Conditions: Colorectal Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 197
Healthy volunteers: no

Brief summary:
This is a Phase 2 multicenter, randomized, parallel arms, double-blind study of vanucizumab to evaluate the efficacy and safety of vanucizumab in combination with oxaliplatin, folinic acid, and 5-fluorouracil (5-FU) (mFOLFOX-6) versus bevacizumab (Avastin) + mFOLFOX-6 in participants with previously untreated metastatic colorectal cancer (mCRC). The study consists of 2 parts: a safety run-in open-label, single-arm part (Part 1) and a randomized, parallel-arms, double-blind part (Part 2). During Part 1 at least 6 eligible participants will receive 2000 milligrams (mg) vanucizumab every 2 weeks + mFOLFOX-6 in order to confirm the dose and schedule that will be used in Part 2. In Part 2, all eligible participants will be randomized in a ratio of 1:1 to receive either mFOLFOX-6 + vanucizumab or mFOLFOX-6 + bevacizumab. Study treatment (induction and maintenance) will be given on Day 1 of each 14-day cycle. Induction therapy will consist of up to 8 cycles of mFOLFOX-6 plus either bevacizumab or vanucizumab. Maintenance therapy will consist of 5-fluorouracil and folinic acid plus either vanucizumab or bevacizumab for up to 24 months or until disease progression, unacceptable toxicity, Investigator decision or consent withdrawal, whichever occurs first.

Detailed description:

Arms:
arm 1: Participants will receive vanucizumab at a dose of 2000 milligram (mg) as intravenous (IV) infusion; oxaliplatin at a dose of 85 mg per meter-squared (mg/m\^2) as IV infusion; folinic acid at a dose of 400 mg/m\^2 as IV infusion; and 5-FU at a dose of 400 mg/m\^2 as starting IV bolus followed by 2400 mg/m\^2 as IV infusion every 2 weeks for up to 8 cycles (approximately 4 months). arm 2: Participants will receive vanucizumab at a dose confirmed during induction as IV infusion; folinic acid at a dose of 400 mg/m\^2 as IV infusion; and 5-FU at a dose of 400 mg/m\^2 as starting IV bolus followed by 2400 mg/m\^2 as IV infusion every 2 weeks until disease progression, unacceptable toxicities, consent withdrawal or Investigator's decision for a maximum of 24 months. arm 3: Participants will receive bevacizumab at a dose of 5 milligram per kilogram (mg/kg) as IV infusion; oxaliplatin at a dose of 85 mg/m\^2 as IV infusion; folinic acid at a dose of 400 mg/m\^2 as IV infusion; and 5-FU at a dose of 400 mg/m\^2 as starting IV bolus followed by 2400 mg/m\^2 as IV infusion every 2 weeks for up to 8 cycles (approximately 4 months). arm 4: Participants will receive vanucizumab at a dose confirmed during part 1 as IV infusion; oxaliplatin at a dose of 85 mg/m\^2 as IV infusion; folinic acid at a dose of 400 mg/m\^2 as IV infusion; and 5-FU at a dose of 400 mg/m\^2 as starting IV bolus followed by 2400 mg/m\^2 as IV infusion every 2 weeks for up to 8 cycles (approximately 4 months). arm 5: Participants will receive bevacizumab at a dose of 5 mg/kg as IV infusion; folinic acid at a dose of 400 mg/m\^2 as IV infusion; and 5-FU at a dose of 400 mg/m\^2 as starting IV bolus followed by 2400 mg/m\^2 as IV infusion every 2 weeks until disease progression, unacceptable toxicities, consent withdrawal or Investigator's decision for a maximum of 24 months. arm 6: Participants will receive vanucizumab at a dose confirmed during part 1 as IV infusion; folinic acid at a dose of 400 mg/m\^2 as IV infusion; and 5-FU at a dose of 400 mg/m\^2 as starting IV bolus followed by 2400 mg/m\^2 as IV infusion every 2 weeks until disease progression, unacceptable toxicities, consent withdrawal or Investigator's decision for a maximum of 24 months.

Interventions: intervention 1: 5-FU intervention 2: Bevacizumab intervention 3: Folinic acid intervention 4: Oxaliplatin intervention 5: Vanucizumab
Intervention descriptions: intervention 1: 5-FU will be administered according to dose and schedule described in respective arm. intervention 2: Bevacizumab will be administered according to dose and schedule described in respective arm. intervention 3: Folinic acid will be administered according to dose and schedule described in respective arm. intervention 4: Oxaliplatin will be administered according to dose and schedule described in respective arm. intervention 5: Vanucizumab will be administered according to dose and schedule described in respective arm.

Protocol document:
Prot_000.pdf: 
 
Official Title: 
 
A PHASE II, MULTICENTER, RANDOMIZED, DOUBLE-BLIND 
STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 
RO5520985 (VANUCIZUMAB) PLUS FOLFOX VERSUS 
BEVACIZUMAB PLUS FOLFOX IN PATIENTS WITH PREVIOUSLY 
UNTREATED METASTATIC COLORECTAL CANCER 
NCT Number: 
NCT02141295 
Document Date: 
Protocol Version 5: 10-Feb-2016 
 
 
 


 
Title
10-Feb-2016 08:25:43
Date and Time (UTC)
Translational Medicine Leader
Approver's Name
FINAL PROTOCOL APPROVAL 
 
CONFIDENTIAL STATEMENT 
 
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. 
 
RO5520985—F. Hoffmann-La Roche Ltd 
Protocol BP29262, Version 5 
PROTOCOL 
TITLE: 
A PHASE II, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND STUDY TO EVALUATE THE EFFICACY 
AND SAFETY OF RO5520985 (VANUCIZUMAB) PLUS 
FOLFOX VERSUS BEVACIZUMAB PLUS FOLFOX IN 
PATIENTS WITH PREVIOUSLY UNTREATED 
METASTATIC COLORECTAL CANCER 
PROTOCOL NUMBER: BP29262 
VERSION: 
5 
EUDRACT NUMBER: 
2013-005108-32 
IND NUMBER: 
120910 
TEST PRODUCT: 
RO5520985 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
See electronic date stamp below 


RO5520985—F. Hoffmann-La Roche Ltd 
Protocol BP29262, Version 5
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ...................................................................................... 9 
1.
BACKGROUND AND RATIONALE............................................................. 28 
1.1 
Background on Disease......................................................... 28 
1.2 
Anti-Angiogenic Treatment of Colorectal Cancer................... 28 
1.2.1 
Anti-VEGF mAb Treatment of Colorectal Cancer .................. 29 
1.2.2
Anti-Angiopoietin-2 Treatment of Colorectal 
Cancer................................................................................... 29 
1.3 
Background on RO5520985 .................................................. 30 
1.3.1
Previous Nonclinical Studies ................................................. 31 
1.3.2
Previous Clinical Studies ....................................................... 32 
1.4 
Study Rationale and Benefit–Risk Assessment..................... 34 
2.
OBJECTIVES.............................................................................................. 36
2.1 
Primary Objective .................................................................. 36 
2.2 
Secondary Objectives............................................................ 36 
2.3 
Exploratory Objectives........................................................... 36 
3.
STUDY DESIGN ......................................................................................... 37 
3.1 
Description of Study .............................................................. 37 
3.1.1
Overview of Study Design ..................................................... 37 
3.1.1.1 
Part I:  Safety Run-In ............................................................. 37 
3.1.1.2 
Part II: Randomization Part.................................................... 38 
3.1.2
Internal Monitoring Committee............................................... 39 
3.1.3
End of Study.......................................................................... 40 
3.1.4
Study Duration....................................................................... 40 
3.2
Rationale for Study Design.................................................... 41 
3.2.1 
Rationale for Selection of RO5520985 Dose and 
Schedule................................................................................ 41 
3.2.2 
Rationale for Safety Run-In (Part I)........................................ 42 
3.2.3 
Rationale for Randomized, Double-Blind Phase II 
Study in First-Line mCRC (Part II) ......................................... 42 
3.2.4 
Rationale for Biomarker Assessments................................... 43 
3.2.4.1 
Biomarker Assessments in Blood.......................................... 43 


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3.2.4.2 
Archival Primary Tumor Tissue.............................................. 44 
3.3 
Outcome Measures ............................................................... 46 
3.3.1 
Safety Outcome Measures .................................................... 46 
3.3.2 
Pharmacokinetic Outcome Measures.................................... 47 
3.3.3 
Efficacy Outcome Measures.................................................. 47 
3.3.3.1 
Primary Outcome Measure.................................................... 47 
3.3.3.2 
Secondary Outcome Measures ............................................. 48 
3.3.4 
Exploratory Outcome Measures ............................................ 48 
4. 
MATERIALS AND METHODS .................................................................... 48 
4.1 
Centers.................................................................................. 48 
4.2 
Study Population ................................................................... 48 
4.2.1 
Recruitment Procedures (Part I and Part II)........................... 49 
4.2.2 
Inclusion Criteria.................................................................... 49 
4.2.3 
Exclusion Criteria................................................................... 50 
4.3 
Method of Treatment Assignment and Blinding..................... 53 
4.4 
Study Treatment.................................................................... 54 
4.4.1 
Formulation, Packaging, and Handling.................................. 54 
4.4.1.1 
RO5520985 ........................................................................... 54 
4.4.1.2 
Bevacizumab and FOLFOX................................................... 55 
4.4.2 
Dosage, Administration, and Compliance.............................. 56 
4.4.2.1 
RO5520985 (Part I) ............................................................... 56 
4.4.2.2 
RO5520985 and Bevacizumab (Part II)................................. 56 
4.4.2.3 
FOLFOX ................................................................................ 57 
4.4.2.4 
Treatment Duration................................................................ 58 
4.4.3 
Accountability of RO5520985 and Bevacizumab................... 58 
4.5 
Concomitant Therapy ............................................................ 59 
4.5.1 
Permitted Therapy ................................................................. 59 
4.5.2 
Prohibited Therapy ................................................................ 59 
4.6 
Study Assessments ............................................................... 61 
4.6.1 
Description of Study Assessments ........................................ 61 
4.6.1.1 
Medical History and Demographic Data ................................ 61 
4.6.1.2 
Cancer History....................................................................... 61 
4.6.1.3 
Physical Examinations........................................................... 61 


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4.6.1.4 
ECOG Performance Status ................................................... 61 
4.6.1.5 
Vital Signs.............................................................................. 62 
4.6.1.6 
Electrocardiograms................................................................ 62 
4.6.1.7 
Transthoracic Echocardiogram/Multiple Gated 
Acquisition Scans .................................................................. 62 
4.6.1.8 
Adverse Events...................................................................... 63 
4.6.1.9 
Concomitant Medication ........................................................ 63 
4.6.1.10 
Safety Laboratory Assessments............................................ 63 
4.6.1.11 
Pharmacokinetic Assessments.............................................. 64 
4.6.1.12 
Human Anti-Human Antibodies ............................................. 65 
4.6.1.13 
Pharmacodynamics and Exploratory Biomarker 
Assessments ......................................................................... 65 
4.6.1.14 
Disease-Specific Assessments.............................................. 67 
4.6.1.15 
Samples for Roche Clinical Repository.................................. 68 
4.6.2 
Timing of Study Assessments ............................................... 72 
4.6.2.1 
Screening and Pretreatment Assessments............................ 72 
4.6.2.2 
Assessments during Treatment............................................. 73 
4.6.2.3 
Assessments at End of Study Visit ........................................ 73 
4.6.2.4 
Follow-Up Assessments ........................................................ 73 
4.6.2.5 
Assessments at Unscheduled Visits...................................... 73 
4.7 
Patient, Study, and Site Discontinuation................................ 73 
4.7.1 
Patient Discontinuation.......................................................... 73 
4.7.1.1 
Discontinuation from Study Drug........................................... 74 
4.7.1.2 
Withdrawal from Study........................................................... 74 
4.7.2 
Study and Site Discontinuation.............................................. 74 
5. 
ASSESSMENT OF SAFETY....................................................................... 75 
5.1 
Safety Parameters and Definitions ........................................ 75 
5.1.1 
Adverse Events ..................................................................... 75 
5.1.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 76 
5.1.3 
Selected Adverse Events....................................................... 76 
5.1.4 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 77 
5.2 
Safety Plan ............................................................................ 77 


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Protocol BP29262, Version 5 
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5.2.1 
Risks for RO5520985 (Vanucizumab) and 
Bevacizumab......................................................................... 77 
5.2.1.1 
Gastrointestinal Perforation ................................................... 78 
5.2.1.2 
Fistula (Other than GI)........................................................... 78 
5.2.1.3 
Hemorrhage........................................................................... 78 
5.2.1.4 
Arterial Hypertension ............................................................. 79 
5.2.1.5 
Thrombotic Microangiopathy ................................................. 80 
5.2.1.6 
Venous Thromboembolic Events........................................... 81 
5.2.1.7 
Arterial Thromboembolic Events............................................ 81 
5.2.1.8 
Congestive Heart Failure....................................................... 82 
5.2.1.9 
Proteinuria ............................................................................. 82 
5.2.1.10 
Wound Healing Complications............................................... 82 
5.2.1.11 
Posterior Reversible Encephalopathy Syndrome .................. 83 
5.2.1.12 
Infusion Related Reactions and Allergic 
Reactions............................................................................... 83 
5.2.1.13 
Immunogenicity ..................................................................... 84 
5.2.1.14 
Ovarian Failure...................................................................... 85 
5.2.1.15 
Peripheral Edema.................................................................. 85 
5.2.1.16 
Pregnancy ............................................................................. 85 
5.2.2 
Risks of 5-FU, Folinic Acid and Oxaliplatin............................ 86 
5.2.3 
Toxicity Management Guideline ............................................ 87 
5.2.3.1 
General Notes ....................................................................... 87 
5.2.3.2 
Guidelines for Toxicity Management of 
Bevacizumab and RO5520985.............................................. 88 
5.2.3.3 
Guidelines for Toxicity Management of FOLFOX .................. 96 
5.2.3.4 
Guidelines for Toxicity Management of 
Capecitabine (Xeloda®) ........................................................ 99 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 101 
5.3.1 
Adverse Event/Serious Adverse Event Reporting 
Period .................................................................................. 101 
5.3.2 
Eliciting Adverse Event Information ..................................... 101 
5.3.3 
Assessment of Severity of Adverse Events ......................... 102 
5.3.4 
Assessment of Causality of Adverse Events ....................... 102 
5.3.5 
Procedures for Recording Adverse Events.......................... 103 


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5.3.5.1 
Diagnosis versus Signs and Symptoms............................... 103 
5.3.5.2 
Adverse Events Occurring Secondary to Other 
Events.................................................................................. 103 
5.3.5.3 
Persistent or Recurrent Adverse Events.............................. 104 
5.3.5.4 
Abnormal Laboratory Values ............................................... 104 
5.3.5.5 
Abnormal Vital Sign Values ................................................. 105 
5.3.5.6 
Abnormal Liver Function Tests............................................ 105 
5.3.5.7 
Deaths ................................................................................. 106 
5.3.5.8 
Preexisting Medical Conditions............................................ 106 
5.3.5.9 
Lack of Efficacy or Worsening of Colorectal 
Cancer................................................................................. 107 
5.3.5.10 
Hospitalization or Prolonged Hospitalization........................ 107 
5.3.5.11 
Overdoses ........................................................................... 107 
5.3.6 
Emergency Medical Contacts.............................................. 108 
5.3.7 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest.................................................................... 108 
5.3.8 
Reporting Requirements for Pregnancies............................ 108 
5.3.8.1 
Pregnancies in Female Patients.......................................... 108 
5.3.8.2 
Pregnancies in Female Partners of a Male 
Patient ................................................................................. 108 
5.3.8.3 
Abortions ............................................................................. 109 
5.3.8.4 
Congenital Anomalies/Birth Defects .................................... 109 
5.4 
Follow-Up of Patients after Adverse Events ........................ 109 
5.4.1 
Investigator Follow-Up......................................................... 109 
5.4.2 
Sponsor Follow-Up .............................................................. 109 
5.5 
Post-Study Adverse Events................................................. 110 
5.6 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 110 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 111 
6.1 
Determination of Sample Size ............................................. 111 
6.2 
Summaries of Conduct of Study.......................................... 111 
6.3 
Analysis Populations ........................................................... 111 
6.3.1 
Safety Analysis Population .................................................. 111 


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6.3.2 
Pharmacokinetic Analysis Population.................................. 112 
6.3.3 
Efficacy Analysis Population................................................ 112 
6.4 
Summaries of Treatment Group Comparability ................... 112 
6.5 
Safety Analyses................................................................... 112 
6.5.1 
Adverse Events ................................................................... 112 
6.5.2 
Clinical Laboratory Test Results.......................................... 112 
6.5.2.1 
Standard Reference Ranges and Transformation 
of Data................................................................................. 113 
6.5.2.2 
Definition of Laboratory Abnormalities................................. 113 
6.5.3 
Vital Signs............................................................................ 114 
6.5.4 
ECG Data Analysis.............................................................. 114 
6.5.5 
Concomitant Medications .................................................... 114 
6.6 
Efficacy Analyses ................................................................ 114 
6.6.1 
Primary Efficacy Endpoint.................................................... 114 
6.6.2 
Secondary Efficacy Endpoints............................................. 115 
6.7 
Exploratory Biomarker Analyses.......................................... 115 
6.8 
Pharmacokinetic Analyses................................................... 116 
6.9 
Other Exploratory Analyses................................................. 116 
6.10 
Interim Analyses.................................................................. 116 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 117 
7.1 
Data Quality Assurance....................................................... 117 
7.2 
Electronic Case Report Forms............................................. 117 
7.3 
Source Data Documentation................................................ 118 
7.4 
Use of Computerized Systems ............................................ 118 
7.5 
Retention of Records........................................................... 119 
8. 
ETHICAL CONSIDERATIONS.................................................................. 119 
8.1 
Compliance with Laws and Regulations .............................. 119 
8.2 
Informed Consent ................................................................ 119 
8.3 
Institutional Review Board or Ethics Committee.................. 120 
8.4 
Confidentiality...................................................................... 121 
8.5 
Financial Disclosure ............................................................ 121 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 121 


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9.1 
Study Documentation .......................................................... 121 
9.2 
Site Inspections ................................................................... 122 
9.3 
Administrative Structure....................................................... 122 
9.4 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 122 
9.5 
Protocol Amendments ......................................................... 123 
10. REFERENCES ......................................................................................... 124 
 
 
LIST OF TABLES 
Table 1 
Cohorts and Dosing Regimen for Part I (Dose Escalation) ......... 32 
Table 2 
Toxicity Management Guideline for Bevacizumab and 
RO5520985................................................................................. 90 
Table 3 
FOLFOX Dose Adjustment ......................................................... 96 
Table 4 
Adverse Event Grading for Neuropathy ...................................... 98 
Table 5 
Recommended Dose Modifications of Capecitabine................. 100 
Table 6 
Adverse Event Severity Grading Scale ..................................... 102 
 
 
LIST OF FIGURES 
Figure 1 
Part I – Safety Run-In ................................................................. 38 
Figure 2 
Part II – Randomization Part....................................................... 38 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments......................................................... 132 
Appendix 2 
Schedule of Pharmacokinetic Assessments for RO5520985.... 135 
Appendix 3 
Schedule of Pharmacokinetic Assessments for FOLFOX 
Components (Part I only) .......................................................... 137 
Appendix 4 
Cockcroft–Gault Formula .......................................................... 138 
Appendix 5 
ECOG Performance Status....................................................... 139 
Appendix 6 
NYHA Classification.................................................................. 140 
Appendix 7 
ICH Guidelines – Topic E2........................................................ 141 
Appendix 8 
RECIST Criteria, Version 1.1 .................................................... 143 


 
RO5520985—F. Hoffmann-La Roche Ltd 
Protocol BP29262, Version 5 
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PROTOCOL SYNOPSIS 
TITLE 
A PHASE II, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND STUDY TO EVALUATE THE EFFICACY 
AND SAFETY OF RO5520985 (VANUCIZUMAB) PLUS 
FOLFOX VERSUS BEVACIZUMAB PLUS FOLFOX IN 
PATIENTS WITH PREVIOUSLY UNTREATED METASTATIC 
COLORECTAL CANCER 
PROTOCOL NUMBER: 
BP29262 
VERSION: 
5 
EUDRACT NUMBER: 
2013-005108-32 
IND NUMBER: 
120910 
TEST PRODUCT: 
RO5520985 
CLINICAL PHASE 
II 
SPONSOR 
F. Hoffmann-La Roche Ltd 
INDICATION 
Patients with metastatic nonresectable colorectal cancer, 
untreated for their metastatic disease 
OBJECTIVES  
Primary 
The primary objective of Study BP29262 is to estimate the 
efficacy of RO5520985 in combination with oxaliplatin, folinic 
acid, and 5 fluorouracil (mFOLFOX-6) vs. bevacizumab in 
combination with mFOLFOX-6, as measured by progression-
free survival (PFS). 
Secondary 
• 
Evaluate the safety and tolerability of RO5520985 in 
combination with mFOLFOX-6 
• 
Estimate the efficacy of RO5520985 in combination with 
mFOLFOX-6, as measured by overall survival, 
objective response rate, and duration of objective 
response 
• 
Characterize the pharmacokinetics of RO5520985 when 
combined with mFOLFOX-6  
Exploratory 
• 
Assess levels of circulating angiogenic factors and 
circulating targets as potentially predictive markers, in 
conjunction with somatic mutations in circulating cell-free 
DNA 
• 
Assess potential response prediction markers of 
RO5520985 in blood  and archival primary tumor tissue  
• 
Explore tumor growth kinetics 
• 
Characterize the PK of selected mFOLFOX-6 
components when combined with RO5520985   
• 
Explore additional parameters on tumor imaging  


 
RO5520985—F. Hoffmann-La Roche Ltd 
Protocol BP29262, Version 5 
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STUDY DESIGN 
This is a Phase II multicenter, randomized, parallel arms, 
double-blind study of RO5520985 to evaluate the efficacy 
and safety of RO5520985 plus mFOLFOX-6 versus 
bevacizumab plus mFOLFOX-6 in patients previously 
untreated mCRC.  The study consists of two parts:  Part I 
(Safety Run-in) open label single arm and Part II 
(Randomization Phase) randomized, parallel arms, 
double-blind study. 
Part I: Safety Run-in 
The safety/tolerability of single agent RO5520985 has been 
investigated in Study BP28179, by which RO5520985 at 
2000 mg Q2W was considered safe and recommended as 
dose for subsequent clinical development. However, the 
combination of RO5520985 with mFOLFOX-6 has not been 
previously studied clinically for safety.  Therefore, during the 
open label safety run-in phase prior to the randomization part 
of the study (Part II) at least 6 eligible patients will be 
exposed to 2000 mg Q2W RO5520985 + mFOLFOX-6, in 
order to confirm the dose and schedule that will be used in 
the randomized part of this study (Part II).  All patients in 
Part I will receive induction and maintenance therapy as 
described for patients in the experimental arm of Part II.   
Treatment of the first 6 patients will be sequential i.e., there 
will be always at least 1 working day between the 
1st RO5520985 administration of one enrolled patient and the 
1st RO5520985 administration of the next enrolled patient.  
Each site enrolling one of the first 6 patients in Part I needs 
to inform the Sponsor about the tolerability (based on 
the assessments being performed as per SoA) by e-mail. 
The e-mail needs to be send after the investigator or 
designee has seen the patient during the Visit on Day 2 of 
Cycle 1 reporting at least the observed AEs/SAEs between 
start of RO5520985 administration and the Visit on the next 
day (C1D2). Only after confirmation by the site that the 1st 
study drug administration was tolerated without any severe 
problems, the next patient can be treated. The Sponsor 
ensures that the site enrolling the subsequent patient will be 
informed latest on the evening prior to the scheduled 
treatment whether the patient can receive the 1st RO5520985 
administration. 
 
After at least 6 patients have been treated by at least two full 
cycles an Internal Monitoring Committee (IMC) will conduct a 
safety analysis prior to initiation of Part II.  If safety signals 
arise from the review and depending on the nature of the 
safety signals, the IMC may recommend to enroll additional 
6-12 patients at lower doses of RO5520985 in combination 
with mFOLFOX-6 before embarking onto Part II of the study 
at the adjusted dose.  In case of unacceptable and/ or non-
manageable toxicity of the combination, the IMC may decide 
to discontinue the study upon completion of Part I.  The IMC 
will operate according to a prespecified safety charter 
outlined in a separate document. 
 
Part II: Randomization Part 
Upon completion of the safety run-in part with selection of 


 
RO5520985—F. Hoffmann-La Roche Ltd 
Protocol BP29262, Version 5 
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the  RP2D of RO5520985 in combination with mFOLFOX-6 
by the IMC, eligible patients will be randomized in a ratio of 
1:1 to receive either mFOLFOX-6 + RO5520985 
(experimental arm) or mFOLFOX-6 + bevacizumab (control 
arm).  
Patients will prospectively be stratified by region (United 
States vs. Rest of World [RoW]) and number of metastatic 
sites (1 vs. >1). 
Study treatment consisting of induction and maintenance 
therapy will be given in cycles repeated every 14 days and 
will consist of: 
Induction therapy  
Up to 8 cycles of mFOLFOX-6 plus either bevacizumab or 
RO5520985. Patients may switch to maintenance therapy 
earlier if oxaliplatin cannot be tolerated. 
Maintenance therapy 
Following induction therapy, oxaliplatin administration will be 
discontinued and patients receive 5-FU/folinic acid plus 
either RO5520985 (experimental arm) or bevacizumab 
(control arm) as maintenance therapy for a maximum period 
of 24 months (calculated from start of maintenance therapy), 
if treatment is not stopped earlier due to disease progession, 
unacceptable toxicity, Investigator decision or consent 
withdrawal. 
If patients stop chemotherapy either in part or in whole, then 
they should continue on RO5520985 treatment or 
bevacizumab for a maximum of 24 months.  
Within Part II of the study, two interim analyses are planned 
after approximately 30 and 50 PFS events.   
NUMBER OF PATIENTS 
Part I (Safety Run-in): 6−18 patients 
Part II (Randomization): 190 patients 
TARGET POPULATION 
Adult patients with metastatic colorectal cancer who have not 
been previously treated with chemotherapy for metastatic 
disease and who are not candidates for potentially curative 
resection. 
INCLUSION/EXCLUSION 
CRITERIA 
Inclusion Criteria 
1. Histologically or cytologically confirmed mCRC not 
amenable to potentially curative resection with at least one 
measurable metastatic lesion, as defined by RECIST v1.1 
a) Representative tumor specimens in FFPE blocks 
(preferred) or slides must be available for central 
extended RAS mutational analysis testing  
2. Signed written informed consent, obtained prior to any 
screening procedure 
3. Age ≥ 18 years 
4. ECOG (WHO) performance status of 0 or 1 
5. Willing and able to comply with the protocol as judged by 
the Investigator 
6. Adequate hematologic function 
a) Absolute neutrophil count (ANC) ≥ 2000 cells/μL 
(without G-CSF support within 2 weeks prior to 
randomization) 
b) Platelet count ≥ 100,000/μL (without transfusion 


 
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Protocol BP29262, Version 5 
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within 2 weeks prior to randomization) 
c) Hemoglobin ≥ 9.0 g/dL 
7. Adequate liver function 
a) AST and ALT ≤ 2.5 × upper limits of normal (ULN) 
or ≤ 5 x ULN in case of liver metastases 
b) Serum bilirubin ≤ 1.5×  ULN (Patients with known 
Gilbert disease who have serum bilirubin level 
≤ 3× ULN may be enrolled) 
c) Serum albumin ≥ 3.0 g/dL 
8. Adequate coagulation function 
a) International normalized ratio (INR) ≤ 1.5 × ULN 
b) Activated partial thromboplastin time 
(aPTT) ≤ 1.5 × ULN  
9. Adequate renal function  
a) Creatinine clearance ≥ 50 mL/min/1.73 m2 on 
the basis of the Cockroft−Gault formula  
b) Urine dipstick for proteinuria < 2+. Patients 
discovered to have ≥ 2+ proteinuria on dipstick 
urinalysis at baseline should undergo a 24-hrs 
urine collection and must demonstrate ≤ 1 g of 
protein in 24 hrs  
10. Adequate cardiovascular function 
a) NYHA stage ≤ 1 
b) Resting blood pressure systolic < 150 mmHg and 
diastolic < 100 mmHg (average of ≥ 3 readings on 
≥ 2 sessions) 
11. Recovery from all reversible adverse events of previous 
medical therapies to baseline or NCI CTCAE Grade 1, 
except for alopecia (any grade) 
12. Negative serum or urine pregnancy test within 7 days prior 
to starting study treatment in premenopausal women and 
women < 2 years after the onset of menopause 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded 
from study entry: 
1. 
Any prior systemic therapy (including chemotherapy, 
antibody therapy, tyrosine kinase inhibitors, 
immunotherapy, hormonal therapy) before Day 1 of 
Cycle 1 for treatment of mCRC 
a) Patients who received prior systemic adjuvant 
therapy or radiotherapy for CRC are not excluded 
if the time interval from last administration of 
adjuvant therapy until disease progression is > 12 
months  
b) Patients who received herbal therapy intended as 
anti-cancer therapy ≥ 2 weeks prior to Day 1 are 
not excluded 
2. Malignancies other than CRC within 5 years prior to 
randomization, except for those with a minimal  risk of 
metastasis or death, such as adequately treated 
carcinoma in situ of the cervix, basal or squamous cell skin 
cancer, localized prostate cancer, ductal carcinoma in situ 


 
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treated surgically with curative intent 
3. Radiotherapy within 28 days and abdominal/ pelvic 
radiotherapy within 60 days prior to Day 1 of Cycle 1, 
except palliative radiotherapy to bone lesions within 7 days 
prior to Day 1 of Cycle 1 
4. Treatment with any other investigational agent or 
participation in another clinical trial with therapeutic intent 
within 28 days prior to Day 1 of Cycle 1 
5. Pregnant or lactating women 
6. Known hypersensitivity reaction to any study medication 
(or excipients) 
7. Any disorder that compromises the ability of the patient to 
provide written informed consent and/or to comply with 
study procedures 
8. Symptomatic CNS metastases or carcinomatous 
meningitis: Asymptomatic patients must be clinically stable 
with regard to their CNS/meningeal metastatic 
involvement, have completed previous therapy (including 
radiation and / or surgery) at least 4 weeks prior to study 
drug administration, are not receiving steroid therapy or 
taper, and are not receiving anti-convulsive medication for 
any CNS involvement 
9. Active infection requiring IV antibiotics 
10. Active autoimmune disease that is not controlled by 
nonsteroidal anti-inflammatory drugs (NSAIDs), inhaled 
corticosteroids, or the equivalent of ≤ 10 mg/day 
prednisone 
11. Sensory peripheral neuropathy ≥ Grade 2 
12. Women of childbearing potential and men unwilling to 
practice an effective method of birth control from screening 
until 6 months after discontinuing study treatment.  
Childbearing potential is defined as sexually mature 
women who have not undergone a hysterectomy, have not 
been naturally post menopausal for at least 23 
consecutive months or have a serum FSH < 40 mIU/mL.  
Effective methods of birth control are defined as surgical 
sterilization [e.g., bilateral tubal ligation, vasectomy], 
hormonal contraception [implantable, patch, oral], or 
double-barrier methods [any double combination of: 
intrauterine device, male or female condom with 
spermicidal gel, diaphragm, sponge, cervical cap]), or 
abstinence from intercourse. Abstinence as a method of 
contraception is only acceptable as “true abstinence”, i.e. 
when it is in line with the preferred and usual lifestyle of 
the patient. Periodic abstinence (e.g., calendar, ovulation, 
symptom-thermal, post-ovulation methods) and withdrawal 
are not acceptable methods of contraception. 
13. Significant cardiovascular or cerebrovascular disease 
within 6 months prior to Day 1 of Cycle 1, including any of 
the following: 
a) Prior history of hypertensive crisis or hypertensive 
encephalopathy 
b) TIA,PRIND or stroke 
c) History of acute coronary syndromes (including 
acute myocardial infarction, unstable angina, 


 
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CABG, coronary angioplasty, or stenting)  
d) Aortic aneurysm requiring surgical repair 
e) Peripheral arterial thrombosis/thromboembolism 
14. Evidence of bleeding diathesis or significant coagulopathy 
(in the absence of therapeutic anticoagulation) 
15. Current use of anticoagulants (e.g., warfarin or any other 
coumadin-derivate coagulants) at therapeutic doses within 
7 days prior to study drug administration. Prophylactic use 
of unfractioned heparin or low molecular weight heparin 
(LMWH) is permitted (e.g., enoxaparin 40 mg QD)  
16. Major surgical procedure, open biopsy, or significant 
traumatic injury within 28 days prior to Day 1 of Cycle 1, 
or abdominal surgery, abdominal interventions  or 
significant abdominal traumatic injury within 60 days 
prior to Day 1 of Cycle 1 or anticipation of need for major 
surgical procedure during the course of the study or 
nonrecovery from side effects of any such procedure 
17. History of intra-abdominal inflammatory process 
within 6 months prior to Day 1 of Cycle 1, including 
but not limited to peptic ulcer disease, diverticulitis, or 
colitis 
18. Colonic prosthesis (stent) implant in place  
 
19. History of abdominal or tracheo-oesophageal fistula or GI 
perforation or intra-abdominal abscess within 6 months 
prior to Day 1  
20. History of intestinal obstruction and/or clinical signs or 
symptoms of GI obstruction including sub-occlusive 
disease related to the underlying disease or a 
requirement for routine parenteral hydration, parenteral 
nutrition, or tube feeding within 6 months prior to Day 1 
of Cycle 1. Patients with signs/symptoms of sub-
/occlusive syndrome/intestinal obstruction at time of 
initial diagnosis may be enrolled if they had received 
definitive (surgical) treatment for symptom resolution 
21. Chronic daily treatment with NSAID (occasional use 
for the symptomatic relief of medical conditions, e.g. 
headache or fever is allowed) 
22. Chronic daily treatment with corticosteroids (dose > 
10 mg/day methylprednisolone equivalent) excluding 
inhaled steroids 
 
23. Evidence of abdominal free air not explained by 
paracentesis or recent surgical procedure 
24. Metastatic disease that involve major airways or blood 
vessels, or centrally located mediastinal tumor masses 
( < 30 mm from the carina) of large volume 
25. History of bronchopulmonary hemorrhage NCI CTCAE ≥ 
Grade 2 or gross hemoptysis (defined as bright red blood 
or ≥ 1/2 teaspoon) within 2 months prior to randomization  
26. Severe, nonhealing or dehiscing wound, active ulcer, or 
untreated bone fracture 
27. Known dihydropyrimidine dehydrogenase deficiency or 
thymidylate synthase gene polymorphism predisposing the 


 
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patient for 5-FU toxicity 
28. Any other condition, diseases, metabolic dysfunction (e.g., 
uncontrolled diabetes mellitus), active or uncontrolled 
infections/inflammation, physical examination finding, 
mental status or clinical laboratory finding giving 
reasonable suspicion of a disease or condition that 
contraindicates patients participation in the clinical study 
due to safety concerns, compliance with clinical study 
procedures or that may affect the interpretation of the 
results 
LENGTH OF STUDY 
The time needed for for study enrollment is estimated to be 
approximately 15 months.  The total duration of the study for 
each patient will be as follows: 
• 
Screening:  Up to 4 weeks 
• 
Treatment period:  Patients will receive induction therapy 
for up to 8 cycles (approximately 4 months), followed by 
maintenance therapy for a maximum of 24 months 
unless the occurrence of disease progression, 
unacceptable toxicities, consent withdrawal or 
Investigator’s decision require treatment cessation. 
• 
EoS Visit:  Up to 6 weeks (5 ± 1 weeks) after last dose of 
RO5520985 
• 
Post study HAHA Visit (optional): 2 months ( ± 14 days) 
after last dose of RO5520985 
• 
Post study follow-up:  All patients will be followed for 
survival (e.g., by phone call or clinic visit) and 
subsequent anticancer therapy approximately every 
3 months after EoS Visit until death, loss to follow-up,  or 
study termination by Roche, whichever occurs first  
End of Study 
After the completion of induction therapy patients will 
continue maintenance therapy for a maximum of 24 months 
unless the occurrence of disease progression, unacceptable 
toxicities, consent withdrawal or Investigator’s decision.  All 
patients, also in case of early discontinuation, will attend a 
safety visit (5 ± 1 weeks) after receiving the last 
administration of RO5520985, which is the End of Study 
(EoS) Visit.  Patients off study will receive standard of care 
for the stage of their disease.  
Follow-up for survival will continue until all patients have 
either died or are lost to follow up, or the sponsor decides to 
end the trial, whichever occurs first. 
The study will formally end once the survival follow-up is 
complete or the last patient has completed the EoS Visit or is 
withdrawn from the study prior to that time (whichever occurs 
last), but may be prematurely terminated by the Sponsor. 
The main analysis and reporting will be conducted once 
approximatelly 80 PFS events have been collected,  When 
the study is formally ended, an additional analysis will be 
performed and appended to the main report. 
SAFETY OUTCOME 
MEASURES 
The safety outcome measures for this study are as follows: 
• 
Incidence and severity of adverse events (AEs) and 
serious adverse events (SAEs) graded according to the 
National Cancer Institute Common Terminology Criteria 


 
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for Adverse Events (NCI CTCAE) v4.03  
• 
Changes in hematology, biochemistry, coagulation, 
specifically those associated with vascular and renal 
function  
• 
Physical examinations (including ECOG), vital signs and 
ECG  
• 
Incidence and titers of human anti-human antibodies 
(HAHAs) 
• 
Adverse events leading to RO5520985, bevacizumab, or 
chemotherapy discontinuation 
• 
Incidence of the following selected adverse events 
according to NCI CTCAE, v4.03: 
Arterial hypertension (Grade ≥ 3) 
Proteinuria (Grade ≥ 3) 
Arterial thromboembolic events (any grade) 
Venous thromboembolic events (Grade ≥ 3) 
Vascular disorder - other: Thrombotic 
microangiopathy (any grade) 
Gastrointestinal perforation (any grade) 
Fistula involving an internal organ (any grade) 
Fistulae (Grade 4) 
Wound dehiscence/complication (Grade ≥ 3) 
Bleeding/hemorrhage (Grade ≥ 3) 
Pulmonary bleeding (Grade ≥ 2)  
CNS bleeding (Grade ≥ 2) 
Congestive heart failure (Grade ≥ 3) 
Reversible posterior leukoencephalopathy 
syndrome (any grade) 
PHARMACOKINETIC 
OUTCOME MEASURES 
The pharmacokinetic (PK) outcome measures for this study 
are as follows: 
• 
The PK profile of RO5520985 will be characterized with 
the plasma concentration-time data following IV 
administration of RO5520985, and will include the 
following parameters: Cmax, Cmin, Tmax, t1/2, AUC, AUCτ, 
CL, Vss, accumulation ratio (RA)  
• 
The PK profiles of oxaliplatin (free and total) and 5-FU 
will be characterized with the plasma concentration-time 
data following IV administration of FOLFOX, and will 
include the following parameters: Cmax, Cmin, Tmax, t1/2, 
AUC (when applicable) 
• 
Additional PK parameters may be evaluated as 
appropriate 
EFFICACY OUTCOME 
MEASURES 
Primary Outcome Measure 
The primary outcome measure for Study BP29262 is 
progression-free survival (PFS), defined as the time from 
randomization to the date of first documented occurrence of 
progression based on RECIST v1.1 criteria as determined by 
the Investigator or death from any cause on study, whichever 
occurs first.  
 


