
14.2.8.2.3 
Summary of Overall Response Rate (Main Definition) by Tumor Colon Location 
MTP 
MTP 
X 
  
14.2.8.3 
Summary of Overall Response Rate (Secondary Definition) 
MTP 
MTP 
X 
  
14.2.8.4.2 
Summary of Overall Response Rate (Secondary Definition) by Tumor Response at 
End of ITP (Based on eCRF Data) 
MTP 
MTP 
X 
  
14.2.8.4.3 
Summary of Overall Response Rate (Secondary Definition) by Tumor Colon Location 
MTP 
MTP 
X 
  
14.2.8.5 
Overall Response Rate (ORR): Odds Ratio 
MTP 
MTP 
X 
  
14.2.9.1 
Summary of Disease Control Rate (Main Definition) 
MTP 
MTP 
X 
  
14.2.9.2 
Summary of Disease Control Rate (Secondary Definition) 
MTP 
MTP 
X 
  
14.2.9.3 
Disease Control Rate (DCR): Odds Ratio 
MTP 
MTP 
X 
  
14.2.10.1 
Summary of Duration of Response and Time to Response (Main Definition) 
MTP 
MTP 
X 
  
14.2.10.2 
Summary of Duration of Response and Time to Response (Secondary Definition) 
MTP 
MTP 
X 
  
14.2.12.1 
Summary of ECOG Performance Status over Time 
MTP 
MTP 
X 
  
14.2.12.2 
Shift from Baseline to ECOG Performance Status at End of MTP 
MTP 
MTP 
X 
  
 
Adverse Events 
 
 
 
 
14.3.1.1.1 
Treatment Emergent Adverse Events (TEAEs) during ITP: Overall Summary  
ITP 
ITP 
X 
  
14.3.1.1.2 
Treatment Emergent Adverse Events (TEAEs) during MTP: Overall Summary 
MTP 
SAF 
X 
X 
14.3.1.1.3 
Post Induction Treatment Adverse Events (AEs): Overall Summary 
Post-
Treatment 
ITP 
X 
  
14.3.1.1.4 
Post Maintenance Treatment Adverse Events (AEs): Overall Summary 
Post-
Treatment 
SAF 
X 
X 
14.3.1.2.1 
Treatment Emergent Adverse Events by SOC and PT and by Worst Intensity during 
ITP 
ITP 
ITP 
X 
  
14.3.1.2.2 
Treatment Emergent Adverse Events by SOC and PT and by Worst Intensity during 
MTP 
MTP 
SAF 
X 
  
14.3.1.2.3 
Treatment Emergent AESI as reported on eCRF by SOC and PT and by Worst 
Intensity during MTP 
MTP 
SAF 
X 
  


 
Bevacizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29112 Cohort 1 (version 1.1) 
96 
Table 
Number 
Table Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
14.3.1.2.4 
Serious Treatment Emergent AESI as reported on eCRF by SOC and PT and by Worst 
Intensity during MTP 
MTP 
SAF 
X 
  
14.3.1.2.5 
Treatment Emergent Adverse Events by SOC and PT during MTP 
MTP 
SAF 
X 
X 
14.3.1.2.6 
Treatment Emergent Adverse Events by SOC and PT during ITP 
ITP 
SAF 
X 
 
14.3.1.3.1 
Treatment Emergent Adverse Events Related to Any Study Drug by SOC and PT 
during ITP 
ITP 
ITP 
X 
  
14.3.1.3.2 
Treatment Emergent Adverse Events Related to FOLFOX by SOC and PT during ITP 
ITP 
ITP 
X 
  
14.3.1.3.3 
Treatment Emergent Adverse Events Related to 5-FU/LV by SOC and PT during ITP 
ITP 
ITP 
X 
  
14.3.1.3.4 
Treatment Emergent Adverse Events Related to Bevacizumab by SOC and PT during 
ITP 
ITP 
ITP 
X 
  
14.3.1.3.5 
Treatment Emergent Adverse Events Related to Any Study Drug by SOC and PT 
during MTP 
MTP 
SAF 
X 
X 
14.3.1.3.6 
Treatment Emergent Adverse Events Related to Fluoropyrimidines by SOC and PT 
during MTP 
MTP 
SAF 
X 
 
14.3.1.3.7 
Treatment Emergent Adverse Events Related to FOLFOX by SOC and PT during MTP 
MTP 
SAF 
X 
 
14.3.1.3.9 
Treatment Emergent Adverse Events Related to Bevacizumab by SOC and PT during 
MTP 
MTP 
SAF 
X 
 
14.3.1.3.10 
Treatment Emergent Adverse Events Related to Cetuximab by SOC and PT during 
MTP 
MTP 
SAF 
X 
 
14.3.1.3.11 
Treatment Emergent Adverse Events Related to Vemurafenib by SOC and PT during 
MTP 
MTP 
SAF 
X 
 
14.3.1.4.1 
Treatment Emergent Adverse Events Leading to Discontinuation of Any Study Drug by 
SOC and PT during ITP 
ITP 
ITP 
X 
  
14.3.1.4.5 
Treatment Emergent Adverse Events Leading to Discontinuation of Any Study Drug by 
SOC and PT during MTP 
MTP 
SAF 
X 
X 
14.3.1.5.1 
Treatment Emergent Adverse Events Leading to Dose Reduction or Interruption of Any 
Study Drug by SOC and PT during ITP 
ITP 
ITP 
X 
  
14.3.1.5.4 
Treatment Emergent Adverse Events Leading to Dose Reduction or Interruption of 
Bevacizumab by SOC and PT during ITP 
ITP 
ITP 
X 
 
14.3.1.5.5 
Treatment Emergent Adverse Events Leading to Dose Reduction or Interruption of Any 
Study Drug by SOC and PT during MTP 
MTP 
SAF 
X 
X 


 
Bevacizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29112 Cohort 1 (version 1.1) 
97 
Table 
Number 
Table Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
14.3.1.5.6 
Treatment Emergent Adverse Events Leading to Dose Reduction or Interruption of 
Fluoropyrimidines by SOC and PT during MTP 
MTP 
SAF 
X 
 
14.3.1.5.8 
Treatment Emergent Adverse Events Leading to Dose Reduction or Interruption of 
Bevacizumab by SOC and PT during MTP 
MTP 
SAF 
X 
 
14.3.1.5.9 
Treatment Emergent Adverse Events Leading to Dose Reduction or Interruption of 
Vemurafenib by SOC and PT during MTP 
MTP 
SAF 
X 
 
14.3.1.5.10 
Treatment Emergent Adverse Events Leading to Dose Reduction or Interruption of 
Cetuximab by SOC and PT during MTP 
MTP 
SAF 
X 
 
14.3.1.6.1 
Treatment Emergent Adverse Events of Grade 3 or More by SOC and PT during ITP 
ITP 
ITP 
X 
  
14.3.1.6.2 
Treatment Emergent Adverse Events of Grade 3 or More by SOC and PT during MTP 
MTP 
SAF 
X 
X 
14.3.1.7.1 
Serious Treatment Emergent Adverse Events by SOC and PT during ITP 
ITP 
ITP 
X 
  
14.3.1.7.2 
Serious Treatment Emergent Adverse Events by SOC and PT during MTP 
MTP 
SAF 
X 
X 
14.3.1.8.1 
Serious Treatment Emergent Adverse Events Related to Any Study Drug by SOC and 
PT during ITP 
ITP 
ITP 
X 
  
14.3.1.8.4 
Serious Treatment Emergent Adverse Events Related to Bevacizumab by SOC and 
PT during ITP 
ITP 
ITP 
X 
  
14.3.1.8.5 
Serious Treatment Emergent Adverse Events Related to Any Study Drug by SOC and 
PT during MTP 
MTP 
SAF 
X 
X 
14.3.1.8.6 
Serious Treatment Emergent Adverse Events Related to Fluoropyrimidines by SOC 
and PT during MTP 
MTP 
SAF 
X 
  
14.3.1.8.7 
Serious Treatment Emergent Adverse Events Related to FOLFOX by SOC and PT 
during MTP 
MTP 
SAF 
X 
  
14.3.1.8.9 
Serious Treatment Emergent Adverse Events Related to Bevacizumab by SOC and 
PT during MTP 
MTP 
SAF 
X 
  
14.3.1.8.10 
Serious Treatment Emergent Adverse Events Related to Vemurafenib by SOC and PT 
during MTP 
MTP 
SAF 
X 
  
14.3.1.8.111 
Serious Treatment-Emergent Adverse Events Related to Cetuximab by SOC and PT 
during MTP 
MTP 
SAF 
X 
  
14.3.1.9.1 
Treatment Emergent Adverse Events with Fatal Outcome by SOC and PT during ITP 
ITP 
ITP 
X 
  
14.3.1.9.2 
Treatment Emergent Adverse Events with Fatal Outcome by SOC and PT during MTP 
MTP 
SAF 
X 
X 


 
Bevacizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29112 Cohort 1 (version 1.1) 
98 
Table 
Number 
Table Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
14.3.1.10.1 
Treatment Emergent AESI Based on eCRF Categories during MTP  
MTP 
SAF 
X 
X 
14.3.1.10.2 
Treatment Emergent AESI Based on eCRF Categories during ITP  
ITP 
ITP 
X 
 
14.3.1.10.3 
Bevacizumab Treatment Emergent AESI Based on Pre-Defined Categories during 
MTP  
MTP 
SAF 
X 
X 
14.3.1.10.4 
Bevacizumab Treatment Emergent AESI Based on Pre-Defined Categories during ITP  
ITP 
ITP 
X 
 
14.3.1.10.6 
Vemurafenib Treatment Emergent AESI Based on Pre-Defined Categories during MTP  MTP 
SAF 
X 
X 
14.3.1.11 
Serious Treatment Emergent AESI Based on eCRF Categories during MTP  
MTP 
SAF 
X 
X 
 
Deaths 
 
 
 
 
14.3.1.12.1 
Deaths within 30 days from Last Day of Treatment of ITP and Reason 
ITP 
ITP 
X 
  
14.3.1.12.2 
Deaths within 30 days from Last Day of Treatment of MTP and Reason  
MTP 
MTP 
X 
X 
14.3.1.12.3 
Deaths within 30 Days from Last Day of Treatment of MTP and Reason  
MTP 
SAF 
X 
X 
14.3.1.12.4 
Post Induction Treatment Deaths and Reason  
Post-
Treatment 
ITP 
X 
  
14.3.1.12.5 
Post Maintenance Treatment Deaths and Reason 
Post-
Treatment 
SAF 
X 
X 
 
Laboratory Parameters 
 
 
 
 
14.3.4.1.1 
Shift Table (Baseline versus Worst On-Treatment) during ITP for CTC Gradable 
Hematology Parameters 
ITP 
ITP 
X 
  
14.3.4.1.2 
Shift Table (Baseline versus Worst On-Treatment) during MTP for CTC Gradable 
Hematology Parameters 
MTP 
SAF 
X 
 
14.3.4.2.1 
Shift Table (Baseline versus Worst On-Treatment) during ITP for CTC Gradable Blood 
Chemistry Parameters  
ITP 
ITP 
X 
 
14.3.4.2.2 
Shift Table (Baseline versus Worst On-Treatment) during MTP for CTC Gradable 
Blood Chemistry Parameters  
MTP 
SAF 
X 
 
14.3.4.3.1 
Shift Table (Baseline versus Worst On-Treatment) during ITP for CTC Gradable 
Coagulation Parameters  
ITP 
ITP 
X 
 
14.3.4.3.2 
Shift Table (Baseline versus Worst On-Treatment) during MTP for CTC Gradable 
Coagulation Parameters  
MTP 
SAF 
X 
 
14.3.4.4.1 
Shift Table (Baseline versus Worst On-Treatment) during ITP for Non CTC Gradable 
Hematology Parameters 
ITP 
ITP 
X 
  


 
Bevacizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29112 Cohort 1 (version 1.1) 
99 
Table 
Number 
Table Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
14.3.4.4.2 
Shift Table (Baseline versus Worst On-Treatment) during MTP for Non CTC Gradable 
Hematology Parameters 
MTP 
SAF 
X 
 
14.3.4.5.1 
Shift Table (Baseline versus Worst On-Treatment) during ITP for Non CTC Gradable 
Blood Chemistry Parameters  
ITP 
ITP 
X 
 
14.3.4.5.2 
Shift Table (Baseline versus Worst On-Treatment) during MTP for Non CTC Gradable 
Blood Chemistry Parameters  
MTP 
SAF 
X 
 
14.3.4.7.1 
Shift Table (Baseline versus Worst On-Treatment) during ITP for Urinalysis Protein 
Dipstick 
ITP 
ITP 
X 
  
14.3.4.7.2 
Shift Table (Baseline versus Worst On-Treatment) during MTP for Urinalysis Protein 
Dipstick 
MTP 
SAF 
X 
 
 
Other Safety Data 
 
 
 
 
14.3.5.1 
Summary of Vital Signs Over Time during ITP 
ITP 
ITP 
X 
  
14.3.5.2 
Summary of Vital Signs Over Time during MTP 
MTP 
SAF 
X 
 
14.3.7 
Summary of Qualitative ECG Assessment over Time  
MTP 
SAF 
X 
 
14.3.8 
Summary of QTcF (in Categories) over Time 
MTP 
SAF 
X 
 
 
List of Outputs: Figures 
 
Figure 
Number 
Figure Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
 
Disposition 
 
 
 
 
14.1.1 
CONSORT Flow Diagram for All Screened Patients 
All 
Screened 
X 
  
14.1.2 
CONSORT Flow Diagram for Patients Randomized in Cohort 1 
All 
MTP 
X 
X 
 
Efficacy 
 
 
 
 
14.2.1.1 
Kaplan Meier Plot of Progression Free Survival - Primary Analysis 
MTP 
MTP 
X 
  
14.2.1.2 
Kaplan Meier Plot of Progression Free Survival - Sensitivity Analysis (Surgery not 
Censored) 
MTP 
MTP 
X 
  


 
Bevacizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29112 Cohort 1 (version 1.1) 
100 
Figure 
Number 
Figure Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
14.2.1.7.2 
Kaplan Meier Plot of Progression Free Survival by Tumor Response at End of ITP (Based 
on eCRF Data) 
MTP 
MTP 
X 
  
14.2.1.7.3 
Kaplan Meier Plot of Progression Free Survival by Tumor Colon Location 
MTP 
MTP 
X 
  
14.2.1.8 
PFS: Proportional Hazard Assumption - Model Checking 
MTP 
MTP 
X 
  
14.2.1.9.1 
Forest Plot of Hazard Ratio for Progression Free Survival by Demographic Characteristics 
Subgroup 
MTP 
MTP 
X 
  
14.2.1.9.2 
Forest Plot of Hazard Ratio for Progression Free Survival by Baseline Disease 
Characteristics Subgroup 
MTP 
MTP 
X 
  
14.2.1.10 
Kaplan Meier Plot with Reverse Censoring of PFS 
MTP 
MTP 
X 
  
14.2.2.1 
Kaplan Meier Plot of Overall Survival 
MTP 
MTP 
X 
X 
14.2.2.2.2 
Kaplan Meier Plot of Overall Survival by Tumor Response at End of ITP (Based on eCRF 
Data) 
MTP 
MTP 
X 
X 
14.2.2.2.3 
Kaplan Meier Plot of Overall Survival by Tumor Colon Location 
MTP 
MTP 
X 
X 
14.2.2.3.1 
Forest Plot of Hazard Ratio for Overall Survival by Demographic Characteristics Subgroup 
MTP 
MTP 
X 
X 
14.2.2.3.2 
Forest Plot of Hazard Ratio for Overall Survival by Baseline Disease Characteristics 
Subgroup 
MTP 
MTP 
X 
X 
14.2.3 
Waterfall Plot of Best Percentage Change from Baseline in Sum of Diameters 
MTP 
MTP 
X 
  
14.2.4.1 
Forest Plot of Odds Ratio for Overall Response Rate (Main Definition) by Demographic 
Characteristics Subgroup 
MTP 
MTP 
X 
  
14.2.4.2 
Forest Plot of Odds Ratio for Overall Response Rate (Main Definition) by Baseline Disease 
Characteristics Subgroup 
MTP 
MTP 
X 
  
 
List of Outputs: Listings 
Listing 
Number 
Listing Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
 
Disposition 
 
 
 
 
16.2.1.1 
Patient Disposition and Study Termination Information 
ITP 
ITP 
X 
X 
16.2.1.2 
Patient Who Discontinue Treatment due to Adverse Event 
ITP 
ITP 
X 
X 


 
Bevacizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29112 Cohort 1 (version 1.1) 
101 
Listing 
Number 
Listing Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
16.2.2 
Major Protocol Deviations from PDMS 
ITP/MTP 
ITP 
X 
X 
16.2.3 
Analysis Population 
ITP/MTP 
ALL 
X 
  
 
Demographics and Baseline Characteristics 
 
 
 
 
16.2.4.1 
Demographics and Baseline Characteristics 
ITP/MTP 
ITP 
X 
  
16.2.4.4 
Baseline Biomarker Status 
MTP 
MTP 
X 
  
16.2.4.5 
Randomization Stratification Factors as per IxRS and eCRF 
MTP 
MTP 
X 
  
16.2.4.6 
Colorectal Cancer History 
ITP 
ITP 
X 
  
16.2.4.7 
Medical History 
ITP 
ITP 
X 
  
16.2.4.8 
Prior Anti-Cancer Therapy 
ITP 
ITP 
X 
  
16.2.4.9 
Cancer Radiotherapy: Prior and On-study 
ITP/MTP 
ITP 
X 
X 
16.2.4.10 
Colorectal Cancer Surgery : Prior and On-Study 
ITP/MTP 
ITP 
X 
X 
16.2.4.11 
Prior and Concomitant Medications  
ITP/MTP 
ITP 
X 
X 
16.2.4.12 
Subsequent Anti-cancer Therapies 
Post-
Treatment 
ITP 
X 
X 
 
Drug Administration 
 
 
 
 
16.2.5.1 
Study Drug Administration for 5-FU 
ITP/MTP 
ITP 
X 
  
16.2.5.2 
Study Drug Administration for Leucovorin 
ITP/MTP 
ITP 
X 
  
16.2.5.3 
Study Drug Administration for Oxaliplatin during ITP 
ITP 
ITP 
X 
  
16.2.5.4 
Study Drug Administration for Bevacizumab 
ITP/MTP 
ITP 
X 
X 
16.2.5.5 
Drug Exposure during ITP 
ITP 
ITP 
X 
  
16.2.5.6 
Study Drug Administration for Cetuximab during MTP 
MTP 
SAF 
X 
X 
16.2.5.7 
Study Drug Administration for Vemurafenib during MTP 
MTP 
SAF 
X 
X 
16.2.5.8 
Drug Exposure during MTP 
MTP 
SAF 
X 
X 
 
Efficacy 
 
 
 
 
16.2.6.1 
Progression Free Survival - Primary Analysis (Surgery Censored) 
MTP 
MTP 
X 
  
16.2.6.2 
Progression Free Survival - Sensitivity Analysis (Surgery not Censored) 
MTP 
MTP 
X 
  
16.2.6.3 
Individual Tumor Assessment and Overall Response as per RECIST v1.1 
ITP/MTP 
ITP 
X 
  


 
Bevacizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29112 Cohort 1 (version 1.1) 
102 
Listing 
Number 
Listing Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
16.2.6.8 
Best Overall Response, Time to Response and Duration of Response 
MTP 
MTP 
X 
  
16.2.6.9 
Overall Survival  
MTP 
MTP 
X 
X 
16.2.6.11 
ECOG performance status 
ITP/MTP 
ITP 
X 
 
16.2.6.12 
Head and Neck Assessment for SCC 
MTP 
MTP 
X 
 
16.2.6.13 
Chest CT  Assessment for SCC 
MTP 
MTP 
X 
 
16.2.6.14 
Dermatology Evaluation 
MTP 
MTP 
X 
 
16.2.6.15 
Anal and Pelvic Exam 
MTP 
MTP 
X 
 
 
Safety 
 
 
 
 
16.2.7.1 
Adverse Events 
ITP/MTP/ 
Post-
treatment 
ITP 
X 
X 
16.2.7.2 
Grade 5 Adverse Events or any Adverse Events with Fatal Outcome 
ITP/MTP/ 
Post-
treatment 
ITP 
X 
X 
16.2.7.3 
Adverse Events Leading to Treatment Discontinuation 
ITP/MTP/ 
Post-
treatment 
ITP 
X 
X 
16.2.7.4 
Adverse Events of Special Interest as Reported on eCRF  
MTP/ Post-
treatment 
ITP 
X 
X 
16.2.7.5 
Deaths 
ITP/MTP/ 
Post-
treatment 
ITP 
X 
X 
16.2.8.1 
Laboratory Values - Hematology 
ITP/MTP 
ITP 
X 
  
16.2.8.1 
Laboratory Values – Blood Chemistry 
ITP/MTP 
ITP 
X 
  
16.2.8.1 
Laboratory Values  - Coagulation 
ITP/MTP 
ITP 
X 
  
16.2.8.2 
Laboratory Abnormalities 
ITP/MTP 
ITP 
X 
  
16.2.8.3 
Urinalysis: Urine Protein Dipstick 
ITP/MTP 
ITP 
X 
  
16.2.8.4 
Urinalysis: 24 Hour Urine Protein  
ITP/MTP 
ITP 
X 
  
16.2.8.5 
Pregnancy Test  
ITP/MTP 
ITP 
X 
  


 
Bevacizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29112 Cohort 1 (version 1.1) 
103 
Listing 
Number 
Listing Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
16.2.9.1 
Vital Signs  
ITP/MTP 
ITP 
X 
  
16.2.9.2 
ECG 
ITP/MTP 
ITP 
X 
  
 


CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
Bevacizumab—F. Hoffmann-La Roche Ltd 
Addendum Statistical Analysis Plan MO29112 Cohort 2 (Version 1.0) 
ADDENDUM TO STATISTICAL ANALYSIS PLAN 
TITLE: 
A MULTI-CENTRE RANDOMISED CLINICAL TRIAL OF 
BIOMARKER-DRIVEN MAINTENANCE TREATMENT FOR 
FIRST-LINE METASTATIC COLORECTAL CANCER (MODUL) 
COHORT 2 
PROTOCOL NUMBER: 
MO29112 
COHORT 2 STUDY 
DRUGS: 
 
atezolizumb (MPDL3280A, RO5541267) 
bevacizumab (RO4876646) 
VERSION NUMBER: 
2.0 
IND NUMBER: 
N/A  
EUDRACT NUMBER: 
2014-001017-61 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
 
Cytel, Inc 
Route de Prébois, 20 
1215 Geneva 15  
Switzerland 
DATE FINAL: 
02 August 2018 
 
 


Bevacizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29112 Cohort 2 (Version 2.0) 
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TABLE OF CONTENTS 
1. 
INTRODUCTION .......................................................................................... 5 
2. 
LIST OF CHANGES COMPARED TO STATISTICAL 
ANALYSIS PLAN V2.0 .................................................................................. 5 
2.1 
Section 4.8.1 (Modification) ..................................................... 5 
2.2 
Section 4.10.1 (Addition) ......................................................... 5 
2.3 
Section 4.11.5 (Addition) ......................................................... 5 
2.4 
Section 4.13.2 (Addition) ......................................................... 5 
2.5 
Section 4.9.2 (Addition) ........................................................... 6 
2.6 
Section 4.11.4 (Addition) ......................................................... 6 
2.7 
Section 4.9.1 (Addition) ........................................................... 6 
3. 
LIST OF ADDITIONAL OUTPUTS ................................................................ 7 
 


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HISTORY CHANGE 
Version 
Date 
Changes 
Final 1.0 
22-Jan-2018 
N/A 
Final 2.0 
02-Aug-2018 
 
Additional analysis on protocol deviations 
 
Additional analysis on PFS considering first 330 
patients randomized 
 
Additional analysis to summarize median follow-
up 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
CSR 
Clinical Study Report  
ECOG 
Eastern Cooperative Oncology Group  
ITP 
Induction Treatment Phase 
MTP 
Maintenance Treatment Phase 
PFS 
progression free survival 
SAP 
statistical analysis plan 
 


Bevacizumab — F. Hoffmann-La Roche Ltd 
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1. 
INTRODUCTION 
The purpose of this addendum is to revise the Statistical Analysis Plan (SAP). The rational 
is based on the Sponsor’s decision to add complementary analyses to the version 2.0 of 
the SAP following the review of the SREP outputs or further analysis required for Clinical 
Study Report (CSR). No changes are applied on analyses that were already described in 
the SAP version 2.0 (15-Sep-2017). 
The changes to be made to the SAP are described in the section 2. 
2. 
LIST OF CHANGES COMPARED TO STATISTICAL ANALYSIS 
PLAN V2.0  
2.1 
SECTION 4.8.1 (MODIFICATION) 
During Data Review on 14-Nov-2017, it was identified that one patient without BRAF 
mutation had ICF signed on 28-June-2016, but should be included in the ALL 
Population. 
SMT decided to change the definition of the ALL population as follow: ‘ALL population 
consists of all patients without a confirmed BRAF mutation result who signed an Inform 
consent form until June 3, 2016 June 28, 2016.’ 
2.2 
SECTION 4.10.1 (ADDITION) 
Baseline biomarker status will be summarized also on the ITP population to compare 
characteristics for patients randomized in MTP versus patients not randomized 
2.3 
SECTION 4.11.5 (ADDITION) 
Some subgroups of interest were included in the forest plot for the progression-free 
survival analysis by subgroups. Kaplan Meier curves will be added for the following 
subgroups: 
 
Gender 
 
Baseline ECOG performance status 
 
Initial diagnosis  
2.4 
SECTION 4.13.2 (ADDITION) 
Treatment emergent adverse events occuring during MTP will also be summarized by 
SOC/PT (regardless of the grades) on the safety population. All summaries planned in 
the SAP were by highest grade. 


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2.5 
SECTION 4.9.2 (ADDITION) 
Major protocol deviations will be summarized separately for deviations occuring: 1) prior 
start of ITP, 2) prior or during ITP. 
2.6 
SECTION 4.11.4 (ADDITION) 
An additional sensitivity analysis will be performed for PFS, considering the first 330 
patients randomized. 
2.7 
SECTION 4.9.1 (ADDITION) 
Duration of follow-up (in months) will be summarized on the MTP population using 
descriptive statistics. Duration of follow-up will be defined as time from randomization to 
death for patients who died, or last known alive date, for patients who were censored. 
 
 
 


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3. 
LIST OF ADDITIONAL OUTPUTS  
Output Number 
Title 
Population 
Adhoc Table 1 
Treatment Emergent Adverse Events by SOC and PT 
during MTP 
SAF Population 
Adhoc Figure 2 
Kaplan Meier Plot of Progression Free Survival by 
Gender 
MTP Population 
Adhoc Figure 3 
Kaplan Meier Plot of Progression Free Survival by 
Baseline ECOG Performance Status 
MTP Population 
Adhoc Figure 4 
Kaplan Meier Plot of Progression Free Survival by 
Initial Diagnosis 
MTP Population 
Adhoc Table 5 
Summary of Baseline Biomarker Status 
ITP Population 
Adhoc Table 6 
Major Protocol Deviations Prior Start of ITP 
ITP Population 
Adhoc Table 7 
Major Protocol Deviations Prior or During ITP 
ITP Population 
Adhoc Table 8 
Summary of PFS Considering the First 330 Patients 
Randomized 
MTP Population 
Adhoc Table 9 
PFS: Hazard Ratio Considering the First 330 Patients 
Randomized 
MTP Population 
Adhoc Figure 10 
Kaplan Meier Plot of PFS Considering the First 330 
Patients Randomized 
MTP Population 
Adhoc Table 11 
Duration of Follow-up 
MTP Population 
 


CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
Bevacizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29112 Cohort 2 (Version 2.0) 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A MULTI-CENTRE RANDOMISED CLINICAL TRIAL OF 
BIOMARKER-DRIVEN MAINTENANCE TREATMENT FOR 
FIRST-LINE METASTATIC COLORECTAL CANCER (MODUL) 
COHORT 2 
PROTOCOL NUMBER: 
MO29112 
COHORT 2 STUDY 
DRUGS: 
 
atezolizumb (MPDL3280A, RO5541267) 
bevacizumab (RO4876646) 
VERSION NUMBER: 
2.0 
IND NUMBER: 
N/A  
EUDRACT NUMBER: 
2014-001017-61 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
 
Cytel, Inc 
Route de Prébois, 20 
1215 Geneva 15  
Switzerland 
DATE FINAL: 
15th September 2017 
 
 


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TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 9 
2. 
STUDY DESIGN ........................................................................................... 9 
2.1 
Protocol Synopsis .................................................................. 12 
2.2 
Outcome Measures ............................................................... 12 
2.2.1 
Primary Efficacy Outcome Measures .................................... 12 
2.2.2 
Secondary Efficacy Outcome Measures ................................ 12 
2.2.2.1 Overall Survival (OS) ............................................................ 12 
2.2.2.2 Best Overall Response (BOR) ............................................. 13 
2.2.2.3 Objective Response Rate (ORR) ......................................... 13 
2.2.2.4 Disease Control Rate (DCR) ................................................ 13 
2.2.2.5 Time to Treatment Response (TTR) ..................................... 14 
2.2.2.6 Duration of Response (DoR) ................................................ 14 
2.2.2.7 Progression Free Survival 2 (PFS2) ..................................... 14 
2.2.2.8 Other .................................................................................... 14 
2.2.3 
Exploratory Efficacy Outcome Measures ............................... 14 
2.2.3.1 PFS in Patients Randomized to Atezolizumab 
according to Modified RECIST (mRECIST) (applicable to 
experimental group only of Cohort 2) ................................................. 14 
2.2.4 
Safety Outcome Measures .................................................... 15 
2.2.5 
Pharmacokinetic (PK) Outcome Measures ............................ 15 
2.2.6 
Exploratory Biomarker Outcome Measures ........................... 15 
2.3 
Determination of Sample Size ............................................... 15 
2.4 
Analysis Timing ..................................................................... 16 
3. 
STUDY CONDUCT ..................................................................................... 17 
3.1 
Randomization Issues ........................................................... 17 
3.2 
Independent Review Facility .................................................. 17 
3.3 
Data Monitoring ..................................................................... 17 
4. 
STATISTICAL METHODS .......................................................................... 18 
4.1 
General Descriptive methods ................................................ 18 
4.2 
Definition of Treatment Phase ............................................... 19 
4.2.1 
Induction Treatment Phase (ITP) ........................................... 19 


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4.2.2 
Maintenance Treatment Phase (MTP) ................................... 19 
4.2.3 
Post-Treatment Follow-up Phase .......................................... 20 
4.3 
Data Convention .................................................................... 20 
4.4 
Computing Environment ........................................................ 21 
4.5 
Grading and Coding of Adverse Events, 
Laboratory Parameters and Medications ............................... 21 
4.6 
Adustments for Covariates .................................................... 22 
4.7 
Subgroup Analysis ................................................................. 22 
4.8 
Analysis Populations ............................................................. 23 
4.8.1 
All Population ......................................................................... 23 
4.8.2 
Randomized Population......................................................... 23 
4.8.3 
Safety Population .................................................................. 24 
4.8.4 
Per Protocol (PP) Population ................................................. 24 
4.8.5 
Pharmacokinetic-Evaluable Population ................................. 24 
4.8.6 
Biomarker-Evaluable Population ........................................... 24 
4.9 
Analysis of Study Conduct ..................................................... 24 
4.9.1 
Patient Disposition ................................................................. 24 
4.9.2 
Protocol Deviations ................................................................ 25 
4.10 
Analysis of Treatment Group Comparability .......................... 26 
4.10.1 
Demographics and Baseline Disease 
Characteristics ......................................................................................... 26 
4.10.2 
Medical History ...................................................................... 28 
4.10.3 
Prior and Concomitant Medications ....................................... 29 
4.10.3.1 Prior Anti-Cancer Treatment/Procedure ............................. 29 
4.10.3.2 Non Anti-Cancer Treatment/Procedure .............................. 29 
4.10.4 
Subsequent Anti-Cancer Therapy ......................................... 30 
4.11 
Efficacy Analysis .................................................................... 31 
4.11.1 
Primary Efficacy Endpoint ...................................................... 31 
4.11.2 
Secondary Efficacy Endpoints ............................................... 32 
4.11.2.1 Overall Survival .................................................................. 32 
4.11.2.2 Overall Response Rate (based on Primary 
Definition of BOR)............................................................................... 32 
4.11.2.3 Overall Response Rate (based on Secondary 
Definition of BOR)............................................................................... 33 


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4.11.2.4 Disease Control Rate ......................................................... 33 
4.11.2.5 Time to Treatment Response ............................................. 33 
4.11.2.6 Duration of Response ......................................................... 33 
4.11.2.7 Progression-Free Survival 2 (PFS 2) .................................. 34 
4.11.2.8 Eastern Cooperative Oncology Group (ECOG) 
Performance Status ............................................................................ 34 
4.11.3 
Exploratory Efficacy Endpoints .............................................. 34 
4.11.3.1 PFS in Patients Randomized to Atezolizumab 
(Anti-PD-L1 Antibody) According to mRECIST 
(Experimental Group Only) ................................................................. 34 
4.11.4 
Sensitivity Analyses ............................................................... 35 
4.11.5 
Subgroup Analyses ............................................................... 37 
4.12 
Pharmacokinetic and Pharmacodynamic 
Analyses ................................................................................ 38 
4.13 
Safety Analyses ..................................................................... 38 
4.13.1 
Exposure of Study Medication ............................................... 38 
4.13.1.1 Treatment Duration and Dose Exposure ............................ 38 
4.13.1.2 Cycle Delay ........................................................................ 44 
4.13.2 
Adverse Events ..................................................................... 45 
4.13.3 
Death ..................................................................................... 49 
4.13.4 
Laboratory Data ..................................................................... 50 
4.13.5 
Vital Signs .............................................................................. 52 
4.13.6 
Other Safety Assessment - Applicable only for 
the experimental group ............................................................................ 52 
4.13.7 
Other Safety Assessment ...................................................... 53 
4.14 
Missing Data .......................................................................... 54 
4.15 
Interim Analyses .................................................................... 56 
5. 
REFERENCES ........................................................................................... 57 
1. 
LIST OF OUTPUTS: TABLES ..................................................................... 94 
2. 
LIST OF OUTPUTS: FIGURES ................................................................ 103 
3. 
LIST OF OUTPUTS: LISTINGS ................................................................ 105 
 
 
 


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LIST OF TABLES 
Table 1: Sample Size Determination per Cohort ................................................ 16 
Table 2: Exposure Definitions for Induction Treatments ..................................... 41 
Table 3: Exposure Definitions for Maintenance .................................................. 42 
Table 4: Adverse Events Definitions ................................................................... 45 
 
 
 
LIST OF APPENDICES 
Appendix 1: Protocol Synopsis ........................................................................... 58 
Appendix 2: Schedule of Assessments for All Patients (Screening / Baseline 
and Induction Treatment Phase) ................................................. 81 
Appendix 3: Schedule of Assessments During Maintenance Phase (Cohort 
2) ................................................................................................. 87 
Appendix 4: SAS code ........................................................................................ 92 
Appendix 5 : List of Outputs ............................................................................... 94 


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HISTORY CHANGE 
Version 
Date 
Changes 
Final 1.0 
17-Feb-2017 
N/A 
Final 2.0 
15-Sep-2017 
 
Change in primary analysis to only consider surgery 
with palliative or curative intent to censor the patients 
for PFS. Indeed, if the patient had a surgery with 
diagnostic intent between baseline tumor assessment 
for MTP and a disease progression, then the PFS 
event will be taken into account in the primary analysis. 
 
Addition of a sensitivity analysis for PFS that is 
considering all PFS events reported during MTP 
regardless of any surgery. 
 
Following CHMP request, addition of Progression-Free 
Survival 2 analysis. 
 
Following regular monitoring of PFS events all groups 
pooled, the cut-off date has been revised from 31-Jul-
2017 to 31-May-2017. 
 
Modification of the best overall response to consider 
the tumor assessments from randomization date 
(instead of start of treatment date), and regardless of a 
surgery. 
 
Addition of clarification to handle AE related to 
FOLFOX starting in MTP phase: Those AEs could not 
be reported as such in current CRF as it was not 
envisioned at the start of the study. A unique text has 
been reported in a comment field, to identify those 
AEs. This unique text will be used to select any AE 
related to FOLFOX during MTP. 
 
Revision of the list of AE tables to be produced by 
replacing some tables by SOC/PT and worst grade by 
tables by SOC/PT only. 
 
Revision of the general section to focus on Cohort 2, 
by removing the information related to the other 
cohorts. 
 
Harmonization of the definitions related to exposure 
(eg. dose intensity, relative dose intensity). 
 
Clarifications of some sections. 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse events of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase  
ANC 
absolute neutrophils count 
aPTT 
activated partial thromboplastin time  
AST 
aspartate aminotransferase  
BMI 
body mass index 
BOR 
best overall response 
BRAFmut 
BRAF mutation 
BSA 
body surface area 
CI 
confidence interval 
CR 
complete response 
CSR 
clinical study report 
DCR 
disease control ate 
DoR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
electronic Case Report Form  
EU 
European Union 
FP 
fluoropyrimidine 
Hb 
hemoglobin 
HER2 
human epidermal growth factor receptor 2 
HER2+ 
human epidermal growth factor receptor 2 positive 
HR 
hazard ratio 
IC 
informed consent 
ICH 
International Conference on Harmonization 
iDMC 
Independent Data Monitoring Committee 
IHC 
immunohistochemistry 
INR 
international normalized ratio  
ITP 
Induction Treatment Phase 
IxRS 
interactive voice or web-based response system  
KM 
Kaplan Meier 
LDH 
lactate dehydrogenase 
mCRC 
metastatic Colorectal Cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRECIST 
modified Response Evalution Criteria in Solid Tumors 


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Abbreviation 
Definition 
MSI-H 
high microsatellite instability 
MSS 
microsatellite stable 
MTP 
Maintenance Treatment Phase 
NCI CTCAE  
National Cancer Institute Common Terminology  
Criteria for Adverse Events  
NE 
not evaluable 
NGS 
next generation sequencing 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PDMS 
protocol deviation management system 
PFS 
progression free survival 
PK 
pharmacokinetic  
PP 
Per protocol 
PR 
partial response 
PS 
performance status 
PT 
preferred term 
PTFUP 
Post-treatment follow-up phase 
RBC 
red blood cell 
RDI 
relative dose intensity 
RECIST 
Response Evaluation Criteria in Solid Tumors  
SAE 
serious adverse event 
SAF 
safety population 
SAP 
statistical analysis plan 
SC 
Steering Committee 
SD 
stable disease 
SI 
Système International  
SOC 
System Organ Class 
SOD 
sum of target lesions diameter 
TEAE 
treatment emergent adverse event 
TSH 
thyroid-stimulating hormone 
TTR 
time to treatment response 
WBC 
white blood cells counts or leukocytes 
 


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1. 
BACKGROUND 
The study is a randomized, multi-center, active-controlled, open-label, parallel-group clinical 
study of biomarker-driven maintenance treatment for first-line metastatic colorectal cancer 
(mCRC) patients.  All patients will receive induction treatment with FOLFOX and bevacizumab. 
Induction treatment will be followed by maintenance treatment with chemotherapy combined 
with targeted therapy within one of several maintenance treatment cohorts. Only those patients 
who experience disease response or disease control during induction and who are not 
assessed as resectable at completion of induction will proceed to further treatment in the 
Maintenance Treatment Phase (MTP) of the study. Patients will be assigned to a maintenance 
treatment cohort based on their primary tumour biomarker results. The primary study objective 
within each cohort is to evaluate progression-free survival (PFS).   
Maintenance treatment cohorts may be added or modified over the course of the study. This 
SAP describes planned analyses of patients who were assigned, or would have been assigned, 
to maintenance treatment Cohort 2 based on their primary tumour biomarker profile. Analyses 
of patients assigned to all other MODUL cohorts will be described in SAPs applicable to each 
specific cohort. 
A Steering Committee (SC) is responsible for overseeing the general conduct of the study.  
In addition, an independent Data Monitoring Committee (iDMC) is responsible for evaluating 
the safety of the patients participating in the trial at regular intervals throughout the study. The 
iDMC makes recommendations as to whether cohort recruitment should continue based on 
benefit-risk evaluations that include efficacy as well as safety data. To minimize the impact of 
such reviews on efficacy endpoint analyses, efficacy data included in these reviews has to be 
specified by the iDMC at a preceding iDMC meeting and has to be documented in the iDMC 
meeting minutes. In addition, the iDMC evaluates the safety data from a prespecified number of 
initial patients for experimental combinations with inadequate prior safety experience to assure 
appropriate dosing (e.g. as required for the initial patients treated with the Cohort 1 
experimental combination of ‘5-FU/LV + cetuximab + vemurafenib’) 
Of note, a preliminary assessment of efficacy of Cohort 2 (according to protocol version 5) was 
conducted by the iDMC on April, 4th 2016. Based on recommendations from the study SC and 
iDMC, the preliminary assessment of efficacy has been removed in protocol version 6 as well 
as the early efficacy assessment as co-primary objective. PFS remained as the primary 
endpoint. Analysis of a co-primary objective is no more mentioned in the Statistical Analysis 
Plan (SAP) that focuses only on the description of the analysis required for Cohort 2.  
 
2. 
STUDY DESIGN 
Patients continuing from the Induction Treatment Phase (ITP) to the Maintenance Treatment 
Phase are assigned to a maintenance treatment cohort based on their primary tumour 
biomarker status. Following eligibility assessment for their assigned cohort, eligible patients are 
randomized to the experimental or control arm within their cohort. 
The study was initiated with 2 maintenance treatment cohorts, Cohorts 1 and 2. Two additional 
cohorts, Cohorts 3 and 4, were added with protocol amendment 5 (protocol version 6). 
Enrolment into the study was stopped temporarily as of June 3, 2016 since patients enrolled in 


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the study at that time were estimated as adequate to fulfil accrual to Cohort 2. Patients enrolled 
in the study after June 2016 cannot be enrolled into Cohort 2. The study restarted with 
amendment 5 that includes additional Cohorts 3 and 4. Further cohorts can be added and/or 
existing cohorts be changed over the course of the study via protocol amendments. 
 
In this open-label study, all patients will receive 8 cycles induction treatment that is considered 
standard in many countries and that has been shown to improve outcomes in the first-line 
setting. Treatment during the ITP, based on investigator’s choice, will be either: 
 
 
Eight 2-week cycles of 5-fluorouracil (5-FU), leucovorin (LV) and oxaliplatin (FOLFOX) 
in combination with bevacizumab 
or 
 
Six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-
week cycles of 5-FU/LV with bevacizumab  
 
Patients who prematurely discontinue study treatment for any reason during ITP, who 
experience progressive disease (PD) at any time during or at the end of the ITP, who are 
evaluated as resectable at the end of ITP, who refuse to proceed to the MTP or who are not 
eligible for any maintenance cohort will undergo a study treatment discontinuation visit and 
enter post-treatment follow-up. Patients who experience disease control or tumor response to 
induction treatment will continue to the randomized MTP of the study wherein the effects of 
experimental and control groups will be compared. Patients enrolled in the study before June 3, 
2016 (i.e. prior to study amendment 5) who do not have BRAFmut disease or whose primary 
tumour biomarker status is unknown for technical reasons are assigned to Cohort 2. Patients 
with BRAFmut disease enrolled prior to study amendment 5 are assigned to Cohort 1. 
Treatment in each cohort is shown in Figure 1.  
BRAFmut patients enrolled prior to study amendment 5 experiencing early disease progression 
during the ITP will have the option of proceeding immediately to receive second-line treatment 
with 5-FU/LV+ cetuximab + vemurafenib according to treatment administration and 
management applicable to Cohort 1. 
The study design applicable to patients enrolled in the study before June 3, 2016 (i.e. prior to 
study amendment 5, protocol version 6) is summarized in Figure 1. 
 
 


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Figure 1: Study Design as per protocol version 5 
 
 
 


 
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Primary objective of this study: 
The primary study objective within each cohort is to evaluate PFS.  
An iDMC is responsible for regularly reviewing safety data. 
 
2.1 
PROTOCOL SYNOPSIS 
The Protocol version 5 synopsis is provided in Appendix 1. For additional details, see the 
Schedule of Assessments in Appendix 2. 
 
2.2 
OUTCOME MEASURES 
As mentioned in the protocol, each cohort will be analysed separately and therefore this SAP 
focuses on the description of the analysis required for cohort 2 data only.  
 
2.2.1 
Primary Efficacy Outcome Measures 
PFS is defined as the time from randomization into the MTP until documented disease 
progression as per investigator assessment using Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 or death from any cause, whichever occurs first. If no progression / 
death is observed at the time of clinical cut-off or by the date of any on-study colorectal anti-
cancer surgery with palliative or curative intent, patients will be censored at the date of the last 
evaluable tumor assessment or date of randomization, whichever comes last. 
(Of note: (i) Progressive disease are identified by the Overalll Response=’PD’, even if solely 
based on symptomatic deterioration, (ii) Only surgery occurring between baseline tumor 
assessment for MTP and PFS events are considered for censoring PFS) 
 
Sensitivity Analysis 
PFS is defined as the time from randomization into the MTP until documented disease 
progression as per investigator assessment using Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 or death from any cause, whichever occurs first. If no progression / 
death is observed at the time of clinical cut-off, patients will be censored at the date of the last 
evaluable tumor assessment or date of randomization, whichever comes last. 
 
 
2.2.2 
Secondary Efficacy Outcome Measures 
2.2.2.1 
Overall Survival (OS) 
OS is defined as the time from randomization into the MTP to time of death from any cause. 
Patients still alive at time of clinical cut-off will be censored at their last date known to be alive 
as defined in section 4.3. For imputation of “Partial Death Date”, please refer to section 4.14. 
 
 
 


 
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2.2.2.2 
Best Overall Response (BOR)  
Main definition 
BOR (e.g. complete response [CR], partial response [PR], stable disease [SD], progressive 
disease [PD], not evaluable [NE]) for the MTP will defined as the best response recorded from 
the randomization date until progressive disease (taking as reference for progressive disease 
the smallest measurements recorded since randomization date). For patients under 
maintenance treatment at time of primary analysis, the BOR will be defined based on available 
tumor assessment at time of clinical cut-off. The overall response per time point reported on the 
electronic Case Report Form (eCRF) by the investigator (as per RECIST v1.1) will be used for 
the derivation of the BOR. No confirmation of response is required as per protocol. 
A minimum interval of 28 days will be considered for SD to be assigned as best overall 
response, i.e. in the case the single response is SD, SD must have been assessed no less 
than 28 days after randomization date of the MTP, otherwise the best overall response will be 
NE. 
If the patient has missing baseline tumor assessment, best overall response will be NE. 
Patients without tumor assessment after randomization will be assigned a tumor response of 
NA (Not applicable). 
Patients with only non-target lesions classified as having an eCRF tumor response status of 
"Non-CR/Non-PD" are classified as SD. 
 
Secondary/Sensitivity definition 
BOR (e.g. CR, PR, SD, PD, NE) for the MTP will defined as the best response recorded from 
the randomization date until end of maintenance treatment or progressive disease whichever 
comes first (taking as reference for progressive disease the smallest measurements recorded 
since randomization date).  
The derivation of the BOR will be the same as for the main definition, the only change being the 
time window during which the best overall response is observed. In other words, the main 
definition for BOR considers all tumor assessments collected on study (i.e. including post-
treatment tumor assessments phase for patients withdrawing maintenance treatment for other 
reason than PD) whereas the secondary/sensitivity definition considers only tumor 
assessments collected on maintenance treatment phase (i.e within 30 days from last day of 
treatment of MTP, up to the day before the start of further anti-cancer therapy, whichever 
comes first). Therefore the secondary/sensitivity analysis regarding BOR is an on-treatment 
analysis.  
 
2.2.2.3 
Objective Response Rate (ORR)  
ORR is defined as the number of patients with a BOR of CR or PR during the MTP phase 
divided by the number of patients in the studied population.  
 
2.2.2.4 
Disease Control Rate (DCR)  
DCR is defined as the number of patients with a BOR during the MTP of CR, PR or SD divided 
by the number of patients in the studied population.  
 


 
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2.2.2.5 
Time to Treatment Response (TTR)  
TTR will be calculated for responders (i.e. patients with a MTP BOR of CR or PR) only. It will 
be defined as the time from randomisation to the first occurrence of a documented objective 
response (CR or PR). 
 
2.2.2.6 
Duration of Response (DoR)  
DoR will be calculated for responders only. It will be defined as the time from the first 
assessment of CR or PR until disease progression or death from any cause, whichever occurs 
first. Patients who do not progress or die after they have had a response are censored at the 
date of their last tumor measurement. 
 
2.2.2.7 
Progression Free Survival 2 (PFS2)  
PFS2 is defined as the time from randomisation to second objective disease progression, or 
death from any cause, whichever first. Patients alive and for whom a second objective disease 
progression has not been observed should be censored at the last time known to be alive and 
without second objective disease progression. 
Of note: Date of second objective disease progression is the first date of progressive disease 
as reported on the ‘Subsequent Anti-Cancer Therapies’ eCRF page. 
 
2.2.2.8 
Other 
 
Change from baseline in tumor size during MTP 
The change from baseline in tumor size at a specific assessment occurring during the 
maintenance treatment phase will be defined as: 
100*((SOD at visit x– baseline SOD) / baseline SOD) 
with: 
 
SOD at visit x corresponding to the Sum Of target lesions Diameter (SOD) at visit  
 
Baseline SOD is the last SOD recorded on or prior to the randomization date in the 
MTP. This baseline assessment should correspond to the tumor assessment performed 
at the end of ITP as defined in section 4.10.1.  
 
 
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) during and after 
MTP 
 
 
2.2.3 
Exploratory Efficacy Outcome Measures 
2.2.3.1 
PFS in Patients Randomized to Atezolizumab according to Modified 
RECIST (mRECIST) (applicable to experimental group only of Cohort 2) 
This endpoint is only applicable to patients randomized to atezolizumab. It is defined as the 
time from randomisation into the MTP until disease progression per Investigator assessment 
using mRECIST (refer to Appendix 8 in protocol version 5) or death from any cause, whichever 


 
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occurs first. Patients without an event at the time of clinical cut-off or by the date of any on-
study colorectal anti-cancer surgery with palliative or curative intent will be censored at the date 
of the last evaluable tumour assessment or date of randomization, whichever comes last. 
 
 
2.2.4 
Safety Outcome Measures 
The safety outcome measures for this study are as follows 
 
Incidence, nature and severity of all adverse events (graded according to National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0)  
 
All serious adverse events (SAEs)  
 
Incidence and reasons for any dose reductions, interruptions or premature 
discontinuation of any component of study treatment  
 
Adverse events of special interest (AESI)*  
 
Clinically significant changes in laboratory values  
 
Vital signs 
*AESI for cohort 2 are only reported for the maintenance phase, since no AESIs are defined 
for the induction phase in protocol version 5.   
2.2.5 
Pharmacokinetic (PK) Outcome Measures 
There are no PK outcome measures for this study. 
 
2.2.6 
Exploratory Biomarker Outcome Measures 
The exploratory biomarker outcome measures for this study include molecular markers/marker 
profiles and efficacy and/or safety outcomes. Efficacy outcomes considered for this analysis 
may include, but are not limited to ORR, PFS and OS, as appropriate. Biomarkers, biomarker 
profiles and microbiomes may be assessed using various methodologies including, but not 
limited to, immunohistochemistry (IHC) (single and multiplex), RNA and DNA analysis (e.g. 
polymerase chain reaction, next generation sequencing [NGS], mutation expression and 
microsatellite instability [MSI] analyses) of tumour and/or blood samples collected from all study 
patients.  
Next-generation sequencing was introduced with protocol amendment 5. Retrospective NGS 
will be conducted on samples collected provided appropriate consent has been obtained. 
Statistical analysis will be covered in a separate SAP. 
 
 
2.3 
DETERMINATION OF SAMPLE SIZE 
Estimates of overall study screening and enrolment will vary with the addition of new 
maintenance treatment cohorts over the course of the study. Approximately 700 patients were 
planned for enrolment in the Induction Treatment Phase of the study as described in protocol 
version 5.0 in order to randomise 126 patients in Cohort 1 and 405 patients in Cohort 2.  


 
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The calculated sample size for each study cohort has been based on an estimated recruitment 
period for 11 months for Cohorts 2 and on the comparison between PFS in the experimental 
and control groups of that cohort. Estimated proportions of the patients enrolled into the study 
that are eligible for each cohort are based on published reports (di Nicolantonio et al. 2008) 
Approximately 25% of all patients enrolled are expected to have disease progression prior to 
randomisation into the Maintenance Treatment Phase (Roche, data on file). Inputs used in 
cohort-specific sample size calculations are provided in Table 1. 
 
Table 1: Sample Size Determination per Cohort 
 
 
Cohort 1 
Cohort 2 
Percent of study population eligible for cohort 
based on biomarker status 
10% 
90% 
Percent of patients eligible for cohort based on 
biomarker status expected to have disease 
progression prior to randomization 
25% 
25% 
Average randomization rate (pts/month) [a] 
3.5 
31.5 
Estimated median PFS [b] (months) - 
Experimental group 
7 
11.5 
Estimated median PFS [b] (months) - Control 
group 
4.9 
7.5 
Hazard ratio (HR) 
0.70 
0.65 
Number of expected PFS events 
96 
259 
Statistical test 
1-sided 
2-sided 
Alpha level 
10% 
5% 
Power 
65% 
90% 
Randomized patients 
126 
405 
Randomization ratio (experimental vs control) 
2:1 
2:1 
Recruitment period (months) 
36 
11 
Time to primary analysis of PFS (months) [c] 
36 
22 
a. Based on 1,680 patients screened over a 3-year recruitment period 
b. Per RECIST 1.1  
c. Time from first patient randomized in cohort 
 
2.4 
ANALYSIS TIMING 
 
The primary analysis for each cohort will be performed based on data collected until the 
analysis cut-off date, defined as the time when the target number of PFS events has been 
reached for that cohort, as shown in Table 1 in the number of expected PFS row. The primary 
analysis for cohort 2 will occur when 259 PFS events have been observed i.e. approximately 
22 months after first patient was randomized.  


 
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Tracking of events will be performed based on the clinical database data to predict the time 
when the number of targeted events is reached. Tracking of events started once accrual of the 
cohort was complete and is done on a monthly basis. As the targeted number of events is 
approached the more frequently the tracking of events might occur. As per prediction at the 
date of signature of the version 1.0 of the SAP and as per Roche Global Medical Team meeting 
on February, 13th 2017, the cut-off date for cohort 2 was initially defined to be 31 July 2017. 
Following regular tracking of events, the cut-off date was revised and set to 31 May 2017.  
The final analysis, which will consist of updating main time-to-event and safety endpoints, will 
take place once the 24-month survival follow-up from the primary cut-off date (i.e. from the date 
when 259 PFS events are reached) is complete. Final results of efficacy and safety parameters 
will be reported in a separate clinical study report (CSR). 
The outputs to be provided for each analysis (primary or final) are listed in Appendix 5. 
Analysis for cohorts other than cohort 2 is not covered in this SAP and will be documented in 
separate SAPs. 
 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION ISSUES 
Patients will be assigned to a cohort based on the results of biomarker assessments conducted 
on archival primary tumour tissue obtained during their initial CRC diagnosis. Once assigned to 
a cohort, patients will be randomized on a 2:1 basis to either the experimental treatment group 
or the control group of that cohort.  Randomization in Cohort 2 will be stratified by geographical 
region (EU, Americas, Africa or Asia), and by patient response after the Induction Treatment 
Phase (CR/PR vs. SD). 
 
3.2 
INDEPENDENT REVIEW FACILITY 
Not applicable. 
3.3 
DATA MONITORING 
An iDMC is responsible for:  
 
evaluating the safety of the patients participating in the trial at regular intervals 
throughout the study, 
 
making recommendations as to whether cohort recruitment should continue based on 
benefit-risk evaluations that include efficacy as well as safety data. To minimize the 
impact of such reviews on efficacy endpoint analyses, efficacy data included in these 
reviews has to be specified by the iDMC at a preceding iDMC meeting and has to be 
documented in the iDMC meeting minutes, 
 
performing a review of the safety data from a prespecified number of initial patients for 
experimental combinations with inadequate prior safety experience to assure 
appropriate dosing (e.g. as required for the experimental combination of ‘5-FU/LV + 
cetuximab + vemurafenib’). 


 
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4. 
STATISTICAL METHODS 
4.1 
GENERAL DESCRIPTIVE METHODS 
Categorical variables 
For categorical variables, summary tabulations of the number and missing observations as well 
as the number and percentage within each category of the parameter will be presented. 
Missing will not be considered as a separate category and thus missing observations will not be 
part of the denominator to compute the percentages. Percentages will be rounded to one 
decimal place. Therefore, there may be cases where for instance the total of the percentages 
does not exactly equal 100%. If number of patients is ‘0’ then 0 will be reported instead of ‘0 
(0.0%)’  
Continuous variables 
For continuous variables, N, the mean, median, standard deviation, 25th and 75th percentile. 
minimum and maximum values will be presented.  
Time-to-event efficacy variables 
Time-to-event efficacy variables (e.g. PFS and OS) summaries will include number of patients 
in the population (N), number of patients with the event of interest, number of patients censored, 
median and two-sided 95% confidence interval (CI) computed according to Brookmeyer and 
Crowley (1982) method. Kaplan-Meier (KM) estimates and median survival times are 
calculated with the PROC LIFETEST procedure in SAS. KM curves (product-limit method) will 
be presented as well as the event rates at certain time points with the relevant CIs calculated 
via log-log transformation method (default option CONFTYPE=LOGLOG in SAS) based on 
standard errors computed using the Greenwood’s formula.  
Cox proportional hazards models 
Cox proportional hazards model will be implemented using PHREG procedure with option 
TIES=EXACT. It assumes that there is a true but unknown ordering for the tied event times as 
contrasted to option TIES=DISCRETE which assumes that the events occurred at exactly the 
same time. 
Missing values 
For categorical variables, summary tabulations of the number and missing observations as well 
as the number and percentage within each category of the parameter will be presented. 
For continuous variable, number of missing is displayed between brackets next to ‘n’, unless 
otherwise specified.  
Decimals 
Mean, standard deviation, and median (Q1 and Q3 if applicable) will be presented with one 
more decimal place compared to the raw data, minimum and maximum will be presented with 
same number of decimal places as the raw data. Hazard ratio, odds ratio will be provided with 


 
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two decimals. P-value will be provided with three decimals. If <0.001, then ‘<0.001’ will be 
displayed. 
 
4.2 
DEFINITION OF TREATMENT PHASE 
In this study, there are 3 treatment phases:  
1. Patients are treated first in the Induction Treatment Phase (ITP) for a planned duration of 
8 cycles, i.e. 16 weeks.  
2. If they do not experience any progressive disease before or at the end of the ITP, are not 
considered resectable at the end of the ITP and do not withdraw from the study and are still 
eligible for any cohort, they are randomized and treated in the Maintenance Treatment 
Phase (MTP). 
3. If they discontinue study treatment for any reason during the Induction or Maintenance 
Treatment Phases, do not withdraw from the study and are still alive, they enter the Post-
Treatment Follow-up Phase. 
 
4.2.1 
Induction Treatment Phase (ITP) 
ITP is defined as the time from first study drug administration until  
 
the day before the randomization for patients continuing treatment in the MTP   
 
the last assessment date otherwise 
 
The first day of treatment in the ITP is defined as the earliest day of a non-null administration 
of any induction phase treatment. 
The last day of treatment in the ITP is defined as the last day of the last initiated cycle of the 
induction phase, or as the death day if the patient died in between. A two-week cycle duration 
is assumed. 
Baseline evaluations for the ITP will be those performed not earlier than 28 days prior to the 
first day of treatment in the induction phase, unless otherwise stated. The latest available 
assessment up to start of the first day of treatment in the induction phase will be considered as 
baseline. For laboratory examinations, weight, vital signs and ECOG PS, assessments 
performed on the first day of treatment of the ITP will be assumed to have been performed 
before drug was given and, thus, will be considered as baseline evaluations. 
On-treatment evaluations for the ITP will be post baseline evaluations performed until 
 
the day before the randomization for patients continuing treatment in the MTP   
 
(including) the study treatment discontinuation visit within 30 days after last day of 
treatment of the ITP (as defined above), for patients not randomized in the MTP. 
 
4.2.2 
Maintenance Treatment Phase (MTP) 
MTP is defined as the time from randomization into MTP until (including) the study treatment 
discontinuation visit in the MTP. 


 
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The first day of treatment in the MTP is defined as the earliest day of a non-null 
administration of any maintenance phase treatments. 
The last day of treatment in the MTP is defined as the last day of the last initiated cycle of the 
maintenance phase, or as the death day if the patient died in between. A two-week cycle 
duration is assumed. 
Baseline evaluations for the MTP will be those performed prior to the first day of treatment in 
the maintenance, unless otherwise stated. The latest available assessment prior to the first day 
of treatment in the maintenance phase will be considered as baseline for safety assessments. 
For laboratory examinations, weight and vital signs, assessments performed on the first day of 
treatment of the MTP will be assumed to have been performed before drug was given and, thus, 
will be considered as baseline evaluations. For subjects randomized but not treated in the MTP, 
the latest available assessment before or on randomization date (including assessments from 
ITP) will be considered as baseline for the MTP.  
For efficacy assessments, the latest available assessment prior or on the randomization date 
will be considered as baseline. 
On-Treatment evaluations for the MTP will be evaluations performed on or after the first day 
of treatment in the MTP within 30 days from last day of treatment in the maintenance phase. 
On-treatment laboratory will be all values collected after the first day of treatment in the 
maintenance phase and within 30 days from last day of treatment in the maintenance phase 
(as defined above). For adverse events, treatment emergent adverse events (TEAEs) will be 
events occurring on or after the first day of treatment in the MTP within 30 days (for patients in 
control group, i.e. not treated with atezolizumab) and 90 days (for patients in experimental 
group, i.e. treated with atezolizumab) from last day of treatment in the maintenance phase (as 
defined above). 
 
4.2.3 
Post-Treatment Follow-up Phase 
Post treatment Follow-up Phase is defined as the time from (excluding) the study treatment 
discontinuation visit until the last available assessment date before clinical cut-off date. For 
patients who discontinue study treatment but without any study treatment discontinuation visit 
date, please refer to 4.14 for imputation of this missing visit date. 
Post-Treatment Follow-up evaluations will be evaluations performed according to the 
protocol after the study treatment discontinuation visit.  
 
4.3 
DATA CONVENTION 
All data will be listed (e.g. pre-treatment serious adverse events), whereas only baseline and 
on-treatment assessments will be considered for summary tables. 
Baseline and on-treatment data will be flagged in the data listings as well as the different 
phases of the study. 
The overall column will not be displayed in any summary tables.  
The following conversion factors will be used to convert days to months or years, where 
applicable:  


 
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 
1 week= 7 days 
 
1 month = 30.4375 days  
 
1 year = 365.25 days 
Age at informed consent (IC) {in years} = (date of informed consent – date of birth) / 365.25 
To calculate duration / time between two dates the following convention will be used: 
[later date] – [earlier date] + 1 day 
Durations and times between two dates will be calculated only when both start and end dates 
are available (imputed dates cannot be used for computation), apart for overall survival when 
date of death has only day as missing).. 
Body surface area (BSA) will be recalculated based on the height and weight of the patient 
using the following formula: 
 BSA (m2) = ([Height {cm} x Weight {kg}] / 3600)½ 
Body mass index (BMI) will be calculated using the following formula: 
BMI (kg/m2) = Weight {kg} / Height2 {m} 
The last known date to be alive will be the latest date among all dates specified in the eCRF 
except the following:  
 
Survival Follow-up date when status is either dead (in this case the date of death is 
specified on the Adverse events or Study Completion/Early Discontinuation or SAE 
reporting summary form) or lost to follow-up (in this case last date known to be alive is 
specified on the Survival follow-up form)  
 
Study Completion/Early Discontinuation date when reason is neither death or lost to 
follow-up. 
 
A sample / record with test ‘Not Done’.  
4.4 
COMPUTING ENVIRONMENT 
All statistical analyses will be performed using SAS statistical software (Version 9.2 or newer 
version), unless otherwise noted.   
 
4.5 
GRADING AND CODING OF ADVERSE EVENTS, LABORATORY 
PARAMETERS AND MEDICATIONS 
Laboratory results, adverse events, and other symptoms will be graded using the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE), version 4.0, 
except where CTC grades are not available. 


 
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Adverse events and relevant Medical History data fields (i.e. prior symptoms / AEs) will be 
coded using the most recent version of Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary available at the time of analysis.  
Prior and concomitant anti-cancer therapy / other medications will be coded using the most up-
to-date version of the in house Genentech Drug Thesaurus Dictionary. 
Dictionary versions used will be displayed in analysis outputs. 
 
4.6 
ADUSTMENTS FOR COVARIATES 
When indicated, efficacy analysis will be adjusted i.e. the covariates will be incorporated in the 
model used to assess the treatment effect upon the efficacy endpoints. The covariates below 
will be considered:  
 
Geographical region as per clinical database: EU, Americas, Africa or Asia. For 
inferential analysis, “EU” will be used as reference. Note: if the number of patients in a 
region is small, the region will be pooled (e.g. EU vs Rest of the world). 
 
Patient response after induction treatment as per eCRF data: CR/PR vs. SD. For 
inferential analysis, “SD” will be used as reference, unless otherwise specified.  
 
4.7 
SUBGROUP ANALYSIS 
The following subgroups will be considered to repeat PFS and OS analysis by subgroup: 
 
Demographic characteristics: 
o Age (<65 years, >= 65 years) 
o Gender (male vs female) 
o Region as per clinical database (EU versus Rest of the World) 
o Tumor response at end of ITP (SD vs. CR/PR) as per eCRF 
o Baseline ECOG performance status (0 vs. 1/2), 
 
Baseline disease characteristics: 
o Initial AJCC/UICC stage (stage I/II/III vs. stage IV) 
o Prior systemic adjuvant therapy (yes vs no) 
o Number of metastatic sites at screening (<2 x vs. >= 2) 
o Liver metastatic site at baseline (yes vs no) 
o Cancer type (colon vs rectal) 
o Tumor colon location (right vs left) 
o Initial diagnosis (synchronous vs metachronous) 
 
Biomarker: 
o RAS status (RASwt vs RASmut) 
o Microsatellite stability status (MSS vs MSI-H) 
o RAS status (RASwt vs RASmut) for MSS patients 
o Tumor colon location (right vs left) for RASwt patients 
o Tumor colon location (right vs left) for RASmut patients 
o Tumor colon location (right vs left) for MSS patients 
 
The subset tumor colon location (left, right) will be derived based on the primary tumor location 
information collected on the colorectal cancer history eCRF page. Right colon is defined as 
patients with ceacum, appendix, ascending colon or right hepatic flexture or transverse colon 


 
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as primary tumor location. Left colon is defined as patients with left splenic flexture or 
descending colon or sigmoid or rectum as primary tumor location. 
The subset cancer type (colon, rectal) will be derived based on the primary tumor location 
collected on the colorectal cancer history eCRF page. Colon cancer type is defined as patients 
with ceacum, appendix, ascending colon or right hepatic flexure or transverse colon or left 
splenic flexure or descending colon or sigmoid as primary tumor location. Rectal cancer type is 
defined as patients with rectum as primary tumor location.  
The subset initial diagnosis (synchronous, metachronous) will be derived based on the time 
from initial histological diagnosis to first diagnosis of metastatic disease. If this time is longer 
than 6 months then the initial diagnosis of the corresponding patient will be considered 
metachronous, or as synchronous otherwise. In case date of first diagnosis of metastatic 
disease is missing, this one will be replaced by the date of first diagnosis of locally recurrent 
disease. In case both are missing, the corresponding patients will be excluded from the 
corresponding subgroup analysis. In case one of the dates (i.e. date of initial histological 
diagnosis or date of first diagnosis of metastatic disease or date of first diagnosis of locally 
recurrent disease) is partially missing, it will be imputed as described in section 4.14.  
 
4.8 
ANALYSIS POPULATIONS 
The following patient populations will be evaluated and used for presentation and analysis of 
the data. 
 
4.8.1 
All Population 
ALL Population: The ALL population consists of all patients without a confirmed  BRAF 
mutation result who signed an Inform consent form until June 3, 2016. 
Induction Treatment Phase (ITP) Population: all patients included in the ALL Population and 
who are treated in the ITP, i.e. who received at least one non-null dose of any study 
medications during the ITP. ITP population is the main population to be used to summarize ITP 
data and Post Induction Treatment data. The 2 following groups will be considered when 
tabulating ITP data:  patients randomized into MTP versus patients not randomized into MTP. 
Post Induction Treatment data will be summarized using one single group, i.e. patients not 
randomized into MTP. ITP population will be the main population for the data listings, unless 
otherwise specified; the 3 following groups will be displayed in listings: patients randomized in 
the experimental group of MTP, patients randomized in the control group of MTP, patients not 
randomized into MTP. 
 
4.8.2 
Randomized Population 
Maintenance Treatment Phase (MTP) Population is defined as all patients randomized into 
the Cohort 2 MTP of the study, irrespective of whether or not they received study medication. 
Patients will be allocated to the treatment group into which they were randomized (as per 
interactive voice or web-based response system [IxRS]). The MTP population is the primary 
population for the analysis of efficacy parameters and baseline characteristics for the MTP. The 
MTP population will be used as well to report the Post Maintenance Treatment data. 


 
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4.8.3 
Safety Population 
Safety (SAF) Population: all patients randomized in Cohort 2 who have been treated, i.e. who 
received at least one non-null dose of any study medications during the MTP. 
Patients will be allocated to the treatment group they actually received using the following rule: 
 
Patients receiving at least one dose (non-null) of atezolizumab, while on treatment will 
be allocated to the experimental group FP+bevacizumab+ atezolizumab. Even if a 
patient was allocated to the control group and received by mistake a dose of 
atezolizumab, then this patient will be reallocated to the experimental group. 
 
Patients who did not receive any dose of atezolizumab will be allocated to the control 
group FP+bevacizumab.  
The SAF population is the primary population for the analysis of MTP safety parameters. 
 
4.8.4 
Per Protocol (PP) Population 
As stated in the protocol, the PP Population will not be defined for this study but major protocol 
violations will be listed.  
 
4.8.5 
Pharmacokinetic-Evaluable Population 
Not applicable. 
 
4.8.6 
Biomarker-Evaluable Population 
Not applicable. 
 
4.9 
ANALYSIS OF STUDY CONDUCT 
This SAP focuses only on the description of the analysis required for cohort 2 data. All MTP 
data will be reported. ITP data for non-BRAF mutant patients randomized and not randomized 
into the MTP will be tabulated in 2 separate columns. Post-treatment data will be reported 
separately for induction and maintenance. This Post-treatment data includes adverse events, 
deaths, subsequent anti-cancer therapies and tumor assessments (until PD if PD not 
experienced before study treatment discontinuation visit), but this last one applies only for Post 
Maintenance treatment.  
 
4.9.1 
Patient Disposition 
The patient disposition table for ITP will be based on the ALL population and will include the 
following information: 
 Number of patients enrolled (ALL) 
 Number of patients not treated in induction who discontinued trial without being treated and 
associated reason 


 
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 Number of patients treated with induction treatment (ITP population)  
 Number of patients who completed the ITP  
 Number of patients treated in induction who discontinued early ITP and reason for early 
discontinuation  
 Number of patients treated in induction and not randomized who went to post-treatment 
follow-up phase post induction 
 Number of patients being treated in induction who discontinued study prior to MTP and 
associated reason 
 
The patient disposition table for MTP will include the following information: 
 Number of randomized patients (MTP population) (percentage based on MTP) 
 Number of randomized patients without being treated in MTP still on-trial  
 Number of randomized patients who discontinued trial without being treated in MTP and the 
corresponding reason for trial discontinuation (percentages based on MTP) 
 Number of treated patients with maintenance treatment (SAF) (percentages based on MTP) 
 Number of patients treated who discontinued all treatments received in MTP and the reason 
for discontinuation from each maintenance treatment (percentage based on MTP). All 
reasons for treatment discontinuation will be displayed and will be taken from the individual 
treatment completion/Early discontinuation eCRF pages. 
 Number of patients treated in MTP who discontinued trial during MTP and the corresponding 
reason for trial discontinuation (percentages based on MTP) 
 Number of patients who entered in the follow-up post-MTP 
 Number of patients being treated in MTP who discontinued trial during follow-up and the 
corresponding reason for trial discontinuation (percentages based on MTP) 
 
A consort flow diagram will be provided to show progress of screened patients who signed an 
informed consent form until June 3, 2016 and especially for non-BRAF mutant patients through 
the different phases (screening, ITP, MTP, end of treatment, follow-up, end of study). 
 
The following supportive listings will be provided: 
 
Patient disposition (including the tumor response status at the end of ITP) and study 
termination information based on ITP 
 
Patients who discontinue treatment due to AE (based on ITP) 
 
4.9.2 
Protocol Deviations 
All major protocol deviations from Protocol Deviation Management System (PDMS) will be 
reported for each phase separately and will be summarized by group. The ITP population will 
be used for ITP data and the MTP population for the MTP data. 


 
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The following will be displayed 
 
Number of patients having at least one major protocol deviation 
 
Number of patients by major protocol deviations category  
Listings for protocol deviations and analysis population will be provided based on ITP 
population. 
 
4.10 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
4.10.1 
Demographics and Baseline Disease Characteristics 
Baseline and demographic characteristics will be summarized using descriptive statistics.  No 
formal statistical comparisons will be performed.  
Summaries of Patient Demographics will be provided based on the ITP and MTP population 
and will present the following information: 
 
Age at informed consent (yrs) 
 
Age categories (yrs) : < 18, 18-64, 65-84, 85 and over 
 
Sex 
 
Ethnicity: Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown  
 
Race  
 
Region: Europe, Americas, Africa, Asia (derived based on country information from the 
clinical database) 
 
Smoking status: Never, Current, Previous 
 
Alcohol use history: Never, Current, Previous 
 
Drug Use: Never, Current, Previous 
 
ECOG Performance Status at baseline: 0,1,> 1,  
 
Baseline Weight (kg) 
 
BMI (see definition in section 4.3) 
 
BSA (see definition in section 4.3) 
 
Baseline Height (cm) 
 
Female reproductive status (for female participants only. Percentage will be based on 
the total number of female patients)  
The summary of patients characteristics based on MTP will include in addition the serology 
results (positive, negative, not done) for the following parameters HIV, Hepatitis B surface 
antigen (HBsAg), Hepatitis B core antibody (HBcAb), HCV Antibody, HCV RNA (only if HCV 
Antibody positive). For the summary based on MTP only, ECOG and weight collected just prior 
to or on the first day of MTP will be used as baseline. Please refer to sections 4.2.1 and 4.2.2 
for further details related to definition of baseline evaluations. 
All the biomarker outcomes of interest as per section 4.7 will be summarized using descriptive 
statistics by treatment group on MTP population: 
Given that the end of the induction phase is the same timepoint as the baseline tumor response 
for the MTP two summary tables presenting the information as mentioned below will be 
produced. One for the tumor response status at the end of the induction phase based on ITP 
and as per data collected on the eCRF and will present the following information. 
 
Number of patients with CR or PR at end of ITP   


 
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 
Number of patients with SD at end of ITP   
 
Number of patients with PD at end of ITP 
 
Number of patients with NE at end of ITP 
 
Number of patients with NA at end of ITP (i.e. no tumor response during ITP)  
 
Another table will be generated for baseline tumor response for the MTP based on MTP and as 
per data collected on the eCRF and will present the following information. 
 
Number of patients with CR or PR at end of ITP   
 
Number of patients with SD at end of ITP 
 
Number of patients with tumor response other than CR, PR or SD at end of ITP    
 
The number of patients in MTP will be summarized by country and study center (as per clinical 
database and by treatment group based on the MTP population.  
In addition, the number of patients will be summarized by the following stratification factors as 
per IxRS, by treatment group on the MTP: 
 
Region 
o European Union 
o Americas  
o Africa 
o Asia 
 
Tumor response at the end of ITP 
o CR/PR 
o SD 
 
A table will show the concordance between the tumor response status at the end of ITP as per 
IxRS and the tumor response status at the end of ITP as per data collected on the eCRF. This 
table will be based on the MTP population and will display the following categories:  
 
CR/PR, SD, Total for the IxRS tumor response 
 
CR, PR, CR/PR, SD for eCRF tumor response 
 
eCRF Tumor response status (CR, PR, SD, PD, NE) at the end of ITP is defined as the last 
tumor response observed during the ITP. Patients without tumor assessment after first day of 
induction treatment will be assigned a tumor response of NA (Not available).  
Patients with only non-target lesions classified as having an eCRF tumor response status at the 
end of the ITP of "Non-CR/Non-PD" are classified as SD for the 2 summary tables mentioned 
above.    
 
Summary of colorectal cancer history will be provided based on the ITP and MTP population 
and will present the following information: 
 
Histological grade at diagnosis 
 
Location of primary tumor 


 
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 
Colon Location: left, right 
 
Cancer type: colon, rectal 
 
Initial AJCC/UICC stage 
 
Initial diagnosis: synchronous, metachronous 
 
Locally recurrent disease: yes, no 
 
Metastatic disease: yes, no 
 
Sites of metastatic disease at time of study enrolment (adrenal gland, ascites, bone, 
liver, lung, mediastinum, skin, other) 
 
Liver as metastatic site: yes, no 
 
Extent of disease by number of sites at time of study enrolment: 0, 1, > 1  
 
Time from initial diagnosis to first dose of ITP (in years) 
 
Time from first diagnosis of locally recurrent disease to first dose of ITP (in years) 
 
Time from first diagnosis of metastatic disease to first dose of ITP (in years)  
 
Number of target lesions at baseline 
 
Of note, if start and/or end dates are incomplete or missing the corresponding time between the 
start and the end date cannot not be derived. In this case, time from initial diagnosis to first 
dose of ITP or time for first diagnosis of locally recurrent disease to first dose of ITP or time 
from first diagnosis of metastatic disease to first dose of ITP cannot not be derived and will be 
missing.  
 
Summary of RECIST tumor-specific characteristics at baseline will be generated on the MTP 
population and will provide the following information: 
 
Number of site/organs involved; 1, 2, >2 
 
Site/organ type involved:  colon, rectum, liver, lung, lymph nodes, peritoneum, brain, 
other   
 
Type of lesions: target only, non-target only, target and non-target lesions 
Of note for the above summary table, tumor-specific characteristics at baseline refer to the 
tumor assessment prior to randomization in MTP, i.e. last tumor assessment from the induction 
treatment phase.  
 
The following listings will be provided: 
 
Patient Demographics based on ITP population 
 
Biomarker status based on MTP population 
 
Serology values and tuberculosis test values (for which results are collected prior to 
randomization only to determine eligibility for randomization in MTP) based on MTP 
population 
 
Patients by randomization stratification factors as per IxRS and eCRF (based on MTP) 
 
Colorectal cancer history based on ITP population 
 
4.10.2 
Medical History 
Medical history, as collected on the “General Medical History and Baseline Conditions” eCRF 
page will be summarized using the ITP and MTP population. This summary table will include 


 
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the number and percentage of patients with at least one medical history by Primary System 
Organ Class (SOC) sorted in a descending order of the total frequency count and by preferred 
term [PT] (sorted in a descending order of the total frequency count within each SOC).  
A patient with more than one occurrence of the same medical history in a particular SOC/PT 
will be counted only once in the total of those experiencing events in that particular system 
organ class/preferred term. 
Medical history data will be listed based on ITP population. 
 
4.10.3 
Prior and Concomitant Medications 
4.10.3.1 
Prior Anti-Cancer Treatment/Procedure 
Prior anti-cancer treatments/procedures summary based on the ITP and MTP population will 
present the following information: 
 
Number of patients with prior colorectal cancer surgery: Yes, No 
 
Number of patients by site of prior colorectal cancer surgery: Colon, Rectum, Colon and 
Rectum, Other.  
 
Number of patients with prior radiotherapy: yes, no 
 
Number of patients with prior anti-cancer therapies: yes, no  
 
Number of patients by setting of prior systemic therapy 
 
Number of patients with prior systemic adjuvant therapy: yes, no  
 
Number of regimens for prior systemic therapy: 0, 1, 2, >=3.  
The following listings will be provided based on the ITP population: 
 
Prior anti-cancer therapy 
 
Prior cancer radiotherapy 
 
Prior cancer colorectal surgery 
 
4.10.3.2 
Non Anti-Cancer Treatment/Procedure 
 
A prior medication/therapy is defined as any medication/therapy with an end date prior to the 
start of the induction treatment. 
Concomitant medication for ITP 
Concomitant medication includes both medication concomitant at baseline and concomitant 
medication initiated post-baseline. It is defined as any medication/therapy with 
 
 start date before or on: 
o the randomization date for patients randomized in the MTP  
o last dosing date of ITP+30 days for patients not randomized in the MTP  
 
and end-date on or after first dosing date of the ITP or with a missing (ongoing) end-
date 
 
Concomitant medication for MTP 
It is defined as any medication/therapy with 


 
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 
start date before or on  last dosing date in the MTP+30 days  
 
and end-date on or after first dosing date of the MTP or with a missing (ongoing) end-
date. 
Post-treatment Medication 
It is defined as any medication/therapy with a start date more than 30 days after the last dosing 
date. 
In case a medication has an incomplete or missing start date/end date, please refer to section 
4.14 for the rules to be applied in order to identify prior, concomitant or post-treatment 
medications.  
Prior and Concomitant Medications/therapies will be summarized. Summary tables will present 
number and percentage of patients with any medication overall and by Drug Thesaurus Class 
and Generic Name. At each level of summation (overall, Drug Thesaurus Class, Generic 
Name), patients reporting more than one medication are counted only once. Drug Thesaurus 
Class will be sorted in a descending order of the total frequency count and the generic names 
with the highest frequency will be displayed first within each Drug Thesaurus class, unless 
otherwise indicated. The analysis population will be the ITP and the MTP population for ITP 
and MTP data, respectively. 
The following tables will be provided: 
 
Prior medications based on ITP population 
 
Concomitant medications for the ITP based on ITP population 
 
Concomitant medications for the MTP based on SAF population 
 
Concomitant radiotherapy performed during the ITP based on ITP population (as 
collected on the On-Study Cancer Radiotherapy eCRF  page): Number of patients with 
radiotherapy, site (colon, other)  and setting (neo-adjuvant, adjuvant, palliative. other) of 
therapy 
 
Concomitant radiotherapy performed during the MTP based on SAF population (as 
collected on the On-Study Cancer Radiotherapy eCRF  page): Number of patients with 
radiotherapy, site (colon, other)  and setting (neo-adjuvant, adjuvant, palliative, other) of 
therapy 
 
Concomitant colorectal cancer surgery during ITP based on ITP: Number of patients 
with at least one surgery, site of surgery, surgical procedure and intent 
 
Concomitant colorectal cancer surgery during MTP based on SAF: Number of patients 
with at least one surgery, site of surgery, surgical procedure  and intent 
 
Corresponding listings will be provided using the ITP population. 
 
4.10.4 
Subsequent Anti-Cancer Therapy 
Post Induction Treatment and Post Maintenance Treatment subsequent anti-cancer therapies 
will be listed using the ITP population who has a study treatment discontinuation visit date.  
 


 
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4.11 
EFFICACY ANALYSIS 
Efficacy analysis will be conducted on the data collected during the MTP/Post maintenance 
treatment (when applicable) and using the MTP population. Analysis will be performed by 
randomized treatment group. Tumor assessments collected during the ITP will be listed only 
but will not be part of the efficacy analysis and will be listed on the ITP population. ITP and 
MTP tumor assessment will be flagged, as appropriate for patients randomized in the MTP.  
All formal statistical tests will be two-sided and performed at an alpha of 5%. Therefore 95% 
two sided CI will be presented. No adjustment will be made for multiplicity of testing secondary 
endpoints or subgroups for single efficacy endpoints. 
 