 
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Protocol BP29262, Version 5 
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Secondary Outcome Measures 
The secondary outcome measures for Study BP29262 are 
as follows: 
• 
Objective response rate (ORR).  Objective response rate 
is defined as the rate of patients with an objective tumor 
response, i.e. partial response (PR) or complete 
response (CR) as determined by the Investigator using 
RECIST v1.1 criteria on two consecutive occasions  at 
least 4 weeks apart 
• 
Duration of response, defined as the first occurrence of 
a documented objective response until the time of 
progression or death from any cause on study 
• 
Overall Survival, defined as the time from randomization 
until death from any cause 
EXPLORATORY OUTCOME 
MEASURES 
The exploratory outcome measures for this study include but 
are not limited to the following: 
• 
Levels of circulating targets by comparing baseline 
versus on-treatment values of Ang-2 and VEGF-A and 
their differential expression/regulation during 
RO5520985 vs. bevacizumab therapy 
• 
Changes of PlGF from baseline during treatment as 
marker of unspecific endothelial stress response and as 
potential response towards RO5520985 
• 
Assessment of tissue and soluble blood markers 
potentially related to predicting clinical benefit or toxicity 
of RO5520985 vs. bevacizumab 
• 
An assessment of tumor growth kinetics will be made by 
comparing post-treatment scans with at least 2 
pretreatment  scans not older than 12 weeks prior to 
C1D1, if available.  
• 
Analysis of additional CT parameters including necrotic 
volume/total tumor volume and intensity to assess their 
potential value as early response prediction markers 
BIOMARKER/GENOTYPING 
SAMPLE COLLECTION 
Pharmacodynamics and Exploratory Biomarker 
Assessments 
The following samples will be collected for exploratory 
analyses: 
• 
Plasma 
• 
Archival primary tumor tissue 
Please note: Soluble biomarkers (plasma) will be assessed 
in Part II patients only. 
Plasma 
Approximately 7.5 mL blood sample, for plasma isolation will 
be obtained for each timepoint.  The plasma will be used for 
the following assessments: 
• 
Levels of circulating targets:  Ang-2 and VEGF-A  
• 
Angiogenesis-related markers (but not limited to): Ang1, 
PlGF, sTie-2, VEGF-C, sVEGF-R1, sVEGF-R2, sVEGF-
R3, SDF-1α, E-selectin, ICAM-1, bFGF, IL-8, PDGF-C, 
CA-IX 
Blood (2mL) for plasma isolation will be obtained at 
baseline, disease progression as well as end of study and 


 
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Protocol BP29262, Version 5 
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be used to measure levels of circulating MMP-2 and MMP-9. 
 
An additional approximate 2 mL blood sample will be 
collected at baseline for potential development of an Ang-2 
companion diagnostic test, as well as a total of 
approximately 6 mL blood for 3 additional measurements of 
Ang-2. 
In addition 10 mL blood sample for plasma isolation will be 
required for the following assessment: 
• 
Dependent on the mutational analysis of the archival 
tissue based on the specific mutation detected, the 
presence of circulating tumor DNA (ctDNA) will be 
assessed at baseline and various time points on 
treatment 
Total blood loss 
The total blood volume loss for plasma and whole blood 
biomarker assessments will be approximately 140 mL up to 
Cycle 13 including the Disease Progression and End of 
Study Visit.  
Archival Primary Tumor Tissue  
Representative tumor specimens in formalin-fixed, paraffin 
embedded blocks (preferred) or slides (35 slides if possible) 
with an associated pathology report are to be obtained for all 
patients from all sites.  Tumor blocks/slides must be sent for 
central extended analysis of the RAS mutational status.  
In addition tumor tissue will be analyzed to assess further 
potential response prediction markers.  This includes the 
analysis of (but is not limited to): 
• 
Target proteins and biomarkers related to their vascular 
signaling including Ang-2, VEGF-A, Ang-1, Tie-2 
• 
Markers of vessel architecture by IHC including CD31, 
CD34, Podoplanin, aSMA, c-C3, Ki67.  The analysis will 
be prioritized based on the amount of material available.  
Additional assessments may be performed. 
• 
Markers characterizing the tumor status including Ki67 
and CAIX.  The analysis will be prioritized based on the 
amount of material available.  Additional assessments 
may be performed. 
• 
Markers of tumor-infiltrating immune cells including CD4, 
CD8, CD3/FOXP3, CD68/CD163, CD3/perforin. The 
analysis will be prioritized based on material and assay 
availability. Additional assesments may be performed.  
• 
Molecular mutational analysis including, but not limited to 
mutational status of EGFR, BRAF, etc. 
INVESTIGATIONAL 
MEDICINAL PRODUCTS 
RO5520985 
RO5520985 will be administered once every two weeks 
(Q2W) at a fixed dose of 2000 mg IV on Day 1 of each Cycle 
prior to mFOLFOX-6.   
 
Bevacizumab 
Bevacizumab will be administered at a dose of 5 mg/kg IV on 
Day 1 of each Cycle prior to mFOLFOX-6.  Bevacizumab will 
be dosed by body weight.  The weight at screening will be 


 
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used for dose calculation for each patient.  Recalculation of 
dosage is not required if weight changes.  
NON-INVESTIGATIONAL 
MEDICINAL PRODUCTS 
Modified FOLFOX-6 (5-FU, folinic acid and oxaliplatin) 
• 
Oxaliplatin at a dose of 85 mg/m2 IV over 120 ( ± 5) 
minutes on Day 1 of each Cycle.   
• 
Folinic acid at a dose of 400 mg/m2, IV over 120 ( ± 15) 
minutes on Day 1 of each Cycle.  As an alternative, 
Levofolinic acid at a dose of 200 mg/m2, IV over 120 
( ± 15)  minutes on Day 1 of each Cycle can be given.  
• 
5-fluorouracil (5-FU) starting bolus on Day 1 of each 
Cycle at a dose of 400 mg/m2 followed by 2400 mg/m2 IV 
permanent infusion for 46 ( ± 2) hrs.  
The preferred order and rate of drug administration may be 
modified based on patient tolerability or institutional 
guidelines. In the event that the full dose of folinic acid 
(racemic leucovorin or levoleucovorin) is unavailable and in 
accordance with NCCN guidelines, the dose may be lowered 
in accordance with the treating physician’s standard practice 
in administering mFOLFOX-6.  In case neither racemic 
leucovorin nor levoleucovorin is available, dose may be 
omitted and patients who tolerate treatment without Grade 2 
or higher toxicity, a modest increase in 5-FU dose (in the 
range of 10%) may be considered. However, standard 
dosing should be resumed when supply is adequate. 
During induction phase substitution of 5-FU/folinic acid is not 
permitted. During the maintenance phase substitution of 
5-FU/folinic acid IV by oral capecitabine is discouraged. 
However, individual patients may receive capecitabine 
without folinic acid according to institutional standards (e.g., 
625 mg/m2 BID continuously during maintenance phase at 
the discretion of the Investigator and in agreement with the 
Sponsor’s medical monitor.  
  
PROCEDURES:   
Physical Examinations 
Physical examinations will occur throughout the study according to the Schedule of 
Assessments (SoA).  A complete physical examination should include an evaluation of the 
head, eyes, ears, nose and throat.  The cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, genitourinary and neurological systems should also be examined.  
Any abnormality identified at baseline should be recorded on the Medical History eCRF. 
At subsequent visits, limited, symptom-directed physical examinations should be performed.  
Changes from baseline abnormalities should be recorded in patient notes.  New or worsened 
clinically significant abnormalities should be recorded as adverse events on the Adverse Event 
eCRF. 
ECOG Performance Status 
Performance Status (PS) will be measured using the ECOG Performance Status Scale.  PS 
will be assessed with each physical exam.  It is recommended, where possible, that a patient’s 
PS will be assessed by the same person throughout the study.   
Vital Signs  
Vital signs will include measurements of blood pressure, respiratory rate, body temperature 
and pulse rate (in sitting position upon resting for 5 minutes).  Medically significant findings 
that are present prior to the start of study treatment must be recorded in the Medical History 


 
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eCRF with “ongoing” ticked.  Medically significant findings made after start of study treatment 
or worsening of those reported at baseline and which meet the definition of an AE must be 
recorded as an AE in the eCRF. 
Electrocardiograms 
A 12-lead ECG will be performed and should be obtained for each patient from the same 
machine, whenever possible, as indicated in the SoA or as clinically indicated.  Triplicate ECG 
recordings will be obtained within approximately 2−5 minutes of each other.  The average of 
the three readings will be used to determine ECG intervals (e.g., PR, QT).   
Transthoracic Echocardiogram/Multiple Gated Acquisition Scans 
TTE (transthoracic echocardiogram) or MUGA (multiple gated acquisition) scan will be 
performed according to the standard practice of the investigational site.  This may be further 
repeated at the Investigator’s discretion if there are signs or symptoms of cardiotoxicity.  TTE 
or MUGA scan will be used to monitor the cardiac parameters of function (i.e., left ventricular 
ejection fraction [LVEF]).   
Adverse events 
Adverse events will be graded according to the NCI Common Terminology Criteria 
(NCI−CTCAE) version 4.03. 
Safety Laboratory Assessments 
The following safety laboratory assessments will be performed according to the SoA: 
• 
Hematology:  Hemoglobin, hematocrit, platelet count, RBC count (erythrocytes), WBC 
count (leukocytes), WBC absolute differential count (neutrophils, eosinophils, basophils, 
lymphocytes, monocytes). 
• 
Serum chemistry:  Na, K, Ca, lipase, glucose, GGT, AST, ALT, LDH, AP, total and direct 
bilirubin, urea, creatinine, total protein, albumin, CK, TSH, CRP and CrCl calculated (by 
Cockroft-Gault formula) or directly measured. 
• 
Coagulation:  INR/PT; aPTT, fibrinogen. 
• 
Blood tumor marker:  CEA 
• 
Urine analysis:  Urine dipstick for proteinuria (24-hrs urine protein analysis in 2+ or greater 
urine dipstick reading).   
• 
Pregnancy test:  All women of childbearing potential (including those who have had a 
tubal ligation) will have a serum or urine pregnancy test at Screening.  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
All samples for safety laboratory assessments will be sent to the study site's local laboratory 
for analysis.  Normal ranges for the study laboratory parameters must be supplied to the CRO 
before the study starts.  The total amount of blood drawn for all above described safety 
parameters will be approximately 12 mL during screening and approximately 12 mL for each 
subsequent safety laboratory assessment.  
Pharmacokinetic Assessments 
Part I of the study 
PK samples for RO5520985 and FOLFOX will be collected as outlined in the SoA.  For each 
scheduled time point of RO5520985 and 5-FU, an approximate venous blood volume of 2 mL 
for each compound will be drawn. For each scheduled time point of oxaliplatin (free and total), 
an approximate venous blood volume of 4 mL will be drawn.. 
In Part I, the total amount of blood drawn for PK (including HAHA) is approximately 149 mL. 
Part II of the study 
Samples for RO5520985 PK analysis will be collected as outlined in the SoA.  Samples from 
patients receiving bevacizumab will be taken as per the RO5520985 schedule to maintain the 
double-blind design of the study, but will not be analyzed.  PK parameters of FOLFOX will not 
be measured in Part II of the study.  At each scheduled timepoint approximately 2 mL of 
venous blood will be drawn.  
In Part II, the total amount of blood drawn for PK (including HAHA) is approximately 70 mL. 


 
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Human Anti-Human Antibodies 
Sampling will be conducted to determine if HAHAs are developed against RO5520985.  
Samples from patients receiving bevacizumab will be taken as per the RO5520985 schedule 
to maintain the double-blind in the study, but will not be analyzed.   For analysis purposes 
approximately 2 mL of venous blood for plasma isolation will be drawn. 
Disease-Specific Assessments 
Tumor and Response Evaluations 
Throughout the trial, the RECIST criteria, v. 1.1 will be applied when assessing any responses 
to the study drug treatment.  All potential sites of tumor lesions will be assessed at baseline by 
radiologic techniques using contrast enhanced CT or MRI imaging.  All tumor lesions at 
baseline need to be recorded as either target or nontarget lesions. 
The minimum schedule of imaging is the thorax, abdomen and pelvis.  If there is any clinical 
suspicion of disease at any site that may not be demonstrated by the minimum schedule, 
further investigations should be performed with a view to documenting the full extent of the 
tumor burden at baseline according to the Investigator’s clinical judgment (and according to 
RECIST). Patients with target lesions that have become centrally necrotic and meet the 
RECIST criteria of progressive disease, but otherwise demonstrate clinical symptoms 
improvement and tumor marker decrement, may remain on study treatment upon decision of 
the Investigator and the Sponsor’s medical monitor. 
STATISTICAL METHODS:  
Safety 
The safety analysis population will include all patients (Part I and 
Part II) who receive any amount of study treatment (5-FU/folic acid, 
oxaliplatin, bevacizumab, or RO5520985).  Patients will be assigned 
to the treatment arm received. 
Safety analyses include: 
• 
Adverse events 
• 
Clinical Laboratory Test Results 
• 
Vital Signs 
• 
ECG Data Analysis 
• 
Concomitant Medications 
Pharmacokinetics 
PK analyses will include all patients who received any amount of 
study treatment (5 FU/folinic acid, oxaliplatin, bevacizumab, or 
RO5520985), the same as the safety analysis population.   
Patients may be excluded from the PK analysis population if they 
significantly violate the eligibility criteria, deviate significantly from the 
protocol or if data are unavailable or incomplete which may influence 
the pharmacokinetic analysis.  Excluded cases will be documented 
together with the reason for exclusion.  All decisions on exclusions 
from the analysis will be made prior to database closure. 
All pharmacokinetic parameters will be presented by listings and 
descriptive summary statistics separately by group or cohorts. 
Additional PK analyses will be conducted as appropriate. 
Efficacy 
Primary and secondary efficacy analyses will be based on the intent 
to treat (ITT) population.  It will include all patients who were 
randomized (Part II only) and received any amount of study 
treatment (5-FU/folic acid, oxaliplatin, bevacizumab, or RO5520985).  
Patients will be assigned to the treatment arm to which they were 
randomized. 
Efficacy analyses include the following.  
Primary Efficacy Endpoint 
• 
Progression-free survival (PFS) defined as the time between 


 
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randomization and the date of first documented disease 
progression or death from any cause on study, whichever occurs 
first. Progression will be based on tumor assessment made by 
the Investigator according to RECIST 1.1 criteria. 
Secondary Efficacy Endpoints 
• 
Objective Response Rate (ORR) determined as the rate of 
patients with an objective tumor response (complete [CR] or 
partial response [PR]).  Objective response (OR) is defined as a 
complete or partial response as determined by the Investigator 
using RECIST v1.1 on two consecutive occasions at least  4 
weeks apart.   
• 
Duration of OR defined as the time from the initial response (CR 
or PR) to disease progression or death from any cause on study.  
This will only be calculated for patients who have a best overall 
response of CR or PR.   
• 
Overall Survival (OS).  OS is defined as the time from 
randomization until death from any cause.  All deaths will be 
included, without regard to whether they occur on study or 
following treatment discontinuation.  For patients who have not 
died, OS will be censored at the last date known to be alive.  
Patients without any post baseline information will be censored at 
the time of randomization. 
Exploratory 
Biomarker Analyses 
Exploratory biomarker parameters may be presented by listings and 
descriptive summary statistics separately by treatment arms. 
All analyses of PD and exploratory biomarkers will be based on the 
safety analysis population of Part II patients, i.e. any Part II patients 
who received any amount of study treatment (5-FU/folic acid, 
oxaliplatin, bevacizumab, or RO5520985). 
To assess predictability of a biomarker, the association between 
clinical outcome and the biomarker level or changes thereof will be 
explored.  Details of the biomarker analysis are provided within the 
Statistical Analysis Plan (SAP). 
Other Exploratory 
Analyses 
PK/PD 
Exploratory graphical analyses of exposure-efficacy relationships 
may be produced  for selected efficacy, PD and/or safety 
measurements if feasible.  A PK/PD modeling approach may be 
considered in order to further explore the exposure-response 
relationship of selected response variables. 
Tumor growth kinetic 
An exploratory assessment of tumor growth kinetics will be made by 
comparing post-treatment scans with at least 2 pre-treatment  scans 
not older than 12 weeks prior to C1D1, if available. The two pre-
treatment scans consists of a pre-study scan (if available) and the 
study baseline scan, and will allow estimation of tumor growth rate 
before start of treatment. If the pre-treatment tumor growth kinetic 
can be assessed, this will then be compared to the growth/shrinkage 
rate after start of treatment. Data will be explored using  linear and/or 
exponential models, as appropriate, in non linear mixed effect 
modelling software. 
SAMPLE SIZE JUSTIFICATION:   
Within Part I, 6-18 patients will be treated with RO5520985 plus mFOLFOX-6. Six patients per 
RO5520985 dose to be tested is considered sufficient to assess the safety and tolerability of 
RO5520985 in combination with mFOLFOX-6.  
Part II of the study will enroll approximately 190 patients, and the primary analysis will be 


 
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performed after approximately 80 investigator assessed PFS events.  The emphasis of the 
efficacy analysis will be on estimation of the magnitude of treatment effect rather than 
hypothesis testing.  This trial is hypothesis-generating and is designed to be able to detect a 
meaningful benefit of the combination therapy of RO5520985 plus  mFOLFOX-6 versus 
bevacizumab plus mFOLFOX-6.  Based on the sample size of 80 events observed in the two 
treatment arms combined, there is an 80% power to detect a HR of 0.574 at a one-sided 
significance level of 0.05. 
Interim Analyses 
Interim safety analysis of Part I patients will be performed by an internal monitoring committee 
(IMC) after all patients have received at least two full cycles.  The IMC may also conduct 
further blinded safety reviews based on safety signals that arise at any time during Part II of 
the study.  
Within Part II of the study, an interim analysis for futility is planned to be conducted after 
approximately 30 PFS events. A cut-off HR of 1.0 has been suggested as non binding futility 
criteria. The probability of observing an HR equal or higher than 0.77 at final analysis, given 
an HR of 1.0 at the interim analysis, will be above 80%. Enrollment will not be stopped during 
the interim analysis.   
Administrative interim analysis, based on efficacy, may also be performed during Part II of the 
study after approximately 30 events and again after 50 events.  The efficacy interim analyses 
are administrative in nature allowing for decision making of subsequent clinical development 
activities (i.e., pivotal Phase III study) of the compound under investigation.  The study will not 
be stopped for efficacy.  Separate from the Safety IMC, there will be in addition an Efficacy 
IMC responsible for the futility/efficacy analysis of Part II.  The details and modalities are 
described in a pre-specified charter outlined in a separate document as well as in the 
statistical analysis plan. 


 
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List of Prohibited Medications 
As a general rule, no concomitant medication will be permitted, with the exception of 
medications to treat AEs, unless the rationale for exception is discussed and clearly 
documented between the Investigator and Clinical Pharmacologist/Clinical Scientist. 
The following treatments are not permitted during the study: 
• 
Any other investigational therapy 
• 
Anticancer therapy (chemotherapy, hormonal, biological or radiation therapy, and surgery) 
other than study treatments 
• 
Radiotherapy, except short course palliation 
If any of these therapies are needed, the patient will be considered to have evidence of 
progressive neoplastic disease and have experienced treatment failure.  This will lead to the 
patient’s discontinuation from the study. 
Furthermore, due to the potential risk of bleeding associated with anti-angiogenic  therapies, 
the following treatments are prohibited: 
• 
Current use of full dose anticoagulants or thrombolytic therapy at therapeutic doses.  
However, if a patient experiences a VTE event while still receiving study drug 
treatment, it may still be possible for him or her to remain on study medication.  
Please see Section 5.2.3.2 (Table 2) for guidance on further treatment with or 
discontinuation of bevacizumab/ RO5520985 therapy. 
• 
Prophylactic use of low dose anticoagulation, unfractionated heparin or low molecular 
weight heparin (LMWH) is permitted.  However, the preferred choice for anticoagulation 
treatment should be LMWH as per ASCO guidelines. The prophylactic use of warfarin or 
coumarin-like products is not permitted. 
• 
Prophylactic use of anticoagulation at baseline and during study treatment for the 
maintenance of patency of permanent indwelling central venous access devices is 
permitted. If a patient suffers a VTE event, while still receiving study treatment, it may still 
be possible for him or her to remain on study treatment (Section 5.2.3) 
In addition, due to the potential risk of severe/fatal infections in patients treated with 5-FU, the 
following treatment is prohibited: 
• 
Vaccination with live vaccines  
 
Also prophylactic use of phenytoin is not allowed in combination with 5-FU. 
Concomitant chronic use of NSAIDs while receiving study drugs is prohibited. However, for 
the symptomatic relief of medical conditions (e.g. headache, fever) sporadic or short-
term intake of oral NSAIDs is allowed, when co-administered proton pump inhibitors to 
reduce potential gastrointestinal damage. Also seek consultation with a gastroenterologist 
as medically indicated. 
Chronic daily treatment with systemic corticosteroids (dose >10 mg/day 
methylprednisolone equivalent) is generally prohibited while on RO5520985/ 
bevacizumab. However, a one-time or medically indicated, short course of higher dose 
(>10 mg/day methylprednisolone equivalent) of systemic corticosteroid use may be 
allowed as agreed by the study investigator and the Medical Monitor. 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
5-FU 
5-fluorouracil 
AE 
adverse events 
ASCO 
American Society of Clinical Oncology 
ASH 
American Society of Hematology 
AUC 
area under the curve 
BID 
twice daily 
C 
Cycle 
CL 
Clearance 
CR 
complete response 
CRC 
colorectal cancer 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
D 
Day 
DP Visit 
Disease Progression visit 
EC 
ethics committee 
ECG 
Electrocardiograms 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
EIH 
entry into human 
EoS 
end of study 
ESF 
Eligibility Screening Form 
ESMO 
European Society of Medical Oncology 
EU 
European Union 
FDA 
U.S. Food and Drug Administration 
FFPE 
formalin-fixed paraffin embedded 
FOLFIRI 
irinotecan, folinic acid, and 5-fluorouracil 
FOLFOX 
oxaliplatin, folinic acid, and 5-fluorouracil 
FSH 
follicle-stimulating hormone 
G-CSF 
granulocyte colony-stimulating factor 
G 
grade 
GIP 
Gastrointestinal perforation 
HAHA 
human anti-human antibody 


 
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HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HUVEC 
human umbilical vein endothelial cell 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IFL 
irinotecan, 5-fluorouracil, and leucovorin 
IMC 
internal monitoring committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
IRB 
institutional review board 
IRR 
infusion-related reactions 
IV 
intravenous 
IxRS 
interactive (voice/web) response system 
LMWH 
low molecular weight heparin 
LPLV 
last patient, last visit 
LVEF 
left ventricular ejection fraction 
mCRC 
metastatic colorectal cancer 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
MVD 
microvessel density 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NSAID 
nonsteroidal anti-inflammatory drug 
OR 
objective response 
ORR 
objective response rate 
OS 
overall survival 
PD 
pharmacodynamic 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PlGF 
placental growth factor 
PR 
partial response 
PRIND 
prolonged reversible ischemic neurologic deficit 
PS 
performance status 
RCR 
Roche Clinical Repository 
RCT 
randomized controlled trials 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RoW 
Rest of World 
RP2D 
recommended Phase II dose 


 
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PRIND 
Prolonged Reversible Ischemic Neurologic Deficit 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SoA 
Schedule of Assessments 
SoC 
Standard of Care 
SPA 
statistical programming analyst 
TGI 
tumor growth inhibition 
TIA 
Transient ischemic attack 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
VEGF 
vascular endothelial growth factor 
XELOX 
oxaliplatin and capecitabine 


 
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1. 
BACKGROUND AND RATIONALE 
1.1 
BACKGROUND ON DISEASE 
Colorectal cancer (CRC), a cancer with origins within the colon or the rectum, is the 
second leading cause of cancer deaths in the Western world in males and females 
(Arnold and Seufferlein 2010).  In 2013, the number of new cases of colon cancer and 
rectal cancer were estimated to be approximately 102,480 and approximately 40,340 
respectively; with an estimated 50,830 people who died from the disease (colon and 
rectal cancer combined) (National Cancer Institute).   
The major cause of death in patients with CRC is distant metastasis 
(Alberts and Wagman 2008).  Depending on the stage of the primary tumor, liver 
metastases are seen in 20−70% of patients with CRC, and lung metastases are seen in 
10−20% (Penna and Nordlinger 2002); with the liver being the only site of metastatic 
spread in 30-40% of patients (Garden et al. 2006).  Without treatment, the median 
survival for patients with metastatic CRC is approximately 1 year (Liu et al. 2003).  
Surgical resection of metastases can improve this result dramatically, with 5-year 
survival rates approaching 27−41% in appropriate patients (Mandala et al. 2007).  
However, only 10−20% of patients with metastatic disease have lesions that are 
considered resectable at presentation (Vilbert et al. 2005).   
The optimal treatment strategy for patients with clearly unresectable metastatic CRC 
(mCRC) is rapidly evolving.  Chemotherapy plays a central role in treatment regimens 
for mCRC and is recommended for use as a treatment in patients with unresectable 
disease or as a neoadjuvant/adjuvant treatment in patients with resectable disease 
(Van Cutsem et al. 2010; Benson et al. 2013).  Typical chemotherapy regimens for 
mCRC include:  Oxaliplatin, folinic acid, and 5-fluorouracil (FOLFOX) or irinotecan, 
folinic acid, and 5-fluorouracil (FOLFIRI) ± bevacizumab, or FOLFOX or FOLFIRI ± 
cetuximab or panitumumab.  
1.2 
ANTI-ANGIOGENIC TREATMENT OF COLORECTAL CANCER 
The process of new blood vessel formation, or angiogenesis, has become an important 
therapeutic target in many different cancers including mCRC.  To grow beyond 1−2 mm 
in diameter, a tumor needs an independent blood supply, which is acquired by the 
overexpression of growth factors that recruit new vasculature from existing blood vessels.  
Disruption of the delicate balance of pro- and anti-angiogenic factors, described as the 
angiogenic switch, results in the creation and maintenance of a growing vascular 
network (Bergers and Benjamin 2003; Ferrara 2004; Hicklin and Ellis 2005).  It has been 
hypothesized that inhibition of angiogenesis in tumors can both impair the formation of 
new tumor blood vessels and possibly ‘normalize’ the existing tumor vasculature, 
causing a more efficient delivery of cytotoxic chemotherapies 
(Grothey and Allegra 2012).  At present, a number of anti-angiogenic agents are in 
clinical development or have been approved for the treatment of patients with mCRC. 