4.11.1 
Primary Efficacy Endpoint 
The primary efficacy objective of this study is to evaluate PFS. 
To answer the primary objective, the following null and alternative hypotheses will be tested  
 
H0: the distribution of the PFS time is the same in the two treatment groups, i.e.   PFS 
(Experimental group) = PFS (Control group) 
 
H1: the distribution of the PFS time is different in the two treatment groups, i.e. PFS 
(Experimental group) ≠ PFS (Control group) 
The primary analysis of PFS will be a comparison between the experimental and the control 
group using an unstratified log-rank test. Please refer to Appendix 4 for the SAS code to be 
used. 
PFS for each treatment group will be estimated using KM product-limit method estimates. PFS 
will be summarized by treatment group and will display the following information: 
 
Number of patients in the population (N) 
 
Number of patients with PFS event  
 
Number of patients censored 
 
Median and two-sided 95% CI computed according to Brookmeyer and Crowley method,  
 
25th and 75th quantile, and the corresponding two-sided 95% CI computed according to 
Brookmeyer and Crowley method,  
 
Minimum and maximum 
 
The PFS rates (with the two-sided 95% CI ) at 3, 6, 9, 12, 15 and 18 months 
 
Unstratified log-rank test p-value 
KM plot of PFS by treatment group will be generated. 
PFS time will be listed on MTP population in a dedicated time to event listing.  
Model checking 
Sensitivity analyses concerning proportional hazards assumption will consist of log-log-Survival 
plots (log(-log(S(t))) vs log(time) by treatment group (plots=(lls) in PROC LIFETEST). 
 


 
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4.11.2 
Secondary Efficacy Endpoints 
4.11.2.1 
Overall Survival 
This study is not powered for OS, so adequately powered statistical testing for this endpoint will 
not be possible. However, the results of an unstratified log-rank test will be provided in an 
exploratory manner to assess the difference between treatment groups for OS. 
The same analysis as those described for the primary endpoint will be repeated for OS on MTP 
population The survival rate will be displayed at the following time points: 6, 9, 12 and higher 
(every 3 months) if appropriate. 
OS time will be listed on MTP population in a dedicated time to event listing.  
 
4.11.2.2 
Overall Response Rate (based on Primary Definition of BOR) 
The Best Overall Response for MTP as per main definition will be tabulated on MTP by 
treatment group. 
ORR for the MTP will be summarized in each treatment group on MTP and will present the 
number and percentage of patients with objective response (CR or PR) as best response along 
with the two-sided 95% Clopper-Pearson confidence interval. The difference in ORR among 
treatment groups will be estimated with associated two-sided 95% CI using the Hauck-
Anderson approach. The treatment difference will be tested using a Chi-square test at a two-
sided alpha level of 5%. 
A logistic regression analysis, using treatment and the stratification factors as covariates will be 
performed. An estimate of the odds ratio with an associated two-sided 95 % confidence interval 
and a p-value for the coefficient will be presented for each covariate, including treatment. 
Please refer to Appendix 4 for the SAS code to be used. The stratification factors: region as per 
clinical database and tumor response at end of induction as per eCRF data will be included as 
covariates as mentioned below: 
 
cov1 (EU vs Americas) 
 
cov2 (EU vs Africa) 
 
cov3 (EU vs Asia)  
 
cov4 (SD vs CR/PR) 
Note: EU and SD will be used as reference. If the number of patients in a region is small, 
regions may be pooled together (e.g. EU vs Rest of the world).  
Forest plots displaying ORR odds ratio from the logistic regression by subgroups will be 
generated, for further details please refer to section 4.11.5. 
Waterfall plots (both treatment groups one the same plot) of the best percentage change from 
baseline in sum of diameter collected during the MTP will be provided.  
 
A listing of tumor assessments per timepoint will be provided based on the ITP. It will include: 
 
MTP/ITP/Post-treatment flag 
 
visit 
 
imaging date  
 
lesions number 


 
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 
location, site/organ, assessment method and type of lesion   
 
diameter (mm) for target lesion, status for non-target lesion 
 
sum of diameter of target lesions (mm)  
 
response per timepoint for target lesion and non-target lesion, presence/absence of  
new lesion(s) 
 
overall Response per timepoint 
Information will be collected from the “RECIST 1.1 Target Lesions”, “RECIST 1.1 Non-Target 
Lesions”, “RECIST 1.1 New Lesions” and "RECIST 1.1 - Overall Response Assessment" eCRF 
pages.  
Another listing based on the MTP population will provide the best overall response (main and 
secondary definitions), time to response and the duration of response. Censored patients for 
the duration of response will be flagged as per section 2.2.2.6. 
 
4.11.2.3 
Overall Response Rate (based on Secondary Definition of BOR) 
The analyses performed for Overall Response Rate for MTP based on main definition of BOR 
will be repeated using secondary definition of BOR (refer to section 0). 
 
4.11.2.4 
Disease Control Rate  
Same analysis as described for ORR for MTP will be provided for the following endpoints: 
 
DCR for MTP based on main definition of BOR using the MTP population 
 
DCR for MTP based on secondary definition of BOR using the MTP population 
All corresponding information will be listed on the MTP population. 
 
4.11.2.5 
Time to Treatment Response 
Time to objective response (CR and PR) for each treatment group will be summarized 
separately based on the main and secondary definition of BOR using descriptive statistics 
(median, minimum and maximum) which will be calculated using PROC UNIVARIATE and are 
based on MTP population restricted to responders. 
Two separate summary tables will be created: one for the time to response by considering all 
tumor assessments as in the main definition of BOR and another one by considering on-
treatment tumor assessment as in the secondary definition of BOR. No formal statistical 
comparisons between the treatment groups are planned.  
Time to response will be listed on MTP. 
 
4.11.2.6 
Duration of Response   
The duration of response (DoR) for each treatment group will be estimated using KM product-
limit method estimates. Summary table for duration of response based on MTP population 
restricted to responders will display, by treatment group, the number of patients with best 
overall response CR or PR (N), number of patients with progression or death, number of 
patients censored, min, max, 25th quantile, 75th quantile and median with the associated two-
sided 95% CIs computed according to Brookmeyer and Crowley method.  


 
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Two separate summary tables will be created: one for duration of response by considering all 
tumor assessments as in the main definition of BOR and another one by considering on-
treatment assessments as in the secondary definition of BOR. 
The duration of response will be compared between the experimental and the control group 
using an unstratified log-rank test. 
Duration of response will be listed on MTP. 
 
4.11.2.7 
Progression-Free Survival 2 (PFS 2) 
PFS2 will be estimated using KM product-limit method estimates. Number of patients in the 
population, number of patients with PFS2 events, number of patients censored, min, max, 25th 
quantile, 75th quantile and median with the associated two-sided 95% CIs computed according 
to Brookmeyer and Crowley method as well as PFS2 rates (with the two-sided 95% CI ) at 6, 9, 
12, 15, 18 months (and higher every 3 months if appropriate) will be reported.  
PFS2 hazard ratio, and its 95% two-sided confidence interval, of experimental group versus 
control group, will be estimated using a Cox proportional hazards model with treatment as the 
single covariate. 
As for OS, despite not being adequately powered for PFS2, an unstratified log-rank test will be 
performed in an exploratory manner to assess the difference between treatment groups. 
KM plot of PFS2 by treatment group will be generated. 
PFS2  time will be listed on MTP population. 
 
4.11.2.8 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
Summary table presenting the number of patients and percentage by ECOG performance 
status will be displayed by visit occurring during the MTP. In addition, a shift table of MTP 
baseline ECOG PS versus ECOG PS at the end of MTP will be provided. Supportive listing will 
be provided for the MTP.  
ECOG PS data will be listed based on the ITP population. ITP and MTP evaluations will be 
flagged.  
 
4.11.3 
Exploratory Efficacy Endpoints 
4.11.3.1 
PFS in Patients Randomized to Atezolizumab (Anti-PD-L1 Antibody) 
According to mRECIST (Experimental Group Only) 
This endpoint will only be assessed in patients from MTP population randomized to the 
experimental group (i.e. patients treated with atezolizumab). The Overall patient response per 
Modified RECIST and per timepoint will be retrieved from the “Modified RECIST Response 
Assessment” eCRF page.  
PFS will be estimated using KM product-limit method estimates. Number of patients in the 
population, number of patients with PFS events, number of patients censored, min, max, 25th 
quantile, 75th quantile and median with the associated two-sided 95% CIs computed according 
to Brookmeyer and Crowley method as well as PFS rates (with the two-sided 95% CI ) at 3-, 6-, 
12- and 18-month will be reported. 


 
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KM plot of PFS for this experimental group will be generated. This KM plot will display the 3 
following curves on the same graph: 
 
KM curves of PFS for the experimental and control group as per RECIST 1.1 
 
KM curve of PFS for the experimental group according to mRECIST 
Supportive listing for Overall Response per timepoint and for PFS as per Modified RECIST will 
be provided. 
 
4.11.4 
Sensitivity Analyses 
In addition, the following sensitivity analyses will be performed on PFS, the primary efficacy 
endpoint: 
 
The PFS hazard ratio, and its 95% two-sided confidence interval, of experimental group 
versus control group, will be estimated using a Cox proportional hazards model with 
treatment as the single covariate. Please refer to Appendix 4 for the SAS code to be 
used. 
 
The PFS hazard ratio, and its 95% two-sided confidence interval, of experimental group 
versus control group, will be estimated using different adjusted Cox proportional 
hazards models, using as covariates the treatment and the stratification factors, i.e. 
region (as per clinical database) and tumor response at the end of induction treatment 
as mentioned below 
o cov1 (EU vs Americas), cov2 (EU vs Africa), cov3 (EU vs Asia) cov4 (SD vs 
CR/PR as per eCRF) 
o cov1 (EU vs Americas), cov2 (EU vs Africa), cov3 (EU vs Asia) cov4 (SD vs 
CR/PR as per IxRS) 
o cov1 (EU vs Rest of the world), cov2 (SD vs CR/PR as per eCRF) 
o cov1 (EU vs Rest of the world), cov2 (SD vs CR/PR as per IxRS) 
Note: If the number of patients in a region is small, only models with pooled region (i.e. EU 
vs Rest of the world) will be considered. 
 
 
A sensitivity analysis will be performed for PFS by considering all PFS events reported 
in MTP regardless of the surgery.   
An unstratified log-rank test will be performed to compare PFS between the 
experimental and the control group. PFS will be estimated for each treatment group 
using KM product-limit method estimates. PFS will be summarized by treatment group 
and will display the information as mentioned in section 4.11.1. The PFS hazard ratio, 
and its 95% two-sided confidence interval, of experimental group versus control group, 
will be estimated using a Cox proportional hazards model with treatment as the single 
covariate. 
 
 
A sensitivity analysis will be performed for PFS, using an on-treatment PFS analysis as 
below:  
The derivation of the PFS will be the same as per section 2.2.1, the only change being 
the time window during which the progression free survival is observed. In other words, 
the primary endpoint PFS considers all tumor assessments and deaths reported on 
study (i.e. including Post Maintenance Treatment tumor assessments for patients 


 
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withdrawing maintenance treatment for other reason than PD) whereas the on-
treatment definition considers only tumor assessments and death reported on 
maintenance treatment (i.e within 30 days from last day of treatment of MTP, up to the 
day before the start of further anti-cancer therapy, whichever comes first).  
Using the on-treatment PFS, an unstratified log-rank test will be performed to compare on-
treatment PFS between the experimental and the control group. On-treatment PFS will be 
estimated for each treatment group using KM product-limit method estimates. On-treatment 
PFS will be summarized by treatment group and will display the information as mentioned 
in section 4.11.1. The on-treatment PFS hazard ratio, and its 95% two-sided confidence 
interval, of experimental group versus control group, will be estimated using a Cox 
proportional hazards model with treatment as the single covariate. 
 
 
A sensitivity analysis will be performed for PFS considering the first 259 PFS events. 
For this sensitivity analysis, PFS definition as per section 2.2.1 will be used and a new 
cut-off date being the date of the 259th PFS event will be applied. For event/censor date 
from the primary analysis that was after the new cut-off date, then the patient will be 
censored at the last tumor assessment available prior the new cut-off date. 
An unstratified log-rank test will be performed to compare PFS considering the first 259 
PFS events between the experimental and the control group. PFS considering the first 259 
PFS events will be estimated for each treatment group using KM product-limit method 
estimates. PFS will be summarized by treatment group and will display the information as 
mentioned in section 4.11.1. The PFS hazard ratio, and its 95% two-sided confidence 
interval, of experimental group versus control group, will be estimated using a Cox 
proportional hazards model with treatment as the single covariate. 
 
 
A sensitivity analysis will be performed for PFS considering the planned sample size as 
per protocol, i.e. the first 405 randomized patients. For this sensitivity analysis, both 
PFS definition as per section 2.2.1 and a subset of the MTP population considering the 
first first 405 randomized patients will be used.  
An unstratified log-rank test will be performed to compare PFS considering the first 405 
randomized patients between the experimental and the control group. PFS considering the 
first 405 randomized patients will be estimated for each treatment group using KM product-
limit method estimates. PFS will be summarized by treatment group and will display the 
information as mentioned in section 4.11.1. The PFS hazard ratio, and its 95% two-sided 
confidence interval, of experimental group versus control group, will be estimated using a 
Cox proportional hazards model with treatment as the single covariate. 
 
 
The OS hazard ratio, and its 95% two-sided confidence interval, of experimental group 
versus control group, will be estimated using a Cox proportional hazards model with 
treatment as the single covariate. Please refer to Appendix 4 for the SAS code to be 
used. 
 
For ORR and DCR, a logistic regression analysis, using treatment as single covariates 
will be performed. An estimate of the odds ratio with an associated two-sided 95 % 
confidence interval and a p-value for the coefficient will be presented for treatment. 
Please refer to Appendix 4 for the SAS code to be used. 
 
To assess any bias regarding the completeness of the follow up to capture PFS events, 
KM curve with reverse censoring will be produced by treatment group. In this analysis, 


 
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censored patients in the primary analysis will be considered as having an event, for 
these patients the event date will be the date of last evaluable tumor assessment or 
date of randomization, whichever comes last. Patients with a PFS event in the primary 
analysis will be censored in this analysis, for these patients the censor date will be the 
earliest date between PD date and death date. 
 
4.11.5 
Subgroup Analyses 
Subgroup analyses of PFS and OS will be conducted on each level of the: 
 
Stratification factors   
 
Tumor colon location subset 
 
Biomarker subset 
Please refer to section 4.7 for the definition of these subsets. 
 
The following information will be provided/computed within each subset: 
 
Number of patients in the subgroup 
 
Number of patients with PFS event  
 
Number of patients censored 
 
Median and two-sided 95% CI computed according to Brookmeyer and Crowley method, 
 
25th and 75th quantile, and the corresponding two-sided 95% CI computed according to 
Brookmeyer and Crowley method, 
 
PFS HR of experimental versus control group and its two-sided 95% CI computed by 
means of an un-stratified Cox proportional hazards model with treatment as the single 
covariate. 
Forest plots presenting the PFS HR of experimental group versus control group and 
corresponding 95% CI obtained from adjusted Cox model for each subset as defined in section 
4.7 will be generated.  
Forest plots presenting the OS HR of experimental group versus control group and 
corresponding 95% CI obtained from adjusted Cox model for each subset as defined in section 
4.7 will be generated.   
Each forest plot will be provided twice one for the baseline characteristics subsets, and another 
one for the biomarker subsets.    
The Best Overall Response for MTP as per main and secondary definition (see section 0) will 
be tabulated on MTP by treatment group on each level of the baseline and biomarker subsets 
as defined in section 4.7  
For each level of the baseline and biomarker subsets as defined in section 4.7, ORR for the 
MTP will be summarized in each treatment group on MTP and will present the number and 
percentage of patients with objective response (CR or PR) as best response along with the 
two-sided 95% Clopper-Pearson confidence interval. The difference in ORR among treatment 
groups will be estimated with associated two-sided 95% CI using the Hauck-Anderson 
approach. 
For each level of the baseline and biomarker subsets as defined in section 4.7, a logistic 
regression analysis, using treatment as single covariate will be performed. An estimate of the 


 
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odds ratio (experimental vs control group) with an associated two-sided 95 % confidence 
interval will be provided. 
Forest plots displaying the ORR odds ratio of experimental group compared to control group 
and corresponding 95% CI from the logistic regression with treatment as unique covariate for 
each subset as defined in section 4.7 will be provided. One forest plot will be generated for 
baseline characteristics subsets, and another one for the biomarker subsets. 
No formal statistical comparisons will be conducted within subsets. 
 
4.12 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Not applicable 
4.13 
SAFETY ANALYSES 
Separate safety summaries will be produced for ITP, MTP, Post Induction Treatment and Post 
Maintenance Treatment.   
For ITP data, outputs will be generated on the ITP displaying randomized vs. non randomized 
patients in MTP. MTP outputs will be based on the SAF population and will be presented by 
treatment group. For Post Induction Treatment data, outputs will be generated on ITP for 
patients who completed study treatment discontinuation visit, whereas for Post Maintenance 
Treatment data, outputs will be generated on MTP for patients who completed study treatment 
discontinuation visit. 
No inferential statistical analyses are planned. 
 
4.13.1 
Exposure of Study Medication 
4.13.1.1 
Treatment Duration and Dose Exposure 
A patient will be considered as having initiated a cycle in the ITP if at least one (non-null) dose 
of any study drugs of the ITP has been administered in the corresponding cycle. 
The overall number of cycles initiated during the ITP is defined as the sum of all initiated cycles 
(as defined above) in the ITP. 
For the MTP, the overall number of cycles initiated (i.e. for drug combination) will be computed 
as the sum of all initiated cycles as defined below: 
 
Day 1 of a cycle is defined as the first day in the considered cycle when treatment is 
administered. 
 
The cycle length is assumed to be 2 weeks 
 
For experimental group: 
o If capecitabine is administered: a cycle will be assumed to be initiated if 
capecitabine and atezolizumab and bevacizumab are administered at any time 
during the same cycle with cycle defined according to atezolizumab and 
bevacizumab cycles 


 
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o If 5-FU/LV or LV substitute is administered: a cycle will be assumed to be 
initiated if atezolizumab, bevacizumab and 5-FU and LV or any LV substitute  
are  administered at any time during the same cycle 
 
For control group: 
o  If capecitabine is administered: a cycle will be assumed to be initiated if 
capecitabine and bevacizumab are administered at any time during the same 
cycle  
o If 5-FU/LV or LV substitute is administered: a cycle will be assumed to be 
initiated if bevacizumab and 5-FU and LV  or any LV substitute are  
administered at any time during the same cycle 
 
The overall duration (in weeks) for all components of maintenance treatment is defined as 
follows:  
 
Experimental group:  
o If capecitabine is administered in the last cycle:  
[MAX( min(last dosing date of capecitabine+6, death date), min(last dosing date of 
bevacizumab+13, death date), min(last dosing date of atezolizumab+13, death date)) – min 
(first dosing date of FP, first dosing date of bevacizumab, first  dosing date  of atezolizumab) 
+ 1]/7  
o If 5-FU/LV is administered in the last cycle: 
[MAX(min(last dosing date of 5-FU/LV+13, death), min(last dosing date of bevacizumab+13, 
death date), min(last dosing date of atezolizumab+13, death date)) – MIN (first dosing date 
of FP, first dosing date of bevacizumab, first dosing date of atezolizumab) + 1]/7  
  with last dosing date of 5-FU/LV = max(last dosing date of 5-FU, last dosing date of LV) 
and first dosing date of 5-FU/LV = min(first dosing date of 5-FU, first dosing date of LV) 
 
Control group:  
o If capecitabine is administered in the last cycle:  
[MAX(min(last dosing date of capecitabine+6, min(last doing date of bevacizumab+13, 
death date)) – MIN (first dosing date FP, first dosing date of bevacizumab) + 1]/7. 
o If 5-FU/LV is administered in the last cycle: 
 [MAX(min(last 
dosing 
date 
of 
5-FU/LV+13, 
death), 
min(last 
dosing 
date 
of 
bevacizumab+13, death date)) – MIN (first dosing date of FP, first dosing date of 
bevacizumab) + 1]/7  
  with first dosing date of FP = min(fist dosing date of 5-FU, first dosing date of LV or any LV 
substitute, first dosing date of capecitabine) and last dosing date of 5-FU/LV = max(first 
dosing date of last administration of 5-FU, first dosing date of last administration of LV or 
any LV substitute)  
 


 
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The number of cycles administered, duration of dosing, cumulative dose, dose intensity and 
relative dose intensity (RDI) definitions are provided for each drug individually in Table 3 and 
Table 4 for induction and maintenance, respectively. 
 
According to protocol, the cycle length is 2 weeks, excepted for capecitabine for which each 
cycle lasts 3 weeks in the experimental arm and is as per local practise in the control arm. A 2-
week cycle schedule will be considered for other drugs than capecitabine and for drug 
combination. For capecitabine, a cycle is defined as any continuous administration separated 
by a rest period, regardless of the duration of the continuous administration and the duration of 
the rest period A patient will be considered as having initiated a cycle in the MTP for a specific 
drug if at least one (non-null) dose of this study drug has been administered in the 
corresponding cycle. 


 
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Table 2: Exposure Definitions for Induction Treatments 
 
FOLFOX 
5-FU/LV 
bevacizumab 
Number of cycle 
sum of all cycles in which at 
least one non-null dose of 
FOLFOX  has been 
administered 
sum of all cycles in which at least 
one non-null dose of 5-FU and LV 
has been administered. Of note, 
consider only cycles where 
oxaliplatin is not administered 
concomitantly with 5-FU/LV.  
sum of all cycles in which at least 
one non-null dose of bevacizumab 
has been administered 
Duration of dosing 
(weeks) (1) 
 
[min (last  date of FOLFOX+13, 
death date) – first FOLFOX 
dosing date+1] / 7 or 
If FOLFOX-4 or FOLFOX-7 or 
modified FOLFOX-7 is 
administered in the last cycle 
initiated  
 [min (last  date of FOLFOX 
+12, death date) – first 
FOLFOX dosing date+1] / 7 
 
max (min(last date of 5-FU+13, 
death date), min(last date of LV+13, 
death date)) – min (first date of 5-
FU, first  date of LV) +1] / 7 
Of note, consider only 
records/cycles where oxaliplatin is 
not administered concomitantly with 
5-FU/LV. 
[min (last date of bevacizumab +13, 
death date)) – (first bevacizumab 
dosing date in the induction) +1]  / 7 
(1) According to the proposed formula, the duration of dosing may be overestimated in case patients discontinued treatment prior to the end of the last 
cycle. 
(2) The baseline weight will be used as reference. If the last available weight of the patient prior to or on the cycle start has changed by 10% or greater (i.e. 
patient has gained or lost more than 10% of their body weight since baseline) the patient new weight will be set as the baseline weight and will be used 
at the patient current and subsequent cycles. If a patient weight has changed by 10% or greater at a later cycle then this new weight will be set as the 
base weight as aforementioned 


 
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Table 3: Exposure Definitions for Maintenance 
 
 
capecitabine 
5-FU 
LV 
bevacizumab 
atezolizumab 
Number of cycle 
The sum of all cycles in which at least one non-null dose of <treatment> has been administered 
Duration of dosing 
(weeks) (1) 
 
[min (last dosing date of <treatment> + x, death date)) – (first <treatment> dosing date in the maintenance) +1] / 7 
Where x=13, excepted for capecitabine where x=6 
For 5-FU and LV, last dosing date of treatment will be replaced by the first dosing date of the last administration 
Actual dose 
<treatment> dose administered (in mg) as collected on the dosing eCRF page (5)  
Unit: mg 
Planned dose 
<treatment> planned dose (in mg) as collected on the dosing eCRF page (5)  
Unit: mg 
Normalized dose 
dose / recalculated BSA(2) 
Unit: mg/m2 
dose / weight(4) 
Unit: mg/kg 
NA 
Cumulative dose  
The cumulative dose will be 
derived for each records as 
below: (end date of 
administration - start date of 
administration +1) * normalized 
actual dose for the record * 2 
Cumulative dose= sum of 
cumulative dose across all 
records  
Unit: mg/m2 
sum of the all <treatment > normalized 
actual doses (in mg/m2) administered in 
all cycles 
 
Unit: mg/m2 
sum of the all 
bevacizumab 
normalized actual 
doses (in mg/kg)  
administered in all 
cycles 
Unit: mg/kg 
sum of the all of 
atezolizumab actual 
doses (in mg)  
administered in all 
cycles 
 
Unit: mg 
Dose intensity 
Cumulative dose / (duration of 
Cumulative dose / duration of dosing  
Cumulative dose / 
Cumulative dose / 


 
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capecitabine 
5-FU 
LV 
bevacizumab 
atezolizumab 
dosing *7) 
Unit: mg/m2/day 
Unit: mg/m2/week 
duration of dosing   
Unit: mg/kg/week 
duration of dosing  
Unit: mg/week 
Cumulative 
planned dose 
(CPD)  
sum of the all  normalized 
planned  doses (in mg/m2) 
reported in all records 
 
sum of the all <treatment > normalized 
planned  doses (in mg/m2) reported in 
all cycles 
 
 
sum of the all 
normalized 
planned  doses (in 
mg/kg) reported in 
all cycles 
 
sum of the all 
planned  doses (in 
mg) reported in all 
cycles  
Planned dose 
intensity 
CPD/ (duration of dosing *7) 
Unit: mg/m2/day 
CPD/ duration of dosing  
Unit: mg/m2/week 
CPD/duration of 
dosing 
Unit: mg/kg 
CPD/duration of 
dosing 
Unit: mg/ week 
 
Relative dose 
intensity (RDI) (%) 
RDI (%) = 100 * (dose intensity) / (planned dose intensity) 
 
 
(1) According to the proposed formula, the duration of dosing may be overestimated in case patients discontinued treatment prior to the end 
of the last cycle. 
(2) The BSA will be recalculated based on the height and weight (see point 3 for identification of weight) of the patient using the formula as 
mentioned in section 4.3.  
(3) The baseline weight will be used as reference. If the last available weight of the patient prior to or on the cycle start has changed by 10% 
or greater (i.e. patient has gained or lost more than 10% of their body weight since baseline) the patient new weight will be set as the 
baseline weight and will be used at the patient current and subsequent cycles. If a patient weight has  changed by 10% or greater at a 
later cycle then this new weight will be set as the baseline weight as aforementioned 
(4) If treatment= 5-FU and in case 5-FU administration was interrupted and then 5-FU administration resumed within a cycle, the actual dose 
within this specific cycle will be equal to the sum of the 5-FU doses administered (in mg)) as collected on the dosing eCRF page 
/recalculated BSA(2) 
 


 
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The following information will be tabulated for the ITP using the ITP population: 
 
Summary of  total number of cycles initiated per patient 
o Total number of cycles initiated (1,2,3,4,5,6,7,8)  
o Summary statistics of total number of cycles initiated 
 
Summary of drug exposure 
o The number of cycles administered and treatment duration (in weeks) for 
bevacizumab, FOLFOX and 5-FU/LV alone 
 
The following information will be tabulated for the MTP using the SAF population:  
 
Summary of overall duration of treatment and overall number of cycles initiated 
o Overall duration of maintenance treatment (in weeks) 
o Overall number of cycles initiated: 1,2,3,4,5,6,7,8,9,10, 10-15, >=15  
o Summary statistics of overall number of cycles initiated per patient 
 
Summary of drug exposure  
o Total number of cycles administered (tabulated separately for each drug ) 
o Duration of dosing (in weeks) (tabulated separately for each drug ) 
o Cumulative dose (tabulated separately for each drug according to definition 
provided in table 3) 
o Dose intensity (tabulated separately for each drug according to definition 
provided in table 3) 
o Relative dose intensity: ≤90%, >90%-≤100%, >100% (tabulated separately for 
each drug according to definition provided in table 3) Note: Number and 
percentage will be based on the patients who received the corresponding drug. 
 
Supportive listings presenting the study drug administration as well as the exposure information 
will be provided separately based on ITP and SAF population for the induction and for the 
maintenance, respectively.  
 
4.13.1.2 
Cycle Delay  
Cycle delay is applicable to the following treatments: FP (5-FU, LV or capecitabine), 
bevacizumab and atezolizumab. 
For 5-FU, LV, bevacizumab and atezolizumab, a cycle delay will be defined as the number of 
days in excess of the expected days between two consecutive doses of <treatment>  (14 days) 
and will be calculated as D1Cn+1 - D1Cn where D1Cn+1 and D1Cn  correspond to date of 
administration of <treatment> in cycle n+1 and cycle n, respectively.  An excess of more than 3 
days will qualified cycle Cn+1 as delayed for <treatment>. Of note, the first cycle (C1) cannot 
be identified as cycle delay.     
For capecitabine, a cycle delay will be defined as the number of days in excess of the expected 
days between two non-zero administrations (21 days, i.e. 14 days of administration and a rest 
period of 7 days) and will be calculated as D1Cn+1 - D1Cn where D1Cn+1 and D1Cn correspond to 
the start date of the first administration of capecitabine in cycle n+1 and cycle n, respectively.  
An excess of more than 3 days will qualify cycle Cn+1 as delayed for capecitabine. Of note, the 
first cycle (C1) cannot be identified as cycle delay.   
The following information will be tabulated for the MTP on the SAF population:  


 
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 
Summary of <treatment> cycle delay (for 5-FU, LV, capecitabine, bevazicumab and 
atezolizumab) at the patient level 
o Number of patients with at least one cycle delayed for <treatment>,  
o Number of patients with 1, 2, 3, ≥3 cycles delayed for <treatment> 
 
Summary of <treatment> cycle delay (for 5-FU, LV, capecitabine, bevazicumab and 
atezolizumab) at the cycle level 
o Number of cycles delayed 
o Length of cycle delayed (>3 -7 days, >7-14, >14-21,  >21)  
 
4.13.2 
Adverse Events 
Adverse events variables are defined in Table 4. 
Table 4: Adverse Events Definitions 
Variable 
Definition 
Treatment 
Emergent 
Adverse Events 
(TEAEs) for the 
induction 
treatment phase 
(1) 
 
Any adverse events (serious and non-serious) with an onset date on (only if the 
“Event occurred prior to first study drug administration” from the AE eCRF page is 
not checked) or after the first day of treatment of the ITP and up to the:  
 
first day of treatment of the MTP (excluding) if it occurs within the 30 days 
from last day of treatment of induction treatment for patients treated with 
maintenance treatment 
 
within 30 days from last day of treatment of induction treatment (as defined 
in section 4.2.1), for patients not treated with maintenance treatment or for 
patients treated with maintenance treatment but with first day of treatment of 
MTP being more than 30 days after last day of treatment of ITP.  
TEAEs for the 
maintenance 
treatment 
phase(1) 
 
Any adverse events (serious and non-serious) with an onset date on (only if the 
“Event occurred prior to first study drug administration” from the AE eCRF page is 
not checked)  or after the first day of treatment of the MTP and up to 30 days (for 
patients in control group, i.e. not treated with atezolizumab) and 90 days (for 
patients in experimental group, i.e. treated with atezolizumab) from the last day of 
treatment of MTP (as defined in section 4.2.2) 
Post induction 
treatment 
Adverse Events  
Any adverse events (serious and non-serious): 
 
with an onset date more than 30 days after the last day of treatment of the 
ITP (as defined in section 4.2.1) for patients not treated with maintenance 
treatment. 
 
with an onset date more than 30 days after the last day of treatment of the 
ITP and prior the first day of treatment of the MTP, for patients treated with 
maintenance treatment with first day of treatment of MTP being more than 
30 days after last day of treatment of ITP.. 
Post maintenance 
treatment 
Adverse events  
Any adverse events (serious and non-serious) with an onset date more than 30 
days (for patients in control group, i.e. not treated with atezolizumab) and more than 
90 days (for patients in experimental group, i.e. treated with atezolizumab) after the 
last day of treatment of the MTP (as defined in section 4.2.2) (as defined in section 


 
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4.2.2). 
Adverse Events 
NCI CTCAE 
grade 
The adverse events grade will be the one with tick box checked for "AE most 
extreme NCI CTCAE grade" 
Serious Adverse 
Events (SAEs) 
Any adverse events qualified as “serious” by the investigator.  
Adverse Events 
with fatal 
outcome 
Any adverse events with outcome of “Fatal”. 
Adverse events 
related to 
<FOLFOX, 
bevacizumab, FP, 
atezolizumab>  
Any adverse events with an “AE suspected to be caused by study drug <FOLFOX, 
bevacizumab, FP, atezolizumab>  as ‘Yes’. 
For AE suspected to be caused by FOLFOX while starting in the maintenance 
phase, the unique text ‘“AE considered related to Folfox”‘ has been reported in the 
comment field ‘ 
Adverse events 
leading to 
<FOLFOX, 
bevacizumab, FP, 
atezolizumab> 
discontinuation 
Any adverse events with an “Action taken with <FOLFOX, bevacizumab, FP, 
atezolizumab> due to SAE/AE” of “drug withdrawn” 
Adverse events of 
Special Interest 
(AESI) as 
reported on eCRF  
AESIs will be selected based on the tick box from the eCRF.  
(1) Of note, in case an event has an incomplete or missing start date, which consequently prevents its 
allocation to only one treatment phase of the study, the event will be allocated to both the induction 
and maintenance phase. Refer to section 4.14 for further details. 
Safety summaries will be produced for the ITP on the ITP population and for the MTP on the 
SAF population, unless otherwise specified. ITP summaries will display patients randomized vs. 
patients not randomized in MTP. MTP summaries will be done by actual maintenance 
treatment group as defined for the SAF. Descriptive statistics will be generated as appropriate. 
No inferential statistical analyses are planned. 
Summaries of adverse events for ITP and MTP will be generated for those events that are 
considered treatment emergent. The AE tables will include the number and percentage of 
patients with at least one AE, by MedDRA primary System Organ Classes (SOC) (sorted in a 
descending order of the total frequency count) and MedDRA Preferred Terms (PT) (sorted by 
descending order of the overall frequency count within each SOC) unless otherwise indicated. 
A patient with more than one occurrence of the same adverse event in a particular system 


 
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organ class/preferred term will be counted only once in the total of those experiencing adverse 
events in that particular system organ class/preferred term. For the overall summary tables, 
information presented by grade will not be restricted to the worst grade per patient i.e. all 
events will be presented.  Any AEs with a missing CTC grade will be reported in the “missing” 
category grade.  
 
An overview table will be produced for the ITP based on the ITP population and will present: 
 
Number of TEAEs 
 
Number of patients with at least one TEAE 
 
Number of patients with at least one TEAE by CTC grade: 1, 2, 3, 4, 5, ≥3,  missing 
 
Number of patients with at least one related TEAE 
o Any study drug  
o FOLFOX 
o 5-FU/LV 
o bevacizumab 
 
Number of patients with at least one serious TEAE 
 
Number of patients with at least one related serious TEAE  
o Any study drug  
o FOLFOX 
o 5-FU/LV 
o bevacizumab 
 
Number of patients with at least one TEAE with fatal outcome 
 
Number of patients with at least one TEAEs leading to treatment discontinuation of: 
o Any study drug  
o FOLFOX 
o 5-FU/LV 
o bevacizumab 
 
An overview table will be produced for the Post Induction Treatment AEs, i.e. occurring more 
than 30 days after last day of treatment during the Induction Phase (as defined in section 4.2.1), 
based on patients from the ITP population who has a study treatment discontinuation visit date. 
This table will present the following information for the non-randomized patients to MTP only: 
 
Number of AEs 
 
Number of patients with at least one AE 
 
Number of patients with at least one AE by CTC grade: 1, 2, 3, 4, 5, ≥3,  missing 
 
Number of patients with at least one related AE  
 
Number of patients with at least one serious AE 
 
Number of patients with at least one related serious AE  
 
Number of patients with at least one AE with fatal outcome 
 
An overview table will be produced for the maintenance phase based on the SAF and will 
present: 
 
Number of TEAEs 
 
Number of patients with at least one TEAE 
 
Number of patients with at least one TEAE by CTC grade: 1, 2, 3, 4, 5, ≥3, missing 
 
Number of patients with at least one related TEAE  


 
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o Any study drug  
o Fluoropyrimidines 
o bevacizumab  
o atezolizumab  
o FOLFOX 
 
Number of patients with at least one serious TEAE 
 
Number of patients with at least one related serious TEAE  
o Any study drug  
o Fluoropyrimidines 
o bevacizumab  
o atezolizumab  
o FOLFOX 
 
Number of patients with at least one TEAE with fatal outcome 
 
Number of patients with at least one TEAEs leading to treatment discontinuation of: 
o Any study drug  
o Fluoropyrimidines 
o bevacizumab  
o atezolizumab  
 
Number of patients with at least one treatment emegent AESI (as reported on eCRF) 
 
Number of patients with at least one serious treatment emergent AESI (as reported on 
eCRF) 
 
An overview table will be produced for the Post Maintenance Treatment AEs, i.e. AEs occurring 
more than 30 days (for patients in control group, i.e. not treated with atezolizumab) and more 
than 90 days (for patients in experimental group, i.e. treated with atezolizumab) after the last 
day of treatment during the Maintenance Phase (as defined in section 4.2.2), based on patients 
from the MTP population who has a study treatment discontinuation visit date. This table will 
present the following information: 
 
Number of AEs 
 
Number of patients with at least one AE 
 
Number of patients with at least one AE by CTC grade: 1, 2, 3, 4, 5, ≥3,  missing 
 
Number of patients with at least one related AE  
 
Number of patients with at least one serious AE 
 
Number of patients with at least one related serious AE  
 
Number of patients with at least one AE with fatal outcome 
 
In addition, the following tables (number and percentage of patients) will be presented for the 
ITP based on the ITP population and will display the number of patients (and corresponding 
number of TEAEs) and percentage with any: 
 
TEAEs by SOC and PT and by Worst Intensity 
 
Grade 3-5 TEAEs by SOC and PT 
 
Related TEAEs by SOC and PT: to any study drugs, FOLFOX, 5 FU/LV, bevacizumab 
 
Serious TEAEs by SOC and PT  
 
Related serious TEAEs by SOC and PT: to any study drugs, FOLFOX, 5 FU/LV, 
bevacizumab 
 
TEAEs leading to treatment discontinuation by SOC and PT: FOLFOX, 5 FU/LV, 
bevacizumab 


 
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 
TEAEs leading to dose reduction or interruption by SOC: any study drugs, FOLFOX, 5 
FU/LV, bevacizumab  
 
Grade 5 TEAEs or TEAEs with fatal outcome by SOC and PT 
 
The following tables will be presented for the MTP only and will display the number and 
percentage of patients (and corresponding number of TEAEs) with any: 
 
TEAEs by SOC and PT and by Worst Intensity  
 
Grade 3-5 TEAEs by SOC and PT 
 
Related TEAEs by SOC and PT: any study drugs, capecitabine, 5-FU/LV, atezolizumab, 
bevacizumab, FOLFOX 
 
Serious TEAEs by SOC and PT  
 
Related Serious TEAEs by SOC and PT: any study drugs, capecitabine, 5-FU/LV, 
atezolizumab, bevacizumab, FOLFOX 
 
Grade 5 TEAEs or TEAEs with fatal outcome by SOC and PT  
 
TEAEs leading to treatment discontinuation by SOC and PT: any study drugs, 
capecitabine, 5-FU/LV, atezolizumab, bevacizumab 
 
TEAEs leading to dose reduction or interruption by SOC and PT: any study drugs, 
capecitabine, 5-FU/LV, atezolizumab, bevacizumab  
 
Treatment emergent AESI by AESI categories, SOC and PT and by Worst Intensity   
 
Serious Treatment emergent AESI by AESI categories, SOC and PT and by Worst 
Intensity 
 
Treatment emergent AESI by AESI categories, SOC and PT   
 
Serious Treatment emergent by AESI categories, SOC and PT  
 
By-patients listings will be provided for AEs; they will include Post-treatment adverse events. 
Appropriate flagging of study phase (ITP/MTP) as well as TEAEs/Post-treatment AEs will be 
done. The following listings will be provided based on ITP population 
 
All adverse events  
 
All Grade 5 adverse events or any adverse events with fatal outcome  
 
All adverse events leading to treatment discontinuation  
 
All AESI (as reported on eCRF)   
 
4.13.3 
Death 
The following summary tables will be provided and will present: 
 
The number of patients who died within 30 days from last day of treatment of the 
ITP (as defined in section 4.2.1) and the corresponding reason of death based on 
ITP population 
 
The number of patients who died more than 30 days from last day of treatment of 
ITP (as defined in section 4.2.1) and the corresponding reason of death based on 
ITP population who has a study treatment discontinuation visit date 
 
The number of patients who died within 30 days from last day of treatment of MTP 
for treated patients or within 30 days from randomization with the corresponding 
cause of death based on MTP population 


 
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 
The number of patients who died within 30 days from last day of treatment of MTP 
(as defined in section 4.2.1) with the corresponding death reason using the SAF 
population 
 
The number of patients who died more than 30 days from last day of treatment of 
maintenance treatment and the corresponding reason of death based on patients 
from the MTP population who has a study treatment discontinuation visit date 
One listing will be generated for deaths based on the ITP population and including appropriate 
flagging of study phase (ITP and MTP) and on-treatment/post-treatment deaths (i.e. within 30 
days from last day of treatment/more than 30 days from last day of treatment).  
All deaths information (including reason and date) will be retrieved from the Study 
Completion/Early Discontinuation eCRF page.  
 
4.13.4 
Laboratory Data 
The following laboratory parameters will be considered as CTC gradable parameters. 
 
Haematology 
 
Absolute Neutrophils Count (ANC)  
 
Hemoglobin (Hb) 
 
Leukocytes/White Blood Cells counts (WBC) 
 
Platelet Count 
 
Blood chemistry 
 
Albumin  
 
Alkaline Phosphatase (ALP)  
 
Calcium 
 
Creatinine  
 
Glucose 
 
Potassium  
 
SGPT or alanine aminotransferase (ALT)  
 
SGOT or aspartate aminotransferase  (AST)  
 
Sodium 
 
Total Bilirubin  
 
Coagulation  
 
international normalized ratio (INR)  
 
activated partial thromboplastin time (aPTT) 
 
The following parameters will be considered as non CTC gradable parameters. 
 
Hematology  
 
Red blood Cell (RBC) 
 
Hematocrit 
 
Lymphocytes 
 
Neutrophils 
 
Eosinophils 


 
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 
Basophils 
 
Monocytes 
 
Blood Chemistry 
 
Blood Urea Nitrogen 
 
Bicarbonate 
 
Chloride Lactate dehydrogenase (LDH) 
 
Phosphorus 
 
Total Protein 
 
Urinalysis 
 
Urine Protein Dipstick 
 
24 hour urine protein 
 
Thyroid 
 
Thyroid-Stimulating Hormone (TSH) 
 
Free T3 
 
Free T4 
 
All laboratory parameter information will be summarized for each phase separately. Laboratory 
information reported in tables will be restricted to the baseline and on-treatment measurements. 
The analysis population will be the ITP and the SAF population for the ITP and MTP, 
respectively.  
Clinical laboratory values will be expressed using Système International (SI) units.  
When applicable, laboratory tables will display their High (hyper)/Low (hypo) values of a 
specific parameter (e.g. calcium (high) and calcium (low) in separate tables. 
In case of missing normal ranges for parameters that are not differential and have only grade 1 
defined from normal ranges (e.g. Neutrophils, WBC, Albumin…) the worst case scenario will be 
applied, i.e. grade 1. 
A “Missing” category will be reported for patients with missing grades or missing reference 
range indicators at baseline and/or on-treatment and patients with no laboratory assessments.  
For hematology, blood chemistry and coagulation parameters which can be graded per CTCAE, 
the information will be summarized by means of a shift table summarizing the baseline grade 
versus the worst CTC grade per patient defined as the highest CTC grade among the on-
treatment evaluations. If there is no on-treatment evaluation then the worst grade will be set to 
‘Missing’. 
Hematology and blood chemistry parameters which cannot be graded per CTCAE, the 
information will be summarized by means of a shift table from baseline category to worst on-
treatment category. The following categories will be used: 
 
Baseline: Low/Normal/High/Missing/Overall 
 
Worst on-treatment: Low/Normal/High/Missing/Overall 
Patient with “High” and “Low” for the same laboratory test (at different visits) is counted for 
each direction in summary tables. 
 


 
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For urinalysis protein dipstick, all non-missing assessments excepted “0-absent” assessment 
will be considered “Present”. A shift table presenting baseline category versus worst on-
treatment category will be produced with the following categories: 
 
Baseline: Absent/Present/Missing/Overall 
 
Worst on-treatment: Absent/Present/Missing/Overall 
For urinalysis, 24 hour urine protein values will not be tabulated but listed only. 
 
All laboratory values will be listed along with CTC grade/category.  Separate listings will be 
generated to include all abnormal laboratory values.  
 
4.13.5 
Vital Signs 
Vital signs parameters include: 
 
Temperature (°C) 
 
Systolic blood pressure (SBP seated position) (mmHg) 
 
Diastolic blood pressure (DBP seated position) (mmHg) 
 
Weight (kg) 
 
BSA (m2) 
 
Heart rate (beats/min) 
 
Respiratory rate (breaths/min) 
 
Vital signs information will be summarized for each phase separately and by treatment group 
when applicable. Vital signs information reported in tables will be restricted to non-missing 
baseline and non-missing on-treatment measurements. The analysis population will be the ITP 
population for the ITP and the SAF population for the MTP.  
Actual value and change from baseline for heart rate and systolic and diastolic blood pressure 
will be summarized by treatment group for each visit using descriptive statistics.  
For the experimental arm, vital signs are collected within 60 minutes before the infusion and at 
other timepoints when clinically indicated and at the first infusion. Only the timepoint ‘Within 60 
minutes before the infusion’ will be included in the summary table.  
All vital signs data including change from baseline (and data reported at timepoints not included 
in the summary table) will be listed. 
 
4.13.6 
Other Safety Assessment - Applicable only for the experimental 
group 
Blood oxygen saturation is measured only in patients randomized to the experimental treatment 
group. Blood oxygen saturation will be measured by pulse oximetry. 
Non-missing pulse oximetry values will be summarized by visit through descriptive statistics. 
Blood oxygen saturation will be listed with the vital signs parameters. 
 


 
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4.13.7 
Other Safety Assessment  
Pregnancy test data will be listed on the ITP population, ITP and MTP data will be flagged. 
 
 
 


 
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4.14 
MISSING DATA 
Imputation of partial/missing death date will be done as follows:  
 
If the date is completely missing, then the day of “Last known to be alive” +1 will be 
used  
 
If only day is missing and year and month are same as “Last known to be alive”, then 
the day of “Last known to be alive”+1 will be used otherwise the 1st day of the month will 
be used 
 
If day and month are missing and year is same as “Last known to be alive”, then the 
“Last known to be alive”+1 will be used, otherwise 1st of January will be used 
 
Partially missing dates for adverse events (AEs) will be imputed as follows. Of note, imputation 
of missing/partial AE date will be done only to identify treatment emergent AEs. 
AE onset dates 
 Partially missing onset dates will be imputed as follows 
 
When only Day is missing :  
o If Month & Year of the onset date are the same as Month & Year of the 
first day of treatment of the induction/maintenance treatment phase, the 
imputed onset date will be imputed as the minimum of the first day of 
treatment of the induction/maintenance treatment phase and the AE 
resolution date (imputed if needed). 
o Otherwise, the missing day will be replaced by “1”. 
 
When Day & Month are missing:  
o If 
Year 
of 
the 
onset 
date 
is 
the 
same 
as 
Year 
of 
the 
induction/maintenance treatment phase, the imputed onset date will be 
imputed as the minimum of the first day of treatment of the 
induction/maintenance treatment phase and the AE resolution date 
(imputed if needed). 
o Otherwise, the missing Day & Month will be replaced by “01JAN”. 
 
 Complete missing onset dates for AEs will be imputed by first day of treatment of 
the induction/maintenance treatment phase and the AE will be considered as 
treatment emergent, unless the end date of the AE (imputed if needed) or the end 
year of the AE (if day and month are missing) is entered and is before the year of 
the first treatment administration of the induction/maintenance treatment phase. 
 
AE resolution dates 
 Incomplete resolution dates will be replaced by the last day of the month (if day is 
missing only), if not resulting in a date later than the date of patient's death. In the 
latter case the date of death will be used to impute the incomplete resolution date 
 In all other cases the incomplete resolution date will not be imputed 
Of note, the above rules may allow allocation of an event to both the ITP and MTP treatment 
phase. 
 
 
 


 
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Partially missing dates for medications/therapies will be imputed as follows. Of note, imputation 
of missing/partial medicationstherapies date will be done only to identify concomitant 
medications/therapies. 
Partial dates will be imputed as follow: 
 
Start dates 
o When only Day is missing : the missing day will be replaced by “1” 
o When Day & Month are missing: the missing Day & Month will be replaced by 
“01JAN”. 
 
End dates 
o When only Day is missing : the missing day will be replaced by the last day of 
the month 
o When Day & Month are missing: the missing Day & Month will be replaced by 
“31DEC”. 
And rules described in section 4.10.3.2 and below will be applied using imputed dates. 
 
In case of complete missing dates, the following will be applied: 
 
If the start date of the medication/therapy is unknown (i.e. complete missing date) and 
there is no end date, medication/therapy is flagged as  taken prior to study but not as 
ongoing then the medication/therapy  will be considered as a prior medication .  
 
If both the start date and end date of the medication/therapy is unknown (i.e. complete 
missing date), then the medication/therapy will be considered as a concomitant 
medication/therapy for both the induction and maintenance phase if the patient is 
treated in the phase of interest. 
 
If the start date of the medicationtherapy is unknown (i.e. complete missing date), but 
the end date is known and is prior to the first dosing date of the considered phase, then 
the medicationtherapy  will not be considered as concomitant for the corresponding 
phase. 
 
If the start date of the medication/therapy is available and the end date is unknown, 
then the medication/therapy will not be considered as prior. Concomitance to ITP/MTP 
will be assessed using the available start date.  
Partially missing dates for surgery will be imputed as follows. Of note, imputation of 
missing/partial surgeries date will be done only to identify concomitant surgeries. 
Partial dates will be compared as follow: 
 
When only Day is missing : Month & Year of the surgery will be compared to Month & 
Year of the first dosing date of interest (either ITP or MTP). If on or after, the surgery will 
be considered as concomitant to the period of interest. If on or before the first doing 
date of ITP, the surgery will be considered as prior. 
 
When Day & Month are missing: Year of the surgery will be compared to Year of the 
dosing date of interest (either ITP or MTP). If on or after, the surgery will be considered 
as concomitant to the period  of interest. If on or before the first doing date of ITP, the 
surgery will be considered as prior. 
Of note, the above rules may allow a medication/procedure to be concomitant to both the ITP 
and MTP treatment phase. 
 


 
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For patients who discontinued study treatment but without any study treatment discontinuation 
visit date, this visit will be imputed as follows: 
 
If patient was treated in the MTP, the last dose will be retrieved from the treatment drug 
completion/early discontinuation page from the eCRF in the maintenance phase. The 
maximum date among the date mentioned for each treatment during MTP + 30 days  
will be considered.  
 
If patient was treated in the ITP, the last dose will be retrieved from the treatment drug 
completion/early discontinuation page from the eCRF in the induction phase. The 
maximum date among the date mentioned for each treatment during ITP + 30 days will 
be considered  
with the following exception: 
o If a patient died within 30 days from last dose, the follow up phase does not exist 
for this patient 
Partially missing dates for date of initial histological diagnosis or date of first diagnosis of 
metastatic disease or date of first diagnosis of locally recurrent disease will be imputed as 
follows: 
Imputation of these partial dates will be done only to determine if the initial diagnosis is 
synchronous or metachronous and only in case the date day is missing. The imputation will 
consist in replacing the missing day by “1”. In case month and/or year are missing, no 
imputation will be done. 
 
No other dates will be imputed, unless otherwise specified. The original incomplete, missing or 
partial dates will be presented in the listings, not the imputed dates 
 
4.15 
INTERIM ANALYSES 
A preliminary evaluation of tumor response will be made by the iDMC once a total of 27 
patients in the experimental treatment arm of the cohort have completed a tumour assessment 
at Month 2 of the Maintenance Treatment Phase to assure these data continue to support an 
early positive benefit-risk ratio and to confirm that continued enrolment into the cohort is 
appropriate. 
No other formal interim analyses on PFS or OS are planned. 


 
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5. 
REFERENCES 
Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response to 
panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008 Dec 
10;26(35):5705-12. doi: 10.1200/JCO.2008.18.0786. Epub 2008 Nov 10. 
 
Ron Brookmeyer and John Crowley, A Confidence Interval for the Median Survival Time. 
Biometrics  Vol. 38, No. 1 (Mar., 1982), 29-41 
 


 
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Appendix 1: Protocol Synopsis 


 
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Appendix 2: Schedule of Assessments for All Patients (Screening / Baseline and Induction 
Treatment Phase) 
 
 
 
 
Patients who have PD during or at end of 
Induction Treatment Phase or who refuse 
Maintenance Treatment or who are not eligible 
for any study cohort 
 
Screening / 
Baseline 
Induction Treatment Phase [a] 
Study Treatment 
Discontinuation 
Visit [b] 
Post-Treatment Follow-
Up Phase [c] 
 
≤ 28 days 
≤ 7 days 
Day 1  
Cycle 1 
Every 2 cycles 
(every 4 weeks) 
(≤ 30 days after last 
dose of study 
treatment) 
Every 3 months 
Informed consent [d] 
x 
 
 
 
 
 
Confirmation of general 
eligibility [e] 
x 
x 
 
As required 
 
 
Demographics and medical 
history [f] 
x 
 
 
 
 
 
Vital signs and weight [g] 
x 
x 
x 
x 
x 
 
Physical examination[h] 
x 
 
x 
x 
x 
 
ECOG performance status [i] 
 
x 
x 
x 
x 
 
Concomitant medications [j] 
x 
x 
x 
x 
x 
 
Haematology and blood 
chemistry [k] 
 
x 
 
x 
x 
 


 
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Patients who have PD during or at end of 
Induction Treatment Phase or who refuse 
Maintenance Treatment or who are not eligible 
for any study cohort 
 
Screening / 
Baseline 
Induction Treatment Phase [a] 
Study Treatment 
Discontinuation 
Visit [b] 
Post-Treatment Follow-
Up Phase [c] 
 
≤ 28 days 
≤ 7 days 
Day 1  
Cycle 1 
Every 2 cycles 
(every 4 weeks) 
(≤ 30 days after last 
dose of study 
treatment) 
Every 3 months 
INR, aPTT (select patients) [l] 
 
x 
 
x 
 
 
Urinalysis (dipstick) [m] 
 
x 
 
x 
x 
 
Pregnancy test [n] 
 
x 
 
If clinically indicated 
 
 
Tumour assessments [o] 
x 
 
 
Mandatory at Week 
16 (end of Induction 
Treatment Phase) 
 
According to local standard of 
care (in applicable patients 
only)` 
Archival primary tumour 
tissue for biomarker 
assessment [p] 
x 
 
 
 
 
 
Metastatic tumour tissue for 
exploratory biomarker 
assessment  [q] 
x 
(optional 
for all 
patients) 
 
 
At PD (Supplemental 
Biomarker Program 
only) 
 
 
 
Whole blood sample [r]   
 
 
x 
 
 
 


 
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Patients who have PD during or at end of 
Induction Treatment Phase or who refuse 
Maintenance Treatment or who are not eligible 
for any study cohort 
 
Screening / 
Baseline 
Induction Treatment Phase [a] 
Study Treatment 
Discontinuation 
Visit [b] 
Post-Treatment Follow-
Up Phase [c] 
 
≤ 28 days 
≤ 7 days 
Day 1  
Cycle 1 
Every 2 cycles 
(every 4 weeks) 
(≤ 30 days after last 
dose of study 
treatment) 
Every 3 months 
Plasma samples [r] 
 
 
x 
Cycles 4, 6 and 8 
 
At time of progression (if 
patient has not yet 
progressed) 
Adverse events (including 
SAEs) [s] 
x 
x 
x 
Every cycle 
x 
x (as applicable) 
Study medication 
administration [t] 
 
 
x  
Administered every 2 weeks 
 
 
Subsequent anti-cancer 
therapies (see [c]) 
 
 
 
 
 
x 
Patient survival (see [c]) 
 
 
 
 
x 
x 
a. With the exception of Cycle 1, all other study visits and assessments during the Treatment Phase should be performed within ± 7 days of the 
scheduled date.  
b. Patients who experience PD during or at the end of the Induction Treatment Phase, or who refuse to go into the Maintenance Treatment Phase 
or who are not eligible for any study cohort, will undergo a Study Treatment Discontinuation Visit 30 days after the last dose of study 
medication.  These patients will then enter the Post-Treatment Follow-up Phase. All patients need to be evaluated for potential resection of 
metastasis at completion of the induction period. This is of particular importance for patients with liver metastases. If the patient is found to be 


 
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resectable they will undergo a Study Treatment Discontinuation Visit within 30 days after the last dose of study treatment and will then enter the 
Post-treatment Follow-up Phase. 
c. Patients in the Post-Treatment Follow-up Phase will be followed up every 3 months during which time subsequent anti-cancer therapies will be 
recorded and survival assessed until the end of the study. Treatment during the Post-Treatment Follow-up Phase is at the Investigator’s 
discretion; BRAFmut patients experiencing early disease progression during the Induction Treatment Phase will have the option of proceeding 
immediately to receive second-line treatment with 5-FU/LV, cetuximab and vemurafenib.  Patients who discontinue study treatment prior to 
disease progression will also continue to be followed for PFS, with disease status followed according to local practice until progression or the 
end of the study, whichever comes first. 
d. 
Written informed consent for participation in the study must be obtained before performing any study-specific screening tests or evaluations.  
However, results from routine assessments conducted prior to informed consent signature may be used as screening assessments as long as 
they were done within 7 days prior to informed consent signature. 
e. The “All Cohort” eligibility criteria are evaluated prior to initiating the first cycle of study treatment during the Induction Treatment Phase.  
f. 
Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, smoking history, use of alcohol and drugs of abuse, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 7 days prior to the Screening visit.  Demographic data will include 
age, sex, and self-reported race/ethnicity (where permitted by federal regulations). 
g. Vital signs include measurements of systolic and diastolic blood pressure while the patient is in a seated position, and temperature.  During 
Screening, weight only required ≤ 7 days. 
h. Baseline assessment requires a complete physical exam. A complete physical examination should include an evaluation of the head, eyes, 
ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological 
systems. Abnormalities identified at Screening / Baseline will be recorded as baseline conditions.  At subsequent visits (or as clinically 
indicated), limited, symptom-directed physical examinations should be performed. Changes from Baseline, with new or worsened clinically 
significant abnormalities, should be reported as AEs if appropriate.  
i. 
ECOG status assessed within 7 days prior to Day 1 of Cycle 1 (Induction Treatment Phase) for eligibility determination.  See Appendix 5. 
j. 
Concomitant medication includes any prescription medications or over-the-counter preparations used by a patient between the 7 days prior to 
the date of informed consent up until the date of study discontinuation.  Only concomitant medications used for supportive care, to alleviate 
symptoms of mCRC, or to treat adverse drug reactions should be recorded on the Concomitant Medications eCRF. At subsequent visits, only 
changes to current medications or medications used since the last documentation of medications will be recorded.  Concomitant medications 
for treatment of AEs related to study medication will continue to be recorded while the AE is being followed. For permitted and prohibited 
concomitant medications, see Section 4.4. 


 
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k. Haematology includes haemoglobin, haematocrit, platelet count, red blood cell count, white blood cell count, and differential. Blood chemistry 
includes ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin, blood urea nitrogen or urea, LDH, creatinine, glucose, calcium, 
phosphorus, sodium, potassium, chloride, and bicarbonate. Hematology and blood chemistry tests must be conducted prior to each treatment 
cycle, with the results available for review prior to start of treatment according to local standards for treatment management. However, only 
tests conducted every second treatment cycle will be recorded in the eCRF. Clinical laboratory results constituting a clinical significant AE 
should be recorded as such.  
l. 
INR and aPTT only for patients receiving anticoagulants while on protocol-specified treatment. 
m. Urinalysis must be performed by dipstick at Baseline and within 48 hours prior to every cycle.  A 24-hour urine collection is needed in the event 
of proteinuria ≥ ± 2 by dipstick test. 
n. Urine or blood pregnancy test, only for women of childbearing potential, including those who have had a tubal ligation.  A serum pregnancy test 
is required within 7 days prior to start of study induction treatment, or within 14 days with a confirmatory urine pregnancy test within 7 days prior 
start of study induction treatment 
o. Will include radiology, chest and abdominal CT or MRI, and other scans to document all sites of disease. Include upper abdomen at Baseline.  
Subsequent tumour assessments will be done according to standard of care at each study centre, with the exception that all patients must have 
a tumour assessment at the end of the Induction Treatment Phase. Tumour assessments are not required for study purposes after disease 
progression has been documented. Patients who discontinue study treatment during the Induction Treatment Phase prior to disease 
progression will also continue to be followed for progressive disease, with disease status followed according to local practice until progression 
or the end of the study, whichever comes first.    
p. Archival tumour tissue (FFPET) block from the primary tumour obtained at the time of the initial diagnosis. Prior to performing any screening 
procedures, the Investigator must ensure that adequate archival tissue from a potential participant’s primary tumour is available for shipping to 
the Sponsor’s designated laboratory during the Screening Phase.  If the tumour block is not available, ≥ 20 slides cut within 2 weeks of shipping 
to the Sponsor’s designated laboratory will be accepted as an alternative.   The sample must be shipped to the designated laboratory with the 
corresponding pathology report during the patient’s Screening Phase.  See Appendix 12. 
q. The core biopsy of metastatic tumour at baseline is optional for all patients. It can be obtained either as part of routine care within 2 months 
before ICF signature or as part of study procedures after ICF signature within the Screening Phase.  For patients in the Supplemental 
Biomarker Program (See Appendix 13), core biopsies of metastasis are also required at time of disease progression.  
r. 
Whole blood and plasma samples will be collected from all study patients for exploratory biomarker analyses unless genomic analysis is not 
allowed per local regulations. In such instances, only plasma samples will be collected.  All samples will be sent to a designated laboratory.  
Samples during treatment should be taken within 48 hours prior to study treatment Day 1 of each cycle indicated, unless otherwise specified 
(see Appendix 12 and Laboratory Manual). 


 
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s. After the signing of the informed consent form, and prior to Day 1 of Cycle 1 (Induction Treatment Phase), any SAEs thought to be related to a 
protocol-mandated intervention should be reported.  Adverse events will be documented at every cycle during treatment. All patients will be 
followed for new AEs for 28 days following the discontinuation of study treatment. At the time of treatment discontinuation, any ongoing AE/SAE 
will be followed until the event resolves, the Investigator assesses the event as stable, the patient is lost to follow-up, dies or withdraws 
consent. Death related to disease progression is not considered to be an SAE. The Sponsor should be notified if the Investigator becomes 
aware of any SAE or AEs of special interest occurring after the end of the adverse event reporting period, regardless of causality. 
t. 
Eligible patients will enter a 4-month Induction Treatment Phase.  Treatment during this phase, based on Investigator’s choice, will be either 
eight 2-week cycles of 5-FU, LV and oxaliplatin (FOLFOX) in combination with bevacizumab or six 2-week cycles of FOLFOX in combination 
with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab. 


 
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Appendix 3: Schedule of Assessments During Maintenance Phase (Cohort 2) 
 
Prior to 
randomization 
Maintenance Treatment Phase 
[a] 
Study Treatment 
Discontinuation Visit 
[b] 
Post-Treatment Follow-
Up Phase [c] 
 
Within 3 weeks of 
completing Induction 
Treatment Phase 
Every 2 cycles (every 4 weeks) 
(≤ 30 days after last 
dose of study 
treatment) 
Every 3 months 
Assignment of cohort [d] 
x 
 
 
 
Confirmation of cohort-
specific eligibility [e] 
x 
 
 
 
Randomisation [f] 
x 
 
 
 
Vital signs and weight [g] 
 
x 
x 
 
Physical examination [h] 
 
x 
x 
 
ECOG performance status [i] 
 
x 
x 
 
Concomitant medications [j] 
 
x 
x 
 
Haematology and blood 
chemistry [k] 
 
x 
x 
 
INR, aPTT (select patients) [l] 
 
According to local standard of care 
 
 
Urinalysis (dipstick) [m] 
 
x 
x 
 
Pregnancy test [n] 
 
As applicable 
 
 
TSH, free T3, free T4 
(Experimental Arm only) 
 
Prior to Cycle 1 then every 3 cycles 
X 
 


 
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Prior to 
randomization 
Maintenance Treatment Phase 
[a] 
Study Treatment 
Discontinuation Visit 
[b] 
Post-Treatment Follow-
Up Phase [c] 
 
Within 3 weeks of 
completing Induction 
Treatment Phase 
Every 2 cycles (every 4 weeks) 
(≤ 30 days after last 
dose of study 
treatment) 
Every 3 months 
Pulse oximetry 
(Experimental Arm only) 
 
Prior to Cycle 1 then every 2 cycles 
X 
 
Tuberculosis test [o] 
x 
 
 
 
HIV, HBV, HCV serology [p]  
X 
 
 
 
Tumour assessments [q] 
 
According to local standard of care. 
Mandatory at Month 2 for First 27 
patients in experimental arm of each 
cohort 
 
According to local standard 
of care (in applicable patients 
only)` 
Metastatic tumour tissue for 
exploratory biomarker 
assessment  [r] 
Supplemental 
Biomarker Program 
only: After completion 
of Induction, but prior 
to start of Maintenance 
Supplemental Biomarker Program only: 
At time of PD 
 
 
Plasma samples [s] 
 
Cycles 1 and 2 
then every 2 cycles thereafter 
And at time of PD 
 
At time of progression (if 
patient has not yet 
progressed) 
Adverse events (including 
SAEs) [t] 
 
Every cycle 
x 
x (as applicable) 


 
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Prior to 
randomization 
Maintenance Treatment Phase 
[a] 
Study Treatment 
Discontinuation Visit 
[b] 
Post-Treatment Follow-
Up Phase [c] 
 
Within 3 weeks of 
completing Induction 
Treatment Phase 
Every 2 cycles (every 4 weeks) 
(≤ 30 days after last 
dose of study 
treatment) 
Every 3 months 
Study medication 
administration [u] 
 
x  
 
 
Subsequent anti-cancer 
therapies (see [c]) 
 
 
 
x 
Patient survival (see [c]) 
 
 
x 
x 
a. With the exception of Cycle 1, all other study visits and assessments during the Treatment Phase should be performed within ± 7 days of the 
scheduled date.  
b. Patients who experience PD at any time during the Maintenance Treatment Phase, or who need to permanently discontinue study medication 
for any reason, will undergo a Study Treatment Discontinuation Visit 30 days after the last dose of study medication.  These patients will then 
enter the Post-Treatment Follow-up. 
c. 
After discontinuation of study treatment, patients will enter the Post-Treatment Follow-up Phase and will be followed up every 3 months during 
which time subsequent anti-cancer therapies will be recorded and survival assessed until the end of the study. Treatment during the Post-
Treatment Follow-up Phase is at the Investigator’s discretion, however, patients treated with atezolizumab should not receive other 
immunomodulatory agents for 10 weeks after study treatment discontinuation.  Patients who discontinue study treatment prior to disease 
progression will also continue to be followed for PFS, with disease status followed according to local practice until progression or the end of the 
study, whichever comes first. 
d. Patients completing the Induction Treatment Phase, and who have not experienced PD can then proceed to the Maintenance Treatment Phase.   
Depending on the patient’s biomarker status (based on the archival sample from initial diagnosis), these patients will be assigned to Cohort 1 – 
BRAFmut or Cohort 2 – No Biomarker.  Patients with an unknown biomarker status due to lack of determinant result (e.g. due to technical issues) 
can still be included in the study and will be assigned to Cohort 2 – No Biomarker. 
e. The cohort-specific exclusion criteria must be assessed prior to randomization to study maintenance treatment but assessment of cohort-
specific eligibility can only be completed after the biomarker analysis results from the patient’s archival tumour tissue from initial diagnosis are 


 
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known. Patients found ineligible for any cohort will undergo a Study Treatment Discontinuation Visit and enter the Post-Treatment Follow-up 
Phase. 
f. 
Each cohort will consist of an experimental treatment arm and a control arm.  Randomised on a 2:1 (experimental:control) basis to either the 
experimental treatment arm or the control arm of that cohort.  See Section 4.2. 
g. Vital signs include measurements of systolic and diastolic blood pressure while the patient is in a seated position, and temperature. For the first 
infusion, the patient’s vital signs (heart rate, respiratory rate, blood pressures, and temperature) should be determined within 60 minutes before 
the infusion, every 15 ± 5 minutes during the infusion, and 30 ± 10 minutes after the infusion. For subsequent infusions, vital signs will be 
collected within 60 minutes before the infusion and should be collected during or after the infusion if clinically indicated or if symptoms occurred 
in the prior infusion. 
h. Physical examinations will be symptom-directed, and will include changes from Baseline (pre-Induction) with new or worsened clinically 
significant abnormalities being reported as AEs if appropriate.  
i. 
See Appendix 5. 
j. 
Concomitant medication includes any prescription medications or over-the-counter preparations used by a patient between the 7 days prior to 
the date of informed consent up until the Study Treatment Discontinuation visit.  Only concomitant medications used for supportive care, to 
alleviate symptoms of mCRC, or to treat adverse drug reactions should be recorded on the Concomitant Medications eCRF. At subsequent 
visits, only changes to current medications or medications used since the last documentation of medications will be recorded. Concomitant 
medications for treatment of AEs related to study medication will continue to be recorded while the AE is being followed.   For permitted and 
prohibited concomitant medications, see Section 4.4. 
k. Haematology includes haemoglobin, haematocrit, platelet count, red blood cell count, white blood cell count, and differential. Blood chemistry 
includes ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin, blood urea nitrogen or urea, LDH, creatinine, glucose, calcium, 
phosphorus, sodium, potassium, chloride, and bicarbonate. Hematology and blood chemistry tests must be conducted prior to each treatment 
cycle, with the results available for review prior to start of treatment according to local standards for treatment management. However, only 
tests conducted every second treatment cycle will be recorded in the eCRF. Clinical laboratory results constituting a clinical significant AE 
should be recorded as such.  
l. 
INR and aPTT only for patients receiving anticoagulants while on protocol-specified treatment. 
m. Urinalysis must be performed by dipstick within 48 hours prior to every cycle.  A 24-hour urine collection is needed in the event of proteinuria ≥ 
± 2 by dipstick test. 
n. Urine or blood pregnancy test, only for women of childbearing potential, including those who have had a tubal ligation.  If urine pregnancy test is 
positive, it must be confirmed by a serum pregnancy test. 
o. Patients with a positive tuberculosis test are not eligible for Cohort 2 and will be excluded from entering the Maintenance Phase of the study. 


 
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p. HIV testing performed in accordance with national and/or institutional guidelines.  HBV serology includes HBsAg and anti-HBc.  HCV serology 
includes anti-HCV. 
q. Tumour assessments according to  RECIST1.1 for Cohort 2 – No Biomarker, and additionally according to mRECIST for the experimental arm 
of Cohort 2 – No Biomarker. Will include radiology, chest and abdominal CT or MRI, and other scans to document all sites of disease. Tumour 
assessments will be done according to standard of care at each study centre, with the exception that the first 27 patients in the experimental 
arm of each cohort must have a tumour assessment at Month 2 of the Maintenance Treatment Phase so that the initial response of each cohort 
can be evaluated. Tumour assessments are not required for study purposes after disease progression has been documented. Patients who 
discontinue study treatment during either the Induction or Maintenance Treatment Phases prior to disease progression will also continue to be 
followed for progressive disease, with disease status followed according to local practice until progression or the end of the study, whichever 
comes first.    
r. 
For patients in the Supplemental Biomarker Program, core biopsies of metastasis are required upon completion of induction treatment prior to 
initiation of maintenance treatment, and at time of disease progression (see Appendix 13).   
s. Plasma samples will be collected from all patients for exploratory biomarker analyses. These samples will be sent to a designated laboratory.  
Samples during treatment should be taken within 48 hours prior to study treatment Day 1 of each cycle indicated, unless otherwise specified 
(see Appendix 12 and the Laboratory Manual). 
t. 
Adverse events will be documented at every cycle during treatment. All patients will be followed for new AEs for 28 days following the 
discontinuation of study treatment. At the time of treatment discontinuation, any ongoing AE/SAE will be followed until the event resolves, the 
Investigator assesses the event as stable, the patient is lost to follow-up, dies or withdraws consent. Death related to disease progression is not 
considered to be an SAE.  The Sponsor should be notified if the Investigator becomes aware of any SAE or AEs of special interest occurring 
after the end of the adverse event reporting period, regardless of causality. 
u. Patients in the Experimental Arm will receive 5-FU or capecitabine 1,600 – 2,400 mg/m2 5-FU administered via 46-hour IV infusion and LV 400 
mg/m2 administered via a 2-hour infusion given day 1 every 2 weeks; or 1000 mg/m2 b.i.d. capecitabine given days 1-14 every 2 weeks 
followed by a one-week treatment break. Atezolizumab at a fixed dose of 800 mg administered via 60-minute IV infusion on Day 1 of every 2-
week cycle (if initial infusion is well tolerated, subsequent infusions will be done over a 30-minute time period) and bevacizumab 5 mg/kg via 
15-30 minute IV infusion on Day 1 of every 2-week cycle.  Patients in the Control arm will receive: 5-FU or capecitabine, dose and schedule will 
be according to local label, where applicable, or otherwise will be determined per the Investigator’s discretion, with bevacizumab 5 mg/kg via 
15-30 minute IV infusion on Day 1 of every 2-week cycle. 


 
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Appendix 4: SAS code 
 
The following SAS code will be used to obtain the log-rank p-value from the unstratified 
log-rank test mentioned in section 4.11.1:  
PROC LIFETEST data=dataset METHOD=KM CONFTYPE=LOGLOG;  
TIME pfstime*censor(1);  
STRATA treat / test=logrank; 
RUN;  
* pfstime represents variable containing event/censor times;  
* censor represents censoring variable (1=censored, 0=event);  
* treat represents treatment group variable;  
Further options to control the output may be added. 
 
 
The following SAS code will be used for the logistic regression mentioned in section 
4.11.2.2:  
PROC LOGISTIC DATA= dataset;  
CLASS treat (ref=’FP+Bev’)strate1 strate2 strate3 strate4/ param=ref;  
MODEL response (event=’1’) = treat strate1 strate2 / alpha=0.05;  
RUN;  
* response represents the response variable;  
* treat represents the treatment group; 
* strate1, strate2, strate3, strate4 represents the categorical covariates 
related to stratification factors as per clinical data based for region and 
as per eCRF data for tumor response;  
Further options to control the output may be added. 
 
The following SAS code will be used to obtain the hazard ratio and corresponding 
confidence interval from the Cox Model with treatment as single covariate mentioned in 
section 4.11.40:  
PROC PHREG data=dataset;  
CLASS treat; 
MODEL pfstime*censor(1)=treat /RL TIES=EXACT;  
RUN;  
* pfstime represents variable containing event/censor times;  
* censor represents censoring variable (1=censored, 0=event);  
* treat represents treatment group variable;  
Further options to control the output may be added.  
 
 
The following SAS code will be used to obtain the hazard ratio and corresponding 
confidence interval from the adjusted Cox Model mentioned in section 4.11.4:  
PROC PHREG data=dataset;  
CLASS treat strate1 strate2 strate3 strate4; 
MODEL pfstime*censor(1)=treat stratum1 stratum2 stratum3 stratum4 /RL 
TIES=EXACT;  
RUN;  
* pfstime represents variable containing event/censor times;  
* censor represents censoring variable (1=censored, 0=event);  
* treat represents treatment group variable;  
* strate1, strate2, strate3, strate4 represents the categorical covariates 
related to stratification factors;  
Further options to control the output may be added.  
 


 
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The following SAS code will be used for the logistic regression with treatment as single 
covariate mentioned in section 4.11.4:  
PROC LOGISTIC DATA= dataset;  
CLASS treat (ref=’FP+Bev’) / param=ref;  
MODEL response (event=’1’) = treat / alpha=0.05;  
RUN;  
* response represents the response variable;  
* treat represents the treatment group; 
Further options to control the output may be added. 
 
 


 
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Appendix 5 : List of Outputs 
1. LIST OF OUTPUTS: TABLES 
Table Number 
Table Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
 
Patient Disposition 
 
 
 
 
14.1.1.1 
Patient Disposition For Induction Treatment Phase 
ITP 
ALL 
X 
 
14.1.1.2 
Patient Disposition For Maintenance Treatment Phase 
MTP 
MTP 
X 
X 
14.1.2.1 
Major Protocol Deviations For Induction Treatment Phase 
ITP 
ITP 
X 
 
14.1.2.2 
Major Protocol Deviations For Maintenance Treatment Phase 
MTP 
MTP 
X 
X 
 
Demographics and Baseline Characteristics 
 
 
 
 
14.1.3.1 
Summary of Baseline and Demographic Characteristics  
ITP 
ITP 
X 
 
14.1.3.2 
Summary of Baseline and Demographic Characteristics  
MTP 
MTP 
X 
 
14.1.3.3 
Summary of Baseline Biomarker Status 
MTP 
MTP 
X 
 
14.1.4.1 
Tumor Response Status (RECIST 1.1) at end of induction (eCRF data)  
ITP 
ITP 
X 
 
14.1.5 
Randomization by Country and Study Center  
MTP 
MTP 
 
 
14.1.6 
Stratification Factors as per IxRS 
MTP 
MTP 
 
 
14.1.7.1 
Tumor Response Status (RECIST 1.1) at end of induction (eCRF data)  
MTP 
MTP 
X 
 
14.1.7.2 
Tumor response (RECIST 1.1) at end of induction as per IxRS versus eCRF data 
MTP 
MTP 
X 
 
14.1.8.1 
Summary of colorectal cancer history 
ITP 
ITP 
X 
 
14.1.8.2 
Summary of colorectal cancer history 
ITP 
MTP 
X 
 
14.1.9 
RECIST Tumor-Specific Characteristics at Baseline 
MTP 
MTP 
X 
 
14.1.10.1 
Medical History  
ITP 
ITP 
X 
 
14.1.10.2 
Medical History  
ITP 
MTP 
X 
 
14.1.11.1 
Summary of Prior Anti-Cancer Treatments/Procedures   
ITP 
ITP 
X 
 
14.1.11.2 
Summary of Prior Anti-Cancer Treatments/Procedures   
ITP 
MTP 
X 
 
14.1.12 
Prior Medications  
ITP 
ITP 
X 
 
14.1.13.1 
Concomitant Medications during the induction phase 
ITP 
ITP 
X 
 
14.1.13.2 
Concomitant Medications during the Maintenance phase 
MTP 
SAF 
X 
X 


 
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Table Number 
Table Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
14.1.14.1 
Concomitant Radiotherapy during the Induction phase 
ITP 
ITP 
X 
 
14.1.14.2 
Concomitant Radiotherapy during the Maintenance phase 
MTP 
SAF 
X 
X 
14.1.15.1 
Concomitant colorectal cancer surgery during the Induction phase 
ITP 
ITP 
X 
 
14.1.15.2 
Concomitant colorectal cancer surgery during the Maintenance phase 
MTP 
SAF 
X 
X 
 
Exposure 
 
 
 
 
14.1.16.1 
Summary of Total Number of Cycles Initiated during ITP 
ITP 
ITP 
X 
 
14.1.16.2 
Summary of drug exposure during ITP 
ITP 
ITP 
X 
 
14.1.17.1 
Summary of overall Duration of Treatment and Number of cycles Initiated during MTP 
MTP 
SAF 
X 
X 
14.1.17.2 
Summary of drug exposure during MTP 
MTP 
SAF 
X 
X 
14.1.17.3 
Summary of Cycles delayed during MTP 
MTP 
SAF 
X 
X 
14.1.17.4 
Summary of cycles delayed (at the cycle level) during MTP 
MTP 
SAF 
X 
X 
 
Efficacy 
 
 
 
 
14.2.1.1 
Summary of Progression Free Survival – Primary Analysis (Surgery Censored) 
MTP 
MTP 
X 
X 
14.2.1.2 
Progression Free Survival: Hazard Ratio  
MTP 
MTP 
X 
X 
14.2.1.3.1 
Summary of Progression Free Survival by Region  
MTP 
MTP 
X 
X 
14.2.1.3.2 
Summary of Progression Free Survival by Tumor Response at end of ITP (based on eCRF 
data) 
MTP 
MTP 
X 
X 
14.2.1.3.3 
Summary of Progression Free Survival by Tumor Colon Location 
MTP 
MTP 
X 
X 
14.2.1.3.4 
Summary of Progression Free Survival by RAS Status 
MTP 
MTP 
X 
X 
14.2.1.3.5 
Summary of Progression Free Survival by Microsatellite Stability Status 
MTP 
MTP 
X 
X 
14.2.1.3.6 
Summary of Progression Free Survival by RAS Status for MSS patients 
MTP 
MTP 
X 
X 
14.2.1.3.7 
Summary of Progression Free Survival by Tumor Colon Location for RAS wt patients 
MTP 
MTP 
X 
X 
14.2.1.3.8 
Summary of Progression Free Survival by Tumor Colon Location for RAS mt patients 
MTP 
MTP 
X 
X 
14.2.1.3.9 
Summary of Progression Free Survival by Tumor Colon Location for MSS patients 
MTP 
MTP 
X 
X 
14.2.2.1 
Summary of Progression Free Survival - Sensitivity Analyses (Surgery not Censored) 
MTP 
MTP 
X 
X 
14.2.2.2 
Progression Free Survival: Hazard Ratio - Sensitivity Analyses (Surgery not Censored) 
MTP 
MTP 
X 
X 
14.2.3.1 
Summary of Progression Free Survival On-Treatment - Sensitivity Analyses 
MTP 
MTP 
X 
X 


 
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Table Number 
Table Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
14.2.3.2 
Progression Free Survival On-Treatment: Hazard Ratio - Sensitivity Analyses 
MTP 
MTP 
X 
X 
14.2.4.1 
Summary of PFS Considering the First 259 Events - Sensitivity Analyses 
MTP 
MTP 
X 
X 
14.2.4.2 
PFS: Hazard Ratio Considering the First 259 Events - Sensitivity Analyses 
MTP 
MTP 
X 
X 
14.2.5.1 
Summary of PFS Considering the First 405 Patients - Sensitivity Analyses 
MTP 
MTP 
X 
X 
14.2.5.2 
PFS: Hazard Ratio Considering the First 405 Patients - Sensitivity Analyses 
MTP 
MTP 
X 
X 
14.2.6 
Summary of Progression Free Survival according to mRECIST 
MTP 
MTP 
X 
X 
14.2.7.1 
Summary of Overall Survival 
MTP 
MTP 
X 
X 
14.2.7.2 
Overall  Survival: Hazard Ratio  
MTP 
MTP 
X 
X 
14.2.7.3.1 
Summary of Overall Survival by Region   
MTP 
MTP 
X 
X 
14.2.7.3.2 
Summary of Overall Survival by Tumor Response at end of ITP (based on eCRF data) 
MTP 
MTP 
X 
X 
14.2.7.3.3 
Summary of Overall Survival by Tumor Colon Location 
MTP 
MTP 
X 
X 
14.2.7.3.4 
Summary of Overall Survival by RAS Status 
MTP 
MTP 
X 
X 
14.2.7.3.5 
Summary of Overall Survival by Microsatellite Stability Status 
MTP 
MTP 
X 
X 
14.2.7.3.6 
Summary of Overall Survival by RAS Status for MSS patients 
MTP 
MTP 
X 
X 
14.2.7.3.7 
Summary of Overall Survival by Tumor Colon Location for RAS wt patients 
MTP 
MTP 
X 
X 
14.2.7.3.8 
Summary of Overall Survival by Tumor Colon Location for RAS mt patients 
MTP 
MTP 
X 
X 
14.2.7.3.9 
Summary of Overall Survival by Tumor Colon Location for MSS patients 
MTP 
MTP 
X 
X 
14.2.8.1 
Summary of Overall Response Rate (main definition) 
MTP 
MTP 
X 
X 
14.2.8.2.1 
Summary of Overall Response Rate (main definition) by Region 
MTP 
MTP 
X 
X 
14.2.8.2.2 
Summary of Overall Response Rate (main definition) by Tumor Response at end of ITP 
(based on eCRF data) 
MTP 
MTP 
X 
X 
14.2.8.2.3 
Summary of Overall Response Rate (main definition) by Tumor Colon Location 
MTP 
MTP 
X 
X 
14.2.8.2.4 
Summary of Overall Response Rate (main definition) by RAS Status 
MTP 
MTP 
X 
X 
14.2.8.2.5 
Summary of Overall Response Rate (main definition) by Microsatellite Stability Status 
MTP 
MTP 
X 
X 
14.2.8.2.6 
Summary of Overall Response Rate (main definition) by RAS Status for MSS patients 
MTP 
MTP 
X 
X 
14.2.8.2.7 
Summary of Overall Response Rate (main definition) by Tumor Colon Location for RAS wt 
patients 
MTP 
MTP 
X 
X 