 
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1.2.1 
Anti-VEGF mAb Treatment of Colorectal Cancer 
The development and use of antiangiogenesis agents, particularly those targeting 
vascular endothelial growth factor (VEGF), has become an integral component of 
anticancer chemotherapy regimens for many tumor types including CRC 
(Meadows et al. 2012; Wang and Lockhart 2012).  Bevacizumab, an anti-VEGF antibody, 
should be considered in patients with metastatic CRC, as it increases the activity of an 
active cytotoxic regimen (Van Cutsem et al. 2010).  In a large Phase III trial (AVF2107g) 
with patients who have mCRC, the addition of bevacizumab to the “IFL” regimen 
(irinotecan plus bolus 5-fluorouracil [5-FU]/leucovorin chemotherapy resulted in a 
clinically and statistically significant increase in overall survival (OS), with a hazard ratio 
(HR) for death of 0.66 (median OS: 20.3 vs. 15.6 months, p < 0.001).  Similar increases 
were seen in progression-free survival (PFS) (10.6 vs. 6.2 months, p < 0.001 HR = 0.54), 
objective response rate (ORR) (44.8% vs. 34.8%), and duration of objective response 
(OR) (10.4 vs. 7.1 months; p < 0.001) for the combination arm versus the chemotherapy 
alone arm (Hurwitz et al. 2004).  On the basis of the survival advantage demonstrated in 
Study AVF2107g, bevacizumab was designated for priority review and was approved by 
the FDA in 2004 and by the EMA in 2005 for for use in combination with infusional 
5-FU−based chemotherapy as first-line treatment for patients with mCRC.  In 
subsequent studies bevacizumab demonstrated improved clinical outcomes in 
combination with nearly all chemotherapy regimens, including intravenous (IV) 
5-FU/leucovorin (Kabbinavar et al. 2005), oral 5-FU (capecitabine) (Tebbutt et al. 2010), 
and IV or oral 5-FU combined with oxaliplatin (FOLFOX or XELOX regimens) 
(Giantonio et al. 2007; Saltz et al. 2008).  Improvements were also suggested when 
bevacizumab was combined with infusional 5-FU and irinotecan (FOLFIRI regimen) 
(Fuchs et al. 2007).  Additional data from a Phase III trial in second-line mCRC (E3200) 
has also demonstrated clinical benefit from bevacizumab when added to chemotherapy.  
In Study E3200, the addition of bevacizumab to FOLFOX second-line chemotherapy 
resulted in improved OS compared with FOLFOX alone (13.0 vs. 10.8 months, 
respectively, p < 0.01 HR = 0.75) in a population of CRC patients who were previously 
treated with a chemotherapy regimen (Giantonio et al. 2007). 
1.2.2 
Anti-Angiopoietin-2 Treatment of Colorectal Cancer 
The VEGF pathway and the angiopoietin-Tie2 receptor axis have distinct roles in the 
regulation of pathologic angiogenesis (Huang et al. 2010).  Angiopoietin-2 (Ang-2) is an 
inhibitory ligand of the Tie-2 receptor that is stored in the Weibel–Palade bodies of 
endothelial cells (Fiedler et al. 2004) and disrupts the integrity of the blood vessel wall, 
thus counteracting vascular normalization (Maisonpierre et al. 1997; 
Scharpfenecker et al. 2005; Falcon et al. 2009).  Ang-2 is overexpressed and appears to 
be a prognostic factor in a number of tumor types, including CRC (Bach et al. 2007).  
High serum Ang-2 levels have been shown to promote metastatic growth 
(Imanishi et al. 2007) and are associated with poorer survival outcomes in colon cancer 
(Volkova et al. 2011). Furthermore, higher tumor Ang-2 expression has been associated 
with lymph node metastasis, venous invasion, and high microvascular density in CRC 


 
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(Chung et al. 2006).  Ang-2 biology is known to be VEGF−dependent and has been 
shown to be downregulated in response to anti-VEGF therapy (Liu et al. 2013).  In fact, 
amongst patients receiving bevacizumab-containing treatment, low Ang-2 baseline 
levels correlated with longer PFS and OS and greater reductions in Ang-2 level also 
predicted for better OS (Goede et al. 2010; Liu et al. 2013).  The consistency of these 
pre- and on-treatment results not only suggests that Ang-2 may be a predictor of benefit 
from anti−VEGF-containing therapy but also underscore the potential value of 
concurrently targeting VEGF and Ang-2/Tie2. Recently, different approaches have been 
described to target the Angiopoietin/Tie axis including Tie2 kinase inhibitors, Fc-fusion 
proteins and monoclonal antibodies with different specificities, and new scaffolds like 
CovX which are presently in pre-clinical or clinical exploration (Brown et al. 2010; 
Huang et al. 2011; Cascone and Heymach 2012).  Trebananib (AMG 386) is an 
investigational, intravenously administered peptide-Fc fusion protein neutralizing the 
interaction between Ang-1 or Ang-2 and the Tie2 receptor that was recently tested as 
second-line treatment for patients who have mCRC (Peeters et al. 2013).  In this Phase 
II study, the combination of trebananib plus FOLFIRI had acceptable toxicity but did not 
prolong PFS compared with placebo plus FOLFIRI, although there was a trend towards 
improved ORR.  The authors concluded that treatment approaches incorporating 
inhibitors of the Ang/Tie2 axis could have potential in the treatment of CRC if 
administered at the right dose/schedule, in less advanced disease and administered in 
combination with VEGF inhibitors.  Trebananib plus bevacizumab in patients with 
chemotherapy-naïve metastatic CRC is under clinical evaluation  in a Phase II study 
(ClinicalTrials.gov, NCT01249521). 
1.3 
BACKGROUND ON RO5520985  
RO5520985 is based on bevacizumab, a monoclonal antibody targeted against VEGF-A, 
as well as a monoclonal antibody targeted against Ang-2 called LC06. It is a bispecific 
monoclonal antibody based on a human IgG1 framework and is comprised of two 
different heavy chains and two different light chains.  One arm of the antibody binds 
Angiopoietin-2 (Ang-2) and the other arm binds Vascular Endothelial Growth Factor A 
(VEGF-A).  Point mutations in the CH3 domain (“Knobs-into-holes”) promote the 
assembly of two different heavy chains.  Exchange of the constant part of the heavy 
chain 1 and constant part of the light chain domains in the Ang-2 binding Fab promote 
the correct assembly of the two different light chains called the “CrossMab approach” 
(Schaefer et al. 2011).  
Ang-2 and VEGF-A cooperatively promote tumor growth in mouse tumor models, as 
demonstrated by the inability of Ang-2 overexpression to stimulate the growth of 
hepatocellular carcinoma unless VEGF-A is simultaneously upregulated 
(Yoshiji et al. 2005).  Thus, selectively targeting both Ang-2 and VEGF-A might increase 
the level of normalization that is achieved by reducing the proportion of unstable blood 
vessels that initiate angiogenesis in cancer patients.  In syngeneic and xenograft mouse 
tumor models, the physical combination of anti-Ang-2 with anti-VEGF-R2 inhibitor or 


 
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anti-VEGF-A antibody led to enhanced anti-tumor activity relative to the use of the single 
agents, supporting the concept that concurrent pathway inhibition may also improve 
anti-angiogenic cancer therapies in the clinic (Hashizume et al. 2010; Brown et al. 2010). 
Further information can be obtained from the RO5520985 Investigator’s Brochure (IB).  
1.3.1 
Previous Nonclinical Studies 
RO5520985 was shown to bind selectively and with high affinity both VEGF-A and Ang-2 
in a concentration dependent manner.  The VEGF-A binding arm is crossreactive to 
VEGF-A in rabbit, cynomolgus monkey, and human but not mouse.  The Ang-2 binding 
arm is cross-reactive to rabbit, cynomolgus monkey, human, and mouse Ang-2. 
In vitro binding of RO5520985 to Ang-2 inhibited (1) binding of the Ang-2 ligand to Tie2 
receptor, and (2) Ang-2−mediated Tie2 phosphorylation.  In vitro binding of RO5520985 
to VEGF inhibited (1) VEGF-A−induced proliferation of HUVEC (human umbilical vein 
endothelial cell) proliferation, and (2) VEGF-A−induced HUVEC migration. 
The anti-angiogenic effect of RO5520985 was investigated in the VEGF-A−induced 
mouse cornea pocket assay.  Systemic administration of either RO5520985 or 
bevacizumab completely abolished VEGF−induced corneal angiogenesis.  Single agent 
treatment with LC06 (Ang-2 inhibitor) exerted a less pronounced effect. 
Tumor growth inhibition (TGI) and improved survival following treatment with 
RO5520985 was demonstrated in vivo in multiple cell lines, patient-derived xenografts, 
and syngeneic mouse models (including gastric, colorectal, lung, breast, ovarian, glioma, 
lymphoma, prostate and pancreatic tumors).  The pharmacokinetics of RO5520985 were 
determined in mice and yielded a typical IgG-like terminal half-life in the range of 
6−7 days.  On the basis of the findings of a dose dependency study in the CRC 
xenograft model Colo205, a dose of 10 mg/kg was considered optimal for use in 
subsequent studies. 
In another Colo205 xenograft study, tumor growth was significantly inhibited by 
single-agent bevacizumab (TGI of 66%) and single-agent LC06 (TGI of 47%), whereas 
the bispecific RO5520985 administered at an equivalent dose in terms of binding sites 
induced tumor stasis and exhibited a TGI of 92% at the end of the study.  Additionally, 
tumor cell dissemination to the lung was reduced by RO5520985 in the same study.  
RO5520985 also showed superior anti-tumor activity compared to the monotherapies in 
small versus large Colo205 and KPL-4 tumors making it an attractive drug because 
vessel structure changes in growing tumors from immature to mature vessels. 
Anti-tumor activity of RO5520985 was also observed in ovarian, pancreatic, prostate and 
lymphoma xenografts.  Combination of anti-VEGF-A and anti-Ang-2 also showed strong 
anti-tumor activity when tested in two syngeneic mouse models (colon and breast) as 
indicated by over 60% TGI. 


 
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Vessel architecture was analyzed in several mouse models.  Microvessel density (MVD) 
was significantly reduced in orthotopic KPL-4 breast cancer xenograft.  Remaining 
vessels were highly covered with pericytes indicating vessel normalization induced by 
RO5520985.  Similar effects were observed in an orthotopic glioblastoma model (U87): 
as compared to anti-Ang-2 or anti-VEGF-A treatment, the combination of anti-Ang-2 and 
anti-VEGF-A antibodies  resulted in superior anti-tumor activity which translated into  
prolonged survival.  MVD and vessel volume were significantly decreased in the anti-
Ang-2/anti-VEGF-A combination group compared to monotherapy.  Vessel architecture 
and function changed towards a more normal vessel phenotype, indicating vessel 
normalization induced by anti-Ang-2/VEGF-A treatment.  This was demonstrated by 
reduced vessel turnover and increased blood cell velocity.  Similar findings regarding 
TGI were observed in a subcutaneous U87 cancer xenograft. 
Further details on nonclinical studies can be found in the RO5520985 IB. 
1.3.2 
Previous Clinical Studies 
Initial clinical experience with RO5520985 is based on the ongoing entry into human, 
Phase I study (Study BP28179; NCT01688206).  This is an open-label, multicenter, 
Phase I dose-escalation study in patients with solid tumors to assess the safety, 
tolerability, PK, PD and preliminary anti-tumor activity of RO5520985.  The study 
consists of three parts:  Part I, a dose escalation phase to evaluate the maximum 
tolerated dose (MTD) and/or recommended as Phase 2 dose (RP2D) followed by Part II 
and Part III, which start in parallel.  Part II is designed to assess the pharmacodynamic 
(PD) effects of RO5520985 in paired tumor biopsies and by tumor imaging and Part III to 
investigate the single agent activity of RO5520985 in patients with platinum 
resistant/refractory ovarian cancer. 
As of the cutoff date (8 January 2014), a total of 42 patients have been treated within 
Part I of the study with intravenous RO5520985 at the dose levels presented in Table 1 . 
Table 1 
Cohorts and Dosing Regimen for Part I (Dose Escalation) 
Dose Escalation Cohorts 
Extension 
Cohorts 
 
Cohort 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Dose (mg/kg) 
3 
6 
12 
19.2 
10 
20 
30 
30 
30 
Regimen 
Q2W 
Q2W 
Q2W 
Q2W 
QW 
QW 
QW 
Q2W 
QW 
Number of patients 
1 
3 
4 
8 
4 
4 
6 
6 
6 
 
The dose-escalation part of the study is completed and the MTD has not been reached.  
Part II and Part III of the study commenced in February 2014. 


 
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Clinical Pharmacokinetics 
Blood samples sufficient for the estimation of PK parameters of RO5520985 have been 
analyzed for all 42 patients treated with RO5520985 in Part I of Study BP28179 using 
both a bi-weekly (Q2W) and weekly (QW) dosing regimen. 
RO5520985 was infused over a 90-minute period for the first dose.  The infusion period 
was reduced to 60 minutes for the second dose and to 30 minutes for all subsequent 
doses.  The PK profile to date shows a near linear increase in exposure (AUC) and peak 
concentrations (Cmax) across the dose-range studied, with low inter-individual variability 
(3−36%) for both Q2W and QW regimens.  The elimination half life following a Q2W 
regimen is 7−9 days. 
Safety 
Within Study BP28179, all patients (42/42, 100.0%) from all cohorts experienced at least 
one adverse event (AE), regardless of causality.  Among the 42 patients, 328 AEs were 
recorded (174 AEs in Q2W, 154 AEs in QW).  The most commonly reported AEs were 
hypertension (50.0% ), asthenia (35.7%), headache (28.6%) and fatigue (19.0%).  The 
majority of the AEs were of Grade 1 or Grade 2 intensity.  Overall, 20 patients 
experienced 33 Grade ≥ 3 AEs; 12 patients in the Q2W schedule experienced 21 
Grade ≥ 3 AEs and 8 patients in the QW schedule had 12 Grade ≥ 3 AEs.  Sixteen of 
these AEs were considered by the Investigator to be related to RO5520985 (10 in QW 
and 6 in Q2W).  Overall, the most frequently reported individual Grade ≥ 3 AE was 
hypertension (19%, 8/42 pts) which was reported in 2 patients in the Q2W schedule and 
6 patients in the QW schedule.  All of these Grade 3 hypertension events were 
considered by the investigator to be related to study treatment. 
Nine SAEs have been reported, 5 of which were judged by the Investigator to be related 
to RO5520985 (Grade 5 pulmonary hemorrhage at 19.2 mg/kg Q2W, Grade 3 
vesico-cutaneous fistula at 12 mg/kg Q2W and in the 30 mg weekly cohort Grade 2 
cerebral hemorrhage, Grade 3 hypertension and Grade 3 thrombotic microangiopathy.  
All related SAEs led to discontinuation of study treatment. 
The fatal pulmonary hemorrhage occurred in a CRC patient receiving 19.2 mg/kg Q2W 
that constituted a DLT; however, this SAE was also reported and judged by the 
Investigator to be possibly related the patient’s underlying tumor disease with a large 
centrally located mediastinal metastasis.  The patient had pre-existing episodes of 
hemoptysis G1 and cough G1 at study entry. 
Anti-tumor activity 
As of the cutoff date (8 January 2014), 32 out of 42 patients were available for 
evaluation of the best overall response according to RECIST criteria.  Among the 
32 patients, 1 patient in the QW schedule (30 mg/kg) had a partial response.  Sixteen 
patients had stable disease (11/22 patients in Q2W, 5/20 patients in QW) and 
15 patients had progressive disease (7/22 patients in Q2W, 8/20 patients in QW) as best 


 
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response.  A total of 8 patients could not yet be assessed for response and for 2 patients 
no assessment is available.  Eligible patients underwent DCE-MRI demonstrating 
moderate to significant on-treatment reductions in parameters representative of vascular 
characteristics in 22/34 (64%) patients evaluated.  DW-MRI showed hints of on-
treatment reduction in cell density and increase in necrosis in 7/25 (28%) patients 
evaluated. 
Updated information is provided in the latest RO5520985 IB.  
1.4 
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT 
Current first- and second-line therapies for mCRC include a variety of different 
oxaliplatin- and irinotecan-based chemotherapy regimens, including FOLFOX and 
FOLFIRI which have similar activity, but different toxicity profiles.  Improved outcomes 
have been demonstrated with chemotherapy combined with therapies targeting the 
EGFR or VEGF(R) pathway (Van Cutsem et al. 2010).  In particular, the addition of 
bevacizumab, a recombinant humanized anti−VEGF-A mAb, to standard 
chemotherapies for mCRC has been shown to improve overall and progression-free 
survival, as well as response rates (Grothey and Allegra 2012).  Hence, the success of 
anti−VEGF-A therapy provides the basic rationale to explore treatment options that 
additionally target key angiogeneic pathways that could further improve upon the clinical 
benefit of bevacizumab. 
The VEGF pathway and the Angiopoietin/Tie2 receptor axis have distinct 
complementary roles in the regulation of tumor angiogenesis, vascular permeability and 
tumor progression; however, compensatory alternative angiogenic pathways are 
potential mechanisms of tumor escape that likely limit the full potential of anti-angiogenic 
monotherapies.  Ang-2 expression has been shown to function as a key regulator of 
tumor angiogenesis and metastasis in colorectal cancer.  Upregulation of Ang-2 is 
associated with tumor invasiveness, adverse prognosis and poor clinical outcome of 
patients with mCRC treated with bevacizumab containing therapy (Chung et al. 2006).  
Recent data have demonstrated that Ang-2 inhibitors, both as single agents or in 
combination with anti-VEGF therapy exert anti-tumor activity in preclinical CRC models  
(Hashizume et al. 2010; Brown et al. 2010; Coxon et al. 2008) and interfere with 
metastasis formation (Mazzieri et al. 2011).   
RO5520985 (Ang-2/VEGF-A CrossMab) is a novel bevacizumab-based bispecific 
human IgG1 antibody acting as a dual-target inhibitor of the two key angiogenic factors 
VEGF-A and Ang-2.  The Ang-2/VEGF-A CrossMab showed potent tumor growth 
inhibition in a panel of orthotopic and subcutaneous syngeneic mouse tumors and 
patient or cell line derived human tumor xenografts, especially at later stages of tumor 
development (Kienast et al. 2013).  In a Colo205 colorectal cancer tumour xenograft 
model, RO5520985 demonstrated superior efficacy (as assessed by TGI) versus the 
single agent inhibitors of VEGF-A and Ang-2.  Additionally, metastatic tumor cell spread 
(through leaky vessels) to the lung was reduced by Ang-2/VEGF-A CrossMab within the 


 
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same model.  Interestingly, RO5520985 also showed superior anti-tumor activity on 
larger tumors compared with the monotherapies, supporting the notion that larger tumors 
consist of different vessel types that do not all respond equally to anti-VEGF-A therapy 
(Nagy and Dvorak 2012).  With regards to the clinical situation, RO5520985-induced 
tumor vessel normalization in various models and had superior anti-tumor activity in 
combination with chemotherapy (docetaxel) vs. bevacizumab plus docetaxel or 
docetaxel alone in an orthotopic KPL-4 breast cancer model, indicative of an improved 
delivery of the cytotoxic combination partner within the tumor tissue (Kienast et al., 2013). 
To date, the observed clinical safety profile of single agent RO5520985 
(ClinicalTrials.gov, NCT01688206) has been consistent with that reported for 
bevacizumab and other inhibitors of the Ang/Tie-2 axis administered to patients with 
advanced solid tumors, however the incidence rates of arterial hypertension and GI-
perforation associated with the use of RO5520985 seems to be higher than those 
reported for bevacizumab.  RO5520985 also appears to impact tumor vascularity and 
showed encouraging anti-tumor activity in this heterogeneous patient population.  The 
medical need for prospective clinical trials to further optimize the standard treatment of  
metastatic CRC is well recognized and supported by current therapy guidelines (NCCN 
Guidelines Version 2.2014).  The purpose of this study is to determine if concurrent  
target inhibition of the VEGF-A and Ang-2 axis by addition of the bispecific mAb 
RO5520985 to standard chemotherapy can improve the outcome of patients with 
metastatic CRC. 
In Part III of the phase 1 study BP28179 of single agent RO5520985 in patients with 
epithelial ovarian, fallopian tube or primary peritoneal cancer, 5 of 41 patients 
(12.2%) developed GI perforation (GIP). Two of these patients had a fatal outcome. 
GI perforation is an identified risk for RO5520985, however, this incidence 
exceeds what has been reported with bevacizumab in ovarian cancer.  
As of the cut-off date (27-Nov 2015) in this study BP29262, the incidence of GIP 
events (including perforation, intra-abdominal abscess, and GI fistula) was 11.1% 
(8/72 patients) in Arm A versus 5.6% (4/71 patients) in Arm B. The GIP events in 
Arm A included a colon perforation following colonoscopy the day before the 
event and a colonic prosthesis perforation. Likewise, a GI tumor perforation in 
Arm A was assessed as unrelated to blinded vanucizumab (RO5520985)/ 
bevacizumab, but as related to a prosthetic breakage. A non-serious GIP event of 
bowel micro-perforation occurring in Arm A did not require patient hospitalization. 
One GIP in Arm A had a fatal outcome in a 
-year old 
 patient. GIP is an 
identified risk for RO5520985/ bevacizumab, however, particularly the reported 
incidence in Arm A of BP29262 exceeds what has been reported with 
bevacizumab in CRC which ranges from 1 to 4 % across treatment lines. Several 
clinical risk factors have been postulated to increase the risk of bowel perforation 
from bevacizumab in metastatic CRC, including a history of peptic ulcer disease, 
diverticulitis/colitis, intestinal obstruction, tumor necrosis, recent sigmoido-


 
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/colonoscopy, stent implants, intact primary tumor, radiotherapy, higher 
cumulative dose of bevacizumab, or emergent surgery while receiving 
bevacizumab (Abu-Hejleh et al 2012; Imbulgoda et al 2015). In response to the GI-
perforation events, additional risk mitigation measures have been introduced into 
study BP29262 (Section 4.2.3 and Section 5.2.3.2). In conclusion, inhibiting tumor 
angiogenesis by dual blockade of the VEGF-A and Ang-2 pathway may represent a 
novel approach for cancer treatment.  The supportive preclinical data set in conjunction 
with an encouraging, preliminary clinical experience of RO5520985, have provided a 
favorable benefit-risk balance for a further clinical investigation of RO5520985 in cancer.  
In regards to the observed GI-perforation rate, the proposed risk mitigation plan 
supports the continuation of study BP29262 while closely monitoring all patients 
for clinical signs and symptoms suggestive of intestinal sub-/occlusion/intestinal 
obstruction or GI-perforation. 
2. 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of Study BP29262 is to estimate the efficacy of RO5520985 in 
combination with oxaliplatin, folinic acid, and 5-fluorouracil (mFOLFOX-6) vs.  
bevacizumab in combination with mFOLFOX-6, as measured by progression-free 
survival (PFS). 
2.2 
SECONDARY OBJECTIVES 
• 
Evaluate the safety and tolerability of RO5520985 in combination with mFOLFOX-6 
• 
Estimate the efficacy of RO5520985 in combination with mFOLFOX-6, as measured 
by overall survival, objective response rate, and duration of objective response 
• 
Characterize the pharmacokinetics of RO5520985 when combined with   
mFOLFOX-6  
2.3 
EXPLORATORY OBJECTIVES 
• 
Assess levels of circulating angiogenic factors and circulating targets as potentially 
predictive markers, in conjunction with somatic mutations in circulating cell-free DNA 
• 
Assess potential response prediction markers of RO5520985 in blood and archival 
primary tumor tissue  
• 
Characterize the PK of selected mFOLFOX-6 components when combined with 
RO5520985   
• 
Explore tumor growth kinetics 
• 
Explore additional parameters on tumor imaging  
 


 
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3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
3.1.1 
Overview of Study Design 
This is a Phase II, multicenter, randomized, parallel arms, double-blind study of 
RO5520985 to evaluate the efficacy and safety of RO5520985 plus mFOLFOX-6 versus 
bevacizumab plus mFOLFOX-6 in patients with previously untreated mCRC.  The study 
consists of two parts:  Part I (Safety Run-in) open label single arm and Part II 
(Randomization Phase) randomized, parallel arms, double-blind study. 
3.1.1.1 
Part I:  Safety Run-in 
The safety/ tolerability of single agent RO5520985 has been investigated in 
Study BP28179, by which RO5520985 at 2000 mg Q2W was considered safe and 
recommended as dose for subsequent clinical development.  However, the combination 
of RO5520985 with mFOLFOX-6 has not been previously studied clinically for safety.  
Therefore, during the open label safety run-in phase prior to the randomization part of 
the study (Part II) at least 6 eligible patients will be exposed to 2000 mg Q2W 
RO5520985 + mFOLFOX-6, in order to confirm the dose and schedule that will be used 
in the randomized part of this study (Part II).  All patients in Part I will receive induction 
and maintenance therapy as described for patients in the experimental arm of Part II.  
Treatment of the first 6 patients will be sequential i.e., there will be always at least 1 
working day between the 1st  RO5520985 administration of one enrolled patient and the 
1st RO5520985 administration of the next enrolled patient.  
Each site enrolling one of the first 6 patients in Part I needs to inform the Sponsor 
about the tolerability (based on the assessments being performed as per SoA) by e-mail.  
The e-mail needs to be send after the investigator or designee has seen the patient 
during the Visit on Day 2 of Cycle 1 reporting at least the observed AEs/SAEs between 
start of RO5520985 administration and the Visit on the next day (C1D2).  Only after 
confirmation by the site that the 1st study drug administration was tolerated without any 
severe problems, the next patient can be treated.  The Sponsor ensures that the site 
enrolling the subsequent patient will be informed latest on the evening prior to the 
scheduled treatment whether the patient can receive the 1st RO5520985 administration. 
After at least 6 patients have been treated by at least two full cycles, an Safety Internal 
Monitoring Committee (IMC) will conduct a safety analysis prior to initiation of Part II.  If 
safety signals arise from the review and depending on the nature of the safety signals, 
the Safety IMC may recommend to enroll additional 6-12 patients at lower doses of 
RO5520985  in combination with mFOLFOX-6 before embarking onto Part II of the study 
at the adjusted dose.  In case of unacceptable and/or non-manageable toxicity of the 
combination, the Safety IMC may decide to discontinue the study upon completion of 
Part I, The Safety IMC will operate according to a prespecified safety charter outlined in 
a separate document.  Further details are provided in Section 3.1.2.  A schema of the 
safety run-in is provided in Figure 1. 




 
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a) Induction therapy 
Up to 8 cycles of mFOLFOX-6 plus either bevacizumab or RO5520985.  Patients may 
switch to maintenance therapy earlier if oxaliplatin cannot be tolerated.   
b) Maintenance therapy 
Following induction therapy, oxaliplatin administration will be discontinued and patients 
receive 5-FU/folinic acid plus either RO5520985 (experimental arm) or bevacizumab 
(control arm) as maintenance therapy for a maximum period of 24 months (calculated 
from start of maintenance therapy), if treatment is not stopped earlier due to disease 
progession, unacceptable toxicity, Investigator decision or consent withdrawal. If patients 
stop chemotherapy either in part or in whole, then they should continue on RO5520985 
treatment or bevacizumab for a maximum of 24 months.  
Within Part II of the study, two interim analyses are planned (Section 6.10) which will be 
conducted by an Efficacy IMC.  
3.1.2 
Internal Monitoring Committee 
There will be two separate Internal Monitoring Committee (IMC) – one for safety and one 
for efficacy. 
The Safety Internal Monitoring Committee (IMC) will be composed of at least a Sponsor 
translational medicine leader/clinical scientist, safety scientist/safety science leader, 
statistical programming analyst (SPA) and biostatistician and will operate according to a 
prespecified safety charter outlined in a separate document.  The primary responsibilities 
of the Safety IMC will be to review the available safety data and to make a 
recommendation to continue, modify, or terminate the study based on the safety data. 
A safety analysis will be conducted by the Safety IMC after at least 6 patients in Part I 
have been treated for at least two full cycles RO5520985 at 2000 mg Q2W plus 
mFOLFOX-6.  If safety signals arise from the review and depending on the nature of the 
safety signals, the Safety IMC may recommend to enroll additional 6-12 patients at lower 
doses of RO5520985 in combination with mFOLFOX-6 before embarking on into Part II 
of the study.  In case of unacceptable safety/toxicity of the combination, the Safety IMC 
may also decide to discontinue the study upon completion of Part I. 
In accordance with the charter, the Safety IMC may also conduct further blinded safety 
reviews based on safety signals that arise at any time during Part II of the study.  In this 
case, the randomization code will be received by an unblided programmer at the 
CRO and the study statistician and statistical programmer will receive the unblinded 
data which will be saved in a restricted area.  Accrual will not be halted while the 
analysis is being conducted.  Outcomes and conclusions of the IMC that affect study 
conduct will be communicated to the U.S. FDA and other regulatory agencies, as well as 


 
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the Investigators for notification of the IRBs/ECs as soon as possible and no more than 
15 days after the analysis is completed. 
Separate from the Safety IMC, there will be in addition an Efficacy IMC responsible for 
the futility/efficacy analysis of Part II.  The details and modalities are described in a pre-
specified charter outlined in a separate document as well as in the statistical analysis 
plan. 
3.1.3 
End of Study 
After the completion of induction therapy patients will continue maintenance therapy for 
a maximum of 24 months unless the occurrence of disease progression, unacceptable 
toxicities, consent withdrawal or Investigator’s decision.  All patients will attend a safety 
visit 5 ( ± 1) weeks after receiving the last administration of RO5520985, which is the 
End of Study (EoS) Visit.  Patients off study will receive standard of care for the stage of 
their disease.  Follow-up for survival will continue until all patients have either died or are 
lost to follow up, or the sponsor decides to end the trial, whichever occurs first. 
The study will formally end once the survival follow-up is complete or the last patient has 
completed the EoS Visit or is withdrawn from the study prior to that time (whichever 
occurs last), but may be prematurely terminated by the Sponsor. The main analysis and 
reporting will be conducted once approximatelly 80 PFS events have been 
collected,  When the study is formally ended, an additional analysis will be performed 
and appended to the main report. 
3.1.4 
Study Duration 
The time needed for study enrollment is estimated to be approximately 15 months.  The 
total duration of the study for each patient will be as follows: 
• 
Screening:  Up to 4 weeks 
• 
Treatment period:  Patients will receive induction therapy for up to 8 cycles 
(approximately 4 months), followed by maintenance therapy for a maximum of 
24 months unless the occurrence of disease progression, unacceptable toxicities, 
consent withdrawal or Investigator’s decision require treatment cessation. 
• 
EoS Visit:  Up to 6 weeks (5 ± 1 weeks) after last dose of RO5520985 
• 
Post study human anti-human antibody (HAHA) Visit (optional): 2 months ( ± 2 wks) 
after last dose of RO5520985 
• 
Post study follow-up:  All patients will be followed for survival (e.g., by phone call or 
clinic visit) and subsequent anticancer therapy approximately every 3 months after 
EoS Visit until death, loss to follow-up,  or study termination by Roche, whichever 
occurs first  
 


 
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3.2 
RATIONALE FOR STUDY DESIGN 
3.2.1 
Rationale for Selection of RO5520985 Dose and Schedule 
The dose selection of RO5520985 was based on clinical safety/tolerability, efficacy, 
pharmacodynamic (incl. functional imaging) and pharmacokinetic data obtained from a 
Phase I entry in human study (BP28179).  Within this study escalating doses of 
RO5520985 were evaluated in 42 patients using either a weekly (QW: 10, 20, and 
30 mg/kg) or bi-weekly (Q2W: 3, 6, 12, 19.2 and 30 mg/kg) dosing schedule, with 
30 mg/kg being the highest dose level tested.  The preliminary safety and tolerability 
profile of RO5520985 has been comparable between QW and Q2W regimens and 
comparable to bevacizumab.  Consistent with the mode of action of a VEGFA-inhibitor, 
arterial hypertension (HTN) was the most frequent adverse event across all dose levels, 
with a higher incidence of grade 3 HTN associated with the weekly regimen (30% vs. 
9%).  However, a MTD was not reached in either dosing schedule.  Based on small 
numbers, increased clinical activity, assessed by the progression-free rate at 8-weeks, 
was observed with escalating doses of RO5520985, reaching its maximum of 83% at 
30 mg/kg Q2W.  The PK profile of RO5520985 exhibited dose proportionality across the 
entire dose range studied (3–30 mg/kg), with an elimination half-life of approximately 
7−9 days, based on a Q2W dosing schedule.  Population PK analysis indicated that 
biweekly dosing of 30 mg/kg results in Ctrough and Cavg of RO5520985 plasma levels (by 
the 2nd cycle) that are comparable to 5 mg/kg Q2W bevacizumab, which is a standard 
dose in combination with chemotherapy (incl. FOLFOX) for the treatment of mCRC.  
Exploratory functional imaging (i.e., DCE-/DW-MRI) analysis indicated vascular effects 
across the dose levels and schedules tested in 22 of 34 evaluable patients; however, 
within the biweekly schedule sustained decrease in vascular characteristics (e.g., vessel 
permeability) and increased on-treatment necrosis appeared to be associated with 
30 mg/kg Q2W.  
Fixed dosing regimens have been recommended as the preferred dosing approach as it 
offers considerable advantages in the ease of dose preparation and thereby avoid 
potential dose calculation errors (Mathijssen et al.  2007, Wang et al. 2009).  The PK 
profile and key PK parameters (Cmax, AUC) of RO5520985 demonstrated a low (< 30%) 
inter-individual variability for both dosing schedules. Based on an average 70 kg patient, 
a dose of 30 mg/kg approximates to a flat dose of 2100 mg.  Further simulations of 
repeated administration of both body weight normalized (30 mg/kg) and flat (2000 mg) 
doses of RO5520985 Q2W indicated that the steady-state systemic exposures, peak 
and trough concentrations would be comparable for the two dosing strategies, with 
similar inter-individual variability.  Hence, flat-fixed dosing of RO5520985 will provide 
consistent exposure across patients and has been proposed for the subsequent clinical 
development. 
Based on these considerations, it was concluded that RO5520985 at 2000 mg Q2W is a 
clinically feasible dosing regimen that has an acceptable safety profile and is potentially 
active when combined with chemotherapeutic agents for the treatment of cancer. 


 
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3.2.2 
Rationale for Safety Run-in (Part I) 
Monoclonal antibodies inhibiting angiogenesis provide modes of action, metabolism and 
clinical toxicity profiles different from traditional chemotherapy agents.  The safety profile 
of bevacizumab in combination with various chemotherapies is well characterized in 
randomized clinical trials and by data from clinical practice.  Bevacizumab is associated 
with increases in the frequency of AEs that are seen with essentially all VEGF-A 
inhibitors, such as hypertension, proteinuria, and thromboembolic events 
(Hurwitz et al. 2013; Mohile et al. 2013).  With few, if any, overlapping toxicities with 
traditional chemotherapies, the primary side effect of bevacizumab is hypertension what 
can easily be managed, requiring the addition or adjustment of oral anti-hypertensives in 
approximately 11% of patients (Hurwitz et al. 2005).  Clinical experience with inhibitors 
of the Angiopoetin/Tie-2 axis, in combination with common chemotherapy regimens and 
bevacizumab has revealed acceptable safety profiles with manageable toxicity 
consistent with prior experience with individual treatments (Mita et al. 2010; 
Peeters et al. 2013; Dieras et al. 2011).  The safety of single agent RO5520985 has 
been investigated in Study BP28179, showing an acceptable toxicity profile consistent 
with that reported for bevacizumab and other inhibitors of the Ang/Tie-2 axis.  However, 
the combination of RO5520985 (2000 mg Q2W) with conventional chemotherapy has 
not been previously explored  for safety in the clinic.  Hence, for the utmost safety of 
study patients, the safety run-in phase (Part I) (Section 3.1.1.1) will first determine the 
RP2D  of RO5520985 in combination with mFOLFOX-6 in at least six previously 
untretated patients with mCRC before embarking on Part II. 
3.2.3 
Rationale for Randomized, Double-blind Phase II Study in First-
line mCRC (Part II) 
Despite recent improvements with the addition of bevacizumab to standard 
oxaliplatin-based treatment regimens, median survival for patients with mCRC is still 
approximately 20 months (Hurwitz et al. 2004), leaving a significant unmet need for more 
efficacious treatments.  Hence, prospective clinical trials to further optimize the standard 
treatment of metastatic colon cancer are needed and supported by current therapy  
guidelines.  The randomized Phase II design (Part II) of this study will allow to accurately 
assess the anti-tumor activity of RO5520985 plus mFOLFOX-6 (‘Experimental Arm’) 
compared to the Standard of Care (SoC) of bevacizumab plus mFOLFOX-6 (‘Control 
Arm’) as first-line treatment of mCRC.  RO5520985 is a novel bevacizumab−based 
bispecific mAb acting as a dual-targeting inhibitor of the two key angiogenic factors, 
VEGF-A and Ang-2. Thus, patients who are randomized to the ‘Experimental Arm’ may 
experience  additional clinical benefit by concurrent Ang-2/VEGF-A inhibition.  In view of 
the potential importance of continuing biological therapy until disease progression and 
minimizing early treatment discontinuation due to chemotherapy-related toxicity, patients 
in this study will receive oxaliplatin for a maximum of 8 cycles during the induction phase 
and can subsequently stay on a well tolerated 5-FU plus RO5520985 or bevacizumab 
based maintenance therapy until documented disease progression or unacceptable 
toxicity for a maximum of 24 months.   


 
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3.2.4 
Rationale for Biomarker Assessments 
The efficacy of bevacizumab has been demonstrated in several randomized controlled 
trials in colorectal cancer.  However, so far the attempts to identify a patient population 
that might benefit most from the combination of bevacizumab with standard therapy 
have failed to define any specific patient subgroup.  Still, ongoing research aims to 
identify a predictive biomarker or combination of biomarkers enabling selection of 
patients that would benefit most from bevacizumab therapy . 
The main objective of the biomarker analyses is to identify biomarkers for prospective 
selection of patients who are most likely to respond to RO5520985 treatment. Therefore, 
biomarker data will be correlated with clinical outcome.  This assessment will be 
performed in archival primary tumor tissue and in blood samples.  A pharmacodynamic 
analysis will be done for the targets, Ang-2 and VEGF-A to confirm MoA and for PK/PD 
correlation. PlGF (placental growth factor) might be a pharmacodynamic (PD) marker of 
endothelial response towards anti-angiogenic treatment, therefore on-treatment samples 
will also be analyzed for PlGF (Xin et al. 2012). 
Patients will be asked for collection of additional blood samples to be stored in the 
Roche Clinical Repository (RCR). 
3.2.4.1 
Biomarker Assessments in Blood 
The objective of the biomarker analyses in plasma is to quantify the levels of circulating 
targets and other angiogenesis-relevant factors for predictive hypothesis generation. 
3.2.4.1.1 
Pharmacodynamic markers 
Angiopoietin-2 (Ang-2) and VEGF-A: Ang-2 and VEGF-A are the targets for 
RO5520985.  Soluble Ang-2 potentially has prognostic/predictive value in patients who 
have CRC treated with bevacizumab (Goede et al. 2010; Liu et al. 2013) and may 
therefore have positive predictive potential for treatment responders.  In addition both 
targets will be analyzed at various timepoints on treatment (Schedule of Assessments 
[SoA], Appendix 1).  This enables the confirmation of the expected results in Phase I 
where decreased levels of biologically active, free (nondrug bound) Ang-2 and VEGF-A 
and increased concentrations of total (free plus drug bound) Ang-2 and VEGF-A were 
observed.  The assessment of their value as PD and/or possible resistance markers 
might help to discriminate between bevacizumab and RO5520985 treatment effects in a 
larger, more homogenous patient population. 
Placental growth factor (PlGF): PlGF showed sustained upregulation following various 
treatments such as bevacizumab, SU11248, AZD2171 (Horowitz et al. 2011, 
Loupakis et al. 2011; Deprimo et al. 2007; Xin et al. 2012) and in the ongoing Phase I 
trial of RO5520985.  The analysis of the induced changes during treatment may help to 
discriminate between bevacizumab versus RO5520985 induced effects. 