 
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Table Number 
Table Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
14.2.8.2.8 
Summary of Overall Response Rate (main definition) by Tumor Colon Location for RAS mt 
patients 
MTP 
MTP 
X 
X 
14.2.8.2.9 
Summary of Overall Response Rate (main definition) by Tumor Colon Location for MSS 
patients 
MTP 
MTP 
X 
X 
14.2.8.2.10 
Summary of Overall Response Rate (main definition) by ECOG performance status (0 vs 
1/2) 
MTP 
MTP 
X 
X 
14.2.8.2.11 
Summary of Overall Response Rate (main definition) by Initial AJCC/UICC stage (stage III, 
stage IV) 
MTP 
MTP 
X 
X 
14.2.8.2.12 
Summary of Overall Response Rate (main definition) by age category In years (<65, >=65) 
MTP 
MTP 
X 
X 
14.2.8.2.13 
Summary of Overall Response Rate (main definition) by liver as metastatic site (yes, no)  
MTP 
MTP 
X 
X 
14.2.8.2.14 
Summary of Overall Response Rate (main definition) by number of metastatic sites at 
screening (<2, >=2)  
MTP 
MTP 
X 
X 
14.2.8.2.15 
Summary of Overall Response Rate (main definition) by gender 
MTP 
MTP 
X 
X 
14.2.8.2.16 
Summary of Overall Response Rate (main definition) by cancer type (colon, rectal) 
MTP 
MTP 
X 
X 
14.2.8.2.17 
Summary of Overall Response Rate (main definition) by initial diagnosis (synchronous vs 
metachronous) 
MTP 
MTP 
X 
X 
14.2.8.3 
Summary of Overall Response Rate (secondary definition) 
MTP 
MTP 
X 
X 
14.2.8.4.1 
Summary of Overall Response Rate (secondary definition) by Region 
MTP 
MTP 
X 
X 
14.2.8.4.2 
Summary of Overall Response Rate (secondary definition) by Tumor Response at end of 
ITP (based on eCRF data) 
MTP 
MTP 
X 
X 
14.2.8.4.3 
Summary of Overall Response Rate (secondary definition) within right or left colon 
MTP 
MTP 
X 
X 
14.2.8.4.4 
Summary of Overall Response Rate (secondary definition) by RAS mutation status 
MTP 
MTP 
X 
X 
14.2.8.4.5 
Summary of Overall Response Rate (secondary definition) by MSI-H or MSS status 
MTP 
MTP 
X 
X 
14.2.8.4.6 
Summary of Overall Response Rate (secondary definition) by RAS mutation status for MSS 
patients 
MTP 
MTP 
X 
X 
14.2.8.4.7 
Summary of Overall Response Rate (secondary definition) within right or left colon for RAS 
wt patients 
MTP 
MTP 
X 
X 
14.2.8.4.8 
Summary of Overall Response Rate (secondary definition) within right or left colon for RAS 
mt patients 
MTP 
MTP 
X 
X 
14.2.8.4.9 
Summary of Overall Response Rate (secondary definition) within right or left colon for MSS 
MTP 
MTP 
X 
X 


 
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Table Number 
Table Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
patients 
14.2.8.4.10 
Summary of Overall Response Rate (secondary definition) by ECOG performance status (0 
vs 1/2) 
MTP 
MTP 
X 
X 
14.2.8.4.11 
Summary of Overall Response Rate (secondary definition) by Initial AJCC/UICC stage 
(stage III, stage IV) 
MTP 
MTP 
X 
X 
14.2.8.4.12 
Summary of Overall Response Rate (secondary definition) by age category In years 
(<65, >=65) 
MTP 
MTP 
X 
X 
14.2.8.4.13 
Summary of Overall Response Rate (secondary definition) by liver as metastatic site (yes, 
no)  
MTP 
MTP 
X 
X 
14.2.8.4.14 
Summary of Overall Response Rate (secondary definition) by number of metastatic sites at 
screening (<2, >=2)  
MTP 
MTP 
X 
X 
14.2.8.4.15 
Summary of Overall Response Rate (secondary definition) by gender 
MTP 
MTP 
X 
X 
14.2.8.4.16 
Summary of Overall Response Rate (secondary definition) by cancer type (colon, rectal) 
MTP 
MTP 
X 
X 
14.2.8.4.17 
Summary of Overall Response Rate (secondary definition) by initial diagnosis (synchronous 
vs metachronous) 
MTP 
MTP 
X 
X 
14.2.8.5 
Overall Response Rate (ORR): Odds Ratio  
MTP 
MTP 
X 
X 
14.2.9.1 
Summary of Disease Control Rate (main definition) 
MTP 
MTP 
X 
X 
14.2.9.2 
Summary of Disease Control Rate (secondary definition) 
MTP 
MTP 
X 
X 
14.2.9.3 
Disease Control Rate (DCR): Odds Ratio  
MTP 
MTP 
X 
X 
14.2.10.1 
Summary of Duration of Response and Time to Response (main definition) 
MTP 
MTP 
X 
X 
14.2.10.2 
Summary of Duration of Response and Time to Response (secondary definition) 
MTP 
MTP 
X 
X 
14.2.11.1 
Summary of Progression Free Survival 2 
MTP 
MTP 
X 
X 
14.2.11.2 
Progression Free Survival 2: Hazard Ratio 
MTP 
MTP 
X 
X 
14.2.12.1 
Summary of ECOG Performance Status over time 
MTP 
MTP 
X 
X 
14.2.12.2 
Shift from baseline to ECOG Performance Status at end of MTP 
MTP 
MTP 
X 
X 
 
Adverse Events 
 
 
 
 
14.3.1.1.1 
Treatment Emergent Adverse Events (TEAEs) during ITP: Overall Summary  
ITP 
ITP 
X 
 
14.3.1.1.2 
Treatment Emergent Adverse Events (TEAEs) during MTP: Overall Summary 
MTP 
SAF 
X 
X 
14.3.1.1.3 
Post Induction Treatment Adverse Events (AEs): Overall Summary 
Post-
ITP who 
X 
 


 
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Table Number 
Table Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
Treatment 
completed 
study 
treatment 
discontinuation 
visit 
14.3.1.1.4 
Post Maintenance Treatment Adverse Events (AEs): Overall Summary 
Post-
Treatment 
SAF who 
completed 
study 
treatment 
discontinuation 
visit 
X 
X 
14.3.1.2.1 
Treatment Emergent Adverse Events by SOC and PT and by Worst Intensity during ITP 
ITP 
ITP 
X 
 
14.3.1.2.2 
Treatment Emergent Adverse Events by SOC and PT and by Worst Intensity during MTP 
MTP 
SAF 
X 
X 
14.3.1.2.3 
Treatment Emergent AESI by Categories, SOC, PT and by Worst Intensity during MTP 
MTP 
SAF 
X 
X 
14.3.1.2.4 
Serious Treatment Emergent AESI by Categories, SOC, PT and by Worst Intensity during 
MTP 
MTP 
SAF 
X 
X 
14.3.1.3.1 
Treatment Emergent Adverse Events Related to Any Study Drug by SOC and PT during ITP 
ITP 
ITP 
X 
 
14.3.1.3.2 
Treatment Emergent Adverse Events Related to FOLFOX by SOC and PT during ITP 
ITP 
ITP 
X 
 
14.3.1.3.3 
Treatment Emergent Adverse Events Related to 5-FU/LV by SOC and PT during ITP 
ITP 
ITP 
X 
 
14.3.1.3.4 
Treatment Emergent Adverse Events Related to bevacizumab by SOC and PT during ITP 
ITP 
ITP 
X 
 
14.3.1.3.5 
Treatment Emergent Adverse Events Related to Any Study Drug by SOC and PT during 
MTP 
MTP 
SAF 
X 
X 
14.3.1.3.6 
Treatment Emergent Adverse Events Related to 5-FU/LV by SOC and PT during MTP 
MTP 
SAF 
X 
X 
14.3.1.3.7 
Treatment Emergent Adverse Events Related to capecitabine by SOC and PT during MTP 
MTP 
SAF 
X 
X 
14.3.1.3.8 
Treatment Emergent Adverse Events Related to atezolizumab by SOC and PT during MTP 
MTP 
SAF 
X 
X 
14.3.1.3.9 
Treatment Emergent Adverse Events Related to bevacizumab by SOC and PT during MTP 
MTP 
SAF 
X 
X 
14.3.1.4.1 
Treatment Emergent Adverse Events Leading to Discontinuation of Any Study Drug by SOC 
and PT during ITP 
ITP 
ITP 
X 
 
14.3.1.4.2 
Treatment Emergent Adverse Events Leading to Discontinuation of FOLFOX by SOC and 
PT during ITP 
ITP 
ITP 
X 
 
14.3.1.4.3 
Treatment Emergent Adverse Events Leading to Discontinuation of 5-FU/LV by SOC and 
ITP 
ITP 
X 
 


 
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Statistical Analysis Plan MO29112 Cohort 2 (version 2.0) 
100 
Table Number 
Table Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
PT during ITP 
14.3.1.4.4 
Treatment Emergent Adverse Events Leading to Discontinuation of bevacizumab by SOC 
and PT during ITP 
ITP 
ITP 
X 
 
14.3.1.4.5 
Treatment Emergent Adverse Events Leading to Discontinuation of Any Study Drug by SOC 
and PT during MTP 
MTP 
SAF 
X 
X 
14.3.1.4.6 
Treatment Emergent Adverse Events Leading to Discontinuation of fluorpyrimidines by SOC 
and PT during MTP 
MTP 
SAF 
X 
X 
 
 
 
 
 
 
14.3.1.4.7 
Treatment Emergent Adverse Events Leading to Discontinuation of atezolizumab by SOC 
and PT during MTP 
MTP 
SAF 
X 
X 
14.3.1.4.8 
Treatment Emergent Adverse Events Leading to Discontinuation of bevacizumab by SOC 
and PT during MTP 
MTP 
SAF 
X 
X 
14.3.1.5.1 
Treatment Emergent Adverse Events Leading to Dose Reduction or Interruption of Any 
Study Drug by SOC and PT during ITP 
ITP 
ITP 
X 
 
14.3.1.5.2 
Treatment Emergent Adverse Events Leading to Dose Reduction or Interruption of FOLFOX 
by SOC and PT during ITP 
ITP 
ITP 
X 
 
14.3.1.5.3 
Treatment Emergent Adverse Events Leading to Dose Reduction or Interruption of 5-FU/LV 
by SOC and PT during ITP 
ITP 
ITP 
X 
 
14.3.1.5.4 
Treatment Emergent Adverse Events Leading to Dose Reduction or Interruption of 
bevacizumab by SOC and PT during ITP 
ITP 
ITP 
X 
 
14.3.1.5.5 
Treatment Emergent Adverse Events Leading to Dose Reduction or Interruption of Any 
Study Drug by SOC and PT during MTP 
MTP 
SAF 
X 
X 
14.3.1.5.6 
Treatment Emergent Adverse Events Leading to Dose Reduction or Interruption of 
fluoropyrimidines by SOC and PT during MTP 
MTP 
SAF 
X 
X 
 
 
 
 
 
 
14.3.1.5.7 
Treatment Emergent Adverse Events Leading to Dose Reduction or Interruption of 
atezolizumab by SOC and PT and by Worst Intensity during MTP 
MTP 
SAF 
X 
X 
14.3.1.5.8 
Treatment Emergent Adverse Events Leading to Dose Reduction or Interruption of 
bevacizumab by SOC and PT and by Worst Intensity during MTP 
MTP 
SAF 
X 
X 
14.3.1.6.1 
Treatment Emergent Adverse Events of Grade 3 or More by SOC and PT during ITP 
ITP 
ITP 
X 
 
14.3.1.6.2 
Treatment Emergent Adverse Events of Grade 3 or More by SOC and PT during MTP 
MTP 
SAF 
X 
X 


 
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Table Number 
Table Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
14.3.1.7.1 
Serious Treatment Emergent Adverse Events by SOC and PT during ITP 
ITP 
ITP 
X 
 
14.3.1.7.2 
Serious Treatment Emergent Adverse Events by SOC and PT during MTP 
MTP 
SAF 
X 
X 
14.3.1.8.1 
Serious Treatment Emergent Adverse Events Related to Any Study Drug by SOC and PT 
during ITP 
ITP 
ITP 
X 
 
14.3.1.8.2 
Serious Treatment Emergent Adverse Events Related to FOLFOX by SOC and PT during 
ITP 
ITP 
ITP 
X 
 
14.3.1.8.3 
Serious Treatment Emergent Adverse Events Related to 5-FU/LV  by SOC and PT during 
ITP 
ITP 
ITP 
X 
 
14.3.1.8.4 
Serious Treatment Emergent Adverse Events Related to bevacizumab by SOC and PT 
during ITP 
ITP 
ITP 
X 
 
14.3.1.8.5 
Serious Treatment Emergent Adverse Events Related to Any Study Drug by SOC and PT 
during MTP 
MTP 
SAF 
X 
X 
14.3.1.8.6 
Serious Treatment Emergent Adverse Events Related to fluoropyrimidines by SOC and PT 
during MTP 
MTP 
SAF 
X 
X 
 
 
 
 
 
 
14.3.1.8.7 
Serious Treatment Emergent Adverse Events Related to FOLFOX by SOC and PT during 
MTP 
MTP 
SAF 
X 
X 
14.3.1.8.8 
Serious Treatment Emergent Adverse Events Related to atezolizumab by SOC and PT 
during MTP 
MTP 
SAF 
X 
X 
14.3.1.8.9 
Serious Treatment Emergent Adverse Events Related to bevacizumab by SOC and PT 
during MTP 
MTP 
SAF 
X 
X 
14.3.1.9.1 
Treatment Emergent Adverse Events with Fatal Outcome by SOC and PT during ITP 
ITP 
ITP 
X 
 
14.3.1.9.2 
Treatment Emergent Adverse Events with Fatal Outcome by SOC and PT during MTP 
MTP 
SAF 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
14.3.1.10 
Treatment Emergent AESI based on eCRF Categories during MTP   
MTP 
SAF 
X 
X 
14.3.1.11 
Serious Treatment Emergent Adverse Events AESI based on eCRF Categories during MTP   MTP 
SAF 
X 
X 
 
Deaths 
 
 
 
 
14.3.1.12.1 
Deaths within 30 days from last day of treatment of ITP and Reason 
ITP 
ITP 
X 
 


 
Bevacizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29112 Cohort 2 (version 2.0) 
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Table Number 
Table Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
14.3.1.12.2 
Deaths within 30 days from last day of treatment of MTP and Reason  
MTP 
MTP 
X 
X 
14.3.1.12.3 
Deaths within 30 days from last day of treatment of MTP and Reason  
MTP 
SAF 
X 
X 
14.3.1.12.4 
Post Induction Treatment Deaths and Reason  
Post-
Treatment 
ITP who 
completed 
study 
treatment 
discontinuation 
visit 
X 
 
14.3.1.12.5 
Post Maintenance Treatment Deaths and Reason 
Post-
Treatment 
MTP who 
completed 
study 
treatment 
discontinuation 
visit 
X 
X 
 
Laboratory Parameters 
 
 
 
 
14.3.4.1.1 
Shift table (baseline versus worst on-treatment)  during ITP for CTC gradable Hematology  
parameters 
ITP 
ITP 
X 
 
14.3.4.1.2 
Shift table (baseline versus worst on-treatment)  during MTP for CTC gradable Hematology  
parameters 
MTP 
SAF 
X 
X 
14.3.4.2.1 
Shift table (baseline versus worst on-treatment)  during ITP for CTC gradable Blood 
Chemistry parameters  
ITP 
ITP 
X 
 
14.3.4.2.2 
Shift table (baseline versus worst on-treatment)  during MTP for CTC gradable Blood 
Chemistry parameters  
MTP 
SAF 
X 
X 
14.3.4.3.1 
Shift table (baseline versus worst on-treatment)  during ITP for CTC gradable Coagulation 
parameters  
ITP 
ITP 
X 
 
14.3.4.3.2 
Shift table (baseline versus worst on-treatment)  during MTP for CTC gradable Coagulation 
parameters  
MTP 
SAF 
X 
X 
14.3.4.4.1 
Shift table (baseline versus worst on-treatment)  during ITP for non CTC gradable 
Hematology  parameters 
ITP 
ITP 
X 
 
14.3.4.4.2 
Shift table (baseline versus worst on-treatment)  during MTP for non CTC gradable 
Hematology  parameters 
MTP 
SAF 
X 
X 
14.3.4.5.1 
Shift table (baseline versus worst on-treatment)  during ITP for non CTC gradable Blood 
ITP 
ITP 
X 
 


 
Bevacizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29112 Cohort 2 (version 2.0) 
103 
Table Number 
Table Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
Chemistry parameters  
14.3.4.5.2 
Shift table (baseline versus worst on-treatment)  during MTP for non CTC gradable Blood 
Chemistry parameters  
MTP 
SAF 
X 
X 
14.3.4.6 
Shift table (baseline versus worst on-treatment)  during MTP for non CTC gradable Thyroid 
parameters  
MTP 
SAF 
X 
X 
14.3.4.7.1 
Shift table (baseline versus worst on-treatment) during ITP for Urinalysis Protein Dipstick 
ITP 
ITP 
X 
 
14.3.4.7.2 
Shift table (baseline versus worst on-treatment) during MTP for Urinalysis Protein Dipstick 
MTP 
SAF 
X 
X 
 
Other Safety Data 
 
 
 
 
14.3.5.1 
Summary of vital signs Over Time during ITP 
ITP 
ITP 
X 
 
14.3.5.2 
Summary of vital signs Over Time during MTP 
MTP 
SAF 
X 
X 
14.3.6 
Summary of blood oxygen saturation Over Time during MTP 
MTP 
SAF 
X 
X 
 
2. LIST OF OUTPUTS: FIGURES 
Figure 
Number 
Figure Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
 
Efficacy 
 
 
 
 
14.1.1 
CONSORT flow Diagram for All Screened Patients 
All 
Screened 
X 
X 
14.1.2 
CONSORT flow Diagram for Patients Randomized in Cohort 2 
MTP 
MTP 
X 
X 
14.2.1.1 
Kaplan Meier Plot of Progression Free Survival - Primary Analysis (Surgery Censored) 
MTP 
MTP 
X 
X 
14.2.1.2 
Kaplan Meier Plot of Progression Free Survival - Sensitivity Analysis (Surgery not Censored)  
MTP 
MTP 
X 
X 
14.2.1.3 
Kaplan Meier Plot of Progression Free Survival On-Treatment - Sensitivity Analysis 
MTP 
MTP 
X 
X 
14.2.1.4 
Kaplan Meier Plot of PFS considering the first 259 events - Sensitivity Analysis 
MTP 
MTP 
X 
X 
14.2.1.5 
Kaplan Meier Plot of PFS considering the first 405 patients - Sensitivity Analysis 
MTP 
MTP 
X 
X 
14.2.1.6 
Kaplan Meier plot of PFS according to mRECIST - Experimental Group 
MTP 
MTP 
X 
X 
14.2.1.7.1  
Kaplan Meier Plot of Progression Free Survival by Region 
MTP 
MTP 
X 
X 
14.2.1.7.2  
Kaplan Meier Plot of Progression Free Survival by Tumor Response at end of ITP (based on eCRF 
data) 
MTP 
MTP 
X 
X 


 
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Statistical Analysis Plan MO29112 Cohort 2 (version 2.0) 
104 
Figure 
Number 
Figure Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
14.2.1.7.3  
Kaplan Meier Plot of Progression Free Survival by Tumor Colon Location 
MTP 
MTP 
X 
X 
14.2.1.7.4  
Kaplan Meier Plot of Progression Free Survival by RAS Status 
MTP 
MTP 
X 
X 
14.2.1.7.5  
Kaplan Meier Plot of Progression Free Survival by Microsatellite Stability Status 
MTP 
MTP 
X 
X 
14.2.1.7.6  
Kaplan Meier Plot of Progression Free Survival by RAS Status for MSS patients 
MTP 
MTP 
X 
X 
14.2.1.7.7  
Kaplan Meier Plot of Progression Free Survival by Tumor Colon Location for RAS wt patients 
MTP 
MTP 
X 
X 
14.2.1.7.8  
Kaplan Meier Plot of Progression Free Survival by Tumor Colon Location for RAS mt patients 
MTP 
MTP 
X 
X 
14.2.1.7.9  
Kaplan Meier Plot of Progression Free Survival by Tumor Colon Location for MSS patients 
MTP 
MTP 
X 
X 
14.2.1.8 
PFS: Proportional Hazard Assumption - Model Checking 
MTP 
MTP 
X 
 
14.2.1.9.1 
Forest Plot of Hazard Ratio for Progression Free Survival by baseline characteristics subgroup 
MTP 
MTP 
X 
X 
14.2.1.9.2 
Forest Plot of Hazard Ratio for Progression Free Survival by biomarker subgroup 
MTP 
MTP 
X 
X 
14.2.1.10 
Kaplan Meier Plot with Reverse Censoring  
MTP 
MTP 
X 
 
14.2.2.1 
Kaplan Meier Plot of Overall Survival 
MTP 
MTP 
X 
X 
14.2.2.2.1  
Kaplan Meier Plot of Overall Survival by Region 
MTP 
MTP 
X 
X 
14.2.2.2.2  
Kaplan Meier Plot of Overall Survival by Tumor Response at end of ITP (based on eCRF data) 
MTP 
MTP 
X 
X 
14.2.2.2.3  
Kaplan Meier Plot of Overall Survival by Tumor Colon Location 
MTP 
MTP 
X 
X 
14.2.2.2.4  
Kaplan Meier Plot of Overall Survival by RAS Status 
MTP 
MTP 
X 
X 
14.2.2.2.5  
Kaplan Meier Plot of Overall Survival by Microsatellite Stability Status 
MTP 
MTP 
X 
X 
14.2.2.2.6  
Kaplan Meier Plot of Overall Survival by RAS Status for MSS patients 
MTP 
MTP 
X 
X 
14.2.2.2.7  
Kaplan Meier Plot of Overall Survival by Tumor Colon Location for RAS wt patients 
MTP 
MTP 
X 
X 
14.2.2.2.8  
Kaplan Meier Plot of Overall Survival by Tumor Colon Location for RAS mt patients 
MTP 
MTP 
X 
X 
14.2.2.2.9  
Kaplan Meier Plot of Overall Survival by Tumor Colon Location for MSS patients 
MTP 
MTP 
X 
X 
14.2.2.3.1  
Forest plot of Hazard Ratio for Overall Survival by baseline characteristics subgroup 
MTP 
MTP 
X 
X 
14.2.2.3.2  
Forest plot of Hazard Ratio for Overall Survival by biomarker subgroup 
MTP 
MTP 
X 
X 
14.2.3 
Waterfall Plot of Best Percentage Change from Baseline in Sum of Diameter 
MTP 
MTP 
X 
 
14.2.4.1 
Forest Plot of Odds Ratio for Overall Response Rate by baseline characteristics subgroup 
MTP 
MTP 
X 
X 
14.2.4.2 
Forest Plot of Odds Ratio for Overall Response Rate by biomarker subgroup 
MTP 
MTP 
X 
X 
14.2.5.1 
Kaplan Meier Plot of Progression Free Survival 2 
MTP 
MTP 
X 
X 


 
Bevacizumab — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29112 Cohort 2 (version 2.0) 
105 
 
3. LIST OF OUTPUTS: LISTINGS 
Listing 
Number 
Listing Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
16.2.1.1 
Patient disposition and Study Termination Information 
ITP 
ITP 
X 
X 
16.2.1.2 
Patient who discontinue treatment due to Adverse Event 
ITP 
ITP 
X 
X 
16.2.2 
Major Protocol Deviations  
ITP/MTP 
ITP 
X 
X 
16.2.3 
Analysis Population 
ITP/MTP 
ITP 
X 
 
 
Demographics and Baseline Characteristics 
 
 
 
 
16.2.4.1 
Demographics and Baseline Characteristics 
ITP/MTP 
ITP 
X 
 
16.2.4.2 
Serology Values 
MTP 
MTP  
X 
 
16.2.4.3 
Tuberculosis Test Values 
MTP 
MTP  
X 
 
16.2.4.4 
Baseline Biomarker Status 
MTP 
MTP  
X 
 
16.2.4.5 
Randomization Stratification Factors as per IxRS and eCRF 
MTP 
MTP 
X 
 
16.2.4.6 
Colorectal Cancer History 
ITP 
ITP 
X 
 
16.2.4.7 
Medical history 
ITP 
ITP 
X 
 
16.2.4.8 
Prior Anti-Cancer Therapy 
ITP 
ITP 
X 
 
16.2.4.9 
Cancer Radiotherapy: Prior and On-Study 
ITP/MTP 
ITP 
X 
X 
16.2.4.10 
Colorectal Cancer Surgery : Prior and On-Study 
ITP/MTP 
ITP 
X 
X 
16.2.4.11 
Prior and Concomitant medications  
ITP/MTP 
ITP 
X 
X 
16.2.4.12 
Subsequent anti-cancer therapies - Post-treatment Follow-up Phase 
Post-
Treatment 
ITP 
X 
X 
 
Drug Administration 
 
 
 
 
16.2.5.1 
Study Drug Administration for 5-FU 
ITP/MTP 
ITP 
X 
X 
16.2.5.2 
Study Drug Administration for Leucovorin 
ITP/MTP 
ITP 
X 
X 
16.2.5.3 
Study Drug Administration for Oxaliplatin during ITP 
ITP 
ITP 
X 
 
16.2.5.4 
Study Drug Administration for bevacizumab 
ITP/MTP 
ITP 
X 
X 


 
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Statistical Analysis Plan MO29112 Cohort 2 (version 2.0) 
106 
Listing 
Number 
Listing Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
16.2.5.5 
Drug exposure during ITP 
ITP 
ITP 
X 
 
16.2.5.6 
Study Drug Administration for capecitabine during MTP 
MTP 
SAF 
X 
X 
16.2.5.7 
Study Drug Administration for atezolizumab during MTP 
MTP 
SAF 
X 
X 
16.2.5.8 
Drug Exposure during MTP 
MTP 
SAF 
X 
X 
 
Efficacy 
 
 
 
 
16.2.6.1 
Progression Free Survival – Primary Analysis (Surgery Censored) 
MTP 
MTP 
X 
X 
16.2.6.2 
Progression Free Survival – Sensitivity Analysis (Surgery not Censored) 
MTP 
MTP 
X 
X 
16.2.6.3 
Individual Tumor Assessment and Overall Response as per RECIST v1.1 
ITP/MTP 
ITP 
X 
X 
16.2.6.4 
Progression Free Survival On-Treatment 
MTP 
MTP 
X 
X 
16.2.6.5 
Progression Free Survival Considering the First 259 Events 
MTP 
MTP 
X 
X 
16.2.6.6 
Individual Tumor Assessment and Overall Response as per mRECIST– Experimental Group 
ITP/MTP 
MTP 
X 
X 
16.2.6.7 
PFS in treated patients with Atezolizumab according to mRECIST – Experimental Group 
MTP 
MTP 
X 
X 
16.2.6.8 
Best Overall Response,  Time to Response and Duration of Response 
MTP 
MTP 
X 
X 
16.2.6.9 
Overall Survival  
MTP 
MTP 
X 
X 
16.2.6.10 
Progression Free Survival 2 
MTP 
MTP 
X 
X 
16.2.6.11 
ECOG performance status 
ITP/MTP 
ITP 
X 
X 
 
Safety 
 
 
 
 
16.2.7.1 
Adverse Events 
ITP/MTP/ 
Post-
treatment 
ITP 
X 
X 
16.2.7.2 
Grade 5 Adverse Events or any Adverse Events with fatal outcome 
ITP/MTP/ 
Post-
treatment 
ITP 
X 
X 
16.2.7.3 
Adverse Events Leading to Treatment Discontinuation 
ITP/MTP/ 
Post-
treatment 
ITP 
X 
X 
16.2.7.4 
Adverse events of Special Interest as reported on eCRF  
MTP/ Post-
treatment 
MTP 
X 
X 
16.2.7.5 
Deaths 
ITP/MTP/ 
ITP 
X 
X 


 
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Statistical Analysis Plan MO29112 Cohort 2 (version 2.0) 
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Listing 
Number 
Listing Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
Post-
treatment 
16.2.8.1. 
Laboratory Values  
ITP/MTP 
ITP  
X 
X 
16.2.8.2 
Laboratory Abnormalities 
ITP/MTP 
ITP  
X 
X 
16.2.8.3 
Urinalysis: Urine Protein Dipstick 
ITP/MTP 
ITP  
X 
X 
16.2.8.4 
Urinalysis: 24 Hour Urine Protein  
ITP/MTP 
ITP 
X 
X 
16.2.8.5 
Pregnancy Test  
ITP/MTP 
ITP  
X 
X 
16.2.9 
Vital Signs  
ITP/MTP 
ITP  
X 
X 
 


CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
Bevacizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29112 Cohort 3 (Version 1.0) 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A MULTI-CENTRE RANDOMISED CLINICAL TRIAL OF 
BIOMARKER-DRIVEN MAINTENANCE TREATMENT FOR 
FIRST-LINE METASTATIC COLORECTAL CANCER (MODUL) 
COHORT 3 
PROTOCOL NUMBER: 
MO29112 
COHORT 3 STUDY 
DRUGS: 
 
bevacizumab (RO4876646) 
pertuzumab (RO4368451) 
trastuzumab (RO0452317) 
VERSION NUMBER: 
1.0 
IND NUMBER: 
N/A  
EUDRACT NUMBER: 
2014-001017-61 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
, Cytel, Inc 
DATE FINAL: 
09th May 2019 
 
 


Bevacizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29112 Cohort 3 (Version 1.0) 
2 
TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 6 
2. 
STUDY DESIGN ........................................................................................... 6 
2.1 
Protocol Synopsis .................................................................... 9 
2.2 
Outcome Measures ................................................................. 9 
2.3 
Determination of Sample Size ................................................. 9 
2.4 
Analysis Timing ..................................................................... 10 
3. 
STUDY CONDUCT ..................................................................................... 10 
3.1 
Randomization Issues ........................................................... 10 
3.2 
Independent Review Facility .................................................. 10 
3.3 
Data Monitoring ..................................................................... 10 
4. 
STATISTICAL METHODS .......................................................................... 11 
4.1 
Definition of Treatment Phase ............................................... 11 
4.1.1 
Induction Treatment Phase (ITP) ........................................... 11 
4.1.2 
Maintenance Treatment Phase (MTP) ................................... 12 
4.2 
Data Convention .................................................................... 12 
4.3 
Computing Environment ........................................................ 12 
4.4 
Grading and Coding of Adverse Events, 
Laboratory Parameters and Medications ............................... 13 
4.5 
Adustments for Covariates .................................................... 13 
4.6 
Subgroup Analysis ................................................................. 13 
4.7 
Analysis Populations ............................................................. 13 
4.7.1 
All Population ......................................................................... 13 
4.7.2 
Randomized Population......................................................... 13 
4.7.3 
Safety Population .................................................................. 13 
4.7.4 
Per Protocol (PP) Population ................................................. 13 
4.7.5 
Pharmacokinetic-Evaluable Population ................................. 14 
4.7.6 
Biomarker-Evaluable Population ........................................... 14 
4.8 
Analysis of Study Conduct ..................................................... 14 
4.8.1 
Patient Disposition ................................................................. 14 
4.8.2 
Protocol Deviations ................................................................ 14 
4.9 
Analysis of Treatment Group Comparability .......................... 14 


Bevacizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29112 Cohort 3 (Version 1.0) 
3 
4.9.1 
Demographics and Baseline Disease 
Characteristics ......................................................................................... 14 
4.9.2 
Medical History ...................................................................... 14 
4.9.3 
Prior and Concomitant Medications ....................................... 14 
4.9.4 
Subsequent Anti-Cancer Therapy ......................................... 14 
4.10 
Efficacy Analysis .................................................................... 14 
4.11 
Pharmacokinetic and Pharmacodynamic 
Analyses ................................................................................ 15 
4.12 
Safety Analyses ..................................................................... 15 
4.12.1 
Exposure of Study Medication ............................................... 15 
4.12.2 
Adverse Events ..................................................................... 19 
4.12.3 
Death ..................................................................................... 20 
4.12.4 
Laboratory Data ..................................................................... 20 
4.12.5 
Vital Signs .............................................................................. 20 
4.12.6 
Other Safety Assessment ...................................................... 21 
4.13 
Missing Data .......................................................................... 22 
4.14 
Interim Analyses .................................................................... 23 
5. 
REFERENCES ........................................................................................... 24 
 
LIST OF TABLES 
Table 1: Biomarker Profile by Cohort .................................................................... 7 
Table 2: Sample Size Determination per Cohort .................................................. 9 
Table 3: Exposure Definitions for Induction Treatments ..................................... 15 
Table 4: Exposure Definitions for Maintenance .................................................. 16 
Table 5: Adverse Events Definitions ................................................................... 19 
 
 
LIST OF APPENDICES 
Appendix 1: Protocol Synopsis ........................................................................... 25 
Appendix 2: Schedule of Assessments for All Patients (Screening / Baseline 
and Induction Treatment Phase) ................................................. 53 
Appendix 3: Schedule of Assessments During Maintenance Phase (Cohort 
3) ................................................................................................. 58 
Appendix 4 : List of Outputs ............................................................................... 64 


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HISTORY CHANGE 
Version 
Date 
Changes 
Final 1.0 
 
N/A 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse events of special interest 
BMI 
body mass index 
BRAFmut 
BRAF mutation 
BSA 
body surface area 
CR 
complete response 
CSR 
clinical study report 
eCRF 
electronic Case Report Form  
EU 
European Union 
HER2 
human epidermal growth factor receptor 2 
HER2+ 
human epidermal growth factor receptor 2 positive 
ICH 
International Conference on Harmonization 
iDMC 
Independent Data Monitoring Committee 
IHC 
immunohistochemistry 
ITP 
Induction Treatment Phase 
IxRS 
interactive voice or web-based response system  
mCRC 
metastatic Colorectal Cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSI-H 
high microsatellite instability 
MSS 
microsatellite stable 
MTP 
Maintenance Treatment Phase 
NCI CTCAE  
National Cancer Institute Common Terminology  
Criteria for Adverse Events  
NGS 
next generation sequencing 
PD 
progressive disease 
PFS 
progression free survival 
PR 
partial response 
SAP 
statistical analysis plan 
SC 
Steering Committee 
SD 
stable disease 
TEAE 
treatment emergent adverse event 
 


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1. 
BACKGROUND 
The study is a randomized, multi-center, active-controlled, open-label, parallel-group clinical 
study of biomarker-driven maintenance treatment for first-line metastatic colorectal cancer 
(mCRC) patients.  All patients will receive induction treatment with FOLFOX and bevacizumab. 
Induction treatment will be followed by maintenance treatment with chemotherapy combined with 
targeted therapy within one of several maintenance treatment cohorts. Only those patients who 
experience disease response or disease control during induction and who are not assessed as 
resectable at completion of induction will proceed to further treatment in the Maintenance 
Treatment Phase (MTP) of the study. Patients will be assigned to a maintenance treatment cohort 
based on their primary tumour biomarker results. The primary study objective within each cohort 
is to evaluate progression-free survival (PFS).   
Maintenance treatment cohorts may be added or modified over the course of the study. This SAP 
describes planned analyses of patients who were assigned, or would have been assigned, to 
maintenance treatment Cohort 3 based on their primary tumour biomarker profile. Given that only 
5 patients were randomized into Cohort 3, only few listings will be provided. The corresponding 
SAP is therefore abbreviated. 
Analyses of patients assigned to all other MODUL cohorts will be described in SAPs applicable 
to each specific cohort. 
A Steering Committee (SC) is responsible for overseeing the general conduct of the study.  
In addition, an independent Data Monitoring Committee (iDMC) is responsible for evaluating the 
safety of the patients participating in the trial at regular intervals throughout the study. The iDMC 
makes recommendations as to whether cohort recruitment should continue based on benefit-risk 
evaluations that include efficacy as well as safety data. To minimize the impact of such reviews 
on efficacy endpoint analyses, efficacy data included in these reviews has to be specified by the 
iDMC at a preceding iDMC meeting and has to be documented in the iDMC meeting minutes.  
 
2. 
STUDY DESIGN 
Patients continuing from the Induction Treatment Phase (ITP) to the Maintenance Treatment 
Phase are assigned to a maintenance treatment cohort based on their primary tumour biomarker 
status. Following eligibility assessment for their assigned cohort, eligible patients are randomized 
to the experimental or control arm within their cohort. 
The study was initiated with 2 maintenance treatment cohorts, Cohorts 1 and 2. Two additional 
cohorts, Cohorts 3 and 4, were added with protocol amendment 5 (protocol version 6).  
In this open-label study, all patients will receive 8 cycles induction treatment that is considered 
standard in many countries and that has been shown to improve outcomes in the first-line setting. 
Treatment during the ITP, based on investigator’s choice, will be either: 
 
 
Eight 2-week cycles of 5-fluorouracil (5-FU), leucovorin (LV) and oxaliplatin (FOLFOX) in 
combination with bevacizumab 
or 
 
Six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week 
cycles of 5-FU/LV with bevacizumab  


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Patients who prematurely discontinue study treatment for any reason during the ITP, who 
experience progressive disease (PD) at any time during or at the end of the ITP, who are 
evaluated as resectable at the end of ITP, who refuse to proceed to the MTP or who are not 
eligible for any maintenance cohort will undergo a study treatment discontinuation visit and enter 
post-treatment follow-up. Patients who experience disease control or tumor response to induction 
treatment will continue to the randomized MTP of the study wherein the effects of experimental 
and control groups will be compared. Patients in screening after June 28, 2016, were assigned 
to Cohort 3 if their primary tumour was HER2+. (Of note: HER2+ is defined as ‘Amplified (>=5CN)’ 
as per FMI next generation sequencing (NGS). To be enrolled in Cohort 3, amplified samples 
should be tested by HER IHC and have IHC>=0. Otherwise, patients were to be checked for 
Cohort 4 eligibility). Treatment in each cohort is shown in Figure 1.  
Table 1: Biomarker Profile by Cohort 
 
 
Biomarker profile 
 
Patients in Screening Prior June 28, 2016 
Patients in Screening After June 28, 2016 
Cohort 1 
BRAFmut 
HER2-/MSS/BRAFmut/RASwt 
Cohort 2 
BRAFwt or biomarker status unknown 
Closed to patients screened after June 3, 
2016 
Cohort 3 
Not applicable 
HER2+ 
Cohort 4 
Not applicable 
HER2-/MSI-H; HER2-/MSS/BRAFwt; HER2-
/MSS/BRAFmut/RASmut 
 


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Figure 1: Study Design as of protocol version 6 
 
 






 
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reviews has to be specified by the iDMC at a preceding iDMC meeting and has to be 
documented in the iDMC meeting minutes. 
 
4. 
STATISTICAL METHODS 
Only listings will be provided. 
4.1 
DEFINITION OF TREATMENT PHASE 
In this study, there are 3 treatment phases:  
1. Patients are treated first in the Induction Treatment Phase (ITP) for a planned duration of 
8 cycles, i.e. 16 weeks.  
2. If they do not experience any progressive disease before or at the end of the ITP, are not 
considered resectable at the end of the ITP and do not withdraw from the study and are still 
eligible for any cohort, they are randomized and treated in the Maintenance Treatment Phase 
(MTP). 
3. If they discontinue study treatment for any reason during the Induction or Maintenance 
Treatment Phases, do not withdraw from the study and are still alive, they enter the Post-
Treatment Follow-up Phase. 
 
4.1.1 
Induction Treatment Phase (ITP) 
ITP is defined as the time from first study drug administration until  
 
the day before the randomization for patients continuing treatment in the MTP   
 
the last assessment date otherwise 
 
The first day of treatment in the ITP is defined as the earliest day of a non-null administration 
of any induction phase treatment. 
The last day of treatment in the ITP is defined as the last day of the last initiated cycle of the 
induction phase, or as the death day if the patient died in between. A two-week cycle duration is 
assumed. 
Baseline evaluations for the ITP will be those performed not earlier than 28 days prior to the 
first day of treatment in the induction phase, unless otherwise stated. The latest available 
assessment up to start of the first day of treatment in the induction phase will be considered as 
baseline. For laboratory examinations, weight, vital signs and ECOG PS, assessments 
performed on the first day of treatment of the ITP will be assumed to have been performed before 
drug was given and, thus, will be considered as baseline evaluations. 
On-treatment evaluations for the ITP will be post baseline evaluations performed until 
 
the day before the randomization for patients continuing treatment in the MTP   
 
(including) the study treatment discontinuation visit within 30 days after last day of 
treatment of the ITP (as defined above), for patients not randomized in the MTP. 
 


 
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4.1.2 
Maintenance Treatment Phase (MTP) 
MTP is defined as the time from randomization into MTP until (including) the study treatment 
discontinuation visit in the MTP. 
The first day of treatment in the MTP is defined as the earliest day of a non-null administration 
of any maintenance phase treatments. 
The last day of treatment in the MTP is defined as the last day of the last initiated cycle of the 
maintenance phase, or as the death day if the patient died in between. A two-week cycle duration 
is assumed. 
Baseline evaluations for the MTP will be those performed prior to the first day of treatment in 
the maintenance, unless otherwise stated. The latest available assessment prior to the first day 
of treatment in the maintenance phase will be considered as baseline for safety assessments. 
For laboratory examinations, weight and vital signs, assessments performed on the first day of 
treatment of the MTP will be assumed to have been performed before drug was given and, thus, 
will be considered as baseline evaluations. For subjects randomized but not treated in the MTP, 
the latest available assessment before or on randomization date (including assessments from 
ITP) will be considered as baseline for the MTP.  
For efficacy assessments, the latest available assessment prior or on the randomization date will 
be considered as baseline. 
On-Treatment evaluations for the MTP will be evaluations performed on or after the first day 
of treatment in the MTP within 30 days from last day of treatment in the maintenance phase. On-
treatment laboratory will be all values collected after the first day of treatment in the maintenance 
phase and within 30 days from last day of treatment in the maintenance phase (as defined above). 
For adverse events, treatment emergent adverse events (TEAEs) will be events occurring on or 
after the first day of treatment in the MTP within 30 days (for patients in control group) and 90 
days (for patients in experimental group) from last day of treatment in the maintenance phase 
(as defined above). 
 