 
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Circulating tumor DNA (ctDNA): Circulating tumor DNA potentially predicts treatment 
response and early disease progression as somatic genetic alterations in most cancers 
and specifically in CRC represent molecular signatures. Following an initially broader 
mutational analysis of the primary tumor tissue DNA, specific mutation(s) will be 
analyzed in the baseline and on-treatment plasma samples (Pantel and Alix-
Panabières 2013; Diehl et al. 2005).  So far there are only few reports on the use of 
ctDNA in CRC, so our data will provide an understanding of the value of liquid biopsies 
in a clinical setting in general and specifically in first-line treatment of mCRC patients. 
3.2.4.1.2 
Predictive Biomarkers 
Besides the possible predictive value of Ang-2, VEGF-A and PlGF (see above) we will 
assess the markers detailed below. 
Angiopoietin-1 (Ang-1), Matrixmetalloproteinase-2 (MMP-2) and 
Matrixmetalloproteinase-9 (MMP-9):  Ang-1 is expressed by pericytes, smooth muscle 
cells and fibroblasts and functions as a strong Tie2 agonist.  Ang-1 regulates vascular 
maturation and stabilization by maintaining endothelial cell survival and quiescence in 
mature vessels.  Ang-1 and Ang-2 are thought to act mainly in an antagonistic manner, 
though Ang-2 has the potential to activate or inactivate Tie-2 in certain contexts 
(Koh 2013).  Considering this potential antagonistic relationship, Ang-1 might have a 
predictive value for therapeutic Ang-2 inhibition.  MMP-2 and MMP-9 play a role in 
cancer progression and metastasis and are both involved in angiogenesis.  MMP-2 
knockout mice show impaired angiogenesis whereas MMP-9 is involved in the 
angiogenic switch of tumor cells (Itoh et al. 1998; Bergers et al. 2000; Mook et al. 2004; 
Roy et al. 2009).  The study will assess whether Ang-1, MMP-2 and/or MMP-9 will be 
predictive for RO5520985 in CRC. 
Additional angiogenesis-related markers:  Various angiogenesis-related markers will 
be assessed at baseline to evaluate their predictive value in CRC patients receiving 
anti-angiogenic treatment.  In case of an emerging predictive marker, its potential to 
differentiate between bevacizumab and RO5520985 treatment will be determined.  
The following exploratory markers will be assessed:  sTie-2, VEGF-C, sVEGF-R1, 
sVEGF-R2, sVEGF-R3, SDF-1α, E-selectin, ICAM-1, bFGF, IL-8, PDGF-C, and CA-IX.  
3.2.4.2 
Archival Primary Tumor Tissue 
Collection of archival primary tumor tissue is mandatory.  The objective of tumor tissue 
biomarker analyses is to assess the targets of RO5520985, vessel− and 
tumor cell−related parameters and tumor-infiltrating immune cells. 
Targets and Receptors:  Analyses are performed to assess if different vessel subtypes 
respond differently to RO5520985 therapy.  For example, it is hypothesized that Ang-2 
positive vessels are more likely to be affected by treatment with RO5520985 than Ang-2 
negative vessels.  In addition, the expression of the RO5520985 targets may be 
associated with response to treatment.  The prevalence of Ang-2 expression in CRC 


 
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tissue is 86% according to own data.  High tissue Ang-2 levels correlate with worse 
clinical outcome and have been shown to drive lymphatic metastasis in breast cancer 
and pancreatic cancer (Sfiligoi et al. 2003; Etoh et al. 2001; Ochiumi et al. 2004). 
VEGF:  VEGF-A as a possible tissue biomarker has been assessed in three trials using 
anti-VEGF-A therapy in CRC.  In the first-line mCRC trial Study NO16966, higher levels 
of tumor VEGF-A were associated with improved PFS, though the quality of 
immunohistochemistry (IHC) was questionable (Foernzler et al. 2010), whereas two 
other trials with mCRC patients (Studies AVF2107 and ML18147) could not show any 
correlation of tissue VEGF-A and clinical outcome (Jubb et al. 2006; Kubicka et al. 2013).  
Still the predictive value of tissue VEGF-A using RO5520985 in CRC has not been 
assessed so far.  VEGF-R2 is the primary receptor that promotes the pro-angiogenic 
function of VEGF-A (Carmeliet et al. 2001) and will be analyzed as well. 
Vessel-related parameters:  MVD, proliferation and apoptosis in endothelial cells and 
maturity of blood vessels will be determined.  In bevacizumab-treated patients who have 
CRC, immature blood vessels have been shown to correlate with poor survival 
(Noonan et al. 2011) and high MVD was prognostic in ovarian cancer patients 
(Rubatt et al. 2009).  Within the study a reduction of MVD and EC proliferation together 
with an increased maturity of remaining blood vessels (Willet et al. 2004, 
Willet et al. 2005, Wedam et al. 2006) during RO5520985 therapy is expected.  
Therefore parameters indicating active angiogenesis such as high MVD and high 
percentage of immature blood vessels, might have predictive value in CRC patients.  
The following markers will be assessed:  CD31, CD34, Podoplanin, αSMA.  The analysis 
will be prioritized based on the amount of material available. 
Tumor cell-related parameters:  Markers reflecting the tumor status such as 
proliferation and hypoxia will be explored.  High Ki67 expression is in general associated 
with higher tumor activity, higher histopathological grading and poorer course of disease. 
CAIX is a marker of hypoxia and high stromal expression has been shown to be 
prognostic in a few tumor entities (Klimowicz et al. 2013; Brockten et al. 2012).  The 
predictive value of Ki67, CA-IX, c-C3, and neuropilin-1 will be explored. 
Tumor-infiltrating immune cells:  The role of tumor-infiltrating macrophages in CRC is 
still controversial and there are reports of a better prognosis and survival rate associated 
with a high number of macrophages (Zhou et al. 2010; Funada et al. 2003; Khorana et al. 
2003) as well as their association with greater depth of tumor invasion, lymph node 
metastasis, and staging (Kang et al. 2010; Pancione et al. 2009; Deschoolmeester et al. 
2011).  Besides macrophages, the immune contexture of the tumor has a major clinical 
impact for prognosis, such as for example the high number of infiltrating T cells in CRC 
(Pages et al. 2005; Galon et al. 2006).  The immune contexture is generally thought as a 
major element to establish the prognosis of patients and guide therapy, though it is not 
expected to be as informative in metastastic disease as in lower stages (Fridman et al. 
2012; Galon et al. 2006).  An additional aspect looking at tumor-infiltrating immune cells 


 
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is the observation that Ang-2 overexpression in tumor tissue enhances the infiltration of 
Tie2-expressing macrophages/monocytes via Tie-2 signaling and augments leukocyte 
extravasation in inflamed tissue (De Palma and Naldini 2011). 
To test the response predictive value of tumor-infiltrating immune cells we will assess 
(but it is not limited to) CD4, CD8, CD3, CD68/CD163, CD3/FOXP3, CD3/perforin.  The 
analysis will be prioritized on the basis of the amount of material available.  Broader 
analysis will be performed using a gene expression analysis technology to assess 
changes at the molecular level. 
Mutational analysis:  In CRC several DNA mutations caused by genomic instability, 
chromosomal aberrations, and DNA promotor hypermethylation have implications on 
prognosis (Cancer Genome Atlas Network 2012; Simons et al. 2013).  Besides mutated 
RAS and BRAF being predictive for anti-EGFR (epidermal growth factor receptor) 
treatment in CRC (Lievre et al. 2006), other genes such as PI3KCA 
[Samuels and Ericson 2006, Liang et al. 2003), PTEN (Tol et al. 2010; Bardelli and 
Siena 2010) and the microsatellite instability (MSI) status (Lothe et al. 1993; 
Popat et al. 2005) have been associated with clinical outcome.  Therefore, a broader 
exploratory mutational analysis including, but not limited to: KRAS, NRAS, EGFR, BRAF, 
PI3KCA, PTEN, MET, APC will be performed.  Additionally, KRAS and NRAS mutational 
analyses will be used for retrospective sub-group analyses. 
In case a new predictive biomarker for anti-angiogenesis treatment with the potential to 
differentiate between anti-VEGF-A and anti-Ang-2/VEGF-A treatment is identified in the 
future, further analysis will be performed using the available samples.  Therefore, 
patients will be asked for specific consent for remaining plasma samples to be stored in 
the Roche Clinical Repository (Section 4.6.1.15) for future research. 
3.3 
OUTCOME MEASURES  
3.3.1 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) 
graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) v4.03  
• 
Changes in hematology, biochemistry, coagulation, specifically those associated 
with vascular and renal function  
• 
Physical examinations (including ECOG), vital signs and ECG  
• 
Incidence and titers of human anti-human antibodies (HAHAs) 
• 
Adverse events leading to RO5520985, bevacizumab, or chemotherapy 
discontinuation 


 
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• 
Incidence of the following selected adverse events  according to NCI CTCAE, v4.03: 
− 
Arterial hypertension (Grade ≥ 3) 
− 
Proteinuria (Grade ≥ 3) 
− 
Arterial thromboembolic events (any grade) 
− 
Venous thromboembolic events (Grade ≥ 3) 
− 
Vascular disorder - other: Thrombotic microangiopathy (any grade) 
− 
Gastrointestinal perforation (any grade) 
− 
Fistula involving an internal organ (any grade) 
− 
Fistulae (Grade 4) 
− 
Wound healing complication (Grade ≥ 3) 
− 
Bleeding/hemorrhage (Grade ≥ 3) 
− 
Pulmonary bleeding (Grade ≥ 2)  
− 
CNS bleeding (Grade ≥ 2) 
− 
Congestive heart failure (Grade ≥ 3) 
− 
Reversible posterior leukoencephalopathy syndrome (any grade) 
 
3.3.2 
Pharmacokinetic Outcome Measures 
The pharmacokinetic (PK) outcome measures for this study are as follows: 
• 
The PK profile of RO5520985 will be characterized with the plasma 
concentration-time data following IV administration of RO5520985, and will include 
the following parameters: Cmax, Cmin, Tmax, t1/2, AUC, AUCτ, CL, Vss, accumulation 
ratio (RA)  
• 
The PK profiles of oxaliplatin (free and total) and 5-FU will be characterized with the 
plasma concentration-time data following IV administration of FOLFOX, and will 
include the following parameters: Cmax, Cmin, Tmax, t1/2, AUC (when applicable) 
• 
Additional PK parameters may be evaluated as appropriate 
 
3.3.3 
Efficacy Outcome Measures 
The primary and secondary efficacy analyses will be based on the efficacy analyses 
population, which includes Part II patients only.  Efficacy for Part I patients will be 
analyzed using descriptive statistics.  
3.3.3.1 
Primary Outcome Measure 
The primary outcome measure for Study BP29262 is progression-free survival, defined 
as the time from randomization to the date of first documented occurrence of 
progression based on RECIST v1.1 criteria (Appendix 8) as determined by the 
Investigator or death from any cause on study, whichever occurs first.  


 
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3.3.3.2 
Secondary Outcome Measures 
The secondary outcome measures for Study BP29262 are as follows: 
• 
Objective response rate (ORR).  Objective response rate is defined as the rate of 
patients with an objective tumor response, i.e. partial response (PR) or complete 
response (CR) as determined by the Investigator using RECIST v1.1 criteria on two 
consecutive occasions at least  4 weeks apart. 
• 
Duration of response, defined as the first occurrence of a documented objective 
response until the time of progression or death from any cause on study 
• 
Overall Survival, defined as the time from randomization until death from any cause 
 
3.3.4 
Exploratory Outcome Measures 
The exploratory outcome measures for both Part I and Part II of the study include but are 
not limited to the following: 
• 
Levels of circulating targets by comparing baseline vs. on-treatment values of Ang-2 
and VEGF-A and their differential expression/regulation during RO5520985 versus 
bevacizumab therapy 
• 
Changes of PlGF from baseline during treatment as marker of unspecific endothelial 
stress response and as potential response towardsRO5520985  
• 
Assessment of tissue and soluble blood markers potentially related to predicting 
clinical benefit or toxicity of RO5520985 vs. bevacizumab 
• 
An assessment of tumor growth kinetics will be made by comparing post-treatment 
scans with at least 2 pre-treatment  scans not older than 12 weeks prior to C1D1, if 
available. The two pre-treatment scans consists of a pre-study scan and the study 
baseline scan. 
• 
Analysis of additional CT parameters including necrotic volume/total tumor volume 
and intensity to assess their potential value as early response prediction markers 
 
4. 
MATERIALS AND METHODS  
4.1 
CENTERS 
This is a multi-center study.  Approximately 50 sites in approximately 7-10 countries will 
participate in the study.  Additional sites may be included as back-up and activated as 
appropriate. 
Administrative and Contact Information, and List of Investigators are provided separately. 
4.2 
STUDY POPULATION 
Adult patients (≥ 18 years) with mCRC who have not been previously treated with 
chemotherapy for metastatic disease and who are not candidates for potentially curative 
resection.  


 
R O 5 5 2 0 9 8 5 — F. H off m a n n- L a R o c h e Lt d 
Pr ot o c ol B P 2 9 2 6 2, V er si o n 5  4 9
 
4. 2. 1
 R e cr uit m e nt
 
Pr o c e d ur e s ( P art I a n d P art II)   
All p ati e nt s m u st pr o vi d e writt e n i nf or m e d c o n s e nt b ef or e a n y st u d y s p e cifi c 
a s s e s s m e nt s or pr o c e d ur e s ar e p erf or m e d.  O n c e t h e p ati e nt h a s si g n e d t h e i nf or m e d 
c o n s e nt, t h e I n v e sti g at or ( or hi s d e si g n e e) c o nt a ct s t h e I x R S t o p erf or m a s cr e e ni n g c all 
f or t h e p ati e nt. T h e sit e will t h e n b e pr o vi d e d wit h a s cr e e ni n g n u m b er.  A n Eli gi bilit y 
S cr e e ni n g F or m ( E S F) d o c u m e nti n g t h e I n v e sti g at or’ s a s s e s s m e nt of e a c h s cr e e n e d 
p ati e nt wit h r e g ar d t o t h e pr ot o c ol’ s i n cl u si o n a n d e x cl u si o n crit eri a i s t o b e c o m pl et e d 
a n d si g n e d b y t h e I n v e sti g at or ( or d e si g n e e).  A p ati e nt E nr oll m e nt a n d I d e ntifi c ati o n 
C o d e Li st m u st al s o b e m ai nt ai n e d b y t h e I n v e sti g at or.  P ati e nt s w h o f ulfill all of t h e 
i n cl u si o n crit eri a a n d n o n e of t h e e x cl u si o n crit eri a ar e eli gi bl e t o p arti ci p at e i n t h e st u d y.  
T h e sit e u s e s t h e I x R S t o o bt ai n a p ati e nt n u m b er.  T h e pr o c e s s i s d e s cri b e d i n 
S e cti o n 4. 3 .  
P ati e nt s w h o e nr oll a n d s u b s e q u e ntl y di s c o nti n u e fr o m t hi s st u d y ar e n ot p er mitt e d t o 
e nr oll a g ai n i nt o t hi s tri al.  
4. 2. 2
 I n cl u si o n
 
Crit eri a  
P ati e nt s eli gi bl e f or i n cl u si o n i n t hi s st u d y f or b ot h P art I a n d P art II h a v e t o m e et all of 
t h e f oll o wi n g crit eri a: 
1.  
Hi st ol o gi c all y or c yt ol o gi c all y c o nfir m e d m C R C n ot a m e n a bl e t o p ot e nti all y c ur ati v e 
r e s e cti o n wit h at l e a st o n e m e a s ur a bl e m et a st ati c l e si o n, a s d efi n e d b y 
R E CI S T v 1. 1 ( A p p e n di x 8 )  
a)  R e pr e s e nt ati v e t u m or s p e ci m e n s i n F F P E bl o c k s ( pr ef err e d) or sli d e s m u st b e 
a v ail a bl e f or c e ntr al e xt e n d e d R A S m ut ati o n al a n al y si s  
2.  Si g n e d writt e n i nf or m e d c o n s e nt, o bt ai n e d pri or t o a n y s cr e e ni n g pr o c e d ur e 
3.
 A g e
 ≥ 1 8 y e ar s 
4.  E C O G ( W H O) p erf or m a n c e st at u s of 0 or 1 ( A p p e n di x 5 ) 
5.  
Willi n g a n d a bl e t o c o m pl y wit h t h e pr ot o c ol a s j u d g e d b y t h e I n v e sti g at or 
6.  A d e q u at e h e m at ol o gi c f u n cti o n 
a)  A b s ol ut e n e utr o p hil c o u nt ( A N C) ≥  2 0 0 0 c ell s/ μ L ( wit h o ut G- C S F [ gr a n ul o c yt e 
c ol o n y- sti m ul ati n g f a ct or] s u p p ort wit hi n 2 w e e k s pri or t o r a n d o mi z ati o n) 
b)  Pl at el et  c o u nt  ≥ 1 0 0, 0 0 0/μ L ( wit h o ut tr a n sf u si o n wit hi n 2 w e e k s pri or 
t o r a n d o mi z ati o n) 
c)  H e m o gl o bi n  ≥ 9. 0 g/ d L 
7.  A d e q u at e li v er f u n cti o n 
a)  A S T a n d A L T ≤ 2. 5 ×  u p p er li mit s of n or m al ( U L N) or ≤ 5 x U L N i n c a s e of li v er 
m et a st a s e s 
b)  S er u m  bilir u bi n  ≤ 1. 5×   U L N. P ati e nt s wit h k n o w n Gil b ert di s e a s e w h o h a v e 
s er u m bilir u bi n l e v el ≤ 3 x U L N m a y b e e nr oll e d 
c)  S er u m  al b u mi n  ≥ 3. 0 g/ d L 


 
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8. 
Adequate coagulation function 
a) International normalized ratio (INR) ≤ 1.5 × ULN 
b) Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN  
9. 
Adequate renal function  
a) Creatinine clearance ≥ 50 mL/min/1.73 m2 on the basis of the Cockroft−Gault 
formula (Appendix 4)  
b) Urine dipstick for proteinuria < 2+. Patients discovered to have ≥ 2+ proteinuria 
on dipstick urinalysis at baseline should undergo a 24-hrs urine collection and 
must demonstrate ≤ 1 g of protein in 24 hrs before starting of dosing 
10. Adequate cardiovascular function 
a) NYHA stage ≤ 1 (Appendix 6) 
b) Resting blood pressure systolic < 150 mmHg and diastolic < 100 mmHg (average 
of ≥ 3 readings on ≥ 2 sessions) 
11. Recovery from all reversible adverse events of previous medical therapies to 
baseline or NCI CTCAE Grade 1, except for alopecia (any grade) 
12. Negative serum or urine pregnancy test within 7 days prior to starting study 
treatment in premenopausal women and women < 2 years after the onset of 
menopause 
 
4.2.3 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Any prior systemic therapy (including chemotherapy, antibody therapy, tyrosine 
kinase inhibitors, immunotherapy, hormonal therapy) before Day 1 of Cycle 1 for 
treatment of mCRC 
a) Patients who received prior systemic adjuvant therapy or radiotherapy for CRC 
are not excluded if the time interval from last administration of adjuvant therapy 
until disease progression  is >  12 months  
b) Patients who received herbal therapy intended as anti-cancer therapy ≥ 2 weeks 
prior to Day 1 are not excluded 
2. 
Malignancies other than CRC within 5 years prior to randomization, except for those 
with a minimal  risk of metastasis or death, such as adequately treated carcinoma in 
situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, 
ductal carcinoma in situ treated surgically with curative intent 
3. 
Radiotherapy within 28 days and abdominal/ pelvic radiotherapy within 60 days 
prior to Day 1 of Cycle 1, except palliative radiotherapy to bone lesions within 7 days 
prior to Day 1 of Cycle 1 
4. 
Treatment with any other investigational agent or participation in another clinical trial 
with therapeutic intent within 28 days prior to Day 1 of Cycle 1 
5. 
Pregnant or lactating women 
6. 
Known hypersensitivity reaction to any study medication (or excipients). 


 
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7. 
Any disorder that compromises the ability of the patient to provide written informed 
consent and/or to comply with study procedures 
8. 
Symptomatic CNS metastases or carcinomatous meningitis. Asymptomatic patients 
must be clinically stable with regard to their CNS/meningeal metastatic involvement, 
have completed previous therapy (including radiation and / or surgery) at least 4 
weeks prior to study drug administration,  are not receiving steroid therapy or taper, 
and are not receiving anti-convulsive medication that were started for any CNS 
involvement   
9. 
Active infection requiring IV antibiotics 
10. Active autoimmune disease that is not controlled by nonsteroidal anti-inflammatory 
drugs (NSAIDs), inhaled corticosteroids, or the equivalent of ≤ 10 mg/day 
prednisone 
11. Sensory peripheral neuropathy ≥ Grade 2 
12. Women of childbearing potential and men unwilling to practice an effective method 
of birth control from screening until 6 months after discontinuing study treatment.  
Childbearing potential is defined as sexually mature women who have not 
undergone a hysterectomy, have not been naturally post-menopausal for at least 23 
consecutive months or have a serum FSH < 40 mIU/mL.  Effective methods of birth 
control are defined as surgical sterilization [e.g., bilateral tubal ligation, vasectomy], 
hormonal contraception [implantable, patch, oral], or double-barrier methods [any 
double combination of: intrauterine device, male or female condom with spermicidal 
gel, diaphragm, sponge, cervical cap]), or abstinence from intercourse. Abstinence 
as a method of contraception is only acceptable as “true abstinence”, i.e. when it is 
in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., 
calendar, ovulation, symptom-thermal, post-ovulation methods) and withdrawal are 
not acceptable methods of contraception. 
13. Significant cardiovascular or cerebrovascular disease within 6 months prior to Day 1 
of Cycle 1, including any of the following: 
a) Prior history of hypertensive crisis or hypertensive encephalopathy 
b) TIA, PRIND or stroke 
c) 
History of acute coronary syndromes (including acute myocardial infarction, 
unstable angina, CABG, coronary angioplasty, or stenting)  
d) Aortic aneurysm requiring surgical repair 
e) Peripheral arterial thrombosis/thromboembolism 
14. Evidence of bleeding diathesis or significant coagulopathy (in the absence of 
therapeutic anticoagulation) 
15. Current use of anticoagulants (e.g., warfarin or any other coumadin-derivate 
coagulants) at therapeutic doses within 7 days prior to study drug administration. 
Prophylactic use of unfractioned heparin or low molecular weight heparin (LMWH) is 
permitted (e.g., enoxaparin 40 mg QD)  


 
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16. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days 
prior to Day 1 of Cycle 1, or abdominal surgery, abdominal interventions  or 
significant abdominal traumatic injury within 60 days prior to Day 1 of Cycle 1 
or anticipation of need for major surgical procedure during the course of the study or 
nonrecovery from side effects of any such procedure. 
17. History of intra-abdominal inflammatory process within 6 months prior to Day 
1 of Cycle 1, including but not limited to peptic ulcer disease, diverticulitis, or 
colitis 
18. Colonic prosthesis (stent) implant in place  
19. History of abdominal or tracheo-oesophageal fistula or GI perforation or 
intra-abdominal abscess within 6 months prior to Day 1 of Cycle1  
20. History of intestinal obstruction and/or clinical signs or symptoms of GI 
obstruction including sub-occlusive disease related to the underlying disease 
or a requirement for routine parenteral hydration, parenteral nutrition, or tube 
feeding within 6 months prior to Day 1 of Cycle 1. Patients with 
signs/symptoms of sub-/occlusive syndrome/intestinal obstruction at time of 
initial diagnosis may be enrolled if they had received definitive (surgical) 
treatment for symptom resolution 
21. Chronic daily treatment with NSAID (occasional use for the symptomatic relief 
of medical conditions, e.g. headache or fever is allowed) 
22. Chronic daily treatment with corticosteroids (dose > 10 mg/day 
methylprednisolone equivalent) excluding inhaled steroids 
23. Evidence of abdominal free air not explained by paracentesis or recent surgical 
procedure  
24. Metastatic disease that involve major airways or blood vessels, or centrally located 
mediastinal tumor masses (< 30 mm from the carina) of large volume 
25. History of broncho-pulmonary hemorrhage NCI CTCAE ≥  Grade 2 or gross 
hemoptysis (defined as bright red blood or ≥ 1/2 teaspoon) within 2 months prior to 
randomization 
26. Severe, nonhealing or dehiscing wound, active ulcer, or untreated bone fracture 
27. Known dihydropyrimidine dehydrogenase deficiency or thymidylate synthase gene 
polymorphism predisposing the patient for 5-FU toxicity 
28. Any other condition, diseases, metabolic dysfunction (e.g., uncontrolled diabetes 
mellitus), active or uncontrolled infections/inflammation, physical examination 
finding, mental status or clinical laboratory finding giving reasonable suspicion of a 
disease or condition that contraindicates patients participation in the clinical study 
due to safety concerns, compliance with clinical study procedures or that may affect 
the interpretation of the results 
 


 
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4.3 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
Part I 
Part I of the study is open label.  After written informed consent has been obtained, sites 
will initially contact the IxRS to record patient details and to have a screening number 
assigned to the patient.  When the screening status of the patient is known, the 
information will be entered onto the IxRS and patients will then be assigned a patient 
number.    
Part II 
After written informed consent has been obtained, sites will initially contact the IxRS to 
record patient details and to have a screening number assigned to the patient. When the 
screening status of the patient is known, the information will be entered into the IxRS 
and patients will then receive a patient number and be assigned to one of the two 
treatment arms. The unblinded pharmacist will prepare the infusion bag for the patient 
and will make sure the clinic staff and patient remain blinded.  Patients should receive 
their first dose of study treatment on the day of randomization, but no later than 3 days 
after randomization.   
Patients will be randomized in a double-blinded fashion in a ratio of 1:1 to receive 
mFOLFOX-6 + RO5520985 (experimental arm) or mFOLFOX-6 + bevacizumab (control 
arm).  Patients will prospectively be stratified by region (United States vs. RoW) and  
number of metastatic sites (1 vs. > 1). These stratification factors were chosen because 
of their potential to affect efficacy and/or safety outcomes, thus minimizing differences in 
treatment arms due to sources other than study treatment.  
Randomization will be based on a pre-specified randomization list and will be stratified 
as described above.  Information on stratification factors will be required from the 
investigator at the time of contacting the IxRS for randomization. Detailed instructions 
regarding the IxRS will be provided to each study center. The randomization numbers 
are to be allocated according to the specification document agreed with the IxRS 
provider. 
Definition of the Double Blind 
For Part II of the study,  with the exceptions described below and in the safety and 
efficacy IMC charters, the randomization list will not be available to the project team at 
Roche or to any personnel at the study centers.  Access to potentially unblinding data 
(i.e., PK data) will be restricted as described below. 
The randomization list will be made available to the qualified individual responsible for 
preparing the study drug, to the individual(s) responsible for PK and PD bioanalysis and 
to statisticians or programmers at Roche/CRO who will provide the selected efficacy 
aggregate data to support the interim futility and administrative analysis as described in 
Section 6.10.  The appropriate randomization list release form shall be used. 


 
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PK/PD data can be received and cleaned on an ongoing basis by the CRO responsible. 
They will handle and clean the data in a secure area which is not accessible by any 
other SMT member with the exception of the SPA and the statistician on the study.  
In addition, a pharmacometrician may be unblinded to enable the frontloading of 
modeling activities.  These activities are solely for building the pharmacometric models 
and frontloading the analyses.  However, if presentation of such analyses to the project 
team is warranted for decision making during the study, data will only be presented 
cumulatively, to prevent unblinding of any given individual treatment assignment prior to 
database lock.  
Emergency Unblinding 
If unblinding is necessary for patient management (in the case of a serious adverse 
event), the Investigator will be able to break the treatment code by contacting the IxRS.  
Treatment codes should not be broken except in emergency situations.  If the 
Investigator wishes to know the identity of the study drug for any other reason, he or she 
should contact the Medical Monitor directly.  The Investigator should document and 
provide an explanation for any premature unblinding (e.g., accidental unblinding, 
unblinding due to a serious adverse event). 
As per health authority reporting requirements, the Sponsor will break the treatment 
code for all unexpected serious adverse events (Section 5.1) that are considered by the 
Investigator to be related to study drug. 
In the event of an emergency, the treatment code for an individual patient will be readily 
available to the Investigator and Sponsor through the IxRS. 
All such occurrences should be documented in the study file.  Treatment codes should 
not be broken except in emergency situations and, if possible, the responsible scientific 
leader should be contacted before the code is broken.  
Whenever disclosure of the identity of the test medication is necessary, adequate 
procedures will be in place to ensure integrity of the data.  Any unblinding, at the 
investigational site end, will be documented in the study report with date, reason for 
identifying the drug and the name of all the person(s) who had to be unblinded. 
Unblinding should not result in the withdrawal of the patients from the study.  Every effort 
should be made to retain unblinded patients. 
4.4 
STUDY TREATMENT 
4.4.1 
Formulation, Packaging, and Handling 
4.4.1.1 
RO5520985  
The investigational medicinal product (IMP) for this study is RO5520985.  It is provided 
as a sterile, colorless to slightly brownish liquid and contains no preservatives.  


 
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Each single-use, 10-mL vial contains 250 mg (nominal) of RO5520985 formulated as 
25 mg/mL in L-histidine buffer solution (approximately pH 6.0) containing sucrose and 
polysorbate 20. 
The recommended storage condition for RO5520985 drug product is between 2°C−8°C 
(36°F−46°F), protected from light.  The nominal fill volume is 10 mL.  A 0.2 μm in-line 
filter must be used for the administration.  For batch-specific instructions and information 
on shelf-life see packaging. Study drug packaging will be overseen by the Sponsor’s 
clinical trial supplies department and will bear a label with the identification required by 
local law, the protocol number, drug identification and dosage.  The packaging and 
labeling of the study medication will be in accordance with Sponsor’s standard and local 
regulations.  The study drug must be stored according to the details on the product label.  
Upon arrival of investigational products at the site, site personnel should check the drug 
packaging for damage and verify proper identity, quantity, integrity of vials and seals and 
temperature conditions, and report any deviations or product complaints to the IxRS and 
monitor upon discovery. Any damaged shipments will be replaced. 
For further details, refer to the RO5520985 IB. 
4.4.1.2 
Bevacizumab and FOLFOX 
Bevacizumab and mFOLFOX-6 are considered to be standard of care and the 
comparator treatment (‘Control Arm’).  FOLFOX is a non-investigational medicinal 
product (non IMP) within this study.  Being the comparator, bevacizumab  is considered 
to be investigational medicinal product (IMP). 
Bevacizumab 
Bevacizumab will be provided by Roche.  Study drug packaging will be overseen by the 
Sponsor’s clinical trial supplies department and will bear a label with the identification 
required by local law, the protocol number, drug identification and dosage.  The 
packaging and labeling of the study medication will be in accordance with the Sponsor’s 
standard and local regulations.  The study drug must be stored according to the details 
on the product label.  Upon arrival, site pharmacy  should check the drug packaging for 
damage and verify proper identity, quantity, integrity of vials and seals and temperature 
conditions, and report any deviations or product complaints to the IxRS and monitor 
upon discovery.  Any damaged shipments will be replaced. 
For further information including storage details, refer to Avastin® full prescribing 
information. 
FOLFOX 
The mFOLFOX-6 regimen contains 5-FU, folinic acid and oxaliplatin.  It will be 
prescribed, sourced and funded according to local standard practice.  For additional 
information including storage details, refer to the respective full prescribing information.  


 
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4.4.2 
Dosage, Administration, and Compliance 
The qualified individual responsible at the pharmacy for dispensing the study drug will 
prepare the assigned dose. This individual will write the date dispensed and patient 
number and initials on the study drug vial label and on the Drug Accountability Record.  
This individual will also record the study drug batch or lot number received by each 
patient during the study. 
4.4.2.1 
RO5520985 (PART I) 
At least 6 patients will receive a fixed dose of 2000 mg RO5520985 IV on Day 1 of each 
Cycle on a Q2W schedule.  Based on the observed toxicity, dose reduction of 
RO5520985 may become necessary.  Therefore the Safety IMC may decide to enroll 
additional 6-12 patients which will be then treated at lower dose(s). 
4.4.2.2 
RO5520985 and Bevacizumab (PART II) 
Dose of RO5520985 / bevacizumab 
a) RO5520985  
Patients randomized to the experimental arm will receive the fixed dose of 
RO5520985 IV on Day 1 of each Cycle on a Q2W schedule as recommended by the 
IMC based on Part I safety data review. 
b) Bevacizumab  
Patients randomized to the control arm will receive bevacizumab at a dose of 
5 mg/kg IV on Day 1 of each Cycle on a Q2W schedule.  Bevacizumab will be dosed 
by body weight.  The weight at screening will be used for dose calculation for each 
patient. Recalculation of dosage is not required if weight changes. 
Please note: Detailed information about the preparation of infusion solution of 
RO5520985 and including information about compatible infusion bags, administration 
sets and in line filters will be provided to the unblinded pharmacy in a separate 
pharmacy manual and in the Avastin® prescribing information, respectively 
Administration of RO5520985/bevacizumab 
The patients will receive either RO5520985 plus mFOLFOX-6 (experimental arm) or 
bevacizumab plus mFOLFOX-6 (control arm) every 2 weeks as described below. The 
first dose of RO5520985/ bevacizumab defines Day 1 of the treatment cycle.  The last 
day of a complete treatment cycle is Day 14.  RO5520985/ bevacizumab will be 
administered as an intravenous infusion only at room temperature through a dedicated 
line with a 0.2 μm in line filter and recommended product contact surfaces.  IV infusion 
pumps should be used to control the infusion rate.  RO5520985/ bevacizumab will be 
given without any routine premedication and prior to mFOLFOX-6. 
RO5520985/ bevacizumab must be administered in a hospital or clinic equipped for 
intravenous chemotherapy.  Full emergency resuscitation facilities should be 


 
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immediately available and patients should be under close supervision of the Investigator 
at all times. 
RO5520985/ bevacizumab will be given over 90 minutes.  Do not administer as an IV 
push or bolus.  If the first infusion is tolerated without signs and symptoms of 
infusion−related reactions (IRR) CTCAE ≥ Grade 2, the second infusion will be 
administered over 60 minutes.  All subsequent infusions may be given over 30 minutes, 
if infusion over 60 minutes is tolerated without an IRR CTCAE ≥ Grade 2. 
For further details regarding administration of RO5520985 and bevacizumab refer to the 
RO5520985 pharmacy manual and full prescribing information of Avastin®, respectively. 
4.4.2.3 
FOLFOX 
All patients of Part I and II regardless of the treatment arm will receive mFOLFOX-6 
every 2 weeks as described below. 
Please note:  Chemotherapy infusion can start only after RO5520985/bevacizumab 
infusion has been completed and patient tolerability was checked.  If an AE has been 
experienced during RO5520985/bevacizumab infusion, chemotherapy may be delayed 
up to a maximum of 24 hours. 
• 
Oxaliplatin at a dose of 85 mg/m2 IV over 120 ( ± 5) minutes on Day 1 of each cycle   
• 
Folinic acid at a dose of 400 mg/m2, IV over 120 ( ± 15) minutes on Day 1 of each 
Cycle.  As an alternative levofolinic acid at a dose of 200 mg/m2, IV over 120 ( ± 15) 
minutes on Day 1 of each cycle can be given.  
• 
5-fluorouracil (5-FU) starting bolus on Day 1 of each Cycle at a dose of 400 mg/m2 
followed by 2400 mg/m2 IV permanent infusion for 46 ( ± 2) hours.  
 
Oxaliplatin will be given concurrently together with folinic acid via a Y-connector. 
Thereafter 5-FU will be administered as described above.  
During induction phase substitution of 5-FU/folinic acid is not permitted.  During the 
maintenance phase substitution of 5-FU/folinic acid IV by oral capecitabine is 
discouraged.  However, individual patients may receive capecitabine without folinic acid 
according to institutional standards (e.g., 625 mg/m2 bid continuously 
(Koopman et al. 2013) at the discretion of the Investigator and in agreement with the 
Sponsor’s medical monitor.  
The preferred order and rate of drug administration may be modified based on patient 
tolerability or institutional guidelines.  In the event that the full dose of folinic acid 
(racemic leucovorin or levoleucovorin) is unavailable and in accordance with NCCN 
guidelines, the dose may be lowered in accordance with the treating physician’s 
standard practice in administering mFOLFOX-6.  In case neither racemic leucovorin nor 
levoleucovorin is available, dose can be omitted and patients who tolerate treatment 


 
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without Grade 2 or higher toxicity, a modest increase in 5-FU dose (in the range of 10%) 
can be considered. However, standard dosing should be resumed when supply is 
adequate. 
For further details of preparation and administration, refer to the pharmacy manual, and 
full prescribing information for the individual components of FOLFOX.  
4.4.2.4 
Treatment Duration 
Oxaliplatin will be administered for a maximum of 8 cycles as part of the induction 
therapy.  Thereafter oxaliplatin administration will be discontinued and the patients 
receive maintenance therapy containing 5-FU/folinic acid plus either  bevacizumab 
(control arm) or RO5520985 (experimental arm) for 24 months if treatment is not 
stopped earlier due to progressive disease, unacceptable toxicity, Investigator decision 
or consent withdrawal. 
If a patient stops chemotherapy either in part or in whole, then they should continue on 
RO5520985 or bevacizumab  for a maximum of 24 months (calculated from start of 
maintenance therapy) if treatment is not stopped earlier due to progressive disease, 
unacceptable toxicity, Investigator decision or consent withdrawal. 
4.4.3 
Accountability of RO5520985 and Bevacizumab 
RO5520985 and bevacizumab will be provided by the Sponsor.  The investigational site 
will acknowledge receipt, confirm the shipment condition and content.  Any damaged 
shipments will be replaced. 
The Investigator is responsible for the control of drugs under investigation.  Adequate 
records of the receipt (e.g., Drug Receipt Record) and disposition (e.g., Drug Dispensing 
Log) of the study drug must be maintained.  The Drug Dispensing Log must be kept 
current and should contain the following information: 
• 
The identification of the patient to whom the study drug was dispensed  
• 
All records and drug supplies must be available for inspection by the Roche/CRO 
Monitor at every monitoring visit 
 
RO5520985 and bevacizumab 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 destruction must be agreed 
upon by the Sponsor.  Local or institutional regulations may require immediate 
destruction of used investigational medicinal product for safety reasons.  In these cases, 
it may be acceptable for investigational study site staff to destroy dispensed product 
before a monitoring inspection provided that source document verification is performed 
on the remaining inventory and reconciled against the documentation of quantity shipped, 
dispensed, returned, destroyed and provided that adequate storage and integrity of drug 
has been confirmed.  Written authorization must be obtained from the sponsor at study 
start up before destruction. 


 
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The site must obtain written authorization from the Sponsor before any RO5520985 or 
bevacizumab is destroyed, and destruction must be documented on the appropriate form. 
Written documentation of destruction must contain the following: 
• 
Identity [batch numbers, Patient Numbers] of product(s) destroyed 
• 
Quantity of product(s) destroyed 
• 
Date of destruction 
• 
Method of destruction 
• 
Name and signature of responsible person or company who destroyed products 
 
Accurate records of RO5520985 and bevacizumab received at, dispensed from, 
returned to, and disposed of by the study site should be recorded on the Drug Inventory 
Log. 
4.5 
CONCOMITANT THERAPY 
Concomitant therapy includes any medication (e.g., prescription drugs, 
over−the−counter drugs, herbal/homeopathic remedies, nutritional supplements) used by 
a patient 4 weeks prior to starting study treatment until End of Study visit.  All 
concomitant medications should be reported to the Investigator and recorded on the 
Concomitant Medications electronic Case Report Form (eCRF).  All therapy and/or 
medication administered to manage adverse events should be recorded on the adverse 
event eCRF. 
4.5.1 
Permitted Therapy  
Patients should be treated for all concomitant medical conditions and adverse events 
according to accepted standards of medical care at the discretion of the Investigator 
except as specifically prohibited in Section 4.5.2.  
All patients are to receive standard supportive care, including blood and platelet 
transfusions, antibiotics, and anti-emetics, as appropriate.  Colony-stimulating factors, 
such as G-CSF and erythropoietin, should be used according to local 
practice/institutional guidelines or the ASCO and ASCO/ASH guidelines, respectively 
(Smith et al. 2006; Rizzo et al. 2010).   
On the basis of clinical experience with RO5520985, IRRs are classified as a potential 
risk of RO5520985 therapy (Section 5.2.1.12). If IRRs occur, patients should be treated 
according to standard treatment of care.  Further details with regard to management of 
IRRs are described in Section 5.2.3.2 (Table 2).  
4.5.2 
Prohibited Therapy 
As a general rule, no concomitant medication will be permitted, with the exception of 
medications to treat AEs, unless the rationale for exception is discussed and clearly 
documented between the Investigator and Clinical Pharmacologist/Clinical Scientist. 


 
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The following treatments are not permitted during the study: 
• 
Any other investigational therapy 
• 
Anticancer therapy (chemotherapy, hormonal, biological or radiation therapy, and 
surgery) other than study treatments 
• 
Radiotherapy, except short course palliation 
 
If any of these therapies are needed, the patient will be considered to have evidence of 
progressive neoplastic disease and have experienced treatment failure.  This will lead to 
the patient discontinuing participation in the study. 
Furthermore, due to the potential risk of bleeding associated with anti-angiogenic 
therapies, the following treatments are prohibited: 
• 
Current use of full dose anticoagulants or thrombolytic therapy at therapeutic doses. 
However, if a patient experiences a VTE event while still receiving study drug 
treatment, it may still be possible for him or her to remain on study 
medication.  Please see Section 5.2.3.2 (Table 2) for guidance on further 
treatment with or discontinuation of bevacizumab/ RO5520985 therapy. 
• 
Prophylactic use of low dose anticoagulation, unfractionated heparin or LMWH is 
permitted.  However, the preferred choice for anticoagulation treatment should be 
LMWH as per ASCO guidelines (Lyman et al. 2007). The prophylactic use of 
warfarin or coumarin-like products is not permitted. 
• 
Prophylactic use of anticoagulation at baseline and during study treatment for the 
maintenance of patency of permanent indwelling central venous access devices is 
permitted. If a patient suffers a VTE event, while on study still receiving study 
treatment, it may still be possible for him or her to remain on study treatment 
(Section 5.2.3).  
 
In addition, due to the potential risk of severe/fatal infections in patients treated with 
5-FU, the following treatment is prohibited: 
• 
Vaccination with live vaccines 
 
Also prophylactic use of phenytoin is not allowed in combination with 5-FU. 
Concomitant chronic use of NSAIDs while receiving study drugs is prohibited. 
However, for the symptomatic relief of medical conditions (e.g. headache, fever) 
sporadic or short-term intake of oral NSAIDs is allowed, when co-administered 
proton pump inhibitors to reduce potential gastrointestinal damage. Also seek 
consultation with a gastroenterologist as medically indicated.  
Chronic daily treatment with systemic corticosteroids (dose >10 mg/day 
methylprednisolone equivalent) is generally prohibited while on RO5520985/ 
bevacizumab. However, a one-time or medically indicated, short course of higher 


 
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dose (>10 mg/day methylprednisolone equivalent) of systemic corticosteroid use 
may be allowed as agreed by the study investigator and the Medical Monitor. 
4.6 
STUDY ASSESSMENTS  
4.6.1 
Description of Study Assessments 
All examinations listed below will be performed according to the SoA (Appendix 1, 
Appendix 2, Appendix 3) for both Part I and Part II of the study, except soluble biomarker 
assessments  in Part I and FOLFOX PK in Part II.  These tables provide the minimum 
requirements for the protocol.  Additional assessments and/or additional parameters 
may be performed as clinically indicated, according to Investigator judgment.   
4.6.1.1 
Medical History and Demographic Data  
Medical history will be taken that describes clinically significant diseases within the 
previous 5 years apart from cancer.  Demographic data to be collected will include date 
of birth and sex.  Additionally, anthropometric measurements will include race, body 
weight (at physical examinations) and body height (body height to be measured during 
screening only).  To explore any potential influence of race on PK and PD, information 
on race will be collected in the eCRF. 
4.6.1.2 
Cancer History 
Cancer history will also be collected including cancer type, cancer location, histology 
date and stage of first diagnosis, tumor stage at study entry, prior anticancer treatment, 
surgery and radiotherapy. 
4.6.1.3 
Physical Examinations 
Physical examinations will occur throughout the study according to the Schedule of 
Assessments (Appendix 1).  A complete physical examination should include an 
evaluation of the head, eyes, ears, nose and throat.  The cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary and neurological systems 
should also be examined.  Any abnormality identified at baseline should be recorded on 
the Medical History eCRF. 
At subsequent visits, limited, symptom-directed physical examinations should be 
performed.  Changes from baseline abnormalities should be recorded in patient notes.  
New or worsened clinically significant abnormalities should be recorded as adverse 
events on the Adverse Event eCRF. 
4.6.1.4 
ECOG Performance Status 
Performance Status (PS) will be measured using the ECOG Performance Status Scale.  
PS will be assessed with each physical exam.  It is recommended, where possible, that 
a patient’s PS will be assessed by the same person throughout the study.   


 
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4.6.1.5 
Vital Signs 
Vital signs will include measurements of blood pressure, respiratory rate, body 
temperature, and pulse rate (in sitting position upon resting for 5 minutes).  Medically 
significant findings that are present prior to the start of study treatment must be recorded 
in the Medical History eCRF with “ongoing” ticked.  Medically significant findings made 
after start of study treatment or worsening of those reported at baseline and which meet 
the definition of an AE (Section 5.3.5.5) must be recorded as an AE in the eCRF. 
4.6.1.6 
Electrocardiograms 
A 12-lead ECG will be performed and should be obtained for each patient from the same 
machine whenever possible as indicated in the SoA (Appendix 1) or as clinically 
indicated.  Triplicate ECG recordings will be obtained within approximately 2−5 minutes 
of each other.  The average of the three readings will be used to determine ECG 
intervals (e.g., PR, QT).   
ECG characteristics, including heart rate, QRS duration, PR, and QT intervals, will be 
recorded on the eCRF.  QTcB (Bazett's correction) and QTcF (Fridericia's correction) 
and RR will be calculated within eCRF.  Changes in T-wave and U-wave morphology 
and overall ECG interpretation by the Investigator or another qualified assessor will be 
documented on the eCRF.  T-wave information will be captured as normal or abnormal, 
U-wave information will be captured in two categories: absent/normal or abnormal. 
The diagnostic comments on the ECG machine printout will not be captured. Significant 
findings must be recorded either as Relevant Medical History/Current Medical 
Conditions (if present before treatment) or as Adverse Events (if newly occurring or 
worsening since starting treatment).  The Investigator or designee must review, sign and 
date all ECG tracings.  Paper copies will be kept as part of the patient's permanent study 
file at the site.  Digital recordings will be stored at the site as well. If considered 
appropriate by Roche, ECGs may be analyzed retrospectively at a central laboratory. 
Whenever possible, the same brand/model of a standard high-quality, high-fidelity 
electrocardiograph machine equipped with computer-based interval measurements 
should be used for each patient.  The conditions should be as close as possible to pre‑
dose time points; this includes but is not limited to food intake, activity level, stressors 
and room temperature. 
4.6.1.7 
Transthoracic Echocardiogram/Multiple Gated Acquisition 
Scans 
TTE (transthoracic echocardiogram) or MUGA (multiple gated acquisition) scan will be 
performed according to the standard practice of the investigational site.  This may be 
further repeated at the Investigator’s discretion if there are signs or symptoms of 
cardiotoxicity.  TTE or MUGA scan will be used to monitor the cardiac parameters of 
function (i.e., left ventricular ejection fraction [LVEF]).  The same method should be 
applied for an individual patient throughout the study.  Preferably the same cardiologist 


 
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should read and report the outcome to minimize variability in results. Copies of all 
echocardiograms/scans performed on patients who experience a ≥  20% decrease in 
LVEF from baseline and whose cardiac ejection fraction is below the institution’s lower 
limit of normal may additionally be required by the Sponsor for review and thus be kept 
as part of the patient's permanent study file at the site. 
4.6.1.8 
Adverse events 
Adverse events will be graded according to the NCI Common Terminology Criteria 
(NCI−CTCAE) version 4.03. 
4.6.1.9 
Concomitant Medication 
Refer to Section 4.5 for details on concomitant medication. 
4.6.1.10 
Safety Laboratory Assessments 
The following safety laboratory assessments will be performed according to the SoA 
(Appendix 1): 
• 
Hematology:  Hemoglobin, hematocrit, platelet count, RBC count (erythrocytes), 
WBC count (leukocytes), WBC absolute differential count (neutrophils, eosinophils, 
basophils, lymphocytes, monocytes). 
• 
Serum chemistry:  Na, K, Ca, lipase, glucose, GGT, AST, ALT, LDH, AP, total and 
direct bilirubin, urea, creatinine, total protein, albumin, CK, TSH, CRP and CrCl 
calculated (by Cockroft-Gault formula) or directly measured. 
• 
Coagulation:  INR/PT; aPTT, fibrinogen 
• 
Blood tumor marker:  CEA 
• 
Urine analysis:  Urine dipstick for proteinuria (24-hrs urine protein analysis in 2+ or 
greater urine dipstick reading).   
• 
Pregnancy test:  All women of childbearing potential (including those who have had 
a tubal ligation) will have a serum or urine pregnancy test at Screening.  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
All samples for safety laboratory assessments will be sent to the study site's local 
laboratory for analysis.  Normal ranges for the study laboratory parameters must be 
supplied to the CRO before the study starts.  The total amount of blood drawn for all 
above described safety parameters will be approximately 12 mL during screening and 
approximately 12 mL for each subsequent safety laboratory assessment.  
Additional blood or urine samples may be taken at the discretion of the Investigator if the 
results of any test fall outside the reference ranges, or clinical symptoms necessitate 
additional testing to monitor patient safety. Where the clinical significance of abnormal 
lab results is considered uncertain, screening lab tests may be repeated before 
randomization to confirm eligibility.  If there is an alternative explanation for a positive 
urine or blood test for drugs of abuse (e.g., previous occasional intake of a medication or 


 
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food containing for example codeine, benzodiazepines or opiates) the test could be 
repeated to confirm washout. 
In the event of unexplained abnormal clinically significant laboratory test values, the 
tests should be repeated immediately and followed up until they have returned to the 
normal range and/or an adequate explanation of the abnormality is found.  
Results of clinical laboratory testing will be recorded on the eCRF or be received as 
electronically produced laboratory reports submitted directly from the local laboratory. 
4.6.1.11 
Pharmacokinetic Assessments 
Part I of the study 
PK samples for RO5520985 and FOLFOX will be collected as outlined in the SoA 
(Appendix 2, Appendix 3).  For each scheduled time point of RO5520985 and 5-FU, an 
approximate venous blood volume of 2 mL for each compound will be drawn. For each 
scheduled time point of oxaliplatin (free and total), an approximate venous blood volume 
of 4 mL will be drawn. In Part I, the total amount of blood drawn for PK (including HAHA) 
is approximately 149 mL. 
Part II of the study 
Samples for RO5520985 PK analysis will be collected as outlined in the SoA 
(Appendix 2).  Samples from patients receiving bevacizumab will be taken as per the 
RO5520985 schedule to maintain the double-blind design of the study, but will not be 
analyzed.  PK parameters of FOLFOX will not be measured in Part II of the study.  At 
each scheduled timepoint approximately 2 mL of venous blood for plasma isolation will 
be drawn. In Part II, the total amount of blood drawn for PK (including HAHA) is 
approximately 70 mL. 
General Instructions For PK Sampling (applies to Part I and Part II) 
All blood samples for PK assessment will be collected from an alternative IV line which 
should be on the opposite arm to that used for administering the infusion. 
The date and time of each PK sample will be recorded. Additional unscheduled PK 
samples will be collected for RO5520985 at time of disease progression or at earliest 
convenience thereafter. 
For each unscheduled PK sample, it is essential to capture on the eCRF the date and 
time of the event necessitating the unscheduled sample (PD) and of the last dose 
preceding the unscheduled sample. 
Instruction manuals and supply kits will be provided for all PK assessments.  For 
collection procedures, storage conditions and shipment instruction, refer to Sample 
Handling and Logistics Manual. 


 
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4.6.1.12 
Human Anti-Human Antibodies 
Sampling will be conducted to determine if HAHAs are developed against RO5520985.  
Samples from patients receiving bevacizumab will be taken as per the RO5520985 
schedule to maintain the double-blind in the study, but will not be analyzed.  In first 
instance only HAHA samples collected at baseline and EoS Visit from patients treated 
with RO5520985 wll be analyzed.  Only in case of positive HAHA titers (in one or both 
samples) or in case of IRRs, the remaining collected blood samples will be analyzed. 
For analysis purposes approximately 2 mL of venous blood for plasma isolation will be 
drawn. 
Samples will be sent to one or several central laboratories or to the Sponsor for analysis. 
Instruction manuals and supply kits will be provided and collection procedures, storage 
conditions and shipment instructions are detailed within the Sample Handling and 
Logistics Manual. 
4.6.1.13 
Pharmacodynamics and Exploratory Biomarker Assessments 
The following samples will be collected for exploratory analyses: 
• 
Plasma 
• 
Archival primary tumor tissue 
 
Note:  Soluble biomarkers (plasma) will not be measured in Part I patients.  
The rationale for their collection is provided in Section 3.2.4.  Additional markers may be 
measured if a strong scientific rationale for these analyses develops.  All data arising 
from the samples will be subject to the confidentiality standards described in Section 8.4.  
The collection time points are specified in the SoA (Appendix 1).  
Note: Samples at Disease Progression visit should be drawn within 1 week after imaging 
shows Disease Progression.  In the event that the EoS Visit overlaps with 
Disease Progression Visit, only 1 sample needs to be drawn.  
On the basis of continuous analysis of the data in this study and other studies, any 
sample type may be stopped at any time if the data from the samples collected does not 
produce useful information. 
For collection procedures, storage conditions and shipment instructions see the 
SampleHandling and Logistics Manual. 
4.6.1.13.1 
Plasma 
Approximately 7.5 mL blood sample for plasma isolation will be obtained for each 
timepoint (Appendix 1).  The plasma will be used for the following assessments: 
• 
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• 
Angiogenesis-related markers (but not limited to): Ang1, PlGF, sTie-2, VEGF-C, 
sVEGF-R1, sVEGF-R2, sVEGF-R3, SDF-1α, E-selectin, ICAM-1, bFGF, IL-8, 
PDGF-C, CA-IX 
 
Blood (2 mL) for plasma isolation will be obtained at baseline, disease progession as well 
as end of study visit and used to measure levels of circulating MMP-2 and MMP-9. 
An additional approximate 2 mL blood sample will be collected at baseline for 
development of an Ang-2 companion diagnostic test, as well as a total of approximately 
6 mL blood for 3 additional measurements of Ang-2 (Appendix 2). 
In addition 10 mL blood sample for plasma isolation will be required for the following 
assessment: 
• 
Dependent on the mutational analysis of the archival tissue (Section 4.6.1.13.2) 
based on the specific mutation detected, the presence of circulating tumor DNA 
(ctDNA) will be assessed at baseline and various time points on treatment (SoA, 
Appendix 1).  
 
Total Blood Loss 
The total blood volume loss for plasma and whole blood biomarker assessments will be 
approximately 140 mL up to Cycle 13 including the Disease Progression and End of 
Study Visit.  
Residual plasma samples will be retained for 15 years to enable validation of companion 
diagnostic tests related to the proposed mechanism of action of the active 
principle RO5520985 from all patients enrolled on the study.  Any residual PD samples 
not to be used for the validation mentioned above will be destroyed 2 years after the 
date of final closure of the clinical database. 
4.6.1.13.2 
Archival Primary Tumor Tissue  
Representative tumor specimens in formalin-fixed, paraffin embedded blocks (preferred) 
or slides (35 slides if possible)  with an associated pathology report are to be obtained 
from all patients at all sites.  Tumor blocks/slides must be sent as indicated in the lab 
manual for central extended RAS mutational analysis.   
In cases where local RAS mutational analysis is available prior to study entry, this 
information will be shared with the Sponsor and collected within eCRF. 
In addition tumor tissue will be analyzed to assess further potential response prediction 
marker.  This includes the analysis of (but is not limited to): 
• 
Target proteins and biomarkers related to their vascular signaling including Ang-2, 
VEGF-A, Ang-1, Tie-2 
• 
Markers of vessel architecture by IHC including CD31, CD34, Podoplanin, aSMA, 
c-C3, Ki67.  The analysis will be prioritized based on the amount of material 
available.  Additional assessments may be performed. 


 
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• 
Markers characterizing the tumor status including Ki67and CAIX.  The analysis will 
be prioritized based on the amount of material available.  Additional assessments 
may be performed. 
• 
Markers of tumor-infiltrating immune cells including CD4, CD8, CD3/FOXP3, 
CD68/CD163,CD3/perforin.  The analysis will be prioritized based on the assay and 
material availability.  Additional assessments may be performed. 
• 
Molecular mutational analysis including, but not limited to mutational status of e.g. 
EGFR, BRAF 
Tumor blocks will be returned to sites latest at study end.  If there is urgent need for the 
block to be returned and this is requested by the Investigator, the blocks will be sent 
back within approximately 2 weeks upon notice.  On the chance that further analyses are 
required, access to the block from the site will be requested again, in the event that it 
was returned already.  Slides will not be returned to the sites. 
Further exploratory analyses, which could lead to hypothesis generation for potential 
response prediction markers, will be performed.  This  includes, but is not limited to, 
gene expression profiling (e.g., with RNA sequencing technology). 
The remaining tissue/slides will be stored in the RCR for 15 years for all consenting 
patients. 
4.6.1.14 
Disease-Specific Assessments 
Tumor and Response Evaluations 
Throughout the trial, the RECIST criteria, v. 1.1 (Appendix 8) will be applied when 
assessing any responses to the study drug treatment.  All potential sites of tumor lesions 
will be assessed at baseline by radiologic techniques using contrast enhanced CT or 
MRI imaging.  All tumor lesions at baseline need to be recorded as either target or 
nontarget lesions.  
The minimum schedule of imaging is the thorax, abdomen, and pelvis.  If there is any 
clinical suspicion of disease at any site that may not be demonstrated by the minimum 
schedule, further investigations should be performed with a view to documenting the full 
extent of the tumor burden at baseline according to the investigator’s clinical judgment.  
Results of tumor assessments using CT/MRI performed prior to obtaining informed 
consent and within 28 days prior to Day 1 may be used; in this case no further CT/MRI is 
required during screening.  Subsequent scans are done every 8 weeks (± 7 days) 
thereafter and at End of Study Visit.  All complete and partial responses must be 
confirmed by a second assessment at least 4 weeks later.  In the event of SD, follow-up 
assessments must have met the RECIST v1.1 SD criteria at least once after study entry 
at a minimum interval of 8 weeks.    
Should a patient discontinue from treatment for any reason other than progression, an 
End of Study CT/MRI is to be performed only if it has not been done ≤  28 days prior.  
Patients who discontinued the study for any other reasons than progression will 


 
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be followed by regular CT assessments according to institutional standard of care 
until documentation of progressive disease, initiation of another anticancer 
therapy (including secondary resection), withdrawal of consent, or death.   
Patients with previously documented tumor progression will not require additional tumor 
reassessment by CT/MRI at End of Study visit. 
If there is suspicion of disease progression based on clinical or laboratory findings 
before the next scheduled assessment, an unscheduled assessment should be 
performed.  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. 
Patients with target lesions that have become centrally necrotic and meet the RECIST 
criteria of progressive disease, but otherwise demonstrate clinical symptoms 
improvement and tumor marker decrement, may remain on study treatment upon 
decision of the Investigator and the Sponsor’s medical monitor. 
If study drug treatment is delayed for any reason, the scheduled tumor assessments 
should still take place within the scheduled assessment window. 
Consistency of consecutive CT or MRI scans should be ensured during all assessments 
for each patient, with the same technique used for evaluating lesions throughout the 
treatment period.  Use of spiral CT or MRI is required for baseline lesions < 20 mm and 
must be documented in medical records and used consistently throughout the study.  
If more than one method is used, select the most accurate method according to 
RECIST v1.1 when recording data.  Other methods (X-ray, ultrasound, etc.) are not 
acceptable for monitoring target lesions.  The use of oral and IV contrast should be used 
consistently where no contraindication exists and where appropriate.  An adequate 
amount of contrast agent should be given, so that the tumor lesions appear with good 
resolution.  If possible, a single radiologist should perform all evaluations for an 
individual patient. 
Note: Any lesions that have been previously treated with radiotherapy should not be 
used as target lesions for tumor assessment.  Exceptions may be made when these 
lesions are the only lesions available for evaluation and have shown definite progression 
since their last radiation treatment. 
4.6.1.15 
Samples for Roche Clinical Repository 
Overview of the Roche Clinical Repository 
The Roche Clinical Repository (RCR) is a centrally administered group of facilities 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 


 
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analysis of RCR specimens will facilitate the rational design of new pharmaceutical 
agents and the development of diagnostic tests, which may allow for individualized drug 
therapy for patients in the future. 
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research. RCR specimens will be used to achieve the 
following objectives: 
• 
To 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 
 
Approval by the Institutional Review Board or Ethics Committee 
Sampling for 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 will not be applicable at that site. 
Rationale 
The pharmacogenetic information gathered through the analysis of specimens in the 
RCR should improve treatment outcome by predicting which patients are more likely to 
respond to specific drug therapies, predicting which patients are susceptible to 
developing adverse side effects and/or predicting which patients are likely to progress to 
more severe disease states. Such genetic samples collected for analysis of heritable 
DNA variations will be double coded: a new independent code will be added to the first 
code to increase confidentiality and data protection (Section 8.4).  The results of 
specimen analysis from the RCR will facilitate the rational design of new pharmaceutical 
agents and the development of diagnostic tests, which may allow for individualized drug 
therapy for subjects in the future. 
All RCR specimens will be destroyed no later than 15 years after the final freeze of the 
respective clinical database unless regulatory authorities require that specimens be 
maintained for a longer period.  The specimens in the RCR will also be made available 
for future biomarker research towards further understanding of RO5520985 treatment of 
CRC, related diseases and adverse events and for the development of potential 
associated diagnostic assays.  The implementation and use of the RCR specimens is 
governed by the Roche Clinical Repository policy to ensure the appropriate use of the 
RCR specimens.  If no consent has been given for long term storage, all samples will be 


 
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destroyed no later than 5 years after the final freeze of the respective clinical database 
unless regulatory authorities require that specimens be maintained for a longer period. 
Sample Collection 
Specimens for dynamic (noninherited: plasma), genetic (inherited: DNA), and tissue 
biomarker discovery and validation will be collected from all consenting patients 
participating in the trial.  Tissue slides and plasma samples will be single coded like any 
other clinical sample (labeled and tracked using the patient’s study identification number), 
DNA samples will be double-coded (refer below to paragraph “Confidentiality” for more 
details). 
Note: No blood samples will be collected for RCR in Part 1 
Blood for Plasma  
Blood (one sample with approximately 6 mL in a tube with EDTA)  for plasma isolation 
will be collected at baseline for biomarker discovery and validation, which may include 
analysis of proteins and metabolites and other candidate advanced biomarkers.  
Blood Sample for Genetic Analysis 
Blood (approximately 6 mL in K3 EDTA) for DNA isolation (e.g., genome-wide 
association studies) will be collected as at baseline.  If, however, the RCR genetic blood 
sample is not collected during the scheduled visit, it may be collected at any time (after 
randomization) during the conduct of the clinical study.  The sample may be tested using 
a variety of methodologies including but not limited to DNA sequencing.  The biological 
specimen collection will be used to understand better protocol treatment effect, adverse 
effects and related disorders.  Since the identification of new markers correlating with 
disease activity and the efficacy or safety of treatment are rapidly evolving, the definitive 
list of analysis remains to be determined. 
For all samples, dates of consent and specimen collection should be recorded on the 
associated RCR page of the eCRF.   
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC−approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
The 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 below. 
Confidentiality for Genetic Biomarker Specimens 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure study subject confidentiality for RCR specimens and associated data.  Upon 


 
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receipt by the RCR, each specimen is "double-coded" by replacing the study subject 
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 labeled with this same independent number. A "linking key" 
between the study subject identification number and this new independent number is 
stored in a secure database system.  Access to the linking key is restricted to authorized 
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 only 
be disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
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. 
Consent to Participate in the Roche Clinical Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR. The Investigator or authorized 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 provide optional RCR specimens.  
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. 


 
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Withdrawal from the Roche Clinical Repository 
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  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 using the RCR Withdrawal Form and, if the trial 
is ongoing, must enter the date of withdrawal on the RCR Research Sample Withdrawal 
of Informed Consent eCRF.  The patient will be provided with instructions on how to 
withdraw consent after the trial is closed.  A patient's withdrawal from Study BP29262 
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 BP29262. 
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 authorized 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. 
4.6.2 
Timing of Study Assessments 
4.6.2.1 
Screening and Pretreatment Assessments 
Written informed consent for participation in the study must be obtained before 
performing any study−specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site. 
All screening and pre-treatment assessments must be completed and reviewed to 
confirm that patients meet all eligibility criteria.  The Investigator will maintain a 
screening log to record details of all patients screened and to confirm eligibility or record 
reasons for screening failure. 
An ESF documenting the Investigator’s assessment of each screened patient with 
regard to the protocol’s inclusion and exclusion criteria is to be completed by the 
Investigator and kept at the investigational site. 
Screening and pretreatment assessments will be performed within 28 days prior to 
Day 1, unless otherwise specified.  In cases with an unexpected delay due to logistical 
or technical reasons, the screening period can be extended.  Extending the screening 
period beyond 28 days requires Sponsor approval.  The approval of extended screening 
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4.6.2.2 
Assessments during Treatment 
Under no circumstances will patients who enroll in this study and have completed 
treatment as specified, be permitted to be allocated a new randomization number and 
re-enroll in the study. 
All assessments must be performed as per SoA (Appendix 1, Appendix 2, Appendix 3).  
Assessments scheduled on the day of study treatment administration should be 
performed prior to administration of study treatment, unless otherwise noted in the SoA.  
All assessments must be performed on the day of the specified visit, unless a time 
window is specified in the SoA.   
4.6.2.3 
Assessments at End of Study Visit 
If, for any reason, study drug treatment is permanently discontinued, the patient will be 
considered to have completed study drug treatment.  Patients who discontinue study 
drug treatment should be scheduled for an End of Study Visit within 5 (±1) weeks after 
discontinuing study drug treatment, at which time all of the assessments listed in the 
SoA (Appendix 1) for the End of Study Visit will be performed.   
4.6.2.4 
Follow-Up Assessments 
All patients will be followed for subsequent anticancer therapy and survival (e.g., by 
phone call) approximately every 3 months after EoS Visit until death, loss to follow-up, or 
study termination by Roche, whichever occurs first.  Anticancer therapy is collected at 
first FU visit and is only collected at the subsequent FU visits if the therapy is 
different from previous one. In addition there will be one optional post study 
assessment for determination of HAHA (Appendix 1).  
After the EoS Visit, adverse events should be followed as outlined in Sections 5.4 and 
5.5.  
4.6.2.5 
Assessments at Unscheduled Visits 
See Appendix 1 for assessments that are required to be performed in case of an 
unscheduled visit. 
4.7 
PATIENT, STUDY, AND SITE DISCONTINUATION 
4.7.1 
Patient Discontinuation 
The Investigator has the right to discontinue a patient from study drug treatment or 
withdraw a patient from the study at any time.  In addition, patients have the right to 
voluntarily discontinue study drug or withdraw from the study at any time for any 
reason.  Reasons for discontinuation of study drug or 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 jeopardize 
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• 
Unacceptable toxicity 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
• 
Disease progression 
• 
Patient noncompliance to the study and/or study procedures 
 
4.7.1.1 
Discontinuation from Study Drug 
Adverse events requiring discontinuation from study drug are described in Section 5.2.3.  
Patients who discontinue study drug prematurely will be asked to return to the clinic for a 
End of Study  Visit (Section 4.6.2.3) and may undergo follow-up assessments 
(Section 4.6.2.4).  The primary reason for premature study drug discontinuation should 
be documented on the appropriate eCRF.  In Part I of the study, patients who 
discontinued study drug during the first two cycles not for safety reasons may be 
replaced at Sponsor discretion. In Part II of the study, patients who discontinue study 
drug prematurely will not be replaced.   
If a patient discontinues therapy for reasons other than progression, the patient will be 
followed by regular CT assessments according to institutionalstandard of care until 
documentation of progressive disease, initiation of another anticancer therapy 
(including secondary resection), withdrawal of consent, or death.  
4.7.1.2 
Withdrawal from Study 
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. 
Patients will not be followed for any reason after consent has been withdrawn.  
Note: Patients withdrawing from the main study have the possibility to provide 
consent to continue in the follow-up phase for collection of further information on 
disease and survival follow-up (Appendix 1 of main ICF). 
In Part I patients who discontinued study drug during the first two cycles not for safety 
reasons may be replaced  at Sponsor discretion.  Patients who withdraw from Part II the 
study will not be replaced.  
4.7.2 
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 adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Unfavorable benefit/ risk- assessment based on interim analysis  
• 
Patient enrollment is unsatisfactory. 