4.2 
DATA CONVENTION 
All data will be listed (e.g. pre-treatment serious adverse events). 
Age at informed consent (IC) {in years} = (date of informed consent – date of birth) / 365.25 
Body surface area (BSA) will be recalculated based on the height and weight of the patient 
using the following formula: 
 BSA (m2) = ([Height {cm} x Weight {kg}] / 3600)½ 
Body mass index (BMI) will be calculated using the following formula: 
BMI (kg/m2) = Weight {kg} / Height2 {m} 
 
4.3 
COMPUTING ENVIRONMENT 
All statistical analyses will be performed using SAS statistical software (Version 9.2 or newer 
version), unless otherwise noted.  
 


 
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4.4 
GRADING AND CODING OF ADVERSE EVENTS, LABORATORY 
PARAMETERS AND MEDICATIONS 
Adverse events and relevant Medical History data fields (i.e. prior symptoms / AEs) will be coded 
using the most recent version of Medical Dictionary for Regulatory Activities (MedDRA) dictionary 
available at the time of analysis.  
Dictionary versions used will be displayed in analysis outputs. 
 
4.5 
ADUSTMENTS FOR COVARIATES 
Not applicable. 
 
4.6 
SUBGROUP ANALYSIS 
Not applicable. 
 
4.7 
ANALYSIS POPULATIONS 
The following patient populations will be evaluated and used for presentation and analysis of the 
data. 
 
4.7.1 
All Population 
ALL Population: The ALL population consists of all screened patients with HER2+ biomarker 
profile enrolled after June 28, 2016.  
Induction Treatment Phase (ITP) Population: all patients included in the ALL Population and 
who are treated in the ITP, i.e. who received at least one non-null dose of any study medications 
during the ITP. The ITP population is the main population to be used to summarize ITP data and 
Post Induction Treatment data. ITP population will be the main population for the data listings; 
the 3 following groups will be displayed in listings: patients randomized in the experimental group 
of MTP, patients randomized in the control group of MTP, patients not randomized into MTP. 
 
4.7.2 
Randomized Population 
Maintenance Treatment Phase (MTP) Population is defined as all patients randomized into 
the Cohort 3 MTP of the study, irrespective of whether or not they received study medication. 
Patients will be allocated to the treatment group into which they were randomized (as per 
interactive voice or web-based response system [IxRS]). 
 
4.7.3 
Safety Population 
Not applicable. 
 
4.7.4 
Per Protocol (PP) Population 
Not applicable. 


 
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4.7.5 
Pharmacokinetic-Evaluable Population 
Not applicable. 
 
4.7.6 
Biomarker-Evaluable Population 
Not applicable. 
 
4.8 
ANALYSIS OF STUDY CONDUCT 
This SAP focuses only on the description of the analysis required for cohort 3 data. 
4.8.1 
Patient Disposition 
Patient disposition (including the tumor response status at the end of ITP) and study termination 
information will be listed on ITP population. 
4.8.2 
Protocol Deviations 
No outputs will be provided. 
 
4.9 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
4.9.1 
Demographics and Baseline Disease Characteristics 
Baseline and demographic characteristics (age, sex, ethnicity, race, smoking status, alcohol use, 
height, weight, BMI, BSA, female reproductive status) will be listed on ITP population. 
4.9.2 
Medical History 
No outputs will be provided. 
4.9.3 
Prior and Concomitant Medications 
No outputs will be provided. 
4.9.4 
Subsequent Anti-Cancer Therapy 
No outputs will be provided. 
 
4.10 
EFFICACY ANALYSIS 
PFS is defined as the time from randomization into the MTP until documented disease 
progression as per investigator assessment using Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 or death from any cause, whichever occurs first. If no progression / death is 
observed at the time of clinical cut-off or by the date of any on-study colorectal anti-cancer 
surgery with palliative or curative intent, patients will be censored at the date of the last evaluable 
tumor assessment or date of randomization, whichever comes last. 
(Of note: (i) Progressive disease are identified by the Overalll Response=’PD’, even if solely 
based on symptomatic deterioration, (ii) Only surgery occurring between baseline tumor 
assessment for MTP and PFS events are considered for censoring PFS) 
PFS time will be listed on MTP population.  
No other efficacy endpoints will be listed. 


 
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4.11 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Not applicable 
4.12 
SAFETY ANALYSES 
4.12.1 
Exposure of Study Medication 
Listing on exposure will be provided for ITP and MTP separately. 
 
Table 3: Exposure Definitions for Induction Treatments 
 
 
FOLFOX 
5-FU/LV 
bevacizumab 
Number of cycles 
sum of all cycles in which 
at least one non-null dose 
of FOLFOX  has been 
administered 
sum of all cycles in which at 
least one non-null dose of 5-FU 
and LV has been administered. 
Of note, consider only cycles 
where oxaliplatin is not 
administered concomitantly with 
5-FU/LV.  
sum of all cycles in 
which at least one 
non-null dose of 
bevacizumab has 
been administered 
Duration of dosing 
(weeks) (1) 
 
[min (last  date of 
FOLFOX+13, death date) 
– first FOLFOX dosing 
date+1] / 7 or 
If FOLFOX-4 or FOLFOX-
7 or modified FOLFOX-7 is 
administered in the last 
cycle initiated  
 [min (last  date of 
FOLFOX +12, death date) 
– first FOLFOX dosing 
date+1] / 7 
 
max (min(last date of 5-FU+13, 
death date), min(last date of 
LV+13, death date)) – min (first 
date of 5-FU, first  date of LV) 
+1] / 7 
Of note, consider only 
records/cycles where oxaliplatin 
is not administered 
concomitantly with 5-FU/LV. 
[min (last date of 
bevacizumab +13, 
death date)) – (first 
bevacizumab dosing 
date in the induction) 
+1]  / 7 
(1) According to the proposed formula, the duration of dosing may be overestimated in case patients 
discontinued treatment prior to the end of the last cycle. 
 
 
 


 
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Table 4: Exposure Definitions for Maintenance 
 
 
 
 
capecitabine 
5-FU or LV  
 
bevacizumab 
trastuzumab 
 
pertuzumab 
Number of 
cycle 
The sum of all cycles in which at least one non-null dose of <treatment> 
has been administered 
 
The sum of all cycles in which at least one non-null dose of <treatment> has been 
administered 
Duration of 
dosing 
(weeks) (1 
[min (last dosing date of <treatment> + x, death date)) – (first <treatment> dosing date in the maintenance) +1] / 7 
Where x=6 for capecitabine,  
      x=13 for 5FU, LV, bevacizumab,  
      x=20 for trastuzumab, pertuzumab 
For 5-FU and LV, last dosing date of treatment will be replaced by the first dosing date of the last administration 
Actual dose  <treatment> dose administered (in mg) as collected on the dosing eCRF page  
Unit: mg 
Planned 
dose  
<treatment> planned dose (in mg) as collected on the dosing eCRF page  
Unit: mg 
Normalized 
dose 
dose / recalculated BSA(2) 
Unit: mg/m2 
dose / weight(3) 
Unit: mg/kg 
dose / weight(3) 
Unit: mg/kg 
NA 
 


 
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capecitabine 
5-FU or LV  
 
bevacizumab 
trastuzumab 
 
pertuzumab 
Cumulative 
dose  
The cumulative 
dose will be 
derived for each 
records as 
below: (end date 
of administration 
- start date of 
administration 
+1) * normalized 
actual dose for 
the record * 2  
Cumulative 
dose= sum of 
cumulative dose 
across all 
records  
Unit: mg/m2  
sum of the all 
<treatment > 
normalized 
actual doses 
(in mg/m2) 
administered 
in all cycles 
 
 
sum of the all bevacizumab 
normalized actual doses (in 
mg/kg)  administered in all cycles 
sum of the all trastuzumab normalized 
actual doses (in mg/kg)  administered 
in all cycles 
sum of the all of pertuzumab actual 
doses (in mg)  administered in all cycles 
Dose 
intensity 
Cumulative dose 
/ (duration of 
dosing *7) 
Unit: mg/m2/day 
Cumulative 
dose / 
duration of 
dosing  
Unit: 
mg/m2/week 
 
Cumulative dose / duration of dosing  
Unit: mg/kg/week 
Cumulative dose / duration of dosing  
Unit: mg/kg/week 
Cumulative dose / (duration of dosing * 
7)  
Unit: mg/day 
Planned 
dose 
intensity  
CPD/(duration of 
dosing *7) 
CPD/duration 
of dosing 
CPD/duration of dosing  
Unit: mg/kg/week 
CPD/duration of dosing  
Unit:  
CPD/(duration of dosing*7) 
Unit: mg/day 


 
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(1) According to the proposed formula, the duration of dosing may be overestimated in case patients discontinued treatment prior to the end of the 
last cycle. 
(2) The BSA will be recalculated based on the height and weight (see point 3 for identification of weight) of the patient using the formula as mentioned 
in section 4.3. 
(3) The baseline weight will be used as reference. If the last available weight of the patient prior to or on the cycle start has changed by 10% or 
greater (i.e. patient has gained or lost more than 10% of their body weight since baseline) the patient new weight will be set as the baseline 
weight and will be used at the patient current and subsequent cycles. If a patient weight has changed by 10% or greater at a later cycle, then 
this new weight will be set as the base weight as aforementioned. 
 
Unit: mg/m2/day  
Unit: 
mg/m2/week 
 
mg/kg/week 
 
Relative 
dose 
intensity 
(RDI) (%) 
100 * (dose intensity) / (planned dose intensity) 


 
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4.12.2 
Adverse Events 
Adverse events variables are defined in Table 5. 
Table 5: Adverse Events Definitions 
 
Variable 
Definition 
Treatment 
Emergent 
Adverse Events 
(TEAEs) for the 
induction 
treatment phase 
(1) 
 
Any adverse events (serious and non-serious) with an onset date on (only if the 
“Event occurred prior to first study drug administration” from the AE eCRF page is 
not checked) or after the first day of treatment of the ITP and up to the:  
 
first day of treatment of the MTP (excluding) if it occurs within the 30 days 
from last day of treatment of induction treatment for patients treated with 
maintenance treatment 
 
within 30 days from last day of treatment of induction treatment (as defined 
in section 4.1.1), for patients not treated with maintenance treatment or for 
patients treated with maintenance treatment but with first day of treatment of 
MTP being more than 30 days after last day of treatment of ITP.  
TEAEs for the 
maintenance 
treatment 
phase(1) 
 
Any adverse events (serious and non-serious) with an onset date on (only if the 
“Event occurred prior to first study drug administration” from the AE eCRF page is 
not checked)  or after the first day of treatment of the MTP and up to 30 days (for 
patients in control group) and 90 days (for patients in experimental group) from the 
last day of treatment of MTP (as defined in section 4.1.2) 
Post induction 
treatment 
Adverse Events  
Any adverse events (serious and non-serious): 
 
with an onset date more than 30 days after the last day of treatment of the 
ITP (as defined in section 4.1.1) for patients not treated with maintenance 
treatment. 
 
with an onset date more than 30 days after the last day of treatment of the 
ITP and prior the first day of treatment of the MTP, for patients treated with 
maintenance treatment with first day of treatment of MTP being more than 
30 days after last day of treatment of ITP.. 
Post maintenance 
treatment 
Adverse events  
Any adverse events (serious and non-serious) with an onset date more than 30 
days (for patients in control group) and more than 90 days (for patients in 
experimental group) after the last day of treatment of the MTP (as defined in section 
4.1.2) (as defined in section 4.1.2). 
Adverse Events 
NCI CTCAE 
grade 
The adverse events grade will be the one with tick box checked for "AE most 
extreme NCI CTCAE grade" 
Serious Adverse 
Events  
Any adverse events qualified as “serious” by the investigator.  


 
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Adverse Events 
with fatal 
outcome 
Any adverse events with outcome of “Fatal”. 
Adverse events 
related to 
<FOLFOX, 
bevacizumab, FP, 
trastuzumab, 
pertuzumab>  
Any adverse events with an “AE suspected to be caused by study drug <FOLFOX, 
bevacizumab, FP, trastuzumab, pertuzumab >  as ‘Yes’. 
For AE suspected to be caused by FOLFOX while starting in the maintenance 
phase, the unique text ‘“AE considered related to Folfox”‘ has been reported in the 
comment field ‘ 
Adverse events 
leading to 
<FOLFOX, 
bevacizumab, FP, 
trastuzumab, 
pertuzumab> 
discontinuation 
Any adverse events with an “Action taken with <FOLFOX, bevacizumab, FP, 
trastuzumab, pertuzumab > due to SAE/AE” of “drug withdrawn” 
Adverse events of 
Special Interest 
(AESI) as 
reported on eCRF  
AESIs will be selected based on the tick box from the eCRF.  
(1) Of note, in case an event has an incomplete or missing start date, which consequently prevents its 
allocation to only one treatment phase of the study, the event will be allocated to both the induction 
and maintenance phase. Refer to section 4.13 for further details. 
 
 
By-patient listings will be provided for all adverse events AEs on ITP population. 
 
4.12.3 
Death 
One listing will be generated for deaths based on the ITP population and including appropriate 
flagging of study phase (ITP and MTP) and on-treatment/post-treatment deaths (i.e. within 30 
days from last day of treatment/more than 30 days from last day of treatment). 
All deaths information (including reason and date) will be retrieved from the Study 
Completion/Early Discontinuation eCRF page.  
4.12.4 
Laboratory Data 
No outputs will be provided. 
 
4.12.5 
Vital Signs 
No outputs will be provided. 
 


 
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4.12.6 
Other Safety Assessment  
No outputs will be provided for other safety assessment (eg. pregnancy test). 
 
 


 
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4.13 
MISSING DATA 
Imputation of partial/missing death date will be done as follows:  
 
If the date is completely missing, then the day of “Last known to be alive” +1 will be used  
 
If only day is missing and year and month are same as “Last known to be alive”, then the 
day of “Last known to be alive”+1 will be used otherwise the 1st day of the month will be 
used 
 
If day and month are missing and year is same as “Last known to be alive”, then the “Last 
known to be alive”+1 will be used, otherwise 1st of January will be used 
 
Partially missing dates for adverse events (AEs) will be imputed as follows. Of note, imputation 
of missing/partial AE date will be done only to identify treatment emergent AEs. 
AE onset dates 
 Partially missing onset dates will be imputed as follows 
 
When only Day is missing:  
o If Month & Year of the onset date are the same as Month & Year of the 
first day of treatment of the induction/maintenance treatment phase, the 
imputed onset date will be imputed as the minimum of the first day of 
treatment of the induction/maintenance treatment phase and the AE 
resolution date (imputed if needed). 
o Otherwise, the missing day will be replaced by “1”. 
 
When Day & Month are missing:  
o If Year of the onset date is the same as Year of the induction/maintenance 
treatment phase, the imputed onset date will be imputed as the minimum 
of the first day of treatment of the induction/maintenance treatment phase 
and the AE resolution date (imputed if needed). 
o Otherwise, the missing Day & Month will be replaced by “01JAN”. 
 
 Complete missing onset dates for AEs will be imputed by first day of treatment of the 
induction/maintenance treatment phase and the AE will be considered as treatment 
emergent, unless the end date of the AE (imputed if needed) or the end year of the 
AE (if day and month are missing) is entered and is before the year of the first 
treatment administration of the induction/maintenance treatment phase. 
 
AE resolution dates 
 Incomplete resolution dates will be replaced by the last day of the month (if day is 
missing only), if not resulting in a date later than the date of patient's death. In the 
latter case the date of death will be used to impute the incomplete resolution date 
 In all other cases the incomplete resolution date will not be imputed 
Of note, the above rules may allow allocation of an event to both the ITP and MTP treatment 
phase. 
 
The original incomplete, missing or partial dates will be presented in the listings, not the 
imputed dates. 
 


 
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4.14 
INTERIM ANALYSES 
 
No formal interim analyses on PFS or OS are planned. 


 
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5. 
REFERENCES 
Seo AN, Kwak Y, Kim DW, et al. HER2 status in colorectal cancer: its clinical significance and 
the relationship between HER2 gene amplification and expression. PLoS One. 2014 May 
30;9(5):e98528. doi: 10.1371/journal.pone.0098528. eCollection 2014.  
 
Ron Brookmeyer and John Crowley, A Confidence Interval for the Median Survival Time. 
Biometrics  Vol. 38, No. 1 (Mar., 1982), 29-41 
 


 
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Appendix 1: Protocol Synopsis 
  


 
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prior to informed consent signature may be used as screening assessments as long as they were done within 7 days prior to informed consent 
signature. 
e. The “All Cohort” eligibility criteria are evaluated prior to initiating the first cycle of study treatment during the Induction Treatment Phase.  
f. 
Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, smoking history, use of alcohol and drugs of abuse, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 7 days prior to the Screening visit.  Demographic data will include 
age, sex, and self-reported race/ethnicity (where permitted by federal regulations). 
g. Vital signs include measurements of systolic and diastolic blood pressure while the patient is in a seated position, and temperature.  During 
Screening, weight only required ≤ 7 days. 
h. Baseline assessment requires a complete physical exam. A complete physical examination should include an evaluation of the head, eyes, 
ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological 
systems. Abnormalities identified at Screening / Baseline will be recorded as baseline conditions.  At subsequent visits (or as clinically 
indicated), limited, symptom-directed physical examinations should be performed. Changes from Baseline, with new or worsened clinically 
significant abnormalities, should be reported as AEs if appropriate.  
i. 
ECOG status assessed within 7 days prior to Day 1 of Cycle 1 (Induction Treatment Phase) for eligibility determination.  See Appendix 8. 
j. 
Concomitant medication includes any prescription medications or over-the-counter preparations used by a patient between the 7 days prior to 
the date of informed consent up until the date of study discontinuation.  Only concomitant medications used for supportive care, to alleviate 
symptoms of mCRC, or to treat adverse drug reactions should be recorded on the Concomitant Medications eCRF. At subsequent visits, only 
changes to current medications or medications used since the last documentation of medications will be recorded.  Concomitant medications 
for treatment of AEs related to study medication will continue to be recorded while the AE is being followed. For permitted and prohibited 
concomitant medications, see Section 4.4. 
k. Haematology includes haemoglobin, haematocrit, platelet count, red blood cell count, white blood cell count, and differential. Blood chemistry 
includes ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin, blood urea nitrogen or urea, LDH, creatinine, glucose, calcium, 
phosphorus, sodium, potassium, chloride, and bicarbonate. Hematology and blood chemistry tests must be conducted prior to each treatment 
cycle, with the results available for review prior to start of treatment according to local standards for treatment management. However, only 
tests conducted every second treatment cycle will be recorded in the eCRF. Clinical laboratory results constituting a clinically significant AE 
should be recorded as such.  
l. 
INR and aPTT are required for all patients at screening but only for patients receiving anticoagulants while on protocol-specified treatment. 
m. Urinalysis must be performed by dipstick at Baseline and within 48 hours prior to every cycle.  A 24-hour urine collection is needed in the event 
of proteinuria ≥ ± 2 by dipstick test. 
n. Urine or blood pregnancy test, only for women of childbearing potential (i.e. not post-menopausal as indicated by < 12 months of non-therapy-
induced amenorrhea, nor surgically sterile [absence of ovaries and/or uterus]), including those who have had a tubal ligation.  A serum 
pregnancy test is required within 7 days prior to start of study induction treatment, or within 14 days with a confirmatory urine pregnancy test 
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o. Will include radiology, chest and abdominal CT or MRI, and other scans to document all sites of disease. Include upper abdomen at Baseline.  
A CT or MRI scan of the brain is required if there is clinical suspicion of CNS metastases at screening/Baseline or at any time during the 
Induction Treatment Phase. Subsequent tumour assessments will be done according to standard of care at each study centre, with the 
exception that all patients must have a tumour assessment at the end of the Induction Treatment Phase. Tumour assessments are not required 
for study purposes after disease progression has been documented. Patients who discontinue study treatment during the Induction Treatment 
Phase prior to disease progression will also continue to be followed for progressive disease, with disease status followed according to local 
practice until progression or May 31, 2019, whichever comes first. After May 31, 2019, disease status will not be collected for the study.    
p. Archival tumour tissue (FFPET) block from the primary tumour obtained at the time of the initial diagnosis. If the tumour block is not available, ≥ 
20 slides cut from the primary tumour sample will be accepted as an alternative.  Before a patient can be enrolled, the sample (block or slides) 
must be shipped to the designated laboratory with the corresponding pathology report and receipt of the shipment must be confirmed by the 
laboratory.  See Appendix 17. 
q. Collection of the optional core biopsy of metastatic tumours was discontinued as of May 2018 (See Appendix 18).  
r. 
Whole blood and plasma samples will be collected from all study patients for exploratory biomarker analyses unless genomic analysis is not 
allowed per local regulations. In such instances, only plasma samples will be collected.  All samples will be sent to a designated laboratory.  
Samples during treatment should be taken within 48 hours prior to study treatment Day 1 of each cycle indicated, unless otherwise specified 
(see Appendix 17 and Laboratory Manual). 
s. After the signing of the informed consent form, and prior to Day 1 of Cycle 1 (Induction Treatment Phase), any SAEs thought to be related to a 
protocol-mandated intervention should be reported.  Adverse events will be documented at every cycle during treatment. All patients will be 
followed for new AEs for 28 days following the discontinuation of study treatment. At the time of treatment discontinuation, any ongoing AE/SAE 
will be followed until the event resolves, the Investigator assesses the event as stable, the patient is lost to follow-up, dies or withdraws 
consent. Death related to disease progression is not considered to be an SAE. The Sponsor should be notified if the Investigator becomes 
aware of any SAE or AEs of special interest occurring after the end of the adverse event reporting period if the event is believed to be related to 
prior study treatment. 
t. 
Eligible patients will enter a 4-month Induction Treatment Phase.  Treatment during this phase, based on Investigator’s choice, will be either 
eight 2-week cycles of 5-FU, LV and oxaliplatin (FOLFOX) in combination with bevacizumab or six 2-week cycles of FOLFOX in combination 
with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab. 
 
 








 
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maintenance treatment cohort.  Cohorts 2 and 4 are closed to further accrual.  Patients with an adequate tumour sample but with unknown 
biomarker status due to lack of determinant result (e.g. due to technical issues) may still be included in the study depending on the addition of 
future cohorts. 
e. The cohort-specific exclusion criteria must be assessed prior to randomization to study maintenance treatment but assessment of cohort-
specific eligibility can only be completed after the biomarker analysis results from the patient’s archival tumour tissue from initial diagnosis are 
known. Patients found ineligible for any cohort will undergo a Study Treatment Discontinuation Visit and enter the Post-Treatment Follow-up 
Phase. 
f. 
Each cohort will consist of an experimental treatment arm and a control arm.  Randomised on a 2:1 (experimental:control) basis to either the 
experimental treatment arm or the control arm of that cohort.  See Section 4.2. 
g. Vital signs include measurements of systolic and diastolic blood pressure while the patient is in a seated position, and temperature. For the 
control arm only, vitals conducted every second treatment cycle only will be recorded in the eCRF. 
h. Physical examinations will be symptom-directed, and will include changes from Baseline (pre-Induction) with new or worsened clinically 
significant abnormalities being reported as AEs if appropriate.  
i. 
See Appendix 8. 
j. 
Concomitant medication includes any prescription medications or over-the-counter preparations used by a patient between the 7 days prior to 
the date of informed consent up until the Study Treatment Discontinuation visit.  Only concomitant medications used for supportive care, to 
alleviate symptoms of mCRC, or to treat adverse drug reactions should be recorded on the Concomitant Medications eCRF. At subsequent 
visits, only changes to current medications or medications used since the last documentation of medications will be recorded. Concomitant 
medications for treatment of AEs related to study medication will continue to be recorded while the AE is being followed.   For permitted and 
prohibited concomitant medications, see Section 4.4. 
k. Haematology includes haemoglobin, haematocrit, platelet count, red blood cell count, white blood cell count, and differential. Blood chemistry 
includes ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin, blood urea nitrogen or urea, LDH, creatinine, glucose, calcium, 
phosphorus, sodium, potassium, chloride, and bicarbonate. Haematology and blood chemistry tests must be conducted prior to each treatment 
cycle, with the results available for review prior to start of treatment according to local standards for treatment management. For the control arm 
only, tests conducted every second treatment cycle only will be recorded in the eCRF. Clinical laboratory results constituting a clinically 
significant AE should be recorded as such.  
l. 
INR and aPTT only for patients receiving anticoagulants while on protocol-specified treatment. 
m. Urinalysis must be performed by dipstick within 48 hours prior to every cycle.  A 24-hour urine collection is needed in the event of proteinuria ≥ 
± 2 by dipstick test. For the control arm only, tests conducted every second treatment cycle only will be recorded in the eCRF. 
n. Urine or blood pregnancy test, only for women of childbearing potential (i.e. not post-menopausal as indicated by < 12 months of non-therapy-
induced amenorrhea, nor surgically sterile [absence of ovaries and/or uterus]), including those who have had a tubal ligation.  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test. In the experimental arm, a serum pregnancy test must be done ≤ 7 
days from maintenance treatment start. Urine pregnancy tests must also be done every 3 cycles during treatment (with result available prior to 
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o. HIV testing performed in accordance with national and/or institutional guidelines.  HBV serology includes HBsAg and anti-HBc.  HCV serology 
includes anti-HCV. Results required to determine eligibility for Cohort 3. 
p. LVEF must be assessed in all Cohort 3 patients prior to randomization. Only experimental arm patients require subsequent LVEF monitoring. 
Subsequent LVEF measurements (using the same method as at baseline) will be conducted every third cycle until Cycle 6 and then every 
fourth cycle until termination of study treatment (i.e., during Cycles 3, 6, 10, 14, etc.), with the results made available prior to administration of 
the subsequent treatment cycle (i.e., prior to Cycles 4, 7, 11, 15, etc.). For patients who stop study drug(s) because of a decrease in LVEF, 
LVEF should be assessed at least every 6 weeks to determine recovery/stabilization (until LVEF recovers to ≥ 50% or 2 years, whichever 
occurs first). In patients who required a repeat LVEF assessment to ensure an acceptable LVEF before continuing trastuzumab/pertuzumab 
treatment, an additional LVEF assessment is to be performed at the next treatment cycle. Note: approval of the Medical Monitor must be 
obtained before continuation of study treatment after delays > 21 days. 
q. Up to and including May 31, 2019, tTumour assessments will be conducted according to RECIST1.1 and will include radiology, chest and 
abdominal CT or MRI, and other scans to document all sites of disease. A CT or MRI scan of the brain is required if there is a clinical suspicion 
of CNS metastases. Disease status during maintenance treatment will be determined based on comparison with the tumortumour assessment 
done at the end of induction treatment. Up to and including May 31, 2019, Ttumour assessments will be conducted every 8 weeks from the start 
of maintenance treatment regardless of treatment delays. After May 31, 2019, disease status will not be collected for the study and tumour assessments 
may be conducting per local practice. Patients who discontinue study treatment during the Maintenance Treatment Phase prior to disease 
progression will also continue to be followed for progressive disease, with disease assessments per RECIST 1.1 conducted every 8 weeks until 
progression or May 31, 2019, whichever comes first. 
r. 
Supplemental Biomarker Program closed as of May 2018. Collection of these samples has been discontinued (see Appendix 18). 
s. Plasma samples will be collected from all patients for exploratory biomarker analyses. These samples will be sent to a designated laboratory.  
Samples during treatment should be taken within 48 hours prior to study treatment Day 1 of each cycle indicated, unless otherwise specified 
(see Appendix 17 and the Laboratory Manual). 
t. 
Adverse events will be documented at every cycle during treatment. Patients in the experimental arm of Cohort 3 will be followed for new AEs 
for 90 days following the discontinuation of study treatment. Patients in the control arm will be followed for new AEs for 28 days following the 
discontinuation of study treatment. At the time of treatment discontinuation, any ongoing AE/SAE will be followed until the event resolves, the 
Investigator assesses the event as stable, the patient is lost to follow-up, dies or withdraws consent. Death related to disease progression is not 
considered to be an SAE.  The Sponsor should be notified if the Investigator becomes aware of any SAE or AEs of special interest occurring 
after the end of the adverse event reporting period if the event is believed to be related to prior study treatment. 
u. Patients in the experimental arm will receive capecitabine 1000 mg/m2 b.i.d. Days 1-14 followed by a one-week treatment break for every 3-
week treatment cycle. Capecitabine dose calculations by body surface area with corresponding tablet counts are provided in Appendix 7. 
Trastuzumab will be administered by IV infusion on Day 1 of every 3-week treatment cycle at an initial loading dose of 8 mg/kg followed by 6 
mg/kg for subsequent doses. Pertuzumab will be administered by IV infusion on Day 1 of each 3-week treatment cycle at an initial fixed loading 
dose of 840 mg followed by 420 mg for subsequent doses. Patients in the control arm will receive: 5-FU or capecitabine, dose and schedule will 
be according to local label, where applicable, or otherwise will be determined per the Investigator’s discretion, with bevacizumab 5 mg/kg via 15 
– 30 minute IV infusion on Day 1 of every 2-week cycle. If a control arm patient receives capecitabine administered according to a 3- week 


 
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cycle, timing of all study procedures and assessments scheduled according to 2-week control arm treatment cycles (e.g. ECOG performance 
status) will be defined by the treatment cycles of concurrently administered bevacizumab. 
 
 


 
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Appendix 4 : List of Outputs 
 
List of Outputs: Listings 
Listing 
Number 
Listing Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
16.2.1.1 
Patient Disposition and Study Termination Information 
ITP 
ITP 
X 
X 
16.2.4.1 
Demographics and Baseline Characteristics 
ITP/MTP 
ITP 
X 
  
16.2.5.5 
Drug Exposure during ITP 
ITP 
ITP 
X 
 
16.2.5.8 
Drug Exposure during MTP 
MTP 
SAF 
X 
 
16.2.6.1 
Progression Free-Survival – Primary Analysis (Surgery Censored) 
MTP 
MTP 
X 
 
16.2.7.1 
Adverse Events 
ITP/MTP/ 
Post-
treatment 
ITP 
X 
X 
16.2.7.5 
Deaths 
ITP/MTP/ 
Post-
treatment 
ITP 
X 
X 
 


CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
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Statistical Analysis Plan MO29112 Cohort 4 (Version 1.0) 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A MULTI-CENTRE RANDOMISED CLINICAL TRIAL OF 
BIOMARKER-DRIVEN MAINTENANCE TREATMENT FOR 
FIRST-LINE METASTATIC COLORECTAL CANCER (MODUL) 
COHORT 4 
PROTOCOL NUMBER: 
MO29112 
COHORT 4 STUDY 
DRUGS: 
 
atezolizumab (MPDL3280A, RO5541267), 
bevacizumab (RO4876646) 
cobimetibib (RO5514041) 
VERSION NUMBER: 
1.0 
IND NUMBER: 
N/A  
EUDRACT NUMBER: 
2014-001017-61 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
, Cytel, Inc 
DATE FINAL: 
9th May 2019 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 8 
2. 
STUDY DESIGN ........................................................................................... 8 
2.1 
Protocol Synopsis .................................................................. 11 
2.2 
Outcome Measures ............................................................... 11 
2.2.1 
Primary Efficacy Outcome Measures .................................... 11 
2.2.2 
Secondary Efficacy Outcome Measures ................................ 11 
2.2.2.1 Overall Survival (OS) ............................................................ 11 
2.2.3 
Safety Outcome Measures .................................................... 12 
2.2.4 
Pharmacokinetic (PK) Outcome Measures ............................ 12 
2.2.5 
Exploratory Biomarker Outcome Measures ........................... 12 
2.3 
Determination of Sample Size ............................................... 12 
2.4 
Analysis Timing ..................................................................... 13 
3. 
STUDY CONDUCT ..................................................................................... 13 
3.1 
Randomization Issues ........................................................... 13 
3.2 
Independent Review Facility .................................................. 14 
3.3 
Data Monitoring ..................................................................... 14 
4. 
STATISTICAL METHODS .......................................................................... 14 
4.1 
General Descriptive methods ................................................ 14 
4.2 
Definition of Treatment Phase ............................................... 15 
4.2.1 
Induction Treatment Phase (ITP) ........................................... 15 
4.2.2 
Maintenance Treatment Phase (MTP) ................................... 16 
4.2.3 
Post-Treatment Follow-up Phase .......................................... 16 
4.3 
Data Convention .................................................................... 17 
4.4 
Computing Environment ........................................................ 17 
4.5 
Grading and Coding of Adverse Events, 
Laboratory Parameters and Medications ............................... 18 
4.6 
Adustments for Covariates .................................................... 18 
4.7 
Subgroup Analysis ................................................................. 18 
4.8 
Analysis Populations ............................................................. 18 
4.8.1 
All Population ......................................................................... 18 


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4.8.2 
Randomized Population......................................................... 19 
4.8.3 
Safety Population .................................................................. 19 
4.8.4 
Per Protocol (PP) Population ................................................. 19 
4.8.5 
Pharmacokinetic-Evaluable Population ................................. 19 
4.8.6 
Biomarker-Evaluable Population ........................................... 19 
4.9 
Analysis of Study Conduct ..................................................... 19 
4.9.1 
Patient Disposition ................................................................. 20 
4.9.2 
Protocol Deviations ................................................................ 21 
4.10 
Analysis of Treatment Group Comparability .......................... 21 
4.10.1 
Demographics and Baseline Disease 
Characteristics ......................................................................................... 21 
4.10.2 
Medical History ...................................................................... 23 
4.10.3 
Prior and Concomitant Medications ....................................... 23 
4.10.3.1 Prior Anti-Cancer Treatment/Procedure ............................. 23 
4.10.3.2 Non Anti-Cancer Treatment/Procedure .............................. 24 
4.10.4 
Subsequent Anti-Cancer Therapy ......................................... 24 
4.11 
Efficacy Analysis .................................................................... 25 
4.11.1 
Primary Efficacy Endpoint ...................................................... 25 
4.11.2 
Secondary Efficacy Endpoints ............................................... 25 
4.11.2.1 Overall Survival .................................................................. 25 
4.11.3 
Exploratory Efficacy Endpoints .............................................. 26 
4.11.4 
Sensitivity Analyses ............................................................... 26 
4.11.5 
Subgroup Analyses ............................................................... 26 
4.12 
Pharmacokinetic and Pharmacodynamic 
Analyses ................................................................................ 26 
4.13 
Safety Analyses ..................................................................... 26 
4.13.1 
Exposure of Study Medication ............................................... 26 
4.13.1.1 Cycle Delay ........................................................................ 32 
4.13.2 
Adverse Events ..................................................................... 33 
4.13.3 
Death ..................................................................................... 37 
4.13.4 
Laboratory Data ..................................................................... 37 
4.13.5 
Vital Signs .............................................................................. 39 
4.13.6 
Other Safety Assessment ...................................................... 40 
4.14 
Missing Data .......................................................................... 41 


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4.15 
Interim Analyses .................................................................... 43 
5. 
REFERENCES ........................................................................................... 44 
 
LIST OF TABLES 
Table 1: Biomarker Profile by Cohort .................................................................... 9 
Table 2: Sample Size Determination per Cohort ................................................ 12 
Table 3: Exposure Definitions for Induction Treatments ..................................... 28 
Table 4: Exposure Definitions for Maintenance .................................................. 29 
Table 5: Adverse Events Definitions ................................................................... 33 
 
 
LIST OF APPENDICES 
Appendix 1: Protocol Synopsis ........................................................................... 45 
Appendix 2: Schedule of Assessments for All Patients (Screening / Baseline 
and Induction Treatment Phase) ................................................. 74 
Appendix 3: Schedule of Assessments During Maintenance Phase (Cohort 
4) ................................................................................................. 79 
Appendix 4: SAS code ........................................................................................ 83 
Appendix 5: List of Outputs ................................................................................ 84 


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HISTORY CHANGE 
Version 
Date 
Changes 
Final 1.0 
 
N/A 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse events of special interest 
BMI 
body mass index 
BRAFmut 
BRAF mutation 
BSA 
body surface area 
CI 
confidence interval 
CR 
complete response 
CSR 
clinical study report 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
electronic Case Report Form  
EU 
European Union 
HER2 
human epidermal growth factor receptor 2 
HER2+ 
human epidermal growth factor receptor 2 positive 
HR 
hazard ratio 
IC 
informed consent 
ICH 
International Conference on Harmonization 
iDMC 
Independent Data Monitoring Committee 
IHC 
immunohistochemistry 
ITP 
Induction Treatment Phase 
IxRS 
interactive voice or web-based response system  
KM 
Kaplan Meier 
mCRC 
metastatic Colorectal Cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSI-H 
high microsatellite instability 
MSS 
microsatellite stable 
MTP 
Maintenance Treatment Phase 
NCI CTCAE  
National Cancer Institute Common Terminology  
Criteria for Adverse Events  
NE 
not evaluable 
NGS 
next generation sequencing 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PDMS 
protocol deviation management system 
PFS 
progression free survival 
PK 
pharmacokinetic  


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Abbreviation 
Definition 
PP 
Per protocol 
PR 
partial response 
PS 
performance status 
PT 
preferred term 
RDI 
relative dose intensity 
RECIST 
Response Evaluation Criteria in Solid Tumors  
SAE 
serious adverse event 
SAF 
safety population 
SAP 
statistical analysis plan 
SC 
Steering Committee 
SD 
stable disease 
SI 
Système International  
SOC 
System Organ Class 
TEAE 
treatment emergent adverse event 
 


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1. 
BACKGROUND 
The study is a randomized, multi-center, active-controlled, open-label, parallel-group clinical 
study of biomarker-driven maintenance treatment for first-line metastatic colorectal cancer 
(mCRC) patients.  All patients will receive induction treatment with FOLFOX and bevacizumab. 
Induction treatment will be followed by maintenance treatment with chemotherapy combined with 
targeted therapy within one of several maintenance treatment cohorts. Only those patients who 
experience disease response or disease control during induction and who are not assessed as 
resectable at completion of induction will proceed to further treatment in the Maintenance 
Treatment Phase (MTP) of the study. Patients will be assigned to a maintenance treatment cohort 
based on their primary tumour biomarker results. The primary study objective within each cohort 
is to evaluate progression-free survival (PFS).   
Maintenance treatment cohorts may be added or modified over the course of the study. This SAP 
describes planned analyses of patients who were assigned, or would have been assigned, to 
maintenance treatment Cohort 4 based on their primary tumour biomarker profile. Analyses of 
patients assigned to all other MODUL cohorts will be described in SAPs applicable to each 
specific cohort. 
A Steering Committee (SC) is responsible for overseeing the general conduct of the study.  
In addition, an independent Data Monitoring Committee (iDMC) is responsible for evaluating the 
safety of the patients participating in the trial at regular intervals throughout the study. The iDMC 
makes recommendations as to whether cohort recruitment should continue based on benefit-risk 
evaluations that include efficacy as well as safety data. To minimize the impact of such reviews 
on efficacy endpoint analyses, efficacy data included in these reviews has to be specified by the 
iDMC at a preceding iDMC meeting and has to be documented in the iDMC meeting minutes.  
 
2. 
STUDY DESIGN 
Patients continuing from the Induction Treatment Phase (ITP) to the Maintenance Treatment 
Phase are assigned to a maintenance treatment cohort based on their primary tumour biomarker 
status. Following eligibility assessment for their assigned cohort, eligible patients are randomized 
to the experimental or control arm within their cohort. 
The study was initiated with 2 maintenance treatment cohorts, Cohorts 1 and 2. Two additional 
cohorts, Cohorts 3 and 4, were added with protocol amendment 5 (protocol version 6).  
In this open-label study, all patients will receive 8 cycles induction treatment that is considered 
standard in many countries and that has been shown to improve outcomes in the first-line setting. 
Treatment during the ITP, based on investigator’s choice, will be either: 
 
 
Eight 2-week cycles of 5-fluorouracil (5-FU), leucovorin (LV) and oxaliplatin (FOLFOX) in 
combination with bevacizumab 
or 
 
Six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week 
cycles of 5-FU/LV with bevacizumab  
 


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Patients who prematurely discontinue study treatment for any reason during the ITP, who 
experience progressive disease (PD) at any time during or at the end of the ITP, who are 
evaluated as resectable at the end of ITP, who refuse to proceed to the MTP, or who are not 
eligible for any maintenance cohort will undergo a study treatment discontinuation visit and enter 
post-treatment follow-up. Patients who experience disease control or tumor response to induction 
treatment will continue to the randomized MTP of the study wherein the effects of experimental 
and control groups will be compared. Patients in screening after Cohort 4 was introduced (i.e. 
after June 28, 2016), were assigned to Cohort 4 if their primary tumour was HER2-/MSI-H, HER2-
/MSS/BRAFwt, or HER2-/MSS/BRAFmut/RASmut (see Table 1). Treatment in each cohort is shown 
in Figure 1.  
Table 1: Biomarker Profile by Cohort 
 
 
Biomarker profile 
 
Patients in Screening Prior June 28, 
2016 
Patients in Screening After June 28, 2016 
Cohort 1 
BRAFmut 
HER2-/MSS/BRAFmut/RASwt 
Cohort 2 
BRAFwt 
or 
biomarker 
status 
unknown 
Closed to patients screened after June 28, 
2016 
Cohort 3 
Not applicable 
HER2+ 
Cohort 4 
Not applicable 
HER2-/MSI-H; 
HER2-/MSS/BRAFwt; 
HER2-/MSS/BRAFmut/RASmut 
 
 
 


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Figure 1: Study Design as of protocol version 6 
 
 


 
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Primary objective of this study: 
The primary study objective within each cohort is to evaluate PFS.  
An iDMC is responsible for regularly reviewing safety data. 
 
2.1 
PROTOCOL SYNOPSIS 
The Protocol version 8 synopsis is provided in Appendix 1. For additional details, see the 
Schedule of Assessments in Appendix 2. 
 