 
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The Sponsor will notify the investigator if the study is placed on hold, or if the Sponsor 
decides to discontinue the study or development program. 
The Sponsor has the right to replace a site at any time. Reasons for replacing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Noncompliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
 
In terminating the study, the Sponsor and the Investigators will assure that adequate 
consideration is given to the protection of the patient’s interests.  The appropriate 
IRB/EC and Regulatory Agencies will be informed accordingly. 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and nonserious adverse events of special interest; measurement 
of protocol−specified safety laboratory assessments; measurement of protocol−specified 
vital signs, ECGs; and other protocol−specified tests that are deemed critical to the 
safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.1.2.  
5.1.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
• 
Any unfavorable 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 5.3.5.9.  
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline. 


 
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• 
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. 
• 
Adverse events 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). 
 
5.1.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Fatal (i.e., the adverse event actually causes or leads to death). 
• 
Life threatening (i.e., the adverse event, in the view of the Investigator, places the 
patient at immediate risk of death). 
 
This does not include any adverse event that had it occurred in a more severe form or 
was allowed to continue might have caused death. 
• 
Requires or prolongs inpatient hospitalization (Section 5.3.5.10).  
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
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 jeopardize 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 adverse event (rated as mild, moderate, or severe, or according to a pre-defined 
grading criteria (e.g. NCI CTCAE criteria; 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 adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the Investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; Section 5.3.7 for 
reporting instructions). 
5.1.3 
Selected Adverse Events  
The incidence of the following selected adverse events (grades according to 
NCI CTCAE v4.03) will be collected: 
• 
Hypertension (Grade ≥ 3) 


 
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• 
Proteinuria (Grade ≥ 3) 
• 
Arterial thromboembolic events (any grade) 
• 
Venous thromboembolic events (Grade ≥ 3) 
• 
Vascular disorder - other:  Thrombotic microangiopathy (any grade) 
• 
Gastrointestinal  perforation (any grade) 
• 
Fistula involving an internal organ (any grade) 
• 
Fistulae (Grade 4) 
• 
Wound healing complication (Grade ≥ 3) 
• 
Bleeding/hemorrhage (Grade ≥ 3) 
• 
Pulmonary bleeding (Grade ≥ 2)  
• 
CNS bleeding (Grade ≥ 2) 
• 
Congestive heart failure (Grade ≥ 3) 
• 
Reversible posterior leukoencephalopathy syndrome (any grade) 
 
5.1.4 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-serious 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 5.3.7 for reporting instructions). Adverse events of 
special interest for this study include the following: 
• 
Cases of an elevated ALT or AST in combination with either an elevated 
bilirubin or clinical jaundice, as defined in Section 5.3.5.6. 
• 
Suspected transmission of an infectious agent by the 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 
SAFETY PLAN 
5.2.1 
Risks for RO5520985 (Vanucizumab) and Bevacizumab 
Information in the following sections is based on the mechanism of action, 
preclinical and clinical data for RO5520985 and bevacizumab.  For further 
information, refer to the RO5520985 (vanucizumab) IB and, the bevacizumab 
(Avastin) prescribing information. 


 
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5.2.1.1 
Gastrointestinal Perforation 
In patients treated with bevacizumab, the incidence of gastrointestinal perforation 
ranged from 0.3 to 3.2% across clinical studies. Fatal outcome was reported in 
approximately a third of serious cases of gastrointestinal perforations, which 
represents between 0.2% - 1% of all bevacizumab treated patients.The majority of 
cases occurred within the first 50 days of initiation of bevacizumab. 
In Study BP28179, 6 events indicative of gastrointestinal perforation were reported 
in 6/115 (5.2%) patients; two of the events had a fatal outcome.  In Part II, a 
-year 
old 
 with metastatic adenocarcinoma of the pancreas developed Grade 4 
gastrointestinal perforation (related). In Part III, 5/41 (12.2%)  patients with 
platinum resistant ovarian cancer developed GI-perforation, two of the events had 
a fatal outcome.  
In the blinded Part 2 of Study BP29262 (vanucizumab or bevacizumab plus 
mFOLFOX-6 in metastatic colorectal cancer), the incidence of GIP events 
(including perforation, intra-abdominal abscess, and GI fistula) was 11.1% (8/72 
patients) in Arm A versus 5.6% (4/71 patients) in Arm B. One/12 patients with GI-
perforation had a fatal outcome.  
5.2.1.2 
Fistula (other than GI) 
Bevacizumab use has been associated with serious cases of fistulae including 
events resulting in death.  Fistulae in the GI tract are common (1−10% incidence) 
in patients with mCRC, but uncommon (0.1−1%) or rare (0.01−0.1%) in other 
indications.  In addition, fistulae that involve areas of the body other than the GI 
tract (e.g., tracheoesophageal, bronchopleural, urogenital, biliary) have been 
reported uncommonly (0.1–1%) in patients receiving bevacizumab in clinical 
studies and postmarketing reports.  Events were reported at various timepoints 
during treatment, ranging from 1 week to > 1 year following initiation of 
bevacizumab, with most events occurring within the first 6 months of therapy. 
In clinical trials with RO5520985, 2 events of fistula formation have been reported 
in 2/123 patients (1.6%) treated with RO5520985, both in Study BP28179: one 
patient with rectal cancer and previous radiotherapy experienced a Grade 3 
vesico-cutaneous fistula, which resolved with conservative management following 
discontinuation of RO5520985 treatment, and a Grade 2 cutaneous fistula was 
reported in one patient with an oral adenoid-cystic carcinoma. 
5.2.1.3 
Hemorrhage 
Risks of hemorrhage, especially tumor-associated hemorrhage, are substantial 
among angiogenesis inhibitors.  Patients with different types of cancer vary in 
their risk of hemorrhage due to the anatomic location of the tumor, its underlying 
biology, or its associated treatment.  Pulmonary hemorrhage is a rare but serious 
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In particular, patients who have squamous non small cell lung cancer are at an 
increased risk of pulmonary hemorrhage owing to the underlying disease process.  
Severe pulmonary hemorrhage is a medical emergency requiring specialized 
management and patients with massive bleeding should be cared for in the 
intensive care unit.   
Treatment with bevacizumab can result in two distinct patterns of bleeding: minor 
hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases 
fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, 
gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal 
bleeding occurred up to five-fold more frequently in patients receiving 
bevacizumab compared to patients receiving only chemotherapy. Across 
indications, the incidence of Grade ≥ 3 hemorrhagic events among patients 
receiving bevacizumab ranged from 1.2 to 4.6%. Serious or fatal pulmonary 
hemorrhage occurred in four of 13 (31%) patients with squamous cell histology 
and two of 53 (4%) patients with non-squamous non-small cell lung cancer 
receiving bevacizumab and chemotherapy compared to none of the 32 (0%) 
patients receiving chemotherapy alone.  In clinical studies in non -small cell lung 
cancer where patients with CNS metastases who completed radiation and surgery 
more than 4 weeks prior to the start of bevacizumab were evaluated with serial 
CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 
83 bevacizumab-treated patients (rate 1.2%, 95% CI 0.06%-5.93%). Intracranial 
hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; 
two patients had Grade 3-4 hemorrhage. 
In clinical trials with RO5520985, 27 AEs suggestive of hemorrhage have been 
reported in 21/123 patients (17%). In Study BP28179, 1 patient experienced a 
Grade 2 cerebral (subarachnoidal) hemorrhage. Three events of hemoptysis were 
reported: 1 patient with a large centrally located mediastinal mass experienced 
hemoptysis (pulmonary hemorrhage) with a fatal outcome; the other 2 events of 
hemoptysis reported in 2 patients were of Grade 1 intensity. The remaining events 
of epistaxis, hematuria, gingival bleeding, eye hemorrhage, mouth hemorrhage, 
melena, blood urine present, vaginal hemorrhage, contusion and purpura were all 
of Grade 1 or 2 intensity. In Study BP29262 (safety run-in), 3 patients experienced 
5 events suggestive of bleeding/hemorrhage: Grade 1 rectal hemorrhage, Grade 1 
epistaxis and gingival bleeding, Grade 1 epistaxis and Grade 2 hemorrhoidal 
hemorrhage. 
5.2.1.4 
Arterial Hypertension 
It has been demonstrated in animal models that VEGF induces endothelium-
dependent coronary artery relaxation. In animals and man, VEGF preferentially 
dilates small arterioles and venules, and by doing so it induces a decrease in 
blood pressure. VEGF induces the phosphorylation of endothelial nitric oxide 
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which directly acts on endothelium. Considering this vasodilative effect of VEGF, 
it can be understood that functional blockade will induce vasoconstriction and 
hypertension. Hypertension in response to angiogenesis inhibitors might not only 
be induced by the lack of vasodilatory effects, but may also be due to a decrease 
in the number of small arteries and arterioles as a consequence of inhibiting new 
vessel formation. Effects of VEGF inhibition on the control of blood pressure by 
the kidney may also be involved after prolonged treatment.  
An increased incidence of arterial hypertension (all grades) has been observed in 
patients treated with bevacizumab. Across clinical studies the incidence of Grade 
3 or 4 hypertension ranged from 5-18%. 
In clinical trials with RO5520985, arterial hypertension was the most common 
adverse event and was reported in 73/123 (59.3%) patients. In Study BP28179, 
68/115 (59.1%) patients reported events of arterial hypertension. In 29 patients 
arterial hypertension was of Grade 3 and in 2 patients of Grade 4; all but one of 
these AEs were considered to be related to study treatment. There has been one 
SAE of Grade 4 hypertensive encephalopathy and one SAE of G4 hypertension. 
 In the safety run-in of Study BP29262, arterial hypertension was reported in 5/8 
patients. Grade 3 arterial hypertension occurred in 3 patients with pre-existing 
hypertension. There were no patients with hypertension Grade ≥ 4. Arterial 
hypertension was transient and adequately controlled by standard oral anti-
hypertensive medication, not requiring discontinuation or reduction in dose of the 
study drug. 
5.2.1.5 
Thrombotic Microangiopathy 
Thrombotic microangiopathy (TMA) is a disorder characterized by microvascular 
thrombosis with thrombocytopenia, hemolytic anemia and red blood cell 
fragmentation. It is most commonly separated into two disorders: hemolytic 
uremic syndrome (HUS) and thrombotic thrombocytopenic purpura. HUS refers to 
the triad of renal failure, thrombocytopenia and microangiopathic hemolytic 
anemia, which is usually demonstrated by red cell fragments and increased serum 
lactate dehydrogenase.  
TMA is labelled for bevacizumab primarily as a renal disorder, which is typically 
manifested as proteinuria. Renal TMA has been reported in patients receiving 
bevacizumab but in the post- marketing setting only. 
In clinical trials with RO5520985, thrombotic microangiopathy was reported in 
2/123 patients (1.6%), both in Study BP28179: one Grade 3 SAE in Part I (30 mg/kg 
QW) which resulted in discontinuation of treatment with RO5520985and one non-
serious event (Grade 1) in Part II: (30 mg/kg Q2W). Both events were assessed as 
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5.2.1.6 
Venous Thromboembolic Events  
An increased incidence of venous thromboembolic events has been observed in 
patients treated with bevacizumab. In clinical trials across indications, the overall 
incidence of venous thromboembolic events ranged from 2.8% to 17.3% in the 
bevacizumab containing arms compared to 3.2% to 15.6% in the chemotherapy 
control arms.  
The underlying mechanism is unclear; however, dysfunctional or damaged 
endothelium is considered, whereas platelets as carriers of VEGF have also been 
suggested to play a role in the increased incidence of these events. Inhibition of 
VEGF-A prevents endothelial cell renewal in response to trauma, resulting in 
dysfunction of the endothelium and exposure of sub-endothelial collagen 
secondary to defects in the lining of the interior vasculature. The exposed sub-
endothelium releases tissue factor, thereby activating the coagulation cascade. 
Although there are numerous mechanisms to control the coagulation cascade, the 
inhibition of VEGF-A eliminates a vital step in normal hemostasis and promotes 
thrombogenic activity. The risk of thrombosis with antiangiogenic therapy may be 
increased by the prothrombotic activity of tumor cells. Malignant cells promote 
thrombosis by a number of different mechanisms, including procoagulant activity, 
fibrinolytic activity, cytokine release, and direct interaction with endothelial cells, 
macrophages, and platelets. 
In clinical trials with RO5520985, 6/123 patients (4.9%) experienced 6 venous 
thromboembolic events: In Study BP28179 2 SAEs of Grade 3 pulmonary 
embolism (not related), leading to withdrawal of RO5520985, a non-serious and 
related AE of Grade 2 deep vein thrombosis, one related non-serious AE of Grade 
2 jugular vein thrombosis and one non-serious unrelated AE of Grade 1 superficial 
thrombophlebitis have been reported. During the safety run-in of Study BP29262, 
1 patient had a non-serious and related AE of Grade 2 venous embolism. 
5.2.1.7 
Arterial Thromboembolic Events  
An increased incidence of arterial thromboembolic events (e.g., new onset or 
worsening of unstable angina, myocardial infarction, transient ischemic attack) 
have been observed in patients treated with bevacizumab. Serious, sometimes 
fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient 
ischemic attacks, myocardial infarction, angina, and a variety of other ATEs 
occurred at a higher incidence in patients receiving bevacizumab compared to 
those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the 
bevacizumab containing arms was 2.6% compared to 0.8% in the control arms. 
Among patients receiving bevacizumab in combination with chemotherapy, the 
risk of developing ATE during therapy was increased in patients with a history of 
arterial thromboembolism, or age greater than 65 years. 


 
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In clinical trials with RO5520985, no arterial thromboembolic events have been 
reported. 
5.2.1.8 
Congestive Heart Failure  
Congestive heart failure (CHF) is expected with bevacizumab. VEGF plays a 
critical role in coordinated tissue growth and angiogenesis in the heart. Blocking 
this pathway may interfere with cardiac remodeling and lead to heart failure. 
Increased peripheral resistance of the vasculature may be responsible for a 
reduced LVEF which may precede CHF.  
Cardiovascular monitoring will be implemented for this study.  Any patient who 
develops symptoms compatible with cardiovascular abnormalities should have 
prompt evaluation by a cardiologist.   
In clinical trials with RO5520985, one SAE of congestive heart failure was reported 
(Study BP29262 safety run-in). 
5.2.1.9 
Proteinuria 
An increased incidence of proteinuria has been observed in patients treated with 
RO5520985. The incidence and severity of proteinuria was increased in patients 
receiving bevacizumab as compared to controls. In a meta-analysis of seven trials 
with bevacizumab in mCRC the incidence of Grade ≥ 3 proteinuria was 1.7% 
(Hurwitz et al 2013). Possible mechanisms include: 1) Role of VEGF pathway in 
maintaining the integrity of the glomerular filtration barrier: VEGF is constitutively 
expressed by podocytes and VEGF receptors are present on normal glomerular 
capillary endothelial cells; 2) Thrombotic microangiopathy: glomerular capillary 
endothelial injury by this process can manifest as proteinuria and could represent 
one permutation of vascular thromboembolic disease seen with bevacizumab. 
This condition is diagnosed by renal biopsy and may not correlate with degree of 
proteinuria; and 3) Mediated through nitric oxide inhibition and associated with 
hypertension: in some patients, both hypertension and proteinuria uniformly 
decreased after cessation of anti-VEGF therapy suggesting a possible 
hemodynamic mechanism similar to the temporary proteinuria related to nitric 
oxide blockage inducing renal hemodynamic alteration occurring after exercise. 
In Study BP28179, 12/115 patients (10.4%) experienced 20 events of proteinuria. 
All but 2 of these events were considered related to treatment with RO5520985. 
One patient had Grade 1 proteinuria (related) in the safety run-in of Study BP29262.  
5.2.1.10 
Wound Healing Complications 
An increased incidence of wound healing complications, including serious and 
fatal complications have been observed in patients treated with bevacizumab. In a 
controlled clinical trial with bevacizumab in patients with mCRC who underwent 
surgery during the course of bevacizumab treatment, there was an increased 


 
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incidence of wound healing complications, including serious and fatal 
complications. In a meta-analysis of seven trials investigating mCRC, the 
incidence of Grade ≥ 3 wound healing adverse events was 0.9% (Hurwitz et al 
2013). 
In clinical trials with RO5520985, one event of Grade 1 wound complication 
assessed as related to treatment with RO5520985 has been reported (Study 
BP28179). 
5.2.1.11 
Posterior Reversible Encephalopathy Syndrome 
Posterior reversible encephalopathy syndrome (PRES), also known as reversible 
posterior leukoencephalopathy syndrome (RPLS), is a rare neurological syndrome 
which can present with the following signs and symptoms among others: seizures, 
headache, altered mental status, visual disturbance, or cortical blindness, with or 
without associated hypertension. Two confirmed cases (0.8%) of PRES have been 
reported in one clinical study with bevacizumab. Symptoms usually resolve or 
improve within days, although some patients have experienced neurologic 
sequelae. 
Although not fully understood, the mechanism of PRES is considered to be 
secondary to failed autoregulation of cerebral blood flow leading to cerebral 
vasogenic edema.  Failed cerebral vascular autoregulation results in 
hyperperfusion and dilatation of cerebral arterioles, disruption of the endothelium, 
immediate breakdown of the blood-brain barrier, and finally, transduction of 
plasma and red blood cells into the interstitium.  Although, inhibition of VEGF 
signaling is implicated in the pathophysiology of this syndrome, the syndrome 
often has other contributing factors and has not yet been replicated after VEGF 
inhibition in preclinical models. 
In clinical trials with RO5520985, no events of PRES have been reported. 
5.2.1.12 
Infusion Related Reactions and Allergic Reactions  
Allergic/anaphylactic reaction may occur following administration of proteins to 
patients (Lenz et al. 2007).  Intravenous administration of therapeutic proteins can 
also be associated with infusion related reactions (IRR) which may be clinically 
indistinguishable from allergic/anaphylactic reactions.  The infusion associated 
symptoms may accompany the first or subsequent drug administrations and may 
include skin rash, fever, chills, shortness of breath, hypotension, headache, 
nausea, and emesis. If severe, the symptoms of IRRs may be clinically 
indistinguishable from true anaphylactic reactions, which also may occur with the 
administration of proteins. Mediators classically associated with IRRs include 
TNF-α, IL-6, IL-8, and interferon (IFN)γ.  


 
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In clinical studies with bevacizumab, IRRs with the first dose of bevacizumab were 
uncommon. Bevacizumab-associated IRRs occurred at an incidence of less than 
3% in a clinical trial setting; severe reactions were noted in 0.2% of patients.  
Therefore, premedications are not routinely administered with the use of 
bevacizumab.   
In vitro cytokine release assay using blood from 28 healthy human donors 
suggested that there is no substantial risk for cytokine release or peripheral 
immune-cell depletion upon first infusion with vanucizumab. 
In Study BP28179, 1 patient experienced Grade 2 IRR considered related to 
RO5520985. In addition, 36/115 patients (31.6%) reported events that occurred 
during RO5520985 infusion or within 24 hours after the end of infusion, were 
assessed as related to RO5520985 and after medical review might suggest signs 
and symptoms of IRR1: influenza-like illness, hypersensitivity, hypertension, chest 
pain, musculoskeletal pain, headache, abdominal pain, nausea, vomiting, asthenia, 
fatigue. In Study BP29262 (safety run-in), 1 patient experienced Grade 2 chills, 
suggestive of IRR. 
Bevacizumab and RO5520985 are to be administered in a controlled setting with 
emergency equipment and staff who have been trained in the management of 
IRRs.  Signs or symptoms of IRR may occur during or shortly after infusion.  If IRR 
occur, the infusion of RO5520985/bevacizumab should be temporarily slowed 
down or interrupted until resolution of symptoms and general standard of care 
should be applied.  Patients will be monitored until complete resolution of 
symptoms and treated as clinically indicated.   
5.2.1.13 
Immunogenicity 
RO5520985 is a recombinant bi-specific mAb with IgG-like properties, and as with 
mAb-based therapies, there exists a potential for development of human anti-
human antibodies (HAHAs) after treatment with RO5520985. The immunogenicity 
risk for RO5520985 will be assessed through plasma samples for detection of 
HAHA at baseline and during and after study treatment and in the event of a 
hypersensitivity reaction CTCAE ≥ Grade 3.  
For bevacizumab, post baseline HAHAs could be detected in less than 1% of 
patients not associated with allergic/hypersensitivity reactions.  
                                            
 
1 According to Protocol BP28179 adverse events should be captured as individual signs and 
symptoms on the Adverse Event eCRF rather than as a diagnosis of infusion-related reaction or 
allergic reaction. This required an additional analysis by the Sponsor to retrospectively identify IRRs 
by filtering on AEs occurring within 24 hours of infusion and drilling down to events of interest, i.e. 
AEs that were assessed as related to treatment with RO5520985 and suggestive of potential signs 
and symptoms of IRR. 


 
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In Study BP28179, 2/115 patients (1.7%) assessed developed HAHAs upon 
treatment with RO5520985. The onset was for one patient treated at 10 mg/kg QW 
after 4 cycles and for the other patient treated at 30 mg/kg QW after 12 cycles, in 
both cases without any associated clinical symptoms or modification in exposure. 
Potential safety concerns associated with mAb-based therapies also includes 
induction of immunogenicity.  The immunogenicity risk for RO5520985 will be 
assessed through plasma samples for detection of HAHA at baseline and during 
and after study treatment and in the event of a hypersensitivity reaction CTCAE 
≥ Grade 3. 
5.2.1.14 
Ovarian Failure 
In preclinical studies with RO5520985 in cynomolgus monkeys, pharmacology-
related findings included the absence of menses, evidenced by histologically 
inactive ovaries and serum hormone peaks in estradiol and progesterone. Inactive 
endometrium was noted which correlated with a lower uterine weight. 
Reversibility of these findings was noted by the end of the recovery phase in all 
treated females. 
In premenopausal women receiving bevacizumab in combination with mFOLFOX 
chemotherapy for adjuvant treatment for colorectal cancer, the incidence of 
ovarian failure was higher compared to those receiving mFOLFOX chemotherapy 
alone. 
In clinical trials with RO5520985, no events suggestive of ovarian failure have 
been reported in patients. 
5.2.1.15 
Peripheral Edema 
An increased incidence of peripheral edema has been observed in patients treated 
with angiopoietin-1 and -2 antagonist Fc fusion protein.  
In clinical trials with RO5520985 events of edema were reported in Study BP28179: 
22 events of peripheral edema in 19 patients (16.5%), 12 events of lymphedema in 
11 patients (9.6%), 5 events of edema in 4 patients (3.5%) and 1 event of localized 
edema (0.9%).  In the safety run-in of Study BP29262 there were 3 events of 
peripheral edema in 2/8 patients and 1 event of eyelid edema in another patient. 
All but one AE were non-serious. Two of the events were of Grade 3, the 
remaining events of Grade 1 or Grade 2. Fifteen patients had AEs that were 
assessed as related to treatment with RO5520985. 
5.2.1.16 
Pregnancy 
No studies assessing the reproductive and developmental toxicity of RO5520985 
have been conducted to date. It is not known whether RO5520985 can cross the 
placenta or cause harm to the fetus when administered to pregnant women or 


 
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whether it affects reproductive capacity.  However, IgG antibodies are known to 
cross the placental barrier, and angiogenesis has been shown to be critically 
important to fetal development.  In the post-marketing setting, cases of foetal 
abnormalities in women treated with bevacizumab alone or in combination with 
known embryotoxic chemotherapeutics have been observed.  Therefore, 
administration of RO5520985 /bevacizumab may inhibit angiogenesis in the fetus 
and and result in an adverse outcome of pregnancy.   
Therefore, RO5520985/bevacizumab should not be used during pregnancy.  Negative 
pregnancy tests and highly effective means of contraception are required for patients 
participating in trials with RO5520985.  
Based on the labeling for bevacizumab, contraceptive measures are 
recommended for at least 6 months following the last dose of RO5520985. 
Pregnancy occurring in the female partner of a man participating in the study 
should also be reported to the Investigator and the Sponsor.  
5.2.2 
Risks of 5-FU, Folinic Acid and Oxaliplatin  
Safety Profile of 5-FU/folinic acid 
5-FU/folinic acid should be given with care to patients who are malnourished and to 
those who have a history of heart disease or hepatic or renal insufficiency.  The main 
toxicities of 5-FU are hematological toxicities, including neutropenia, thrombocytopenia, 
and anemia; and GI toxicities, including diarrhea, stomatitis, vomiting, and GI ulceration.  
GI toxicities may be exacerbated by leucovorin administration.  In addition, 5-FU has 
been associated with ocular toxicity, including corneal epithelia erosion and excessive 
lacrimation; hand-foot syndrome; allergic reactions; central neurological toxicity, 
including acute cerebellar syndrome and nystagmus; and, rarely, cardiotoxicity, including 
arrhythmias, myocardial ischemia, and angina.  Patients with a known dihydropyrimidine 
dehydrogenase deficiency or thymidylate synthase gene polymorphism who may be 
predisposed to 5-FU toxicity will be excluded.  5-FU may interact with warfarin. Patients 
should avoid prolonged exposure to sunlight because of the risk of photosensitivity 
during treatment with 5-FU. For a full safety profile of 5-FU, please refer to 5-Fluorouracil 
full prescribing information.  
Folinic acid may enhance toxicities associated with 5-FU.  For a full safety profile of 
folinic acid (e.g. Leucovorin), refer to full prescribing information of folinic acid.   
Individual patients may be switched to oral capecitabine during maintenance treatment. 
For respective toxicity information and guidelines refer to Section 5.2.3.  
Safety Profile of Oxaliplatin 
In prior clinical trials of oxaliplatin, the following safety signals were identified: sensory 
and/or motor neuropathy, allergic reactions, pharyngolaryngeal dysesthesia, interstitial 
lung disease/pulmonary fibrosis, hepatotoxicity, and hematologic toxicity.  


 
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Peripheral neuropathy has not been observed to date with single-agent RO5520985.  All 
patients must have been recovered from reversible adverse events of previous medical 
therapies, except alopecia prior study entry.  Patients will be monitored throughout the 
study for new peripheral neuropathy through assessment of adverse events and physical 
examinations.  Modifications of oxaliplatin administration in response to neuropathy are 
described in Section 5.2.3.3.  
For more details regarding the safety profile of oxaliplatin, refer to oxaliplatin 
(e.g., Eloxatin®) full prescribing information. 
5.2.3 
Toxicity Management Guideline  
5.2.3.1 
General Notes 
Reasons for dose modifications or delays, the supportive measures taken, 
and the outcome will be documented in the patient's chart and recorded in the eCRF.  
The severity of adverse events will be graded according to the NCI CTCAE v4.03 
grading system. 
• 
For any concomitant conditions already apparent at baseline, the dose modifications 
will apply according to the corresponding shift in toxicity grade, if the Investigator 
feels it is appropriate.  For example, if a patient has Grade 1 asthenia at baseline 
that increases to Grade 2 during treatment, this will be considered a shift of one 
grade and treated as Grade 1 toxicity for dose-modification purposes. 
• 
For toxicities that are considered by the Investigator to be unlikely to develop into 
serious or life-threatening events, treatment will be continued at the same dose 
without reduction or interruption.   
• 
In the absence of progressive disease, any delay or discontinuation of 
chemotherapy or biological therapy does not affect continuation of the other 
component(s) of study treatment.  
Oxaliplatin should be administered during Induction therapy for up to 8 Cycles 
but can be discontinued earlier in case of unacceptable toxicity. 
Bevacizumab and RO5520985 should be continued to progression 
or unacceptable toxicity for a maximum of 24 months (calculated from start of 
maintenance therapy) in patients who have discontinued their course of 
chemotherapy due to intolerable toxicity.  
Patients should continue 5-FU/leucovorin to intolerable toxicity or for a 
maximum of 24 months (calculated from start of maintenance therapy) in the 
event that they cannot tolerate bevacizumab/RO5520985. 
The doses of bevacizumab/RO5520985 will not be reduced or modified.   
Dose adjustments of bevacizumab for body weight changes are not required. 
• 
Where several toxicities with different grades or severity occur at the same time, the 
dose modifications should be according to the highest grade observed. 


 
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• 
If, in the opinion of the Investigator, a toxicity is considered to be due solely to one 
chemotherapy drug, the dose of the other chemotherapy drug does not require 
modification. 
• 
No dose reductions or interruptions will be required for anemia (non-hemolytic) 
because it can be satisfactorily managed per treating physician’s 
institutional guidelines. 
• 
When a treatment cycle is temporarily interrupted because of toxicity caused by 
bevacizumab/RO5520985 and/or the chemotherapy regimen, the treatment cycles 
will be re-started such that bevacizumab/RO5520985 infusions remain synchronized 
with the chemotherapy.  
• 
If it is anticipated that chemotherapy will be delayed by ≥ 2 weeks, then 
bevacizumab/RO5520985 should be given without the chemotherapy if there is no 
contraindication 
 
5.2.3.2 
Guidelines for Toxicity Management of Bevacizumab and 
RO5520985 
Table 2  below provides a guideline how to manage certain toxicities, which are 
expected due to class-labeling for anti-VEGF molecules on the market including 
bevacizumab and on the basis of the Phase I study for RO5520985 (Study BP28179). 
Temporary suspension of treatment with bevacizumab/RO5520985 must occur if a 
patient experiences a serious adverse event or Grade 3 or 4 nonserious adverse event 
that is  
1) Not addressed by Table 2  
and  
2) Assessed by the Investigator as related to bevacizumab/RO5520985.   
If the event resolves to Grade ≤ 1 within or equal to 42 days, bevacizumab/RO5520985 
may be restarted at the same dose level.  If bevacizumab/RO5520985 is delayed for 
> 42 days due to toxicity, the patient must be permanently discontinued from 
bevacizumab/RO5520985 therapy.   
It should be noted that the 42-day window for resolution of toxicity begins on the day that 
the decision is made to delay a scheduled administration of bevacizumab/RO5520985 
and not on the day that the study drugs were most recently administered. 
The appropriate interval between the last dose of bevacizumab/RO5520985 and major 
surgery is unknown.  The half-life of bevacizumab and RO5520985 is approximately 21 
and 9 days, respectively. For the purpose of the blinded study elective surgery should be 
delayed whenever possible, but if necessary, bevacizumab/RO5520985 should be held 
for at least 28 days prior to the procedure.  Re-initiation of bevacizumab/RO5520985 
following surgery should not occur for at least 28 days and until wounds have fully 


 
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healed.  Re-initiation of bevacizumab/ RO5520985 after surgery requires documented 
approval from the Medical Monitor. 
The site should advice their study patients to immediately contact the Investigator 
in case they experience clinical symptoms suggestive of intestinal sub-
/occlusion/intestinal obstruction or GI-perforation such as acute, persisting and/or 
increasing abdominal pain, nausea and vomiting, etc. in order to initiate the 
appropriate diagnostic (incl. physical examination, laboratory tests and abdominal 
imaging) and therapeutic (incl. non-/surgical procedures) measures for this 
condition. It is also recommended to perform endoscopic evaluation in any patient 
during treatment with RO5520985/bevacizumab upon presentation with symptoms 
that may be related to a GI ulcer.  
 


 
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Table 2 
Toxicity Management Guideline for Bevacizumab and RO5520985 
Dose Management for Adverse Events 
Event 
Action to Be Taken 
Hypertension  
Grade 1 or 2 
No study treatment modifications 
Grade 3 
If not controlled to 150/100 mmHg by medication within 14 days, discontinue bevacizumab/RO5520985 
Grade 4  
(including hypertensive 
encephalopathy) 
Discontinue bevacizumab/RO5520985 
Hemorrhage  
Grade 1 or 2 non-pulmonary or 
non-CNS events 
No study treatment modifications 
Grade 3 non-pulmonary or 
non-brain or non-spinal cord 
hemorrhage 
Patients will have bevacizumab/RO5520985, and chemotherapy held until all of the following criteria are met: 
• The bleeding has resolved and hemoglobin is stable within 14 days after onset 
• There is no bleeding diathesis that would increase the risk of therapy 
• There is no anatomic or pathologic condition that significantly increases the risk of hemorrhage recurrence 
Patients who experience a repeat Grade 3 hemorrhagic event will be discontinued from bevacizumab/RO5520985 
Grade 4 non-pulmonary or 
non-brain or non-spinal cord 
hemorrhage 
Discontinue bevacizumab/RO5520985 
Grade 1 pulmonary or brain or 
spinal cord hemorrhage 
Patients will have bevacizumab/RO5520985, and chemotherapy held until all of the following criteria are met: 
• The bleeding has resolved and hemoglobin is stable within 14 days after onset 
• There is no bleeding diathesis that would increase the risk of therapy 
• There is no anatomic or pathologic condition that significantly increases the risk of hemorrhage recurrence 
Grade 2, 3, or 4 pulmonary or 
brain or spinal cord 
hemorrhage 
Discontinue bevacizumab/RO5520985 


 
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Table 2 
Toxicity Management Guideline for Bevacizumab and RO5520985 (cont.) 
Venous thromboembolic event  
 
Grade 1 or 2 not requiring 
full−dose anti-coagulation 
No study treatment modifications 
Grade 2 or 3, requiring 
full−dose anti-coagulation 
≤14 days 
If duration of full-dose anticoagulation is ≤14 days , bevacizumab/RO5520985, and chemotherapy should be held until the 
full-dose anticoagulation period is over.   
 
Grade 3, requiring full-dose 
anti-coagulation >14 days 
 
 
 
 
Grade 4 
 
If the planned duration of full-dose anticoagulation is > 2 weeks, bevacizumab/RO5520985 and chemotherapy 
may be resumed after 2 weeks of full-dose anticoagulation if all of the following criteria are met: 
• 
LMWH or other anticoagulant dosing must be stable prior to restarting study treatment.   
• 
The patient must not have had a Grade 3 or 4 hemorrhagic event while on anticoagulation.  
 
Discontinue bevacizumab/RO5520985 
Arterial thromboembolic event  
(New onset, worsening, or unstable 
angina, myocardial infarction, 
transient ischemic attack, 
cerebrovascular accident, and any other 
arterial thromboembolic event) 
 
≥ Grad 3 
Discontinue bevacizumab/RO5520985 
Thrombotic microangiopathy  
(A pathological process of microvascular 
thrombosis, consumptive 
thrombocytopenia and microangiopathic 
haemolytic anaemia leading to end-
organ ischaemia and infarction) 
 
Any Grade 
Discontinue bevacizumab/RO5520985 
 
 


 
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Table 2 
Toxicity Management Guideline for Bevacizumab and RO5520985 (cont.) 
Left ventricular systolic 
dysfunction/ Congestive heart 
failure 
 
Grade 1 or 2 
No study treatment modifications 
Grade ≥ 3 
Discontinue bevacizumab/RO5520985 


 
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Table 2 
Toxicity Management Guideline for Bevacizumab and RO5520985 (cont.) 
Proteinuria 
 
Grade 1 (urine dipstick 1 + or 
urine collection 0.15 to 
1.0 g/24 hrs) 
No study treatment modifications 
Grade 2 (urine dipstick 2 +  to 
3 +  or urine collection > 1.0 to 
3.5 g/24 hrs) 
For 2 +  dipstick, may administer bevacizumab/RO5520985 and obtain 24-hrs urine prior to next dose of 
bevacizumab/RO5520985. 
For 3 +  dipstick, obtain 24-hrs urine prior to administration of bevacizumab/RO5520985. Hold bevacizumab/RO5520985 
treatment for proteinuria ≥ 2 g/24 hrs and resume when proteinuria is < 2 g/24 hrs a 
Grade 3  
(urine dipstick 4 + or urine 
collection > 3.5 g/24 hrs)  
Hold bevacizumab/RO5520985 treatment.  Resume when proteinuria is < 2 g/24 hrs a 
Grade 4  
(nephrotic syndrome) 
Discontinue bevacizumab/RO5520985  
GI perforation 
 
Any grade 
Discontinue bevacizumab/RO5520985 
Fistula  
 
Any grade fistula involving an 
internal organ 
Discontinue bevacizumab/RO5520985 
Confirmed sub occlusive/occlusive syndrome/intestinal obstruction (Ileus)  
Any grade  
Discontinue bevacizumab/RO5520985 
Wound healingcomplication  
 
Grade 1 or 2 
No study treatment modifications 
Grade 3, requiring surgical 
intervention 
Discontinue bevacizumab/RO5520985 
 
Grade 4 
Discontinue bevacizumab/RO5520985 
GI-ulcer 
 
Grade 1 or 2 
Withold study drug treatment with bevacizumab/RO5520985. Resume when ulcer resolves to Grade 0. 


 
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Table 2 
Toxicity Management Guideline for Bevacizumab and RO5520985 (cont.) 
Grade ≥ 3 
Discontinue bevacizumab/RO5520985 
Entero-/Colitis 
 
Grade 1 
No study treatment modifications 
Grade 2 and 3 
Withold study drug treatment with bevacizumab/RO5520985. Resume when colitis improves to Grade 0 or 1 
Grade 4 
Discontinue bevacizumab/RO5520985 


 
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Table 2 
Toxicity Management Guideline for Bevacizumab and RO5520985 (cont.) 
Posterior reversible 
encephalopathy syndrome 
 
Any grade 
(confirmed by MRI) 
Discontinue bevacizumab/RO5520985 
Infusion-related reaction (IRR) 
If an IRR develops, the infusion of RO5520985/bevacizumab should be temporarily slowed down or interrupted. The 
patient should be monitored until complete resolution of the symptoms and treated as clinically indicated. Treatment or 
concomitant medication may include acetaminophen/ paracetamol, antihistamine, IV saline, oxygen, bronchodilators, 
corticosteroids and vasopressors depending on the symptoms. 
If the infusion is interrupted: 
• In the event of IRR CTCAE Grade 1, upon resolution of symptoms, the infusion will resume at the same rate (the rate 
being used at the time that the IRR occurred) 
• In the event of IRR CTCAE Grade 2, upon resolution of symptoms, the infusion will resume at one-half the previous 
rate.  
• In the event of IRR CTCAE Grade 3 or CTCAE Grade 4 (which may include pulmonary or cardiac events) or an 
anaphylactic reaction, the infusion must be stopped and the patient should receive aggressive treatment.  Patients 
experiencing IRR CTCAE Grade 4 must be permanently discontinued from study drug treatment. 
For patients who already experienced IRR CTCAE ≥ Grade 2, the infusion rate for all subsequent 
RO5520985/bevacizumab infusion, should be reduced at one-half of the previous rate and premedication may be given 
30 minutes prior to infusion including: 
• Paracetamol (500−1000 mg) 
• H1-receptor antagonist e.g., diphenhydramine (25−50 mg PO or IV) or an alternative anti-histamine at an adequate 
dose 
• Hydrocortisone (200 mg IV) or equivalent dose of another corticosteroid as clinically indicated 
• H2-receptor antagonist (e.g., ranitidine; cimetidine) as clinically indicated 
CNS = central nervous system; GI = gastrointestinal; INR = international normalized ratio; IRR = infusion-related reaction; IV = intravenous; 
LMWH = low molecular weight heparin; MRI = magnetic resonance imaging; PO = per os/by mouth. 
a All proteinuria values are from 24-hour urine. 


 
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5.2.3.3 
Guidelines for Toxicity Management of FOLFOX 
Dose modifications listed below are guidelines for the management of 
chemotherapy−specific toxicities.  The treating physician may use discretion in modifying 
or accelerating the dose modification guidelines described below, depending upon the 
severity of toxicity and an assessment of the risk versus benefit for the patient with the 
goal of maximizing patient compliance and access to supportive care. 
If oxaliplatin treatment is discontinued, patients are encouraged to continue 
chemotherapy with 5-FU/folinic acid + bevacizumab/RO5520985.  Then, if 5-FU/folinic 
acid are discontinued, patients should continue to take bevacizumab/RO5520985 
treatment until documented progressive disease or unacceptable toxicity for a maximum 
of 24 months. 
Patients who experience chemotherapy-related toxicities < Grade 3 that are intolerable 
may discontinue chemotherapy treatment at the discretion of the Investigator.  For these 
patients, RO5520985 and bevacizumab should continue.   
Once chemotherapy is discontinued completely, it cannot be restarted.  All patients will 
continue protocol-specified tumor assessments until documented progressive disease 
and will then have follow-up assessments for OS and subsequent anticancer therapy. 
Dose adjustments at the start of each 14-day cycle will be based on nadir hematologic 
counts or maximum nonhematologic toxicity from the preceding cycle of therapy.  Once 
a dose reduction is made, the dose will not be re-escalated during subsequent cycles 
(Table 3 for chemotherapy dose reduction levels). 
Patients who require reductions below the −2 dose level should be discontinued from 
that chemotherapy agent. If the recommended action below in response to a specific 
toxicity is not applicable (e.g., oxaliplatin was previously discontinued), the action 
recommended for the next occurrence of that toxicity should be followed.  
Table 3 
FOLFOX Dose Adjustment 
 
 
Oxaliplatin 
5-FU Bolus 
5-FU Infusion 
Starting Dose mg/m2 
85 
400 
2400 
−1 Dose Level mg/m2 
65 
0 
2000 
−2 Dose Level mg/m2 
50 
0 
1600 
FU = 5-fluorouracil. 
 
Modifications for Hematologic Toxicity 
Investigators should be vigilant and alert to early and overt signs of myelosuppression, 
infection, or febrile neutropenia so that these complications can be promptly and 
appropriately managed.  Patients should be made aware of these signs and encouraged 


 
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to seek medical attention at the earliest opportunity.  Colony stimulating factors may be 
used as detailed in Section 4.5.1.  
Chemotherapy treatment should not be administered until ANC ≥ 1000/μL and platelets 
≥ 75,000/μL. 
For Grade 4 neutropenia or febrile neutropenia, Grade 4 thrombocytopenia, Grade 3 
thrombocytopenia with bleeding, or a >2 week dose delay due to prolonged ANC or 
platelet recovery (to ANC ≥ 1000/μL and platelets ≥ 75,000/μL): 
• 
First occurrence:  Omit the bolus dose of 5-FU permanently and reduce infusional 
5-FU and oxaliplatin by one dose level each for subsequent cycles 
• 
Second occurrence:  Reduce infusional 5-FU and oxaliplatin by an additional dose 
level each for subsequent cycles 
• 
Third occurrence:  Discontinue chemotherapy, continue bevacizumab/ RO5520985 
 
For the first occurrence of Grade 3 neutropenia without fever or Grade 3 
thrombocytopenia without bleeding, the 5-FU bolus should be omitted permanently. If 
hematologic toxicity recurs, consideration should be given to reducing the doses 
of infusional 5-FU and oxaliplatin for subsequent cycles. 
Chemotherapy should be discontinued if ANC and platelets do not recover to ≥ 1000/μL 
and ≥ 75,000/μL, respectively, after treatment is delayed by 3 weeks. 
Modifications for Oxaliplatin-Induced Neurotoxicity  
For neuropathy (sensory, motor, or cranial neuropathy, as graded per Table 4) attributed 
to oxaliplatin dose modifications should be carried out as follows: 
• 
For Grade 1 neuropathy at the time of planned re-treatment:  continue planned 
treatment.  
• 
For Grade 2 neuropathy at the time of planned re-treatment or Grade 3 at any time: 
First occurrence:  Withhold oxaliplatin until symptoms resolve (up to 2 weeks) to 
Grade ≤ 1 and then reduce the dose of oxaliplatin 1 dose level 
Second occurrence:  Withhold oxaliplatin until symptoms resolve (up to 2 weeks) 
to Grade ≤ 1 and then reduce the dose of oxaliplatin 1 dose level 
Third occurrence, requirement to reduce oxaliplatin dose below −2 dose level or 
failure to resolve to Grade 1 within 2 weeks:  Discontinue oxaliplatin  
• 
For Grade 4 neuropathy occurring at any time, discontinue oxaliplatin therapy. 


 
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Table 4 
Adverse Event Grading for Neuropathy 
 
Grade 
Description 
1 
Asymptomatic; loss of deep tendon reflexes or paresthesia  
2 
Moderate symptoms; limiting instrumental ADL 
3 
Severe symptoms; limiting self-care ADL 
4 
Life-threatening consequences; urgent intervention indicated 
5 
Death  
ADL = activities of daily living.  
Source:  National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0. 
 
If pseudolaryngopharyngeal dysesthesia occurs, subsequent doses of oxaliplatin may be 
administered as a 6-hour infusion, and folinic acid should be administered during the last 
2 hours of infusion. 
Modifications for Other Nonhematologic Toxicity 
For other Grade 3 or 4 or persistent intolerable Grade 2 nonhematologic toxicity (e.g., 
fatigue, diarrhea, hand-foot syndrome, hepatic toxicity, respiratory symptoms, etc.) 
attributed to chemotherapy, chemotherapy can be held until adverse event resolution 
(Grade ≤ 1) for up to a maximum of 4 weeks.   
• 
First occurrence: omit the bolus dose of 5-FU permanently, reduce the 5-FU 
infusional dose 1 dose level and/or reduce oxaliplatin 1 dose level for subsequent 
cycles 
• 
Second occurrence of Grade 4 toxicity: discontinue the chemotherapy regimen, 
continue bevacizumab/RO5520985 
• 
Second and third occurrences of Grade 3 or intolerable Grade 2 toxicity: if indicated 
reduce the 5-FU infusional dose 1 dose level and/or reduce oxaliplatin 1 dose level 
for subsequent cycles 
• 
Fourth occurrence of Grade 3 or intolerable Grade 2 toxicity: discontinue 
the chemotherapy regimen, continue bevacizumab/RO5520985 
 
No dose reduction should be made for Grade 1 and 2 toxicities, except for those 
considered intolerable to the patient due to prolonged duration or adverse effects on 
quality of life. 
When oxaliplatin is discontinued (i.e., post Cycle 8 or due to toxicity), 5-FU and folinic 
acid should be continued to disease progression or intolerable toxicity. Oxaliplatin should 
not be restarted after being discontinued on this study. 
Any contraindications and special warnings and precautions for the use of FOLFOX 
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prescribing information of 5-FU and oxaliplatin are contraindicated in patients receiving 
5-FU and oxaliplatin. 
Patients may be premedicated with 5-HT3 receptor antagonists or other standard of care 
methods to control nausea and vomiting.  For symptoms of diarrhea and/or abdominal 
cramping, patients should be instructed to begin taking loperamide 2 mg orally at the 
time of the first liquid stool and continue 2 mg approximately every 2 hours until at least 
12 hours after the last liquid stool, with oral rehydration. Calcium and magnesium salts 
may be administered to patients with acute symptomatic neurotoxicity at the discretion of 
the treating physician. 
Other Toxicity 
For any Grade 3 or 4 toxicity not mentioned above, the treatment should be withheld 
until the patient recovers completely or to Grade 1 toxicity for up to a maximum of 
4 weeks.  
5.2.3.4 
Guidelines for Toxicity Management of Capecitabine (Xeloda®) 
During induction phase substitution of 5-FU/folinic acid is not permitted.  During the 
maintenance phase substitution of 5-FU/folinic acid IV by oral capecitabine is 
discouraged.  However, individual patients may receive capecitabine without folinic acid 
according to institutional standards (e.g., 625 mg/m2 bid continuously) at the discretion 
of the Investigator and in agreement with the Sponsor’s medical monitor. 
Patients treated with capecitabine should be carefully monitored for toxicity.  Most 
adverse events are reversible and do not require permanent discontinuation of therapy, 
although doses may have to be withheld or reduced.  Most common adverse reactions 
(≥ 30%) were diarrhea, hand-and-foot syndrome, nausea, vomiting, abdominal pain, 
fatigue/weakness, and hyperbilirubinemia. 
Toxicity due to capecitabine administration may be managed by symptomatic treatment 
and/or modification of the capecitabine dose (treatment interruption or dose reduction).  
Once the dose has been reduced it should not be increased at a later time.  
For those toxicities considered by the treating physician to be unlikely to become serious 
or life-threatening treatment can be continued at the same dose without reduction or 
interruption.  Patients taking capecitabine should be informed of the need to interrupt 
treatment immediately if moderate or severe toxicity occurs.  Doses of capecitabine 
omitted for toxicity are not replaced.  Table 5 shows the recommended dose 
modifications following toxicity related to capecitabine. 


 
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Table 5 
Recommended Dose Modifications of Capecitabine  
Grade a 
Dose changes within a treatment cycle 
Dose adjustment for 
next cycle 
(% of starting dose) 
Grade 1 
Maintain dose level 
Maintain dose level 
Grade 2 
 
 
1st appearance 
100% 
2nd appearance 
75% 
3rd appearance 
 
Interrupt until resolved to Grade 0 - 1  
50% 
4th appearance 
Discontinue treatment permanently 
Not applicable 
Grade 3 
 
 
1st appearance 
75% 
2nd appearance 
Interrupt until resolved to Grade 0−1 
 
50% 
3rd appearance 
Discontinue treatment permanently 
Not applicable 
Grade 4 
 
 
1st appearance 
Discontinue permanently 
or 
If physician deems it to be in the 
patient’s best interest to continue, 
interrupt until resolved to Grade 0−1 
50% 
2nd appearance 
Discontinue permanently 
Not applicable 
a According to the National Cancer Institute of Canada Clinical Trial Group (NCIC CTG) Common Toxicity Criteria 
(version 1) or the Common Terminology Criteria for Adverse Events (CTCAE) of the Cancer Therapy Evaluation 
Program, US National Cancer Institute, version 3.0.  
 
Please note the following warnings and precautions associated with capecitabine: 
• 
Diarrhea:  May be severe. Interrupt capecitabine treatment immediately until 
diarrhea resolves or decreases to Grade 1.  Recommend standard anti-diarrheal 
treatments.  
• 
Dehydration: Dehydration should be prevented or corrected at the onset.  Patients 
with anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become 
dehydrated.  If Grade 2 (or higher) dehydration occurs, capecitabine treatment 
should be immediately interrupted and the dehydration corrected.  Treatment should 
not be restarted until the patient is rehydrated and any precipitating causes have 
been corrected or controlled. 
• 
Hand-and-Foot Syndrome (Grade 2 or 3):  Interrupt capecitabine treatment until the 
event resolves or decreases in intensity.  
• 
Hyperbilirubinemia (Grade 2−4):  Interrupt capecitabine treatment immediately until 
the hyperbilirubinemia resolves or decreases in intensity.  


 
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• 
Severe skin reactions:  Capecitabine should be permanently discontinued in 
patients who experience a severe skin reaction possibly attributable to capecitabine 
treatment.  
• 
Hematologic:  Do not treat patients with neutrophil counts <1.5 x 109/L or 
thrombocyte counts <100 x 109/L.  If Grade 3−4 neutropenia or thrombocytopenia 
occurs, stop therapy until condition resolves. 
For more details regarding the safety profile ofpecitabine, refer to full prescribing 
information of Capecitabine (Xeloda®). 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (Section 5.2.1.16 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 adverse event recorded on the Adverse Event eCRF, the Investigator will make 
an assessment of seriousness (Section 5.1.2 for seriousness criteria), severity 
(Section 5.3.3), and causality (Section 5.3.4).  
5.3.1 
Adverse Event/Serious Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record.  Adverse events will then be reported on the 
Adverse Event eCRF as follows: 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported 
(e.g., serious adverse events related to invasive procedures such as biopsies).  Any 
other adverse event should not be reported. 
After initiation of study drug, all adverse events/serious adverse events, regardless of 
relationship to study drug, will be reported until 28 days after the last dose of study drug. 
After a period of 28 days from the last dose of study drug, Investigators should report 
any deaths, serious adverse events, or other adverse events of concern that are 
believed to be related to prior treatment with study drug (Section 5.5).   
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of nondirective 
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?” 


 
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5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v4.03) will be used for 
assessing adverse event severity.  Table 6 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 6 
Adverse Event Severity Grading Scale 
 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note: Based on the NCI CTCAE (v4.03), which can be found at: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-
06-14_QuickReference_8.5x11.pdf 
 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, feeding one's self, using the 
toilet, and taking medications, as performed by patients who are not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious adverse event 
(Section 5.3.7 for reporting instructions), per the definition of serious adverse event in Section 5.1.2. 
d Grade 4 and 5 events must be reported as serious adverse events (Section 5.3.7 for reporting instructions), per the 
definition of serious adverse event in Section 5.1.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly.  The following guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug  
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
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• 
Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event 
For patient 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 adverse 
events on the Adverse Event eCRF. Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Diagnosis versus Signs and Symptoms 
Infusion-Related Reactions 
Adverse events that occur during or within 24 hours after study drug infusion and are 
judged to be related to study drug infusion should be captured as a diagnosis (e.g. 
infusion related reaction or anaphylactic reaction as appropriate),  on the Adverse 
Event eCRF. In addition the individual signs and symptoms should be reported on 
the comment section of the Adverse Event eCRF.  
Other Adverse Events  
For adverse events, 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 characterized 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 subsequently established, all previously 
reported adverse events based on signs and symptoms should be nullified and replaced 
by one adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis. 
5.3.5.2 
Adverse Events Occurring Secondary to Other Events 
In general, adverse events occurring 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.  However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events 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 hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 


 
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• 
If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF. 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity of the event should be recorded, and the 
severity should be updated to reflect the most extreme severity any time the event 
worsens. If the event becomes serious, the Adverse Event eCRF should be updated to 
reflect this. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs. Each recurrence of an adverse event should be recorded 
separately on the Adverse Event eCRF. 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result 
should be reported as an adverse event 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 (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 adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., 
alkaline phosphatase and bilirubin 5 times the upper limit of normal (ULN) associated 
with cholecystitis), only the diagnosis (i.e., cholecystitis) 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 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia”. 


 
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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. 
5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result should 
be reported as an adverse event 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 adverse event. 
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 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 Liver Function Tests 
Patients who have Liver Metastases 
For patients who have liver metastases, the conditions set out below apply. 
The finding of an elevated ALT or AST (> 5 × 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.  
Therefore, Investigators must report as an adverse event the occurrence of either of the 
following: 
• 
Treatment-emergent ALT or AST > 5 × baseline value in combination with total 
bilirubin > 2 × ULN (of which 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST >  5 × baseline value in combination with clinical 
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Patients who do not have Liver Metastases 
For patients who do not have liver metastases, the conditions set out below apply. 
The finding of an elevated ALT or AST (>  3 × ULN) 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.  
Therefore, Investigators must report as an adverse event the occurrence of either of the 
following: 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
• 
Treatment-emergent ALT or AST > 3 × ULN 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 (Section 5.3.5.1) and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event), either as a serious adverse event or a non-serious adverse event of special 
interest (Section 5.3.7). 
5.3.5.7 
Deaths 
For this protocol, mortality is an efficacy endpoint. Deaths that occur during the protocol‑
specified adverse event reporting period (Section 5.3.5.7) that are attributed by the 
Investigator solely to progression of CRC should be recorded only on the End of Study 
Visit 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 
(Section 5.3.5.7).  
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 only be used for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a patient with or without 
preexisting heart disease, within 1 hour of 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 post-study survival follow-up, deaths attributed to progression of CRC should be 
recorded only on the Disease and Survival Folllow-up eCRF. 
5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the General Medical History eCRF. 


 
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A preexisting medical condition should be recorded as an adverse event 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 preexisting condition has changed by including applicable descriptors (e.g., 
“more frequent headaches”). 
5.3.5.9 
Lack of Efficacy or Worsening of Colorectal Cancer 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  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 criteria.  In rare cases, the determination of 
clinical progression will be based on symptomatic deterioration.  However, every effort 
should be made to document progression using objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event. 
5.3.5.10 
Hospitalization or Prolonged Hospitalization  
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious 
adverse event in Section 5.1.2), except as outlined below. 
The following hospitalization scenarios are not considered to be serious adverse events: 
• 
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 preexisting 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 suffered an adverse event 
• 
Hospitalization due solely to progression of the underlying cancer 
• 
Hospitalization due to secondary resection 
 
5.3.5.11 
Overdoses 
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied. An overdose or incorrect administration of study drug is not 
an adverse event unless it results in untoward medical effects. 
Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration eCRF. 


 
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All adverse events associated with an overdose or incorrect administration of study drug 
should be recorded on the Adverse Event eCRF. If the associated adverse event fulfills 
serious criteria, the event should be reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; Section 5.3.7 and Section 5.4). 
5.3.6 
Emergency Medical Contacts 
To ensure the safety of study patients, an Emergency Medical Call Center 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 
Responsible, and track all calls. The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week. Toll-free numbers for the Help Desk and 
Medical Responsible contact information will be distributed to all Investigators ("Protocol 
Administrative and Contact Information & List of Investigators"). 
5.3.7 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
For reports of serious adverse events (Sections 5.1.2 and 5.3.7), Investigators should 
record all case details that can be gathered on the Serious Adverse Reporting Form and 
forward this form to the SAE Responsible within 24 hours. 
The study will comply with all local regulatory requirements and adhere to the full 
requirements of the ICH Guideline for Clinical Safety Data Management, Definitions and 
Standards for Expedited Reporting, Topic E2 will be adhered to (Appendix 7). 
5.3.8 
Reporting Requirements for Pregnancies 
5.3.8.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
Investigator if they become pregnant during the study or within 6 months after the last 
dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed by 
the Investigator and submitted to the sponsor within 24 hours after learning of the 
pregnancy.  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. 
5.3.8.2 
Pregnancies in Female Partners of a Male Patient 
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 by the Investigator and submitted to the sponsor within 24 hours 
after learning of the pregnancy.  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. 


 
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Once the authorization has been signed, the Investigator will update the Clinical Trial 
Pregnancy Reporting Form with additional information on the course and outcome of the 
pregnancy.  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. 
5.3.8.3 
Abortions 
Any spontaneous abortion should be classified as a serious adverse event (as the 
Sponsor considers spontaneous abortions to be medically significant events), recorded 
on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; Section 5.3.7).  
5.3.8.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient or female partner 
of a male patient exposed to study drug should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; Section 5.3.7). 
5.4 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.4.1 
Investigator Follow-Up 
The Investigator should follow each adverse event 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 serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (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 
and reported according to the instructions provided in Section 5.3.8. 
5.4.2 
Sponsor Follow-Up 
For serious adverse events and pregnancies, the Sponsor or a designee may follow up 
by telephone, fax, electronic mail, and/or a monitoring visit to obtain additional case 
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. 


 
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5.5 
POST-STUDY ADVERSE EVENTS 
At the study completion/early termination visit, the Investigator should instruct each 
patient to report to the investigator any subsequent adverse events 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 adverse events after the 
end of the adverse event reporting period (defined as 28 days after the last dose of 
study drug).  However, the Sponsor should be notified if the Investigator becomes aware 
of any death, other serious adverse event occurring after the end of the adverse event 
reporting period, if the event is believed to be related to prior study drug 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 patient that participated in this study. 
The Investigator should report these events to Roche Safety Risk Management on the 
Adverse Event eCRF. If the Adverse Event eCRF is no longer available, the Investigator 
should report the event directly to Roche Safety Risk Management via telephone 
("Protocol Administrative and Contact Information & List of Investigators"). 
During post-study survival follow-up, deaths attributed to progression of CRC should be 
recorded only on the Survival eCRF. 
5.6 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events 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 adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents: 
• 
RO5520985: Investigator's Brochure; DSCI 
• 
Local prescribing information for bevacizumab,  
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. 
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 


 
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6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The data will be analyzed by the Sponsor and/or designated CRO.  Any data analysis 
carried out independently by the Investigator should be submitted to the Sponsor before 
publication or presentation.  The data will be summarized with respect to demographic 
and baseline characteristics, efficacy, safety,  pharmacokinetics and biomarkers 
observations and measurements.  The core analysis will be based on all patients data 
up to the time when approximatelly 80 events (PFS) have been observed in Part II of the 
study.  The additional data for any patient continuing to receive study treatment past this 
time, as allowed by the protocol, will be further summarized in subsequent extension 
report once the study is terminated. 
6.1 
DETERMINATION OF SAMPLE SIZE 
This Phase II trial is designed to make a preliminary evaluation of the efficacy and safety 
of RO5520985 plus mFOLFOX-6 versus bevacizumab plus mFOLFOX-6 in patients with 
previously untreated mCRC.  
Within Part I, 6 -18 patients will be treated with RO5520985 plus mFOLFOX-6.  Six 
patients per RO5520985 dose to be tested is considered sufficient to assess the safety 
and tolerability of RO5520985 in combination with mFOLFOX-6.  
Part II of the study will enroll approximately 190 patients, and the primary analysis will be 
performed after approximately 80 investigator assessed PFS events.  If the drop-out rate 
is higher than expected, additional patients might be enrolled to ensure sufficient data to 
evaluate the efficacy and safety profile of the investigational treatment. 
The emphasis of the efficacy analysis will be on estimation of the magnitude of treatment 
effect rather than hypothesis testing.  This trial is hypothesis-generating and is designed 
to be able to detect a meaningful benefit of the combination therapy of RO5520985 plus  
mFOLFOX-6 versus bevacizumab plus mFOLFOX-6.  Based on the sample size of 
80 events observed in the two treatment arms combined, there is an 80% power to 
detect a HR of 0.574 at a one-sided significance level of 0.05. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Descriptive statistics will be used in evaluating the conduct of the study.  Enrollment, 
study treatment administration, and discontinuations from the study will be summarized 
by part and treatment arm.  Listing of major protocol deviations will be produced. 
6.3 
ANALYSIS POPULATIONS 
6.3.1 
Safety Analysis Population 
The safety analysis population will include all patients (Part I and Part II) who receive 
any amount of study treatment (5-FU/folic acid, oxaliplatin, bevacizumab, or 
RO5520985).  Patients will be assigned to the treatment arm received.  


 
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6.3.2 
Pharmacokinetic Analysis Population 
PK analyses will include all patients who received any amount of study treatment 
(5-FU/folinic acid, oxaliplatin, bevacizumab, or RO5520985), the same as the safety 
analysis population.   
Patients may be excluded from the PK analysis population if they significantly violate the 
eligibility criteria, deviate significantly from the protocol or if data are unavailable or 
incomplete which may influence the pharmacokinetic analysis.  Excluded cases will be 
documented together with the reason for exclusion.  All decisions on exclusions from the 
analysis will be made prior to database closure. 
6.3.3 
Efficacy Analysis Population 
Primary and secondary efficacy analyses will be based on the intent to treat (ITT) 
population.  It will include all patients who were randomized (Part II only) and received 
any amount of study treatment (5-FU/folic acid, oxaliplatin, bevacizumab, or 
RO5520985).  Patients will be assigned to the treatment arm to which they were 
randomized.  
6.4 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic and baseline characteristics (e.g., age and sex) will be summarized using 
means, standard deviations, medians, and ranges for continuous variables and 
proportions for categorical variables, as appropriate.  Summaries will be presented by 
“overall” patient population and by treatment arm within each part. 
Exposure to study medications will be summarized by total duration of study medication, 
number of cycles started and cumulative dose using descriptive statistics.  Dose 
interruptions and their reasons will be presented by schedule and dose level. 
6.5 
SAFETY ANALYSES 
Safety analysis will be performed for all the patients in the safety analysis population.  All 
safety parameters will be analyzed using descriptive statistics, summarized and 
presented in tables.  
6.5.1 
Adverse Events 
The original terms recorded on the eCRF by the Investigator for adverse events will be 
standardized by the Sponsor.  Adverse events will be listed and summarized by mapped 
term and appropriate thesaurus level. 
6.5.2 
Clinical Laboratory Test Results 
All clinical laboratory data will be stored on the database in the units in which they were 
reported.  Patients listings and summary statistics at each assessment time will be 
presented using the International System of Units (SI units; Système International 


 
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d’Unités).  Laboratory data not reported in SI units will be converted to SI units before 
processing. 
Laboratory test values will be presented by individual listings with flagging of values 
outside the normal ranges. 
For laboratory data, summary tables of change from baseline over time based on SI 
(Standard International) units will be displayed.  Shifts in toxicity grade from baseline to 
the worst grade observed during treatment will be presented for selected laboratory 
parameters. Additional figures/tables/listings may be produced as deemed appropriate. 
6.5.2.1 
Standard Reference Ranges and Transformation of Data 
Roche standard reference ranges, rather than the reference ranges of the Investigator, 
will be used for all parameters.  For most parameters, the measured laboratory test 
result will be assessed directly using the Roche standard reference range.  Certain 
laboratory parameters will be transformed to Roche’s standard reference ranges. 
A transformation will be performed on certain laboratory tests that lack sufficiently 
common procedures and have a wide range of Investigator ranges (e.g., enzyme tests 
that include AST, ALT, and alkaline phosphatase and total bilirubin).  Since the standard 
reference ranges for these parameters have a lower limit of zero, only the upper limits of 
the ranges will be used in transforming the data. 
6.5.2.2 
Definition of Laboratory Abnormalities 
For all laboratory parameters included the local laboratory reference ranges will be used. 
In the event that the local laboratory does not have laboratory reference ranges, the 
Roche predefined standard reference range will be used.  Laboratory values falling 
outside this standard reference range will be labeled “H” for high or “L” for low in patient 
listings of laboratory data. 
In addition to the standard reference range, a marked reference range has been 
predefined by Roche for each laboratory parameter.  The marked reference range is 
broader than the standard reference range.  Values falling outside the marked reference 
range that also represent a defined change from baseline will be considered marked 
laboratory abnormalities (i.e., potentially clinically relevant).  If a baseline value is not 
available for a patient, the midpoint of the standard reference range will be used as the 
patient’s baseline value for the purposes of determining marked laboratory 
abnormalities.  Marked laboratory abnormalities will be labeled in the patient listings as 
“HH” for very high or “LL” for very low. 


 
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6.5.3 
Vital Signs 
Vital signs data will be presented by individual listings with flagging of values outside the 
normal ranges and flagging of marked abnormalities.  In addition, tabular summaries will 
be used, as appropriate.  Additional figures/tables/listings may be produced as deemed 
appropriate. 
6.5.4 
ECG Data Analysis 
ECG data will be presented by individual listings with flagging of values outside the 
normal ranges and flagging of marked abnormalities. In addition, tabular summaries will 
be used, as appropriate. 
6.5.5 
Concomitant Medications 
The original terms recorded on the patients’ eCRF by the Investigator for concomitant 
medications will be standardized by the sponsor by assigning preferred terms. 
Concomitant medications will be presented in summary tables and listings. 
6.6 
EFFICACY ANALYSES 
The primary analysis and secondary analysis will be based on the efficacy analysis 
population.  The core analysis will be based on all patients data up to the time when 
approximatelly 80 events (PFS) have been observed in Part II of the study.  The 
additional data for any patient continuing to receive study treatment past this time, as 
allowed by the protocol, will be further summarized in subsequent extension report once 
the study is terminated. 
6.6.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint of this study is PFS.  PFS is defined as the time between 
randomization and the date of first documented disease progression or death from any 
cause on study, whichever occurs first. Progression will be based on tumor assessment 
made by the Investigator according to RECIST 1.1 criteria (Appendix 8).  Death on study 
is defined as death from any cause within 30 days of the last study treatment. 
Patients without an event on study will be censored at the date of the last tumor 
assessment when the patient was known to be progression free either during follow up 
or during study treatment.  Patients without or unknown post baseline assessments but 
known to be alive will be censored at day of randomization plus 1. Kaplan-Meier 
methods will be used to estimate median PFS for each treatment arm.  The stratified 
Cox proportional hazard model will be used to estimate the hazard ratio (i.e., the 
magnitude of the treatment effect) and the corresponding 95% confidence interval.  The 
stratification factors are number of metastatic sites (1 vs.> 1) and country/region.  
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6.6.2 
Secondary Efficacy Endpoints 
Objective Response Rate (ORR) 
Objective response rate (ORR) is determined as the rate of patients with an objective 
tumor response (complete [CR] or partial response [PR]).  Objective response (OR) is 
defined as a complete or partial response as determined by the Investigator using 
RECIST v1.1 on two consecutive occasions at least 4 weeks apart.  Patients without a 
post-baseline tumor assessment will be regarded as nonresponders.  An estimate of the 
objective response rate and 95% confidence intervals (Casella 1986) will be calculated 
for each treatment arm. Confidence intervals for the difference in objective response rate 
will be calculated.   
Duration of Objective Response (OR) 
For patients with an OR, duration of OR is defined as the time from the initial response 
(CR or PR) to disease progression or death from any cause on study.  This will only be 
calculated for patients who have a best overall response of CR or PR.  Methods for 
handling censoring and for analysis are the same as those described for PFS.  No 
adjustments will be made to account for the non-random nature of this comparison. 
Overall Survival (OS) 
OS is defined as the time from randomization until death from any cause.  All deaths will 
be included, without regard to whether they occur on study or following treatment 
discontinuation.  For patients who have not died, OS will be censored at the last date 
known to be alive.  Patients without any post baseline information will be censored at the 
time of randomization. Analysis methods are the same as those described for PFS. 
Subgroup analyses of the above endpoints (primary and secondary) will be performed to 
evaluate the clinical outcome for important clinical covariates. Details of the sub group 
analyses will be provided in the statistical analysis plan. 
6.7 
EXPLORATORY BIOMARKER ANALYSES  
Exploratory biomarker parameters may be presented by listings and descriptive 
summary statistics separately by treatment arms. 
All analyses of PD and exploratory biomarkers will be based on the safety analysis 
population, in other words, any patients who received any amount of study treatment 
(5-FU/folic acid, oxaliplatin, bevacizumab, or RO5520985). 
For the analysis of PD biomarkers the primary evaluation will be based on the observed 
change from baseline.  Both actual values and estimated parameters will be presented 
in summary tables and graphically.  
To assess predictability of a biomarker, the association between clinical outcome and 
the biomarker level or changes thereof will be explored.  Details of the biomarker 
analysis will be provided within the Statistical Analysis Plan (SAP). 