2.2 
OUTCOME MEASURES 
As mentioned in the protocol, each cohort will be analysed separately and therefore this SAP 
focuses on the description of the analysis required for cohort 4 data only, i.e. applicable to 
enrolled patients eligible for cohort 4 based on primary tumour biomarker status.  
 
2.2.1 
Primary Efficacy Outcome Measures 
PFS is defined as the time from randomization into the MTP until documented disease 
progression as per investigator assessment using Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 or death from any cause, whichever occurs first. If no progression / 
death is observed at the time of clinical cut-off or by the date of any on-study colorectal anti-
cancer surgery with palliative or curative intent, patients will be censored at the date of the 
last evaluable tumor assessment or date of randomization, whichever comes last. 
(Of note: (i) Progressive disease are identified by the Overalll Response=’PD’, even if solely 
based on symptomatic deterioration, (ii) Only surgery occurring between baseline tumor 
assessment for MTP and PFS events are considered for censoring PFS) 
 
2.2.2 
Secondary Efficacy Outcome Measures 
2.2.2.1 
Overall Survival (OS) 
OS is defined as the time from randomization into the MTP to time of death from any cause. 
Patients still alive at time of clinical cut-off will be censored at their last date known to be alive 
as defined in section 4.3. For imputation of “Partial Death Date”, please refer to section 4.14. 
No other secondary efficacy outcome measures (eg. Overall response rate, disease control 
rate, time to treatment response, duration of response etc…) will be analysed for Cohort 4. 
 
 
 






 
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treatment group or the control group of that cohort.  Randomization in Cohort 4 will be 
stratified by geographical region (EU vs rest of the world), patient response after the Induction 
Treatment Phase (CR/PR vs. SD), microsatellite stability (MSI-H vs MSS), and RAS status 
(wild-type KRAS and NRAS vs mutant KRAS and/or NRAS). 
 
3.2 
INDEPENDENT REVIEW FACILITY 
Not applicable. 
3.3 
DATA MONITORING 
An iDMC is responsible for:  
 
evaluating the safety of the patients participating in the trial at regular intervals 
throughout the study, 
 
making recommendations as to whether cohort recruitment should continue based on 
benefit-risk evaluations that include efficacy as well as safety data. To minimize the 
impact of such reviews on efficacy endpoint analyses, efficacy data included in these 
reviews has to be specified by the iDMC at a preceding iDMC meeting and has to be 
documented in the iDMC meeting minutes, 
 
4. 
STATISTICAL METHODS 
4.1 
GENERAL DESCRIPTIVE METHODS 
Categorical variables 
For categorical variables, summary tabulations of the number and missing observations as 
well as the number and percentage within each category of the parameter will be presented. 
Missing will not be considered as a separate category and thus missing observations will not 
be part of the denominator to compute the percentages. Percentages will be rounded to one 
decimal place. Therefore, there may be cases where for instance the total of the percentages 
does not exactly equal 100%. If number of patients is ‘0’ then 0 will be reported instead of ‘0 
(0.0%)’  
Continuous variables 
For continuous variables, N, the mean, median, standard deviation, 25th and 75th percentile, 
minimum and maximum values will be presented.  
Time-to-event efficacy variables 
Time-to-event efficacy variables (e.g. PFS and OS) summaries will include number of patients 
in the population (N), number of patients with the event of interest, number of patients 
censored, median and two-sided 95% confidence interval (CI) computed according to 
Brookmeyer and Crowley (1982) method. Kaplan-Meier (KM) estimates and median survival 
times are calculated with the PROC LIFETEST procedure in SAS. KM curves (product-limit 
method) will be presented as well as the event rates at certain time points with the relevant 
CIs calculated via log-log transformation method (default option CONFTYPE=LOGLOG in 
SAS) based on standard errors computed using the Greenwood’s formula.  
Cox proportional hazards models 


 
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Cox proportional hazards model will be implemented using PHREG procedure with option 
TIES=EXACT. It assumes that there is a true but unknown ordering for the tied event times 
as contrasted to option TIES=DISCRETE which assumes that the events occurred at exactly 
the same time. 
Missing values 
For categorical variables, summary tabulations of the number and missing observations as 
well as the number and percentage within each category of the parameter will be presented. 
For continuous variable, number of missing is displayed between brackets next to ‘n’, unless 
otherwise specified.  
Decimals 
Mean, standard deviation, and median (Q1 and Q3 if applicable) will be presented with one 
more decimal place compared to the raw data, minimum and maximum will be presented with 
same number of decimal places as the raw data. Hazard ratio, odds ratio will be provided with 
two decimals. P-value will be provided with three decimals. If <0.001, then ‘<0.001’ will be 
displayed. 
 
4.2 
DEFINITION OF TREATMENT PHASE 
In this study, there are 3 treatment phases:  
1. Patients are treated first in the Induction Treatment Phase (ITP) for a planned duration 
of 8 cycles, i.e. 16 weeks.  
2. If they do not experience any progressive disease before or at the end of the ITP, are 
not considered resectable at the end of the ITP and do not withdraw from the study and 
are still eligible for any cohort, they are randomized and treated in the Maintenance 
Treatment Phase (MTP). 
3. If they discontinue study treatment for any reason during the Induction or Maintenance 
Treatment Phases, do not withdraw from the study and are still alive, they enter the Post-
Treatment Follow-up Phase. 
 
4.2.1 
Induction Treatment Phase (ITP) 
ITP is defined as the time from first study drug administration until  
 
the day before the randomization for patients continuing treatment in the MTP   
 
the last assessment date otherwise 
 
The first day of treatment in the ITP is defined as the earliest day of a non-null 
administration of any induction phase treatment. 
The last day of treatment in the ITP is defined as the last day of the last initiated cycle of 
the induction phase, or as the death day if the patient died in between. A two-week cycle 
duration is assumed. 
Baseline evaluations for the ITP will be those performed not earlier than 28 days prior to 
the first day of treatment in the induction phase, unless otherwise stated. The latest available 
assessment up to start of the first day of treatment in the induction phase will be considered 
as baseline. For laboratory examinations, weight, vital signs and ECOG PS, assessments 


 
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performed on the first day of treatment of the ITP will be assumed to have been performed 
before drug was given and, thus, will be considered as baseline evaluations. 
On-treatment evaluations for the ITP will be post baseline evaluations performed until 
 
the day before the randomization for patients continuing treatment in the MTP   
 
(including) the study treatment discontinuation visit within 30 days after last day of 
treatment of the ITP (as defined above), for patients not randomized in the MTP. 
 
4.2.2 
Maintenance Treatment Phase (MTP) 
MTP is defined as the time from randomization into MTP until (including) the study treatment 
discontinuation visit in the MTP. 
The first day of treatment in the MTP is defined as the earliest day of a non-null 
administration of any maintenance phase treatments. 
The last day of treatment in the MTP is defined as the last day of the last initiated cycle of 
the maintenance phase, or as the death day if the patient died in between. A two-week cycle 
duration is assumed. 
Baseline evaluations for the MTP will be those performed prior to the first day of treatment 
in the maintenance, unless otherwise stated. The latest available assessment prior to the first 
day of treatment in the maintenance phase will be considered as baseline for safety 
assessments. For laboratory examinations, weight and vital signs, assessments performed 
on the first day of treatment of the MTP will be assumed to have been performed before drug 
was given and, thus, will be considered as baseline evaluations. For subjects randomized but 
not treated in the MTP, the latest available assessment before or on randomization date 
(including assessments from ITP) will be considered as baseline for the MTP.  
For efficacy assessments, the latest available assessment prior or on the randomization date 
will be considered as baseline. 
On-Treatment evaluations for the MTP will be evaluations performed on or after the first 
day of treatment in the MTP within 30 days from last day of treatment in the maintenance 
phase. On-treatment laboratory will be all values collected after the first day of treatment in 
the maintenance phase and within 30 days from last day of treatment in the maintenance 
phase (as defined above). For adverse events, treatment emergent adverse events (TEAEs) 
will be events occurring on or after the first day of treatment in the MTP within 30 days (for 
patients in control group, i.e. not treated with atezolizumab) and 90 days (for patients in 
experimental group, i.e. treated with atezolizumab) from last day of treatment in the 
maintenance phase (as defined above). 
 
4.2.3 
Post-Treatment Follow-up Phase 
Post treatment Follow-up Phase is defined as the time from (excluding) the study treatment 
discontinuation visit until the last available assessment date before clinical cut-off date. For 
patients who discontinue study treatment but without any study treatment discontinuation visit 
date, please refer to 4.14 for imputation of this missing visit date. 
Post-Treatment Follow-up evaluations will be evaluations performed according to the 
protocol after the study treatment discontinuation visit.  
 


 
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4.3 
DATA CONVENTION 
All data will be listed (e.g. pre-treatment serious adverse events), whereas only baseline and 
on-treatment assessments will be considered for summary tables. 
Baseline and on-treatment data will be flagged in the data listings as well as the different 
phases of the study. 
The overall column will not be displayed in any summary tables.  
The following conversion factors will be used to convert days to months or years, where 
applicable:  
 
1 week= 7 days 
 
1 month = 30.4375 days  
 
1 year = 365.25 days 
Age at informed consent (IC) {in years} = (date of informed consent – date of birth) / 365.25 
To calculate duration / time between two dates the following convention will be used: 
[later date] – [earlier date] + 1 day 
Durations and times between two dates will be calculated only when both start and end dates 
are available (imputed dates cannot be used for computation), apart for overall survival when 
date of death has only day as missing). 
Body surface area (BSA) will be recalculated based on the height and weight of the patient 
using the following formula: 
 BSA (m2) = ([Height {cm} x Weight {kg}] / 3600)½ 
Body mass index (BMI) will be calculated using the following formula: 
BMI (kg/m2) = Weight {kg} / Height2 {m} 
The last known date to be alive will be the latest date among all dates specified in the eCRF 
except the following:  
 
Survival Follow-up date when status is either dead (in this case the date of death is 
specified on the Adverse events or Study Completion/Early Discontinuation or SAE 
reporting summary form) or lost to follow-up (in this case last date known to be alive 
is specified on the Survival follow-up form)  
 
Study Completion/Early Discontinuation date when reason is either death or lost to 
follow-up. 
 
A sample / record with test ‘Not Done’.  
4.4 
COMPUTING ENVIRONMENT 
All statistical analyses will be performed using SAS statistical software (Version 9.2 or newer 
version), unless otherwise noted.   
 


 
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4.5 
GRADING AND CODING OF ADVERSE EVENTS, LABORATORY 
PARAMETERS AND MEDICATIONS 
Laboratory results, adverse events, and other symptoms will be graded using the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE), version 
4.0, except where CTC grades are not available. 
Adverse events and relevant Medical History data fields (i.e. prior symptoms / AEs) will be 
coded using the most recent version of Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary available at the time of analysis.  
Prior and concomitant anti-cancer therapy / other medications will be coded using the most 
up-to-date version of the in house Genentech Drug Thesaurus Dictionary. 
Dictionary versions used will be displayed in analysis outputs. 
 
4.6 
ADUSTMENTS FOR COVARIATES 
When indicated, efficacy analysis will be adjusted i.e. the covariates will be incorporated in 
the model used to assess the treatment effect upon the efficacy endpoints. The covariate 
below will be considered:  
 
Patient response after induction treatment as per eCRF data: CR/PR vs. SD. For 
inferential analysis, “SD” will be used as reference, unless otherwise specified.  
(Of note: no adjustment will be made for region since most of patients are in Europe.) 
 
4.7 
SUBGROUP ANALYSIS 
No subgroup analysis will be performed for Cohort 4.  
 
4.8 
ANALYSIS POPULATIONS 
The following patient populations will be evaluated and used for presentation and analysis of 
the data. 
 
4.8.1 
All Population 
ALL Population: The ALL population consists of all screened patients with HER2-/MSI-H; 
HER2-/MSS/BRAFwt; HER2-/MSS/BRAFmut/RASmut biomarker profile who entered study 
screening after June 28, 2016.  
Induction Treatment Phase (ITP) Population: all patients included in the ALL Population 
and who are treated in the ITP, i.e. who received at least one non-null dose of any study 
medications during the ITP. The ITP population is the main population to be used to 
summarize ITP data and Post Induction Treatment data. The 2 following groups will be 
considered when tabulating ITP data:  patients randomized into MTP versus patients not 
randomized into MTP. Post Induction Treatment data will be summarized using one single 
group, i.e. patients not randomized into MTP. ITP population will be the main population for 
the data listings, unless otherwise specified; the 3 following groups will be displayed in listings: 
patients randomized in the experimental group of MTP, patients randomized in the control 
group of MTP, patients not randomized into MTP. 
 


 
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4.8.2 
Randomized Population 
Maintenance Treatment Phase (MTP) Population is defined as all patients randomized into 
the Cohort 4 MTP of the study, irrespective of whether or not they received study medication. 
Patients will be allocated to the treatment group into which they were randomized (as per 
interactive voice or web-based response system [IxRS]). The MTP population is the primary 
population for the analysis of efficacy parameters and baseline characteristics for the MTP. 
The MTP population will be used as well to report the Post Maintenance Treatment data. 
 
4.8.3 
Safety Population 
Safety (SAF) Population: all patients randomized in Cohort 4 who have been treated, i.e. 
who received at least one non-null dose of any study medications during the MTP. 
Patients will be allocated to the treatment group they actually received using the following 
rule: 
 
Patients receiving at least one dose (non-null) of cobimetinib or atezolizumab, while 
on treatment will be allocated to the experimental group cobimetinib+atezolizumab. 
Even if a patient was allocated to the control group and received by mistake a dose 
of cobimetinib or atezolizumab, then this patient will be reallocated to the experimental 
group. 
 
Patients who did not receive any dose of cobimetinib or atezolizumab will be allocated 
to the control group FP+bevacizumab.  
The SAF population is the primary population for the analysis of MTP safety parameters. 
 
4.8.4 
Per Protocol (PP) Population 
As stated in the protocol, the PP Population will not be defined for this study but major protocol 
violations will be listed.  
 
4.8.5 
Pharmacokinetic-Evaluable Population 
Not applicable. 
 
4.8.6 
Biomarker-Evaluable Population 
Not applicable. 
 
4.9 
ANALYSIS OF STUDY CONDUCT 
This SAP focuses only on the description of the analysis required for cohort 4 data. All MTP 
data will be reported. ITP data for patients with HER2-/MSI-H; HER2-/MSS/BRAFwt; HER2-
/MSS/BRAFmut/RASmut biomarker profile randomized and not randomized into the MTP will be 
tabulated in 2 separate columns. Post-treatment data will be reported separately for induction 
and maintenance treatments. This Post-treatment data includes adverse events, deaths, 
subsequent anti-cancer therapies and tumor assessments (until PD if PD not experienced 
before study treatment discontinuation visit), but this last one applies only for Post 
Maintenance treatment.  
 


 
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4.9.1 
Patient Disposition 
The patient disposition table for ITP will be based on the ALL population and will include the 
following information: 
 Number of patients enrolled (ALL) 
 Number of patients not treated in ITP who discontinued trial without being treated and 
associated reason 
 Number of patients treated with induction treatment (ITP population)  
 Number of patients who completed the ITP  
 Number of patients treated in induction who discontinued early ITP and reason for early 
discontinuation  
 Number of patients treated in induction and not randomized who went to post-treatment 
follow-up phase post induction 
 Number of patients being treated in induction who discontinued study prior to MTP and 
associated reason 
 
The patient disposition table for MTP will include the following information: 
 Number of randomized patients (MTP population) (percentage based on MTP) 
 Number of randomized patients without being treated in MTP still on-trial  
 Number of randomized patients who discontinued trial without being treated in MTP and 
the corresponding reason for trial discontinuation (percentages based on MTP) 
 Number of treated patients with maintenance treatment (SAF) (percentages based on 
MTP) 
 Number of patients treated who discontinued all treatments received in MTP and the 
reason for discontinuation from each maintenance treatment (percentage based on MTP). 
All reasons for treatment discontinuation will be displayed and will be taken from the 
individual treatment completion/Early discontinuation eCRF pages. 
 Number of patients treated in MTP who discontinued trial during MTP and the 
corresponding reason for trial discontinuation (percentages based on MTP) 
 Number of patients who entered in the follow-up post-MTP 
 Number of patients being treated in MTP who discontinued trial during follow-up and the 
corresponding reason for trial discontinuation (percentages based on MTP) 
 
A consort flow diagram will be provided to show progress of screened patients and especially 
for patients with HER2-/MSI-H; HER2-/MSS/BRAFwt; HER2-/MSS/BRAFmut/RASmut biomarker 
profile.  Another diagram for patients randomized in Cohort 4 will be provided.  
 
The following supportive listings will be provided: 
 
Patient disposition (including the tumor response status at the end of ITP) and study 
termination information based on ITP 
 
Patients who discontinue treatment due to AE (based on ITP) 
 


 
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4.9.2 
Protocol Deviations 
All major protocol deviations from Protocol Deviation Management System (PDMS) will be 
reported for each phase separately and will be summarized by group. The ITP population will 
be used for ITP data and the MTP population for the MTP data. 
The following will be displayed 
 
Number of patients having at least one major protocol deviation 
 
Number of patients by major protocol deviations category  
Listings for protocol deviations will be provided based on ITP population. Listing for analysis 
population will be provided on ALL population. 
 
4.10 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
4.10.1 
Demographics and Baseline Disease Characteristics 
Baseline and demographic characteristics will be summarized using descriptive statistics.  No 
formal statistical comparisons will be performed.  
Summaries of Patient Demographics will be provided based on the ITP and MTP population 
and will present the following information: 
 
Age at informed consent (yrs) 
 
Age categories (yrs): < 18, 18-64, 65-84, 85 and over 
 
Sex 
 
Ethnicity: Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown  
 
Race  
 
Region: Europe, Americas, Africa, Asia (derived based on country information from 
the clinical database) 
 
Smoking status: Never, Current, Previous 
 
Alcohol use history: Never, Current, Previous 
 
Drug Use: Never, Current, Previous 
 
ECOG Performance Status at baseline: 0,1,> 1,  
 
Baseline Weight (kg) 
 
BMI (see definition in section 4.3) 
 
BSA (see definition in section 4.3) 
 
Baseline Height (cm) 
 
Female reproductive status (for female participants only. Percentage will be based 
on the total number of female patients)  
The summary of patient’s characteristics based on MTP will include in addition the serology 
results (positive, negative, not done) for the following parameters HIV, Hepatitis B surface 
antigen (HBsAg), Hepatitis B core antibody (HBcAb), HCV Antibody, HCV RNA (only if HCV 
Antibody positive). For the summary based on MTP only, ECOG and weight collected just 
prior to or on the first day of MTP will be used as baseline. Please refer to sections 4.2.1 and 
4.2.2 for further details related to definition of baseline evaluations. 
All the biomarker outcomes will be summarized using descriptive statistics by treatment group 
on MTP population: 
Given that the end of the induction phase is the same timepoint as the baseline tumor 
response for the MTP, two summary tables presenting the information as mentioned below 
will be produced. One for the tumor response status at the end of the induction phase based 
on ITP population and as per data collected on the eCRF and will present the following 
information. 


 
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 
Number of patients with CR or PR at end of ITP   
 
Number of patients with SD at end of ITP   
 
Number of patients with PD at end of ITP 
 
Number of patients with NE at end of ITP 
 
Number of patients with NA at end of ITP (i.e. no tumor response during ITP)  
 
The number of patients in MTP population will be summarized by country and study center 
(as per clinical database) and by treatment group based on the MTP population.  
In addition, the number of patients will be summarized by the following stratification factors 
as per IxRS, by treatment group on the MTP: 
 
Region 
o European Union 
o Rest of the world 
 
Tumor response at the end of ITP 
o CR/PR 
o SD 
 
Microsatellite stability 
o MSI-H 
o MSS 
 
RAS status 
o Wild-type KRAS and NRAS 
o mutant KRAS and/or NRAS 
 
A table will show the concordance between the tumor response status at the end of ITP as 
per IxRS and the tumor response status at the end of ITP as per data collected on the eCRF. 
This table will be based on the MTP population and will display the following categories:  
 
CR/PR, SD, Total for the IxRS tumor response 
 
CR, PR, CR/PR, SD for eCRF tumor response 
 
eCRF Tumor response status (CR, PR, SD, PD, NE) at the end of ITP is defined as the last 
tumor response observed during the ITP. Patients without tumor assessment after first day 
of induction treatment will be assigned a tumor response of NA (Not available).  
Patients with only non-target lesions classified as having an eCRF tumor response status at 
the end of the ITP of "Non-CR/Non-PD" are classified as SD for the 2 summary tables 
mentioned above.    
 
Summary of colorectal cancer history will be provided based on the ITP and MTP population 
and will present the following information: 
 
Histological grade at diagnosis 
 
Location of primary tumor 
 
Colon Location: left, right 
 
Cancer type: colon, rectal 
 
Initial AJCC/UICC stage 
 
Initial diagnosis: synchronous, metachronous 
 
Locally recurrent disease: yes, no 
 
Metastatic disease: yes, no 


 
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 
Sites of metastatic disease at time of study enrolment (adrenal gland, ascites, bone, 
liver, lung, mediastinum, skin, other) 
 
Liver as metastatic site: yes, no 
 
Extent of disease by number of sites at time of study enrolment: 0, 1, > 1  
 
Time from initial diagnosis to first dose of ITP (in years) 
 
Time from first diagnosis of locally recurrent disease to first dose of ITP (in years) 
 
Time from first diagnosis of metastatic disease to first dose of ITP (in years)  
 
Number of target lesions at baseline 
 
Of note, if start and/or end dates are incomplete or missing the corresponding time between 
the start and the end date cannot be derived. In this case, time from initial diagnosis to first 
dose of ITP or time for first diagnosis of locally recurrent disease to first dose of ITP or time 
from first diagnosis of metastatic disease to first dose of ITP cannot be derived and will be 
missing.  
 
The following listings will be provided: 
 
Patient Demographics based on ITP population 
 
Biomarker status based on MTP population 
 
Patients by randomization stratification factors as per IxRS and eCRF (based on 
MTP) 
 
Colorectal cancer history based on ITP population 
 
4.10.2 
Medical History 
Medical history, as collected on the “General Medical History and Baseline Conditions” eCRF 
page will be summarized using the ITP population. The summary table will include the number 
and percentage of patients with at least one medical history by Primary System Organ Class 
(SOC) sorted in a descending order of the total frequency count and by preferred term [PT] 
(sorted in a descending order of the total frequency count within each SOC).  
A patient with more than one occurrence of the same medical history in a particular SOC/PT 
will be counted only once in the total of those experiencing events in that particular system 
organ class/preferred term. 
 
4.10.3 
Prior and Concomitant Medications 
4.10.3.1 
Prior Anti-Cancer Treatment/Procedure 
Prior anti-cancer treatments/procedures summaries based on the ITP population will present 
the following information: 
 
Number of patients with prior colorectal cancer surgery: Yes, No 
 
Number of patients by site of prior colorectal cancer surgery: Colon, Rectum, Colon 
and Rectum, Other.  
 
Number of patients with prior radiotherapy: yes, no 
 
Number of patients with prior anti-cancer therapies: yes, no  
 
Number of patients by setting of prior systemic therapy 
 
Number of patients with prior systemic adjuvant therapy: yes, no  
 
Number of regimens for prior systemic therapy: 0, 1, 2, >=3.  
The following listings will be provided based on the ITP population: 
 
Prior anti-cancer therapy 


 
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 
Prior and on-study cancer radiotherapy 
 
Prior and on-study cancer colorectal surgery 
 
4.10.3.2 
Non Anti-Cancer Treatment/Procedure 
 
A prior medication/therapy is defined as any medication/therapy with an end date prior to the 
start of the induction treatment. 
Concomitant medication for ITP 
Concomitant medication includes both medication concomitant at baseline and concomitant 
medication initiated post-baseline. It is defined as any medication/therapy with 
 
 start date before or on: 
o the randomization date for patients randomized in the MTP  
o last dosing date of ITP+30 days for patients not randomized in the MTP  
 
and end-date on or after first dosing date of the ITP or with a missing (ongoing) end-
date 
 
Concomitant medication for MTP 
It is defined as any medication/therapy with 
 
start date before or on last dosing date in the MTP+30 days  
 
and end-date on or after first dosing date of the MTP or with a missing (ongoing) 
end-date. 
Post-treatment Medication 
It is defined as any medication/therapy with a start date more than 30 days after the last 
dosing date. 
In case a medication has an incomplete or missing start date/end date, please refer to section 
4.14 for the rules to be applied in order to identify prior, concomitant or post-treatment 
medications.  
Prior Medications/therapies will be summarized. Summary tables will present number and 
percentage of patients with any medication overall and by Drug Thesaurus Class and Generic 
Name. At each level of summation (overall, Drug Thesaurus Class, Generic Name), patients 
reporting more than one medication are counted only once. Drug Thesaurus Class will be 
sorted in a descending order of the total frequency count and the generic names with the 
highest frequency will be displayed first within each Drug Thesaurus class, unless otherwise 
indicated. The analysis population will be the ITP population and the MTP population for ITP 
data and MTP data, respectively. 
The following tables will be provided: 
 
Concomitant medications during MTP based on MTP population 
 
4.10.4 
Subsequent Anti-Cancer Therapy 
Post Induction Treatment and Post Maintenance Treatment anti-cancer therapies will be 
listed using the ITP population patients who have a study treatment discontinuation visit date.  
 


 
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4.11 
EFFICACY ANALYSIS 
Efficacy analysis will be conducted on the data collected during the MTP/Post maintenance 
treatment (when applicable) and using the MTP population. Analysis will be performed by 
randomized treatment group. Tumor assessments collected during the ITP will not be part of 
the efficacy analysis.  
As Cohort 4 will not reach its target sample size, the analysis is not event driven as described 
in the study protocol, but is time driven instead. As a consequence, all p-values will be 
reported descriptively only, due to low power. All formal statistical tests will be two-sided and 
performed at an alpha of 5%, therefore 95% two sided CI will be presented. No adjustment 
will be made for multiplicity of testing secondary endpoints. 
4.11.1 
Primary Efficacy Endpoint 
The primary efficacy objective of this study is to evaluate PFS. 
To answer the primary objective, the following null and alternative hypotheses will be tested  
 
H0: the distribution of the PFS time is the same in the two treatment groups, i.e.   
PFS (Experimental group) = PFS (Control group) 
 
H1: the distribution of the PFS time is different in the two treatment groups, i.e. PFS 
(Experimental group) ≠ PFS (Control group) 
The primary analysis of PFS will be a comparison between the experimental and the control 
group using an unstratified log-rank test. Please refer to Appendix 4 for the SAS code to be 
used. 
PFS for each treatment group will be estimated using KM product-limit method estimates. 
PFS will be summarized by treatment group and will display the following information: 
 
Number of patients in the population (N) 
 
Number of patients with PFS event  
 
Number of patients censored 
 
Median and two-sided 95% CI computed according to Brookmeyer and Crowley 
method,  
 
25th and 75th quantile, and the corresponding two-sided 95% CI computed 
according to Brookmeyer and Crowley method,  
 
Minimum and maximum 
 
The PFS rates (with the two-sided 95% CI) at 3, 6, 9, 12, 15 and 18 months 
 
Unstratified log-rank test p-value 
KM plot of PFS by treatment group will be generated. 
PFS time will be listed on MTP population in a dedicated time to event listing.  
 
4.11.2 
Secondary Efficacy Endpoints 
4.11.2.1 
Overall Survival 
This study is not powered for OS, so adequately powered statistical testing for this endpoint 
will not be possible. However, the results of an unstratified log-rank test will be provided in an 
exploratory manner to assess the difference between treatment groups for OS. 
The same analysis as those described for the primary endpoint will be repeated for OS on 
MTP population The survival rate will be displayed at the following time points: 6, 9, 12 and 
higher (every 3 months) if appropriate. 
OS time will be listed on MTP population in a dedicated time to event listing.  
 


 
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4.11.3 
Exploratory Efficacy Endpoints 
Not Applicable. 
4.11.4 
Sensitivity Analyses 
In addition, the following sensitivity analyses will be performed on PFS, the primary efficacy 
endpoint: 
 
The PFS hazard ratio, and its 95% two-sided confidence interval, of experimental 
group versus control group, will be estimated using a Cox proportional hazards model 
with treatment as the single covariate. Please refer to Appendix 4 for the SAS code to 
be used. 
 
The PFS hazard ratio, and its 95% two-sided confidence interval, of experimental 
group versus control group, will be estimated using different adjusted Cox proportional 
hazards models, using as covariates the treatment and one of the stratification factors, 
i.e. response at the end of induction treatment as mentioned below 
o cov1 (SD vs CR/PR as per eCRF) 
o cov1 (SD vs CR/PR as per IxRS) 
Note: No adjustment on the region will be performed as almost all the patients are in 
Europe. 
 
The OS hazard ratio, and its 95% two-sided confidence interval, of experimental group 
versus control group, will be estimated using a Cox proportional hazards model with 
treatment as the single covariate. Please refer to Appendix 4 for the SAS code to be used. 
 
4.11.5 
Subgroup Analyses 
No subgroup analysis will be performed for Cohort 4. 
 
4.12 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Not applicable 
4.13 
SAFETY ANALYSES 
Separate safety summaries will be produced for ITP and MTP.   
For ITP data, outputs will be generated on the ITP displaying randomized vs. non randomized 
patients in MTP. MTP outputs will be based on the SAF population and will be presented by 
treatment group.  
No inferential statistical analyses are planned. 
 
4.13.1 
Exposure of Study Medication 
A patient will be considered as having initiated a cycle in the ITP if at least one (non-null) 
dose of any study drugs of the ITP has been administered in the corresponding cycle. 
The overall number of cycles initiated during the ITP is defined as the sum of all initiated 
cycles (as defined above) in the ITP. 
For the MTP, the overall number of cycles initiated (i.e. for drug combination) will be computed 
as the sum of all initiated cycles as defined below: 


 
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 
Day 1 of a cycle is defined as the first day in the considered cycle when treatment is 
administered. 
 
The cycle length is assumed to be 2 weeks 
 
For experimental group: 
o a cycle will be assumed to be initiated if cobimetinib and atezolizumab are 
administered at any time during the same cycle 
 
For control group: 
o  If capecitabine is administered: a cycle will be assumed to be initiated if 
capecitabine and bevacizumab are administered at any time during the same 
cycle  
o If 5-FU/LV or LV substitute is administered: a cycle will be assumed to be 
initiated if bevacizumab and 5-FU and LV or any LV substitute are 
administered at any time during the same cycle 
 
The overall duration (in weeks) for all components of maintenance treatment is defined as 
follows:  
 
Experimental group:  
 [MAX(min(last dosing date of cobimetinib+6, death date), min(last dosing date of 
atezolizumab+13, death date)) – MIN (first dosing date of cobimetinib, first dosing date of 
atezolizumab) + 1]/7  
 
Control group:  
o If capecitabine is administered in the last cycle:  
[MAX(min(last dosing date of capecitabine+6, min(last doing date of bevacizumab+13, 
death date)) – MIN (first dosing date FP, first dosing date of bevacizumab) + 1]/7. 
o If 5-FU/LV is administered in the last cycle: 
 [MAX(min(last dosing date of 5-FU/LV+13, death), min(last dosing date of 
bevacizumab+13, death date)) – MIN (first dosing date of FP, first dosing date of 
bevacizumab) + 1]/7  
  with first dosing date of FP = min(fist dosing date of 5-FU, first dosing date of LV or any 
LV substitute, first dosing date of capecitabine) and last dosing date of 5-FU/LV = 
max(first dosing date of last administration of 5-FU, first dosing date of last administration 
of LV or any LV substitute)  
 
The number of cycles administered, duration of dosing, cumulative dose, dose intensity and 
relative dose intensity (RDI) definitions are provided for each drug individually in Table 2 and 
Table 3 for induction and maintenance, respectively. 
According to protocol, the cycle length is 2 weeks, excepted for capecitabine in the control 
arm for which each cycle length is as per local practise. A 2-week cycle schedule will be 
considered for drugs other than capecitabine and for the drug combinations. For capecitabine, 
a cycle is defined as any continuous administration separated by a rest period, regardless of 
the duration of the continuous administration and the duration of the rest period. A patient will 
be considered as having initiated a cycle in the MTP for a specific drug if at least one (non-
null) dose of this study drug has been administered in the corresponding cycle. 


 
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Table 3: Exposure Definitions for Induction Treatments 
 
FOLFOX 
5-FU/LV 
bevacizumab 
Number of cycles 
sum of all cycles in which at 
least one non-null dose of 
FOLFOX  has been 
administered 
sum of all cycles in which at least 
one non-null dose of 5-FU and LV 
has been administered. Of note, 
consider only cycles where 
oxaliplatin is not administered 
concomitantly with 5-FU/LV.  
sum of all cycles in which at least 
one non-null dose of bevacizumab 
has been administered 
Duration of dosing 
(weeks) (1) 
 
[min (last  date of FOLFOX+13, 
death date) – first FOLFOX 
dosing date+1] / 7 or 
If FOLFOX-4 or FOLFOX-7 or 
modified FOLFOX-7 is 
administered in the last cycle 
initiated  
 [min (last  date of FOLFOX 
+12, death date) – first 
FOLFOX dosing date+1] / 7 
 
max (min(last date of 5-FU+13, 
death date), min(last date of LV+13, 
death date)) – min (first date of 5-
FU, first  date of LV) +1] / 7 
Of note, consider only 
records/cycles where oxaliplatin is 
not administered concomitantly with 
5-FU/LV. 
[min (last date of bevacizumab +13, 
death date)) – (first bevacizumab 
dosing date in the induction) +1]  / 7 
(1) According to the proposed formula, the duration of dosing may be overestimated in case patients discontinued treatment prior to the end of 
the last cycle. 
 
 
 
 


 
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Table 4: Exposure Definitions for Maintenance 
 
 
 
 
Capecitabine 
5-FU or LV  
 
bevacizumab 
atezolizumab 
cobimetinib 
Number of cycle 
The sum of all cycles in which at least one non-null dose of <treatment> has been administered 
Duration of dosing 
(weeks) (1) 
[min (last dosing date of <treatment> + x, death date)) – (first <treatment> dosing date in the maintenance) +1] / 7 
Where x=6 for capecitabine, cobimetinib  
     x=13 for 5FU, LV, bevacizumab, atezolizumab 
For 5-FU and LV, last dosing date of treatment will be replaced by the first dosing date of the last administration 
Actual dose  
<treatment> dose administered (in mg) as collected on the dosing eCRF page   
Unit: mg 
Planned dose  
<treatment> planned dose (in mg) as collected on the dosing eCRF page   
Unit: mg 
Normalized dose 
dose / recalculated BSA(2) 
Unit: mg/m2 
dose / weight(3) 
Unit: mg/kg 
NA 
NA 


 
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Capecitabine 
5-FU or LV  
 
bevacizumab 
atezolizumab 
cobimetinib 
Cumulative dose  
The cumulative dose will be 
derived for each records as 
below: (end date of 
administration - start date 
of administration +1) * 
normalized actual dose for 
the record * 2  
Cumulative dose= sum of 
cumulative dose across all 
records  
Unit: mg/m2 
sum of the all 
<treatment > normalized 
actual doses (in mg/m2) 
administered in all cycles 
 
 
sum of the all bevacizumab 
normalized actual doses (in 
mg/kg)  administered in all cycles 
sum of the all of 
atezolizumab actual 
doses (in 
mg)  administered in all 
cycles 
The cumulative dose will 
be derived for each 
records as below: (end 
date of administration - 
start date of 
administration +1) * 
actual dose for the 
record  
Cumulative dose= sum 
of cumulative dose 
across all records  
Unit: mg 
Dose intensity 
Cumulative dose / (duration 
of dosing *7) 
Unit: mg/m2/day 
Cumulative dose / 
duration of dosing  
Unit: mg/m2/week 
 
Cumulative dose / duration of dosing  
Unit: mg/kg/week 
Cumulative dose / 
duration of dosing  
Unit: mg/week 
Cumulative dose / 
(duration of dosing * 7)  
Unit: mg/day 
Cumulative planned 
dose (CPD) 
Sum of all normalized 
planned dose (in mg/m2) in 
all cycles   
Sum of all normalized 
planned dose (in mg/m2) 
in all cycles  
 
Sum of all normalized planned dose 
(in mg/kg) in all cycles  
 
Sum of the all planned 
doses (in mg) reported 
in all cycles  
 
Sum of all planned doses 
(in mg) in all cycles 
where ‘Planned 
treatment break as per 
protocol’ is not ticked 
Planned dose 
intensity  
CPD/(duration of dosing *7) 
Unit: mg/m2/day  
CPD/duration of dosing 
Unit: mg/m2/week 
CPD/duration of dosing  
Unit: mg/kg/week 
 
CPD/duration of dosing  
Unit: mg/ week  
 
CPD/(Duration of dosing 
*7) 
Unit: mg/day 


 
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(1) According to the proposed formula, the duration of dosing may be overestimated in case patients discontinued treatment prior to the end of the 
last cycle. 
(2) The BSA will be recalculated based on the height and weight (see point 3 for identification of weight) of the patient using the formula as mentioned 
in section 4.3. 
(3) The baseline weight will be used as reference. If the last available weight of the patient prior to or on the cycle start has changed by 10% or 
greater (i.e. patient has gained or lost more than 10% of their body weight since baseline) the patient new weight will be set as the baseline 
weight and will be used at the patient current and subsequent cycles. If a patient weight has changed by 10% or greater at a later cycle, then 
this new weight will be set as the base weight as aforementioned. 
Relative dose 
intensity (RDI) (%) 
100 * (dose intensity) / (planned dose intensity) 


 
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The following information will be tabulated for the ITP using the ITP population: 
 
Summary of total number of cycles initiated per patient 
o Total number of cycles initiated (1,2,3,4,5,6,7,8)  
o Summary statistics of total number of cycles initiated 
 
The following information will be tabulated for the MTP using the SAF population:  
 
Summary of overall duration of treatment and overall number of cycles initiated 
o Overall duration of maintenance treatment (in weeks) 
o Overall number of cycles initiated: 1,2,3,4,5,6,7,8,9,10, 10-15, >=15  
o Summary statistics of overall number of cycles initiated per patient 
 
Summary of drug exposure  
o Total number of cycles administered (tabulated separately for each drug ) 
o Duration of dosing (in weeks) (tabulated separately for each drug ) 
o Cumulative dose (tabulated separately for each drug according to definition 
provided in table 3) 
o Dose intensity (tabulated separately for each drug according to definition provided 
in table 3) 
o Relative dose intensity: ≤90%, >90%-≤100%, >100% (tabulated separately for 
each drug according to definition provided in table 3) Note: Number and 
percentage will be based on the patients who received the corresponding drug. 
 
Supportive listings presenting the study drug administration as well as the exposure information 
will be provided separately based on ITP population and SAF population for the induction and 
for the maintenance, respectively.  
 
4.13.1.1 
Cycle Delay  
Cycle delay is applicable to the following treatments: FP (5-FU, LV or capecitabine), and 
bevacizumab. 
Cycle delay is defined as follow:  
 
For 5-FU, LV, bevazicumab, atezolizumab which have planned cycle of 2 weeks: 
A cycle delay for <treatment> will be defined as the number of days in excess of the expected 
days between two consecutive doses of <treatment> (14 days) and will be calculated as D1Cn+1 
- D1Cn where D1Cn+1 and D1Cn  correspond to date of administration of <treatment> in cycle 
n+1 and cycle n, respectively.  An excess of more than 3 days will qualified cycle Cn+1 as delayed 
for <treatment>. Of note, the first cycle (C1) cannot be identified as cycle delay.  
 
For capecitabine: 
Cycle delay will be defined as the number of days in excess of the expected days between two 
non-zero administrations (21 days, i.e. 14 days of administration and a rest period of 7 days) and 
will be calculated as D1Cn+1 - D1Cn where D1Cn+1 and D1Cn correspond to the start date of 
the first administration of capecitabine in cycle n+1 and cycle n, respectively.  An excess of more 
than 3 days will qualify cycle Cn+1 as delayed for capecitabine. Of note, the first cycle (C1) 
cannot be identified as cycle delay.  
 
For cobimetinib, which has planned cycle of 4 weeks (3 weeks on, 1 week off):  


 
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Cycle delay will be defined as the number of days in excess of the expected days between two 
non-zero administrations (28 days, i.e. 21 days of administration and a rest period of 7 days) and 
will be calculated as D1Cn+1 - D1Cn where D1Cn+1 and D1Cn correspond to the start date of 
the first administration of cobimetinib in cycle n+1 and cycle n, respectively. An excess of more 
than 3 days will qualify cycle Cn+1 as delayed for cobimetinib. Of note, the first cycle (C1) cannot 
be identified as cycle delay. 
Cycle delay will be displayed in listing. 
 
4.13.2 
Adverse Events 
Adverse events variables are defined in Table 5. 
Table 5: Adverse Events Definitions 
 
Variable 
Definition 
Treatment 
Emergent 
Adverse Events 
(TEAEs) for the 
induction 
treatment phase 
(1) 
 
Any adverse events (serious and non-serious) with an onset date on (only if the 
“Event occurred prior to first study drug administration” from the AE eCRF page is 
not checked) or after the first day of treatment of the ITP and up to the:  
 
first day of treatment of the MTP (excluding) if it occurs within the 30 days 
from last day of treatment of induction treatment for patients treated with 
maintenance treatment 
 
within 30 days from last day of treatment of induction treatment (as defined 
in section 4.2.1), for patients not treated with maintenance treatment or for 
patients treated with maintenance treatment but with first day of treatment of 
MTP being more than 30 days after last day of treatment of ITP.  
TEAEs for the 
maintenance 
treatment 
phase(1) 
 
Any adverse events (serious and non-serious) with an onset date on (only if the 
“Event occurred prior to first study drug administration” from the AE eCRF page is 
not checked)  or after the first day of treatment of the MTP and up to 30 days (for 
patients in control group, i.e. not treated with atezolizumab) and 90 days (for 
patients in experimental group, i.e. treated with atezolizumab) from the last day of 
treatment of MTP (as defined in section 4.2.2) 
Post induction 
treatment 
Adverse Events  
Any adverse events (serious and non-serious): 
 
with an onset date more than 30 days after the last day of treatment of the 
ITP (as defined in section 4.2.1) for patients not treated with maintenance 
treatment. 
 
with an onset date more than 30 days after the last day of treatment of the 
ITP and prior the first day of treatment of the MTP, for patients treated with 
maintenance treatment with first day of treatment of MTP being more than 
30 days after last day of treatment of ITP.. 


 
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Post maintenance 
treatment 
Adverse events  
Any adverse events (serious and non-serious) with an onset date more than 30 
days (for patients in control group, i.e. not treated with atezolizumab) and more than 
90 days (for patients in experimental group, i.e. treated with atezolizumab) after the 
last day of treatment of the MTP (as defined in section 4.2.2) (as defined in section 
4.2.2). 
Adverse Events 
NCI CTCAE 
grade 
The adverse events grade will be the one with tick box checked for "AE most 
extreme NCI CTCAE grade" 
Serious Adverse 
Events (SAEs) 
Any adverse events qualified as “serious” by the investigator.  
Adverse Events 
with fatal 
outcome 
Any adverse events with outcome of “Fatal”. 
Adverse events 
related to 
<FOLFOX, 
bevacizumab, FP, 
atezolizumab, 
cobimetinib>  
Any adverse events with an “AE suspected to be caused by study drug <FOLFOX, 
bevacizumab, FP, atezolizumab, cobimetinib>  as ‘Yes’. 
For AE suspected to be caused by FOLFOX while starting in the maintenance 
phase, the unique text ‘“AE considered related to Folfox”‘ has been reported in the 
comment field ‘ 
Adverse events 
leading to 
<FOLFOX, 
bevacizumab, FP, 
atezolizumab, 
cobimetinib> 
discontinuation 
Any adverse events with an “Action taken with <FOLFOX, bevacizumab, FP, 
atezolizumab, cobimetinib> due to SAE/AE” of “drug withdrawn” 
Adverse events of 
Special Interest 
(AESI) as 
reported on eCRF  
AESIs will be selected based on the tick box from the eCRF.  
<Bevacizumab, 
atezolizumab> 
AESIs based on 
pre-defined terms 
AESIs will be selected from AEs based on the <bevacizumab, atezolizumab> list of 
pre-defined terms.  
(1) Of note, in case an event has an incomplete or missing start date, which consequently prevents its 
allocation to only one treatment phase of the study, the event will be allocated to both the induction 
and maintenance phase. Refer to section 4.14 for further details. 


 
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Safety summaries will be produced for the ITP on the ITP population and for the MTP on the SAF 
population, unless otherwise specified. ITP summaries will display patients randomized vs. 
patients not randomized in MTP. MTP summaries will be done by actual maintenance treatment 
group as defined for the SAF. Descriptive statistics will be generated as appropriate. No 
inferential statistical analyses are planned. 
Summaries of adverse events for ITP and MTP will be generated for those events that are 
considered treatment emergent. The AE tables will include the number and percentage of 
patients with at least one AE, by MedDRA primary System Organ Classes (SOC) (sorted in a 
descending order of the total frequency count) and MedDRA Preferred Terms (PT) (sorted by 
descending order of the overall frequency count within each SOC) unless otherwise indicated. A 
patient with more than one occurrence of the same adverse event in a particular system organ 
class/preferred term will be counted only once in the total of those experiencing adverse events 
in that particular system organ class/preferred term. For the overall summary tables, information 
presented by grade will not be restricted to the worst grade per patient i.e. all events will be 
presented.  Any AEs with a missing CTC grade will be reported in the “missing” category grade.  
 
An overview table will be produced for the ITP based on the ITP population and will present: 
 
Number of TEAEs 
 
Number of patients with at least one TEAE 
 
Number of patients with at least one TEAE by CTC grade: 1, 2, 3, 4, 5, ≥3, missing 
 
Number of patients with at least one related TEAE 
o Any study drug  
o FOLFOX 
o 5-FU/LV 
o bevacizumab 
 
Number of patients with at least one serious TEAE 
 
Number of patients with at least one related serious TEAE  
o Any study drug  
o FOLFOX 
o 5-FU/LV 
o bevacizumab 
 
Number of patients with at least one TEAE with fatal outcome 
 
Number of patients with at least one TEAEs leading to treatment discontinuation of: 
o Any study drug  
o FOLFOX 
o 5-FU/LV 
o bevacizumab 
 
An overview table will be produced for the maintenance phase based on the SAF and will present: 
 
Number of TEAEs 
 
Number of patients with at least one TEAE 
 
Number of patients with at least one TEAE by CTC grade: 1, 2, 3, 4, 5, ≥3, missing 
 
Number of patients with at least one related TEAE  
o Any study drug  
o Fluoropyrimidines 
o bevacizumab  


 
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o atezolizumab 
o cobimetinib 
o  FOLFOX 
 
Number of patients with at least one serious TEAE 
 
Number of patients with at least one related serious TEAE  
o Any study drug  
o Fluoropyrimidines 
o bevacizumab  
o atezolizumab 
o cobimetinib  
o FOLFOX 
 
Number of patients with at least one TEAE with fatal outcome 
 
Number of patients with at least one TEAEs leading to treatment discontinuation of: 
o Any study drug  
o bevacizumab  
o atezolizumab 
o cobimetinib  
 
Number of patients with at least one treatment emegent AESI (as reported on eCRF) 
 
Number of patients with at least one treatment emegent AESI (based on list of pre-
defined terms) 
o bevacizumab, 
o atezolizumab 
 
Number of patients with at least one serious treatment emergent AESI (as reported on 
eCRF) 
 
In addition, the following tables (number and percentage of patients) will be presented for the 
ITP based on the ITP population and will display the number of patients (and corresponding 
number of TEAEs) and percentage with any: 
 
TEAEs by SOC and PT  
 
TEAEs by SOC and PT and by Worst Intensity 
 
Related TEAEs by SOC and PT: any study drugs, bevacizumab, 
 
TEAEs leading to treatment discontinuation by SOC and PT: any study drugs 
 
TEAEs leading to dose reduction or interruption by SOC and PT: bevacizumab  
 
Serious TEAEs by SOC and PT  
 
Related serious TEAEs by SOC and PT: to any study drugs, bevacizumab 
 
Treatment emergent AESI by AESI eCRF categories, SOC and PT   
 
Bevacizumab treatment emergent AESI based on pre-defined categories  
 
The following tables will be presented for the MTP only and will display the number and 
percentage of patients (and corresponding number of TEAEs) with any: 
 
TEAEs by SOC and PT  
 
TEAEs by SOC and PT and by Worst Intensity  
 
Related TEAEs by SOC and PT: any study drugs, atezolizumab, bevacizumab, 
cobimetinib  
 
Serious TEAEs by SOC and PT  
 
Grade 5 TEAEs or TEAEs with fatal outcome by SOC and PT  
 
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 
TEAEs leading to dose reduction or interruption by SOC and PT: atezolizumab, 
cobimetinib 
 
Related serious TEAEs by SOC and PT: to any study drugs, atezolizumab, 
bevacizumab, cobimetinib 
 
Treatment emergent AESI by AESI eCRF categories, SOC and PT   
 
Bevacizumab treatment emergent AESI based on pre-defined categories during MTP 
 
Atezolizumab treatment emergent AESI based on pre-defined categories during MTP 
 
 
By-patient listings will be provided for AEs; they will include Post-treatment adverse events. 
Appropriate flagging of study phase (ITP/MTP) as well as TEAEs/Post-treatment AEs will be 
done. The following listings will be provided based on ITP population 
 
All adverse events  
 
All Grade 5 adverse events or any adverse events with fatal outcome  
 
All adverse events leading to treatment discontinuation  
 
All AESI (as reported on eCRF)   
 
4.13.3 
Death 
The following summary tables will be provided and will present: 
 
The number of patients who died within 30 days from last day of treatment of MTP 
(as defined in section 4.2.1) with the corresponding death reason using the SAF 
population 
 
The number of patients who died more than 30 days from last day of treatment of 
maintenance treatment and the corresponding reason of death based on patients 
from the MTP population who has a study treatment discontinuation visit date 
One listing will be generated for deaths based on the ITP population and including appropriate 
flagging of study phase (ITP and MTP) and on-treatment/post-treatment deaths (i.e. within 30 
days from last day of treatment/more than 30 days from last day of treatment).  
All deaths information (including reason and date) will be retrieved from the Study 
Completion/Early Discontinuation eCRF page.  
4.13.4 
Laboratory Data 
The following laboratory parameters will be considered as CTC gradable parameters. 
 
Haematology 
 
Absolute Neutrophils Count (ANC)  
 
Hemoglobin (Hb) 
 
Leukocytes/White Blood Cells counts (WBC) 
 
Platelet Count 
 
Blood chemistry 
 
Albumin  
 
Alkaline Phosphatase (ALP)  
 
Calcium 
 
Creatinine  


 
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 
Creatine phosphakinase 
 
Glucose 
 
Potassium  
 
SGPT or alanine aminotransferase (ALT)  
 
SGOT or aspartate aminotransferase (AST)  
 
Sodium 
 
Total Bilirubin 
 
Magnesium 
 
Amylase 
 
Lipase 
 
Coagulation  
 
international normalized ratio (INR)  
 
activated partial thromboplastin time (aPTT) 
 
The following parameters will be considered as non CTC gradable parameters. 
 
Hematology  
 
Red blood Cell (RBC) 
 
Hematocrit 
 
Lymphocytes 
 
Neutrophils 
 
Eosinophils 
 
Basophils 
 
Monocytes 
 
Blood Chemistry 
 
Blood Urea Nitrogen 
 
Bicarbonate 
 
Chloride Lactate dehydrogenase (LDH) 
 
Phosphorus 
 
Total Protein 
 
Urinalysis 
 
Urine Protein Dipstick 
 
24-hour urine protein 
 
Thyroid 
 
Thyroid-Stimulating Hormone (TSH) 
 
Free T3 
 
Free T4 
 
All laboratory parameter information will be summarized for MTP only. Laboratory information 
reported in tables will be restricted to the baseline and on-treatment measurements. The analysis 
population will be the SAF population for the MTP.  
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When applicable, laboratory tables will display their High (hyper)/Low (hypo) values of a specific 
parameter (e.g. calcium (high) and calcium (low) in separate tables. 
In case of missing normal ranges for parameters that are not differential and have only grade 1 
defined from normal ranges (e.g. Neutrophils, WBC, Albumin…) the worst case scenario will be 
applied, i.e. grade 1. 
A “Missing” category will be reported for patients with missing grades or missing reference range 
indicators at baseline and/or on-treatment and patients with no laboratory assessments.  
For hematology, blood chemistry and coagulation parameters which can be graded per CTCAE, 
the information will be summarized by means of a shift table summarizing the baseline grade 
versus the worst CTC grade per patient defined as the highest CTC grade among the on-
treatment evaluations. If there is no on-treatment evaluation, then the worst grade will be set to 
‘Missing’. 
Hematology and blood chemistry parameters which cannot be graded per CTCAE, the 
information will be summarized by means of a shift table from baseline category to worst on-
treatment category. The following categories will be used: 
 
Baseline: Low/Normal/High/Missing/Overall 
 
Worst on-treatment: Low/Normal/High/Missing/Overall 
Patient with “High” and “Low” for the same laboratory test (at different visits) is counted for each 
direction in summary tables. 
For urinalysis protein dipstick, all non-missing assessments excepted “0-absent” assessment will 
be considered “Present”. A shift table presenting baseline category versus worst on-treatment 
category will be produced with the following categories: 
 
Baseline: Absent/Present/Missing/Overall 
 
Worst on-treatment: Absent/Present/Missing/Overall 
For urinalysis, 24-hour urine protein values will not be tabulated but listed only. 
4.13.5 
Vital Signs 
Vital signs parameters include: 
 
Temperature (°C) 
 
Systolic blood pressure (SBP seated position) (mmHg) 
 
Diastolic blood pressure (DBP seated position) (mmHg) 
 
Weight (kg) 
 
BSA (m2) 
 
Heart rate (beats/min) 
 
Respiratory rate (breaths/min) 
 
Vital signs information will be summarized for each phase separately and by treatment group 
when applicable. Vital signs information reported in tables will be restricted to non-missing 
baseline and non-missing on-treatment measurements. The analysis population will be the  SAF 
population for the MTP.  
Actual value and change from baseline for heart rate and systolic and diastolic blood pressure 
will be summarized by treatment group for each visit using descriptive statistics. For the 
experimental arm, vital signs are collected within 60 minutes before the infusion and at other 


 
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timepoints when clinically indicated and at the first infusion. Only the timepoint ‘Within 60 minutes 
before the infusion’ will be included in the summary table. 
 
4.13.6 
Other Safety Assessment  
Blood oxygen saturation is measured only in patients randomized to the experimental treatment 
group. Blood oxygen saturation will be measured by pulse oximetry. 
Non-missing pulse oximetry values will be summarized by visit through descriptive statistics. 
 
 
 


 
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4.14 
MISSING DATA 
Imputation of partial/missing death date will be done as follows:  
 
If the date is completely missing, then the day of “Last known to be alive” +1 will be used  
 
If only day is missing and year and month are same as “Last known to be alive”, then the 
day of “Last known to be alive”+1 will be used otherwise the 1st day of the month will be 
used 
 
If day and month are missing and year is same as “Last known to be alive”, then the “Last 
known to be alive”+1 will be used, otherwise 1st of January will be used 
 
Partially missing dates for adverse events (AEs) will be imputed as follows. Of note, imputation 
of missing/partial AE date will be done only to identify treatment emergent AEs. 
AE onset dates 
 Partially missing onset dates will be imputed as follows 
 
When only Day is missing:  
o If Month & Year of the onset date are the same as Month & Year of the 
first day of treatment of the induction/maintenance treatment phase, the 
imputed onset date will be imputed as the minimum of the first day of 
treatment of the induction/maintenance treatment phase and the AE 
resolution date (imputed if needed). 
o Otherwise, the missing day will be replaced by “1”. 
 
When Day & Month are missing:  
o If Year of the onset date is the same as Year of the induction/maintenance 
treatment phase, the imputed onset date will be imputed as the minimum 
of the first day of treatment of the induction/maintenance treatment phase 
and the AE resolution date (imputed if needed). 
o Otherwise, the missing Day & Month will be replaced by “01JAN”. 
 
 Complete missing onset dates for AEs will be imputed by first day of treatment of the 
induction/maintenance treatment phase and the AE will be considered as treatment 
emergent, unless the end date of the AE (imputed if needed) or the end year of the 
AE (if day and month are missing) is entered and is before the year of the first 
treatment administration of the induction/maintenance treatment phase. 
 
AE resolution dates 
 Incomplete resolution dates will be replaced by the last day of the month (if day is 
missing only), if not resulting in a date later than the date of patient's death. In the 
latter case the date of death will be used to impute the incomplete resolution date 
 In all other cases the incomplete resolution date will not be imputed 
Of note, the above rules may allow allocation of an event to both the ITP and MTP treatment 
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Partially missing dates for medications/therapies will be imputed as follows. Of note, imputation 
of missing/partial medicationstherapies date will be done only to identify concomitant 
medications/therapies. 
Partial dates will be imputed as follow: 
 
Start dates 
o When only Day is missing: the missing day will be replaced by “1” 
o When Day & Month are missing: the missing Day & Month will be replaced by 
“01JAN”. 
 
End dates 
o When only Day is missing: the missing day will be replaced by the last day of the 
month 
o When Day & Month are missing: the missing Day & Month will be replaced by 
“31DEC”. 
And rules described in section 4.10.3.2 and below will be applied using imputed dates. 
 
In case of complete missing dates, the following will be applied: 
 
If the start date of the medication/therapy is unknown (i.e. complete missing date) and 
there is no end date, medication/therapy is flagged as taken prior to study but not as 
ongoing then the medication/therapy will be considered as a prior medication.  
 
If both the start date and end date of the medication/therapy is unknown (i.e. complete 
missing date), then the medication/therapy will be considered as a concomitant 
medication/therapy for both the induction and maintenance phase if the patient is treated 
in the phase of interest. 
 
If the start date of the medicationtherapy is unknown (i.e. complete missing date), but the 
end date is known and is prior to the first dosing date of the considered phase, then the 
medicationtherapy will not be considered as concomitant for the corresponding phase. 
 
If the start date of the medication/therapy is available and the end date is unknown, then 
the medication/therapy will not be considered as prior. Concomitance to ITP/MTP will be 
assessed using the available start date.  
Partially missing dates for surgery will be imputed as follows. Of note, imputation of 
missing/partial surgeries date will be done only to identify concomitant surgeries. 
Partial dates will be compared as follow: 
 
When only Day is missing: Month & Year of the surgery will be compared to Month & 
Year of the first dosing date of interest (either ITP or MTP). If on or after, the surgery will 
be considered as concomitant to the period of interest. If on or before the first doing date 
of ITP, the surgery will be considered as prior. 
 
When Day & Month are missing: Year of the surgery will be compared to Year of the 
dosing date of interest (either ITP or MTP). If on or after, the surgery will be considered 
as concomitant to the period of interest. If on or before the first doing date of ITP, the 
surgery will be considered as prior. 
Of note, the above rules may allow a medication/procedure to be concomitant to both the ITP 
and MTP treatment phase. 
 
 


 
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For patients who discontinued study treatment but without any study treatment discontinuation 
visit date, this visit will be imputed as follows: 
 
If patient was treated in the MTP, the last dose will be retrieved from the treatment drug 
completion/early discontinuation page from the eCRF in the maintenance phase. The 
maximum date among the date mentioned for each treatment during MTP + 30 days will 
be considered.  
 
If patient was treated in the ITP, the last dose will be retrieved from the treatment drug 
completion/early discontinuation page from the eCRF in the induction phase. The 
maximum date among the date mentioned for each treatment during ITP + 30 days will 
be considered  
with the following exception: 
o If a patient died within 30 days from last dose, the follow up phase does not exist 
for this patient 
Partially missing dates for date of initial histological diagnosis or date of first diagnosis of 
metastatic disease or date of first diagnosis of locally recurrent disease will be imputed as follows: 
Imputation of these partial dates will be done only to determine if the initial diagnosis is 
synchronous or metachronous and only in case the date day is missing. The imputation will 
consist in replacing the missing day by “1”. In case month and/or year are missing, no imputation 
will be done. 
 
No other dates will be imputed, unless otherwise specified. The original incomplete, missing or 
partial dates will be presented in the listings, not the imputed dates. 
 
4.15 
INTERIM ANALYSES 
 
No formal interim analyses on PFS or OS are planned. 


 
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5. 
REFERENCES 
Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response to 
panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008 Dec 
10;26(35):5705-12. doi: 10.1200/JCO.2008.18.0786. Epub 2008 Nov 10. 
 
Ron Brookmeyer and John Crowley, A Confidence Interval for the Median Survival Time. 
Biometrics  Vol. 38, No. 1 (Mar., 1982), 29-41 
 


 
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Appendix 1: Protocol Synopsis 
  


 
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prior to informed consent signature may be used as screening assessments as long as they were done within 7 days prior to informed consent 
signature. 
e. The “All Cohort” eligibility criteria are evaluated prior to initiating the first cycle of study treatment during the Induction Treatment Phase.  
f. 
Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, smoking history, use of alcohol and drugs of abuse, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 7 days prior to the Screening visit.  Demographic data will include 
age, sex, and self-reported race/ethnicity (where permitted by federal regulations). 
g. Vital signs include measurements of systolic and diastolic blood pressure while the patient is in a seated position, and temperature.  During 
Screening, weight only required ≤ 7 days. 
h. Baseline assessment requires a complete physical exam. A complete physical examination should include an evaluation of the head, eyes, 
ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological 
systems. Abnormalities identified at Screening / Baseline will be recorded as baseline conditions.  At subsequent visits (or as clinically 
indicated), limited, symptom-directed physical examinations should be performed. Changes from Baseline, with new or worsened clinically 
significant abnormalities, should be reported as AEs if appropriate.  
i. 
ECOG status assessed within 7 days prior to Day 1 of Cycle 1 (Induction Treatment Phase) for eligibility determination.  See Appendix 8. 
j. 
Concomitant medication includes any prescription medications or over-the-counter preparations used by a patient between the 7 days prior to 
the date of informed consent up until the date of study discontinuation.  Only concomitant medications used for supportive care, to alleviate 
symptoms of mCRC, or to treat adverse drug reactions should be recorded on the Concomitant Medications eCRF. At subsequent visits, only 
changes to current medications or medications used since the last documentation of medications will be recorded.  Concomitant medications 
for treatment of AEs related to study medication will continue to be recorded while the AE is being followed. For permitted and prohibited 
concomitant medications, see Section 4.4. 
k. Haematology includes haemoglobin, haematocrit, platelet count, red blood cell count, white blood cell count, and differential. Blood chemistry 
includes ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin, blood urea nitrogen or urea, LDH, creatinine, glucose, calcium, 
phosphorus, sodium, potassium, chloride, and bicarbonate. Hematology and blood chemistry tests must be conducted prior to each treatment 
cycle, with the results available for review prior to start of treatment according to local standards for treatment management. However, only 
tests conducted every second treatment cycle will be recorded in the eCRF. Clinical laboratory results constituting a clinically significant AE 
should be recorded as such.  
l. 
INR and aPTT are required for all patients at screening but only for patients receiving anticoagulants while on protocol-specified treatment. 
m. Urinalysis must be performed by dipstick at Baseline and within 48 hours prior to every cycle.  A 24-hour urine collection is needed in the event 
of proteinuria ≥ ± 2 by dipstick test. 
n. Urine or blood pregnancy test, only for women of childbearing potential (i.e. not post-menopausal as indicated by < 12 months of non-therapy-
induced amenorrhea, nor surgically sterile [absence of ovaries and/or uterus]), including those who have had a tubal ligation.  A serum 
pregnancy test is required within 7 days prior to start of study induction treatment, or within 14 days with a confirmatory urine pregnancy test 
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o. Will include radiology, chest and abdominal CT or MRI, and other scans to document all sites of disease. Include upper abdomen at Baseline.  
A CT or MRI scan of the brain is required if there is clinical suspicion of CNS metastases at screening/Baseline or at any time during the 
Induction Treatment Phase. Subsequent tumour assessments will be done according to standard of care at each study centre, with the 
exception that all patients must have a tumour assessment at the end of the Induction Treatment Phase. Tumour assessments are not required 
for study purposes after disease progression has been documented. Patients who discontinue study treatment during the Induction Treatment 
Phase prior to disease progression will also continue to be followed for progressive disease, with disease status followed according to local 
practice until progression or May 31, 2019, whichever comes first. After May 31, 2019, disease status will not be collected for the study.    
p. Archival tumour tissue (FFPET) block from the primary tumour obtained at the time of the initial diagnosis. If the tumour block is not available, ≥ 
20 slides cut from the primary tumour sample will be accepted as an alternative.  Before a patient can be enrolled, the sample (block or slides) 
must be shipped to the designated laboratory with the corresponding pathology report and receipt of the shipment must be confirmed by the 
laboratory.  See Appendix 17. 
q. Collection of the optional core biopsy of metastatic tumours was discontinued as of May 2018 (See Appendix 18).  
r. 
Whole blood and plasma samples will be collected from all study patients for exploratory biomarker analyses unless genomic analysis is not 
allowed per local regulations. In such instances, only plasma samples will be collected.  All samples will be sent to a designated laboratory.  
Samples during treatment should be taken within 48 hours prior to study treatment Day 1 of each cycle indicated, unless otherwise specified 
(see Appendix 17 and Laboratory Manual). 
s. After the signing of the informed consent form, and prior to Day 1 of Cycle 1 (Induction Treatment Phase), any SAEs thought to be related to a 
protocol-mandated intervention should be reported.  Adverse events will be documented at every cycle during treatment. All patients will be 
followed for new AEs for 28 days following the discontinuation of study treatment. At the time of treatment discontinuation, any ongoing AE/SAE 
will be followed until the event resolves, the Investigator assesses the event as stable, the patient is lost to follow-up, dies or withdraws 
consent. Death related to disease progression is not considered to be an SAE. The Sponsor should be notified if the Investigator becomes 
aware of any SAE or AEs of special interest occurring after the end of the adverse event reporting period if the event is believed to be related to 
prior study treatment. 
t. 
Eligible patients will enter a 4-month Induction Treatment Phase.  Treatment during this phase, based on Investigator’s choice, will be either 
eight 2-week cycles of 5-FU, LV and oxaliplatin (FOLFOX) in combination with bevacizumab or six 2-week cycles of FOLFOX in combination 
with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab. 
 
 








 
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d. Patients completing the Induction Treatment Phase, and who have not experienced PD can then proceed to the Maintenance Treatment 
Phase.   Depending on the patient’s biomarker status (based on the archival sample from initial diagnosis), these patients will be assigned to a 
maintenance treatment cohort.  Cohorts 2 and 4 are closed to further accrual.  Patients with an adequate tumour sample but with unknown 
biomarker status due to lack of determinant result (e.g. due to technical issues) may still be included in the study depending on the addition of 
future cohorts. 
e. The cohort-specific exclusion criteria must be assessed prior to randomization to study maintenance treatment but assessment of cohort-
specific eligibility can only be completed after the biomarker analysis results from the patient’s archival tumour tissue from initial diagnosis are 
known. Patients found ineligible for any cohort will undergo a Study Treatment Discontinuation Visit and enter the Post-Treatment Follow-up 
Phase. 
f. 
Each cohort will consist of an experimental treatment arm and a control arm.  Randomised on a 2:1 (experimental:control) basis to either the 
experimental treatment arm or the control arm of that cohort.  See Section 4.2. 
g. Vital signs include measurements of systolic and diastolic blood pressure while the patient is in a seated position, and temperature. 
Experimental arm only:  For the first atezolizumab infusion, the patient’s vital signs (heart rate, respiratory rate, blood pressures, and 
temperature) should be determined within 60 minutes before the infusion, every 15 ± 5 minutes during the infusion, and 30 ± 10 minutes after 
the infusion. For subsequent infusions, vital signs will be collected within 60 minutes before the infusion and should be collected during or after 
the infusion if clinically indicated or if symptoms occurred in the prior infusion. Vital sign measurements from every second treatment cycle only 
will be recorded in the eCRF. 
h. Physical examinations will be symptom-directed, and will include changes from Baseline (pre-Induction) with new or worsened clinically 
significant abnormalities being reported as AEs if appropriate.  
i. 
See Appendix 8. 
j. 
Concomitant medication includes any prescription medications or over-the-counter preparations used by a patient between the 7 days prior to 
the date of informed consent up until the Study Treatment Discontinuation visit.  Only concomitant medications used for supportive care, to 
alleviate symptoms of mCRC, or to treat adverse drug reactions should be recorded on the Concomitant Medications eCRF. At subsequent 
visits, only changes to current medications or medications used since the last documentation of medications will be recorded. Concomitant 
medications for treatment of AEs related to study medication will continue to be recorded while the AE is being followed.   For permitted and 
prohibited concomitant medications, see Section 4.4. 
k. Haematology includes haemoglobin, haematocrit, platelet count, red blood cell count, white blood cell count, and differential. Blood chemistry 
includes ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin, blood urea nitrogen or urea, LDH, creatinine, glucose, calcium, 
phosphorus, sodium, potassium, chloride, bicarbonate. For experimental arm only patients, blood chemistry will also include magnesium, 
creatine phosphokinase, lipase and amylase. Haematology and blood chemistry tests must be conducted prior to treatment administration on 
Day 1 of each treatment cycle with the results available for review prior to start of treatment according to local standards for treatment 
management. Clinical laboratory results from every second cycle only will be recorded in the CRF. Clinical laboratory results constituting a 
clinically significant AE should be recorded as such.  
 


 
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Appendix 4: SAS code 
 
The following SAS code will be used to obtain the log-rank p-value from the unstratified 
log-rank test mentioned in section 4.11.1:  
PROC LIFETEST data=dataset METHOD=KM CONFTYPE=LOGLOG;  
TIME pfstime*censor(1);  
STRATA treat / test=logrank; 
RUN;  
* pfstime represents variable containing event/censor times;  
* censor represents censoring variable (1=censored, 0=event);  
* treat represents treatment group variable;  
Further options to control the output may be added. 
 
 
The following SAS code will be used to obtain the hazard ratio and corresponding 
confidence interval from the Cox Model with treatment as single covariate mentioned in 
section 4.11.44.11.1:  
PROC PHREG data=dataset;  
CLASS treat; 
MODEL pfstime*censor(1)=treat /RL TIES=EXACT;  
RUN;  
* pfstime represents variable containing event/censor times;  
* censor represents censoring variable (1=censored, 0=event);  
* treat represents treatment group variable;  
Further options to control the output may be added.  
 
 
The following SAS code will be used to obtain the hazard ratio and corresponding 
confidence interval from the adjusted Cox Model mentioned in section 4.11.4:  
PROC PHREG data=dataset;  
CLASS treat strate1; 
MODEL pfstime*censor(1)=treat stratum1 /RL TIES=EXACT;  
RUN;  
* pfstime represents variable containing event/censor times;  
* censor represents censoring variable (1=censored, 0=event);  
* treat represents treatment group variable;  
* strate1 represents the categorical covariates related to stratification 
factors;  
Further options to control the output may be added.  
 


 
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Appendix 5: List of Outputs 
List of Outputs: Tables 
 
Table Number 
Table Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
 
Patient Disposition 
 
 
 
 
14.1.1.1 
Patient Disposition For Induction Treatment Phase 
ITP 
ALL 
X 
  
14.1.1.2 
Patient Disposition For Maintenance Treatment Phase 
MTP 
MTP 
X 
X 
14.1.1.3 
Duration of Follow-up 
MTP 
MTP 
X 
X 
14.1.2.1 
Major Protocol Deviations For Induction Treatment Phase 
ITP 
ITP 
X 
  
14.1.2.2 
Major Protocol Deviations For Maintenance Treatment Phase 
MTP 
MTP 
X 
X 
 
Demographics and Baseline Characteristics 
 
 
 
 
14.1.3.1 
Summary of Baseline and Demographic Characteristics  
ITP 
ITP 
X 
  
14.1.3.2 
Summary of Baseline and Demographic Characteristics  
MTP 
MTP 
X 
  
14.1.3.3 
Summary of Baseline Biomarker Status 
MTP 
MTP 
X 
  
14.1.4.1 
Tumor Response Status (RECIST 1.1) at End of Induction (eCRF data)  
ITP 
ITP 
X 
  
14.1.5 
Randomization by Country and Study Center  
MTP 
MTP 
X 
  
14.1.6 
Stratification Factors as per IxRS 
MTP 
MTP 
X 
  
14.1.7.2 
Tumor Response (RECIST 1.1) at End of Induction as per IxRS versus eCRF 
Data 
MTP 
MTP 
X 
  
14.1.8.1 
Summary of Colorectal Cancer History 
ITP 
ITP 
X 
  
14.1.8.2 
Summary of Colorectal Cancer History 
ITP 
MTP 
X 
  
14.1.10.1 
Medical History  
ITP 
ITP 
X 
  
14.1.11.1 
Summary of Prior Anti-Cancer Treatments/Procedures  
ITP 
ITP 
X 
  
14.1.13.2 
Concomitant Medications during the Maintenance Phase  
MTP 
SAF 
X 
  
 
Exposure 
 
 
 
 
14.1.16.1 
Summary of Total Number of Cycles Initiated during ITP 
ITP 
ITP 
X 
  
14.1.17.1 
Summary of Overall Duration of Treatment and Number of Cycles Initiated 
during MTP 
MTP 
SAF 
X 
X 


 
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Table Number 
Table Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
14.1.17.2 
Summary of Drug Exposure during MTP 
MTP 
SAF 
x 
x 
 
Efficacy 
 
 
 
 
14.2.1.1 
Summary of Progression Free Survival - Primary Analysis (Surgery Censored)  
MTP 
MTP 
X 
 
14.2.1.2 
Progression Free Survival: Hazard Ratio 
MTP 
MTP 
X 
  
14.2.7.1 
Summary of Overall Survival 
MTP 
MTP 
X 
X 
14.2.7.2 
Overall Survival: Hazard Ratio 
MTP 
MTP 
X 
X 
 
Adverse Events 
 
 
 
 
14.3.1.1.1 
Treatment Emergent Adverse Events (TEAEs) during ITP: Overall Summary  
ITP 
ITP 
X 
  
14.3.1.1.2 
Treatment Emergent Adverse Events (TEAEs) during MTP: Overall Summary 
MTP 
SAF 
X 
X 
14.3.1.2.1 
Treatment Emergent Adverse Events by SOC and PT and by Worst Intensity 
during ITP 
ITP 
ITP 
X 
  
14.3.1.2.2 
Treatment Emergent Adverse Events by SOC and PT and by Worst Intensity 
during MTP 
MTP 
SAF 
X 
x  
14.3.1.2.5 
Treatment Emergent Adverse Events by SOC and PT during MTP 
MTP 
SAF 
X 
X 
14.3.1.2.6 
Treatment Emergent Adverse Events by SOC and PT during ITP 
ITP 
SAF 
X 
 
14.3.1.3.1 
Treatment Emergent Adverse Events Related to Any Study Drug by SOC and 
PT during ITP 
ITP 
ITP 
X 
 
14.3.1.3.4 
Treatment Emergent Adverse Events Related to Bevacizumab by SOC and PT 
during MTP 
 
 
x 
 
14.3.1.3.5 
Treatment Emergent Adverse Events Related to Any Study Drug by SOC and 
PT during MTP 
MTP 
SAF 
X 
X 
14.3.1.3.8 
Treatment Emergent Adverse Events Related to Atezolizumab by SOC and PT 
during MTP 
MTP 
SAF 
X 
X 
14.3.1.3.9 
Treatment Emergent Adverse Events Related to Bevacizumab by SOC and PT 
during MTP 
MTP 
SAF 
X 
X 
14.3.1.3.11 
Treatment Emergent Adverse Events Related to Cobimetinib by SOC and PT 
during MTP 
MTP 
SAF 
X 
X 
14.3.1.4.1 
Treatment Emergent Adverse Events Leading to Discontinuation of Any Study 
Drug by SOC and PT during ITP 
ITP 
ITP 
X 
 


 
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Table Number 
Table Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
14.3.1.4.5 
Treatment Emergent Adverse Events Leading to Discontinuation of Any Study 
Drug by SOC and PT during MTP 
MTP 
SAF 
X 
X 
14.3.1.5.4 
Treatment Emergent Adverse Events Leading to Dose Reduction or Interruption 
of Bevacizumab by SOC and PT during ITP 
ITP 
ITP 
X 
 
14.3.1.5.7 
Treatment Emergent Adverse Events Leading to Dose Reduction or Interruption 
of Atezolizumab by SOC and PT during MTP 
MTP 
SAF 
x 
X 
14.3.1.5.11 
Treatment Emergent Adverse Events Leading to Dose Reduction or Interruption 
of Cobimetinib by SOC and PT during MTP 
MTP 
SAF 
x 
x 
14.3.1.7.1 
Serious Treatment Emergent Adverse Events by SOC and PT during ITP 
ITP 
ITP 
x 
 
14.3.1.7.2 
Serious Treatment Emergent Adverse Events by SOC and PT during MTP 
MTP 
SAF 
X 
X 
14.3.1.8.1 
Serious Treatment Emergent Adverse Events Related to Any Study Drug by 
SOC and PT during ITP 
ITP 
ITP 
x 
 
14.3.1.8.4 
Serious Treatment Emergent Adverse Events Related to Bevacizumab by SOC 
and PT during ITP 
ITP 
ITP 
x 
 
14.3.1.8.5 
Serious Treatment Emergent Adverse Events Related to Any Study Drug by 
SOC and PT during MTP 
MTP 
SAF 
x 
x 
14.3.1.8.8 
Serious Treatment Emergent Adverse Events Related to Atezolizumab by SOC 
and PT during MTP 
MTP 
SAF 
x 
x 
14.3.1.8.9 
Serious Treatment Emergent Adverse Events Related to Bevacizumab by SOC 
and PT during MTP 
MTP 
SAF 
x 
x 
14.3.1.8.12 
Serious Treatment Emergent Adverse Events Related to Cobimetinib by SOC 
and PT during MTP 
MTP 
SAF 
x 
x 
14.3.1.9.2 
Treatment Emergent Adverse Events with Fatal Outcome by SOC and PT during 
MTP 
MTP 
SAF 
X 
X 
14.3.1.10.1 
Treatment Emergent AESI Based on eCRF Categories during MTP  
MTP 
SAF 
X 
X 
14.3.1.10.2 
Treatment Emergent AESI Based on eCRF Categories during ITP  
ITP 
ITP 
X 
 
14.3.1.10.3 
Bevacizumab Treatment Emergent AESI Based on Pre-Defined Categories 
during MTP  
MTP 
SAF 
X 
X 
14.3.1.10.4 
Bevacizumab Treatment Emergent AESI Based on Pre-Defined Categories 
during ITP  
ITP 
ITP 
X 
 


 
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Table Number 
Table Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
14.3.1.10.5 
Atezolizumab Treatment Emergent AESI Based on Pre-Defined Categories 
during MTP  
MTP 
SAF 
X 
X 
 
Deaths 
 
 
 
 
14.3.1.12.3 
Deaths within 30 Days from Last Day of Treatment of MTP and Reason  
MTP 
SAF 
X 
X 
14.3.1.12.5 
Post Maintenance Treatment Deaths and Reason 
Post-
Treatment 
SAF 
X 
X 
 
Laboratory Data 
 
 
 
 
14.3.4.1.2 
Shift Table (Baseline versus Worst On-Treatment) during MTP for CTC 
Gradable Hematology Parameters 
MTP 
SAF 
x 
 
14.3.4.2.2 
Shift Table (Baseline versus Worst On-Treatment) during MTP for CTC 
Gradable Blood Chemistry Parameters  
MTP 
SAF 
x 
 
14.3.4.3.2 
Shift Table (Baseline versus Worst On-Treatment) during MTP for CTC 
Gradable Coagulation Parameters  
MTP 
SAF 
x 
 
14.3.4.4.2 
Shift Table (Baseline versus Worst On-Treatment) during MTP for Non CTC 
Gradable Hematology Parameters 
MTP 
SAF 
x 
 
14.3.4.5.2 
Shift Table (Baseline versus Worst On-Treatment) during MTP for Non CTC 
Gradable Blood Chemistry Parameters  
MTP 
SAF 
x 
 
14.3.4.6 
Shift Table (Baseline versus Worst On-Treatment) during MTP for Non CTC 
Gradable Thyroid Parameters  
MTP 
SAF 
x 
 
14.3.4.7.2 
Shift Table (Baseline versus Worst On-Treatment) during MTP for Urinalysis 
Protein Dipstick 
MTP 
SAF 
x 
 
 
Vital Signs 
 
 
 
 
14.3.5.2 
Summary of Vital Signs Over Time during MTP 
MTP 
SAF 
x 
 
14.3.6 
Summary of Blood Oxygen Saturation Over Time during MTP 
MTP 
SAF 
x 
 
 
 
 


 
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Statistical Analysis Plan MO29112 Cohort 4 (Version 1.0) 
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List of Outputs: Figures 
 
Figure 
Number 
Figure Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
 
Disposition 
 
 
 
 
14.1.1 
CONSORT Flow Diagram for All Screened Patients 
All 
Screened 
X 
  
14.1.2 
CONSORT Flow Diagram for Patients Randomized in Cohort 4 
All 
MTP 
X 
X 
 
Efficacy 
 
 
 
 
14.2.1.1 
Kaplan Meier Plot of Progression Free Survival - Primary Analysis 
MTP 
MTP 
X 
  
14.2.2.1 
Kaplan Meier Plot of Overall Survival 
MTP 
MTP 
X 
X 
 
List of Outputs: Listings 
Listing 
Number 
Listing Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
 
Disposition 
 
 
 
 
16.2.1.1 
Patient Disposition and Study Termination Information 
ITP 
ITP 
X 
X 
16.2.1.2 
Patient Who Discontinue Treatment due to Adverse Event 
ITP 
ITP 
X 
X 
16.2.2 
Major Protocol Deviations from PDMS 
ITP/MTP 
ITP 
X 
x 
16.2.3 
Analysis Population 
ITP/MTP 
ALL 
X 
  
 
Demographics and Baseline Characteristics 
 
 
 
 
16.2.4.1 
Demographics and Baseline Characteristics 
ITP/MTP 
ITP 
X 
  
16.2.4.4 
Baseline Biomarker Status 
MTP 
MTP 
X 
  
16.2.4.5 
Randomization Stratification Factors as per IxRS and eCRF 
MTP 
MTP 
X 
  
16.2.4.6 
Colorectal Cancer History 
ITP 
ITP 
X 
  
16.2.4.8 
Prior Anti-Cancer Therapy 
ITP 
ITP 
X 
  
16.2.4.9 
Cancer Radiotherapy: Prior and On-study 
ITP/MTP 
ITP 
X 
 
16.2.4.10 
Colorectal Cancer Surgery : Prior and On-Study 
ITP/MTP 
ITP 
X 
 


 
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Listing 
Number 
Listing Title 
Phase 
Population 
Primary 
analysis 
Final 
Analysis 
16.2.4.12 
Subsequent Anti-cancer Therapies 
Post-
Treatment 
ITP 
X 
 
 
Drug Administration 
 
 
 
 
16.2.5.5 
Drug Exposure during ITP 
ITP 
ITP 
X 
  
16.2.5.8 
Drug Exposure during MTP 
MTP 
SAF 
X 
X 
 
Efficacy 
 
 
 
 
16.2.6.1 
Progression Free Survival - Primary Analysis (Surgery Censored) 
MTP 
MTP 
X 
  
16.2.6.9 
Overall Survival  
MTP 
MTP 
X 
X 
 
Safety 
 
 
 
 
16.2.7.1 
Adverse Events 
ITP/MTP/ 
Post-
treatment 
ITP 
X 
X 
16.2.7.2 
Grade 5 Adverse Events or any Adverse Events with Fatal Outcome 
ITP/MTP/ 
Post-
treatment 
ITP 
X 
X 
16.2.7.3 
Adverse Events Leading to Treatment Discontinuation 
ITP/MTP/ 
Post-
treatment 
ITP 
X 
X 
16.2.7.4 
Adverse Events of Special Interest as Reported on eCRF  
MTP/ Post-
treatment 
ITP 
X 
X 
16.2.7.5 
Deaths 
ITP/MTP/ 
Post-
treatment 
ITP 
X 
X