 
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6.8 
PHARMACOKINETIC ANALYSES 
All pharmacokinetic parameters will be presented by listings and descriptive summary 
statistics separately by group or cohorts. 
Individual and mean plasma RO5520985, oxaliplatin (free and total), and 5-FU 
concentration versus time data will be tabulated and plotted.  The plasma 
pharmacokinetics of RO5520985, oxaliplatin, and 5-FU will be summarized by estimating 
total exposure (area under the curve [AUC]), maximum concentration, total clearance, 
volume of distribution at steady−state, and terminal half-life (when applicable).  These 
parameters will be tabulated and summarized (arithmetic mean, standard deviation, 
geometric mean, coefficient of variation, median, minimum, and maximum).  Interpatient 
variability and drug accumulation will be evaluated. 
Additional PK analyses will be conducted as appropriate. 
6.9 
OTHER EXPLORATORY ANALYSES  
PK/PD Modeling 
Exploratory graphical analyses of exposure-efficacy relationships may be produced  for 
selected efficacy, PD and/or safety measurements if feasible.  A PK/PD modeling 
approach may be considered in order to further explore the exposure-response 
relationship of selected response variables. 
Tumor Growth Kinetics 
An exploratory assessment of tumor growth kinetics will be made by comparing post-
treatment scans with at least 2 pre-treatment  scans not older than 12 weeks prior to 
C1D1, if available. The two pre-treatment scans consists of a pre-study scan (if available) 
and the study baseline scan, and will allow estimation of tumor growth rate before start 
of treatment.  If the pre-treatment tumor growth kinetic can be assessed, this will then be 
compared to the growth/shrinkage rate after start of treatment.  Data will be explored 
using linear and/or exponential models, as appropriate, in non linear mixed effect 
modelling software. 
6.10 
INTERIM ANALYSES 
As decribed in Section 3.1.2 interim safety analysis of Part I patients will be performed 
by an Safety IMC after all patients have received at least two full cycles.  The Safety IMC 
may also conduct further reviews based on safety signals that arise at any time during 
Part II of the study. Details of the interim safety analysis will be described in the Safety 
IMC charter.  The purpose of the Safety IMC is to facilitate a formal review of the safety 
data, but the Safety IMC is not an external data monitoring committee.  It will consist of 
at least a Sponsor Translational Medicine Leader/Clinical Scientist, Safety 
Scientist/Safety Science Leader, Statistical Programming Analyst (SPA) and 
Biostatistician.  


 
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Within Part II of the study, an interim analysis for futility is planned to be conducted after 
approximately 30 PFS events. A cut-off HR of 1.0 has been suggested as non binding 
futility criteria. The probability of observing an HR equal or higher than 0.77 at final 
analysis, given an HR of 1.0 at the interim analysis, will be above 80%. Enrollment will 
not be stopped during the interim analysis.  Administrative interim analysis, based on 
efficacy, may also be performed during Part II of the study after approximately 30 events 
and again after approximately 50 events.  The results will be used by the Sponsor solely 
for the decision making regarding activities for further clinical development of the 
compound under investigation.  The study will not be stopped for efficacy.   
Separate from the Safety IMC, there will be in addition an Efficacy IMC responsible for 
the futility/efficacy analysis of Part II.  The details and modalities are described in a pre-
specified charter outlined in a separate document as well as in the statistical analysis 
plan. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
A contract research organization (CRO) will be responsible for data management of this 
study, including quality checking of the data. Sites will be responsible for data entry into 
the Electronic Data Capture (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 Handling Manual that describes the quality checking to be 
performed on the data. Central laboratory data and other electronic data will be sent 
directly to the CRO, using the CRO's standard procedures to handle and process the 
electronic transfer of these data. 
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  
Data for this study will be captured via an online EDC system. The data collected in the 
source documents is entered onto the study eCRF.  An audit trail will maintain a record 
of initial entries and changes made; reasons for change; time and date of entry; and user 
name of person authorizing entry or change.  For each patient enrolled, an eCRF must 
be completed and electronically signed by the principal Investigator or authorized 
delegate from the study staff.  If a patient withdraws from the study, the reason must be 
noted on the eCRF.  If a patient is withdrawn from the study because of a 
treatment−limiting adverse event, thorough efforts should be made to clearly document 
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The Investigator should ensure the accuracy, completeness and timeliness of the data 
reported to the sponsor/CRO in the eCRFs and in all required reports. 
eCRFs will be submitted electronically to the Sponsor/CRO and should be handled in 
accordance with instructions from the Sponsor/CRO. 
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 authorized 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, data to be entered directly into the eCRFs (i.e., no prior written or 
electronic record of the data) and considered source data must be defined in the Trial 
Monitoring Plan. 
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 investigational site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s 
computerized 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 computerized systems used 
in clinical research.  An acceptable computerized data collection system allows 
preservation of the original entry of data.  If original data are modified, the system should 


 
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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, ePRO data (if applicable), 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, patient 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 United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws. Studies conducted in the EU/EEA will comply 
with the EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form will be provided to each site.  If 
applicable, it 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 Informed Consent Forms must be provided to the Sponsor for health 
authority submission purposes according to local requirements. 
The Informed Consent Forms must be signed and dated by the patient or the patient’s 
legally authorized representative before his or her participation in the study.  The case 
history or clinical records for each patient shall document the informed consent process 
and that written informed consent was obtained prior to participation in the study. 
The Informed Consent Forms should be revised whenever there are changes to study 
procedures or when new information becomes available that may affect the willingness 


 
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of the patient to participate.  The final revised IRB/EC-approved Informed 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 Informed 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 Informed 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 Informed Consent Forms for continued 
participation in the study. 
A copy of each signed Informed Consent Form must be provided to the patient or the 
patient’s legally authorized representative. All signed and dated Informed Consent 
Forms must remain in each patient’s study file or in the site file and must be available for 
verification by study monitors at any time. 
For sites in the United States, each Informed Consent Form may also include patient 
authorization to allow use and disclosure of personal health information in compliance 
with the U.S. Health Insurance Portability and Accountability Act of 1996 (HIPAA). If the 
site utilizes a separate Authorization Form for patient authorization for use and 
disclosure of personal health information under the HIPAA regulations, the review, 
approval, and other processes outlined above apply except that IRB review and approval 
may not be required per study site policies. 
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 (Section 9.5). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
Investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written 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. 


 
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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 only be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
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. 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. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for one year after completion of the study (i.e., LPLV, or the date 
at which the last data point from the last patient, which is required for statistical analysis 
is received, whichever is the later date. 
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, which includes an audit trail containing a complete record of all changes 
to data. 
Roche shall also submit a Development Safety Update Report (DSUR) once a year to 
the EC and CAs according to local regulatory requirements and timelines of each 
country participating in the study. 
Sampling for the RCR is contingent on review and approval for the exploratory 
biomarker assessments and written informed consent by an appropriate regulatory body 


 
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(depending on the country where the study is performed) and a site’s IRB/EC.  If a 
regulatory or site’s IRB/EC does not approve the sampling for the exploratory 
assessments the section on biomarker sampling will not be applicable.It is the 
understanding of the sponsor that this protocol (and any modifications) as well as 
appropriate consent procedures and advertisements, will be reviewed and approved by 
an IRB.  This board must operate in accordance with the current Federal Regulations.  
The sponsor will be sent a letter or certificate of approval prior to initiation of the study, 
and also whenever subsequent amendments/modifications are made to the protocol.  
Roche shall also submit an IND Annual Report to FDA according to local regulatory 
requirements and timelines. 
9.2 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized 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. 
9.3 
ADMINISTRATIVE STRUCTURE 
The sponsor of the trial is F. Hoffmann-La Roche Ltd.  The study will be managed by 
F. Hofmann-La Roche Ltd. and a Contract Research Organisation (CRO).  The CRO will 
provide clinical operations and data management.  Approximately 50 sites in 
approximately 7−10 countries will participate to enroll approximately 200 - 210 patients.   
The study is divided in 2 parts: Part I of the study is single-arm, open-label and will 
assess the safety of RO5520985 in combination with mFOLFOX-6 in 6-18 patients prior 
embarking to the randomized part of the study. Part II is parallel arm, double-blind and 
patients will be randomized in a ratio of 1:1 to receive either RO5520985 plus 
mFOLFOX-6 (experimental arm) or bevacizumab plus mFOLFOX6 (control arm).  The 
study site will obtain the patient’s unique identification number and treatment assignment 
from the IxRS.    
Central laboratories will be used for a subset of laboratory assessments.  
9.4 
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. 
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally 


 
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support publication of multicenter trials only in their entirety and not as individual center 
data. In this case, a coordinating Investigator will be designated by mutual agreement. 
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. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
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. 
9.5 
PROTOCOL AMENDMENTS 
Any substantial protocol amendments will be prepared by the Sponsor.  Substantial 
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 any non-substantial changes, as defined by 
regulatory requirements. 


 
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124 
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Appendix 1 Schedule of Assessments 
Treatment Cycle (14 days) 
 
Screening / 
Baseline 
1 
2 
3 
4 
5 
6-8 
9 
10-12 
13 
≥14 
Day 
-28 
to -1 
-7 
to -1 
1 
2 
1 
1 
1 
1 
1 
1 
1 
1 
1 
DP 
Visit 
EoS 
Visit 
a 
Post 
Study 
Visit 
b 
Survival 
Status 
Follow 
up 
c  
RO5520985 or bevacizumab 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
mFOLFOX-6 Administration  
(Induction therapy for up to 8 Cycles) 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
5-FU/folinic acid  
(Maintenance therapy for up to 24 months)
  
 
 
 
 
 
 
 
 
 
X 
d 
X 
X 
X 
 
 
 
 
Written Informed Consent 
e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Cancer History  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Body Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archival Primary Tumor Tissue 
 
 
X (to be provided within first 4 weeks of treatment) 
 
 
 
 
Serum/Urine Pregnancy Test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
f 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
TTE or MUGA  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Physical Exam. and Body Weight
 g 
X 
 
X 
h 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Hematology/Biochem./Coagulation 
g 
X 
 
X 
h 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Vital Signs 
i 
X 
 
X 
h 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
ECOG Performance Status 
g 
X 
 
X 
h 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Urinalysis (dipstick for proteinuria) 
g,j 
X 
 
X 
h 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
RECIST Tumor Assessment 
k 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
Tumor marker every 2
nd cycle (CEA) 
X 
 
 
 
 
X 
 
X 
X 
o 
X 
X 
o 
X 
 
X 
X 
 
 
Plasma samples for Biomarkers 
l, m Part  II 
 
 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Plasma for MMP-2 and MMP-9 l - Part II  
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Plasma for circulating tumor DNA 
l  Part II 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
RCR – Plasma - Part II
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RCR – Blood for DNA isolation - Part II 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HAHA 
n 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
X (opt) 
 


 
RO5520985—F. Hoffmann-La Roche Ltd 
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Appendix 1 Schedule of Assessments (cont.) 
 
Treatment Cycle (14 days) 
 
Screening / 
Baseline 
1 
2 
3 
4 
5 
6-8 
9 
10-12 
13 
≥14 
Day 
-28 
to -1 
-7 
to -1 
1 
2 
1 
1 
1 
1 
1 
1 
1 
1 
1 
DP 
Visit 
EoS 
Visit 
a 
Post 
Study 
Visit 
b 
Survival 
Status 
Follow 
up 
c  
AEs and Concomitant Medication 
Continuously monitored. Prior first study drug administration only SAEs related to protocol mandated procedures 
to be reported. For AE and SAE reporting period refer to Section 5.3.1.  
 
 
PK blood samples 
Refer to separate PK tables in Appendix 2 and Appendix 3  
 
 
Plasma samples for Ang-2 
Refer to separate PK table in Appendix 2  
 
 
AE = adverse event; DP = disease progression; ECG = electrocardiogram; ECOG =  Eastern Cooperative Oncology Group; EoS =  end of study; HAHA = human anti-human ant body; 
MUGA = multigated acquisition scan; PK = pharmacokinetic; RCR = Roche Clinical Repository; SAE = serious adverse event; TTE = two dimensional transthoracic echocardiography.  
NOTE:  All assessments on dosing days need to be performed prior to dosing except otherwise specified. 
a End of Study Visit to occur within 5 (± 1) weeks after discontinuing study drug treatment. 
b 
Post Study Visit to occur 2 months (±14 days) after last dose of treatment. 
c 
Survival Status Follow up Visits approximately every 3 months after EoS Visit until death, loss to follow-up, or study termination by Roche, whichever occurs first. 
d After induction therapy has been completed, maintenance treatment will start at the following cycle; however, latest from Cycle 9 onwards, for a maximum of 24 months. 
e Informed consent must be obtained prior to any study-related procedures.   
f 
12-lead ECG:  In triplicates with 2−5 minutes between readings.  ECG during treatment needs to be performed 4 (±2) hrs after end of infusion  
g Pre-infusion assessments of hematology, biochemistry, coagulation, urinalysis, physical examination/body weight, and ECOG: time window of -3 days. 
h 
If certain screening assessments are performed one day prior to the 1
st administration of study drug, the assessments do not have to be repeated on Day 1 Cycle 1.  
i 
Vital signs: On infusion days: Predose, at end of infusion, 1 hr (±15 min)  , 2 hrs (±30 min)  and 4 hrs (±1.5 hr) after end of infusion. For patients who discontinue treatment with 
RO5520985/bevacizumab but continue with chemotherapy the frequency of the vital signs assessment can be reduced as follows: pre-infusion and either  at end of infusion or  at 1hr 
(±15 min) post infusion.  
j 
Urinalysis (urine dipstick for proteinuria): 24-hrs urine protein analysis in ≥2+ dipstick reading (with result available prior next dosing). 
k RECIST tumor assessment: Performed every 8 weeks (±7 days). Results of tumor assessments using CT/MRI prior to obtaining informed consent and within 28 days prior to Day 1 
may be used; If patient is discontinued from treatment for any reason other than progression, an end of study CT/MRI is to be performed only if it has not been done ≤28 days prior to 
this day. IPatients with previously documented tumor progression will not require additional tumor-reassessment by CT/MRI at End of Study visit. If a patient discontinues therapy 
for reasons other than progression, the patient will be followed by regular CT assessments according to institutional standard of care until documentation of 
progressive disease, initiation of another anticancer therapy (including secondary resection), withdrawal of consent, or death.  Optional radiology report from latest pre-
study CT scan  not older than 12 weeks prior to C1D1 should be provided for assessment of tumor growth kinetics within 6 weeks of patient entering the study. 
l 
Plasma samples for biomarkers, MMP-2, MMP-9 and circulating tumor DNA: Samples at DP visit should be drawn within 1 week after imaging shows DP. In case EoS Visit overlaps 
with DP Visit only one sample needs to be drawn. For patients who discontinue RO5520985/bevacizumab but continue with chemotherapy the assessments can be skipped . 


 
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Appendix 1 Schedule of Assessments (cont.) 
 
m Additional 2 mL EDTA plasma will be collected at baseline prior dosing.  
n HAHA  additional sample to be taken  in case of NCI CTC-AE ≥ Grade3 IRR. In case a patient discontinues RO5520985/bevacizumab but continues with chemotherapy the 
assessment  at  EOS Visit  can be skipped. 
o Blood Tumor marker (CEA) to be assessed baseline and every 2nd Cycle under treatment, i.e. C3, C5, C7, C9, C11, C13, C15, etc. 


 
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Appendix 2 Schedule of Pharmacokinetic Assessments for 
RO5520985 
(Part I) 
Cycle 
Day 
Time from start of 
infusion (h) 
PK Sampling 
Predose 
X 
End of Infusion 
X 
1 (± 0.25) 
X 
2 (± 0.25) 
X 
1 
4 (± 1) 
X  
2 
24 (± 4) 
X 
4 
72 (± 24) 
X a 
6 
120 (± 24) 
X a 
Cycle 1 
8 
168 (± 24) 
X a 
Pre-dose 
X 
Cycle 2 – Cycle 5 
1 
End of Infusion 
X 
Pre-dose 
X 
End of Infusion 
X 
1 (± 0.25) 
X 
2 (± 0.25) 
X 
1 
4 (± 1) 
X  
2 
24 (± 4) 
X  
4 
72 (± 24) 
  X a 
6 
120 (± 24) 
  X a 
Cycle 6 
8 
168 (± 24) 
X 
Pre-dose 
X 
Cycle 7-8 
1 
End of Infusion 
X 
Disease progression b 
 
 
X 
End of Study Visit 
 
 
X 
PK = pharmacokinetic. 
a In Cycle 1, only one of the PK samples to be taken on Day 4, Day 6 and Day 8 is mandatory and 
can be chosen at the investigators discretion. In Cycle 6 one of the samples to be taken on D4 
and D6 can be skipped at investigators discretion 
b Unscheduled PK samples will be taken at the time of disease progression (samples at 
DP Visit should be drawn within 1 week after imaging shows disease progression).  In case 
DP Visit overlaps with EoS Visit, only the EoS Visit sample should be drawn.  
 


 
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 Appendix 2 Schedule of Pharmacokinetic Assessments for 
RO5520985 (cont.)  
(Part II) 
Cycle 
Day 
Time from start of 
infusion (h) 
PK Samplingd 
Predose 
X 
End of Infusion 
X 
1 (± 0.25) 
X 
2 (± 0.25) 
X 
1 
4 (± 1) 
  X c 
2 
24 (± 4) 
X 
4 
72 (± 24) 
  X a  
6 
120 (± 24) 
  X a 
Cycle 1 
8 
168 (± 24) 
  X a 
Pre-dose 
X 
Cycle 2 – Cycle 7 
1 
End of Infusion 
X 
Pre-dose 
X 
End of Infusion 
X 
1 (± 0.25) 
X 
2 (± 0.25) 
X 
1 
4 (± 1) 
  X c 
2 
24 (± 4) 
  X c 
4 
72 (± 24) 
  X a 
6 
120 (± 24) 
  X a 
Cycle 8 
8 
168 (± 24) 
X 
Disease progression b 
 
 
X 
End of Study Visit 
 
 
X 
PK = pharmacokinetic. 
a In Cycle 1, only one of the PK samples to be taken on Day 4, Day 6 and Day 8 is mandatory and 
can be chosen at the investigators discretion. In Cycle 8, one of the samples to be taken on D4 
and D6 can be skipped at investigators discretion 
b Unscheduled PK samples will be taken at the time of disease progression (samples at 
DP Visit should be drawn within 1 week after imaging shows disease progression.  In case 
DP Visit overlaps with EoS Visit, only the EoS Visit sample should be drawn.  
c An additional blood sample will be drawn for measurement of Ang-2 (free and total). The 
assessment can be skipped for patients who discontinue treatment with 
RO5520985/bevacizumab but continue with chemotherapy. 
d  For patients who discontinue treatment with RO5520985/bevacizumab but continue with 
chemotherapy the PK assessments can be skipped. 
 


 
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Appendix 3 Schedule of Pharmacokinetic Assessments for 
FOLFOX Components (Part I only) 
Cycle 
Day 
Time from start of 
infusion of each 
individual agent 
Oxaliplatin 
5-FU bolus 
Predose 
X 
X 
End of bolus 5-FU 
 
X 
30 minutes 
X 
 
1 hour  
X 
X 
2 hours 
X 
 
2,5 hours 
X 
 
3 hours 
X 
X 
1 
4 hours 
X 
 
Cycle 1 
2 
24 hours 
X 
 
Predose 
X 
X 
End of bolus 5-FU 
 
X 
30 minutes 
X 
 
1 hour  
X 
X 
2 hours 
X 
 
2,5 hours 
X 
 
3 hours 
X 
X 
1 
4 hours 
X 
 
Cycle 6 
2 
24 hours 
X 
 
 
5-FU = 5-fluorouracil; IV = intravenous. 
mFOLFOX-6 will be administered as follows after Infusion of RO5520985/ bevacizumab: 
 
1. 
Oxaliplatin 85 mg/m2 IV concurrently (using a y connector) with folinic acid 400 mg/m2 IV (or 200 
mg/m2 I-isomer form) over 120 minutes 
2. 
5-FU 400 mg/m2 administered as an IV bolus   
3. 
5-FU 2400 mg/m2, continuous IV infusion over 46 +/- 2 hours 
 


 
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Appendix 4  
Cockcroft–Gault Formula 
 
Creatinine Clearance (mL/min) for Males 
 
(140 – age [years] × body weight [kg]) 
 
Creatinine Clearance = 
(72 × serum creatinine [mg/dL]) 
 
 
 
 
Creatinine Clearance (mL/min) for Females 
 
(140 – age [years] × body weight [kg]) 
Creatinine Clearance =
(72 × serum creatinine [mg/dL]) 
× 0.85 
 
 
 
 
 


 
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Appendix 5 ECOG Performance Status 
 
Patients will be graded according to the ECOG Performance Status scale and criteria as 
described below: 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light housework, office work.  
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  
Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined teo bed or chair more than 50% of 
waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair. 
5 
Dead 
ECOG = Eastern Cooperative Oncology Group. 
a As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., 
Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity and Response Criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5: 649-655, 1982. 
 


 
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Appendix 6 NYHA Classification 
 
 Class I  
Patients with cardiac disease but without resulting limitations of physical 
activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
Class II 
Patients with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity results in 
fatigue, palpitation, dyspnea, or anginal pain. 
Class III 
Patients with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary physical activity 
causes fatigue, palpitation, dyspnea, or anginal pain. 
Class IV 
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of cardiac insufficiency or of the 
anginal syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort is increased. 
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co. 
1994:253–256. 
 


 
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Appendix 7 ICH Guidelines – Topic E2 
 
A serious adverse event is any experience that suggests a significant hazard, 
contraindication, side effect or precaution.  It is any AE that at any dose fulfills at least 
one of the following criteria: 
• 
Is fatal; [results in death] [NOTE: death is an outcome, not an event] 
• 
Is Life-Threatening   [NOTE: the term "Life-Threatening" refers to an event in which 
the patient was at immediate risk of death at the time of the event; it does not refer 
to an event which could hypothetically have caused a death had it been more 
severe]. 
• 
Required in-patient hospitalization or prolongation of existing hospitalization; 
• 
Results in persistent or significant disability/incapacity; 
• 
Is a congenital anomaly/birth defect; 
• 
Is medically significant or requires intervention to prevent one or other of the 
outcomes listed above. 
 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting to the sponsor is appropriate in other situations, such as important medical 
events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the patient or may require intervention to prevent one of the 
outcomes listed in the definitions above. These situations should also usually be 
considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
An unexpected AE is one, the nature or severity of which is not consistent with the 
applicable product information. 
Causality is initially assessed by the Investigator. For Serious Adverse Events, causality 
can be one of 2 possibilities: 
• 
No (unrelated; equals not drug related).  
• 
Yes (remotely, possibly, probably or definitely drug related). 
 
The term severe is a measure of intensity, thus a severe AE is not necessarily serious. 
For example, nausea of several hours' duration may be rated as severe, but may not be 
clinically serious. 
 
 


 
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Appendix 7 ICH Guidelines – Topic E2 (cont.) 
A serious adverse event occurring during the study or which comes to the attention of 
the Investigator within 15 days after stopping the treatment or during the protocol-
defined follow-up period (protocol section 5.3.1), if this is longer, whether considered 
treatment-related or not, must be reported. In addition, a serious adverse event that 
occurs after this time, if considered related to test “drug”, should be reported. 
Such preliminary reports will be followed by detailed descriptions later which will include 
copies of hospital case reports, autopsy reports and other documents when requested 
and applicable. 
For serious adverse events, the following must be assessed and recorded on the AEs 
page of the eCRF: intensity, relationship to test substance, action taken, and outcome to 
date. 
The Investigator must notify the Ethics Review Committee/Institutional Review Board of 
a serious adverse event in writing as soon as is practical and in accordance with 
international and local laws and regulations. 
 


 
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Appendix 8 RECIST Criteria, Version 1.1 
 
(excerpt from original publication) 
 
 
Measurability of tumor at baseline 
De nitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-
measurable as follows: 
Measurable Tumor lesions 
Tumor 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. See also below ‘Baseline documentation of 
target and non-target lesions’ for information on lymph node measurement.  
Non-measurable Tumor lesions 
Non-measurable tumor lesions encompass 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, in ammatory breast disease, 
lymphangitic 
involvement 
of 
skin 
or 
lung, 
peritoneal 
spread, 
abdominal 
masses/abdominal organomegaly identi ed by physical exam that is not measurable by 
reproducible imaging techniques. 
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  lms are not considered adequate imaging 
techniques to measure bone lesions. However, these techniques can be used to 
con rm the presence or disappearance of bone lesions. 


 
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Appendix 8 RECIST Criteria, Version 1.1 (cont.) 
• 
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 de nition of measurability described above. 
• 
Blastic bone lesions are non-measurable. 
 
Cystic lesions: 
• 
Lesions that meet the criteria for radiographically de ned simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by de nition, simple cysts. 
• 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the de nition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Lesions with prior local treatment: 
• 
Tumor 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.  
 
Speci cations by methods of measurements 
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.  
Method of assessment 
The same method of assessment and the same technique should be used to 
characterize each identi ed 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 
super cial and ≥ 10 mm diameter as assessed using calipers (e.g. skin nodules). For the 
case of skin lesions, documentation by color 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. 
 


 
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Appendix 8 RECIST Criteria, Version 1.1 (cont.) 
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 de ned and surrounded by aerated lung. Still, non-contrast CT is preferred over 
chest X-ray. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has de ned 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). 
If prior to enrolment it is known that a patient is not able to undergo CT scans with IV 
contrast due to allergy or renal insufficiency, the decision as to whether a non-contrast 
CT or MRI (with or without IV contrast) will be used to evaluate the patient at baseline 
and follow-up, should be guided by the tumor type under investigation and the anatomic 
location of the disease. For patients who develop contraindications to contrast after 
baseline contrast CT is done, the decision as to whether non-contrast CT or MRI 
(enhanced or non-enhanced) will be performed, should also be based on the tumor type, 
anatomic location of the disease and should be optimized to allow for comparison to the 
prior studies if possible. Each case should be discussed with the radiologist to determine 
if substitution of these other approaches is possible and, if not, the patient should be 
considered not evaluable from that point forward. 
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 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 identi ed by ultrasound in the 
course of the study, con rmation 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 utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to con rm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response or surgical resection is an endpoint. 


 
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Appendix 8 RECIST Criteria, Version 1.1 (cont.) 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response. If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in complete response. Because tumor markers 
are disease speci c, instructions for their measurement should be incorporated into 
protocols on a disease speci c basis. Speci c guidelines for both CA-125 response (in 
recurrent ovarian cancer) and PSA response (in recurrent prostate cancer), have been 
published. In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use 
in  rst-line trials in ovarian cancer. 
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 tumor types 
such as germ cell tumors, where known residual benign tumors 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 con rmation of the 
neoplastic origin of any effusion that appears or worsens during treatment can be 
considered if the measurable tumor has met criteria for response or stable disease in 
order to differentiate between response (or stable disease) and progressive disease.  
Tumor response evaluation 
Assessment of overall tumor burden and measurable disease 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor 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 tumor response is the primary endpoint. Measurable disease 
is de ned by the presence of at least one measurable lesion (as detailed above). In 
studies where the primary endpoint is tumor progression (either time to progression or 
proportion with progression at a  xed 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.  
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  ve lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identi ed 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 (one site) and four lesions (two sites), respectively, will be recorded. 
Other lesions in that organ will be recorded as non-measurable lesions (even if size is 
greater than 10mm by CT scan). 


 
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Appendix 8 RECIST Criteria, Version 1.1 (cont.) 
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 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 tumor. Pathological nodes which are 
de ned as measurable and may be identi ed 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 tumor. 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 x 30 mm has a short axis of 20 mm and quali es 
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 
characterize any objective tumor regression in the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be 
identi ed 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 report form (e.g. ‘multiple 
enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
Response criteria 
This section provides the de nitions of the criteria used to determine objective tumor 
response for target lesions.  
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. 


 
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Appendix 8 RECIST Criteria, Version 1.1 (cont.) 
• 
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). 
• 
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. 
 
Special notes on the assessment of target lesions 
Lymph nodes: Lymph nodes identi ed 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 complete response criteria are met, since a normal lymph node is de ned 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 them as 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 and BML (below measurable limit) should 
be ticked (Note: It is less likely that this rule will be used for lymph nodes since they 
usually have a de nable 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 and BML should also be ticked).  
 
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. 


 
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Appendix 8 RECIST Criteria, Version 1.1 (cont.) 
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm and in that case BML should not be ticked. (BML is 
equivalent to a less than sign <). 
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’. 
Evaluation of non-target lesions 
This section provides the de nitions of the criteria used to determine the tumor 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 speci ed in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short 
axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. 
(Note: the appearance of one or more new lesions is also considered progression). 
Special notes on assessment of progression of non-target 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 in a magnitude that, even in 
presence of SD or PR in target disease, the overall tumor 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 qualify 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. 


 
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Appendix 8 RECIST Criteria, Version 1.1 (cont.) 
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 
quanti ed (by de nition: 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 tumor 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 localized 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. 
New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no speci c criteria for 
the identi cation of new radiographic lesions; however, the  nding of a new lesion 
should be unequivocal: i.e. not attributable to differences in scanning technique, change 
in imaging modality or  ndings thought to represent something other than tumor (for 
example, some ‘new’ bone lesions may be simply healing or  are 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. 
A lesion identi ed 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 brain 
CT or MRI 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 con rm 
there is de nitely a new lesion, then progression should be declared using the date of 
the initial scan. 
 


 
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Appendix 8 RECIST Criteria, Version 1.1 (cont.) 
(18)F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) 
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 identi ed according to the following algorithm: 
• 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
• 
No FDG-PET at baseline and a positive FDG-PET at follow-up: 
o If the positive FDG-PET at follow-up corresponds to a new site of disease 
con rmed by CT, this is PD. 
o If the positive FDG-PET at follow-up is not con rmed 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). 
o 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. 
 
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 con rmation. 
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  ndings 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 con rmatory measurement. Speci cally, in non-randomised trials where 
response is the primary endpoint, con rmation of PR or CR is needed to deem either 
one the ‘best overall response’. This is described further below. 
Time point response 
It is assumed that at each protocol speci ed time point, a response assessment occurs. 
Table 1 below provides a summary of the overall response status calculation at each 
time point for patients who have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used. 


 
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Appendix 8 RECIST Criteria, Version 1.1 (cont.) 
Missing assessments and not-evaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that time point, unless 
a convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned time point response. This would be most likely 
to happen in the case of PD. 
For example, if a patient had a baseline sum of 50 mm with three measured lesions and 
at follow-up only two lesions were assessed, but those gave a sum of 80 mm, the patient 
will have achieved PD status, regardless of the contribution of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done, 
or could not be assessed because of poor image quality or obstructed view, the 
Response for Target Lesions should be “Unable to Assess” since the patient is not 
evaluable. Similarly, if one or more non-target lesions are indicated as ‘not assessed’, 
the response for non-target lesions should be “Unable to Assess” (except where there is 
clear progression). Overall response would be “Unable to Assess” if the target response 
is “Unable to Assess” (except where this is clear evidence of progression) as this 
equates with the case being not evaluable at that time point. 
Best overall response: all time points 
The best overall response will be determined by statistical programming once all the 
data for the patient is known. 
 


 
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Appendix 8 RECIST Criteria, Version 1.1 (cont.) 
 
 
 


 
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Appendix 8 RECIST Criteria, Version 1.1 (cont.) 
 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (< 10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted 
earlier, this means that patients with CR may not have a total sum of ‘zero’ on the case 
report form (eCRF). 
In trials where con rmation 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 con rmed 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 Tables 1–3. 
Conditions that de ne ‘early progression, early death and non-evaluability’ are study 
speci c and should be clearly described in each protocol (depending on treatment 
duration, treatment periodicity). 
 


 
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Appendix 8 RECIST Criteria, Version 1.1 (cont.) 
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 ( ne 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  brosis or scarring. The use of FDG-PET in this 
circumstance should be prospectively described in the protocol and supported by 
disease speci c 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  ndings 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 con rmed, the date of 
progression should be the earlier date when progression was suspected. 
 
 
 
 
 

SAP_001.pdf: 
 
Official Title: 
 
A PHASE II, MULTICENTER, RANDOMIZED, DOUBLE-BLIND 
STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 
RO5520985 (VANUCIZUMAB) PLUS FOLFOX VERSUS 
BEVACIZUMAB PLUS FOLFOX IN PATIENTS WITH PREVIOUSLY 
UNTREATED METASTATIC COLORECTAL CANCER 
NCT Number: 
NCT02141295 
Document Date: 
SAP Version 1.1: 09-Sep-2016 
 
 
 


 
 
CONFIDENTIAL 
 
This is a F.Hoffman –La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F.Hoffman –La Roche Ltd. 
 
RO5520985—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP29262 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A PHASE II, MULTICENTER, RANDOMIZED,DOUBLE-BLIND 
STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 
RO5520985 PLUS FOLFOX VERSUS BEVACIZUMAB PLUS 
FOLFOX IN PATIENTS WITH PREVIOUSLY UNTREATED 
METASTATIC COLORECTAL CANCER 
PROTOCOL NUMBER: 
BP29262 
STUDY DRUG: 
RO5520985 
VERSION NUMBER: 
1.1 
IND NUMBER: 
120910  
EUDRACT NUMBER: 
2013-005108-32  
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
 
 
DATE FINAL: 
August 18, 2016 
DATE(S) AMENDED 
09 September 2016 


RO5520985—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP29262 
 
2 
09 September 2016: List of prognostic variable for subgroup analysis has been 
expanded on clinical science request. 
 


RO5520985—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP29262 
3 
 
TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 5 
2. 
STUDY DESIGN ........................................................................................... 5 
2.1 
Protocol Synopsis .................................................................... 7 
2.2 
Outcome Measures ................................................................. 7 
2.2.1 
Primary Efficacy Outcome Measures ...................................... 7 
2.2.2 
Secondary Efficacy Outcome Measures .................................. 8 
2.2.3 
Exploratory Efficacy Outcome Measures ................................. 8 
2.2.4 
Pharmacokinetic Efficacy Outcome Measures ........................ 9 
2.2.5 
Safety Outcome Measures ...................................................... 9 
2.3 
Determination of Sample Size ................................................. 9 
2.4 
Analysis Timing ..................................................................... 10 
3. 
STUDY CONDUCT ..................................................................................... 11 
3.1 
Randomization Issues ........................................................... 11 
3.2 
Data Monitoring ..................................................................... 11 
4. 
STATISTICAL METHODS .......................................................................... 11 
4.1 
Analysis Populations ............................................................. 11 
4.1.1 
ITT Population ....................................................................... 11 
4.1.2 
Pharmacokinetic-Evaluable Population ................................. 11 
4.1.3 
Safety Population .................................................................. 12 
4.2 
Analysis of Study Conduct ..................................................... 12 
4.3 
Analysis of Treatment Group Comparability .......................... 12 
4.4 
Efficacy Analysis .................................................................... 13 
4.4.1 
Primary Efficacy Endpoint ...................................................... 13 
4.4.2 
Secondary Efficacy Endpoints ............................................... 14 
4.4.3 
Sensitivity Analyses ............................................................... 14 
4.4.3.1 Unstratified Analysis for Progression-Free 
Survival 14 
4.4.3.2 PFS including death outside the 30 days window ................ 14 
4.4.3.3 PFS on study ........................................................................ 15 
4.4.3.4 Censoring pattern evaluation ............................................... 15 


RO5520985—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP29262 
4 
4.4.3.5 Time to surgery evaluation ................................................... 15 
4.4.3.6 Prognostic factors assessment ............................................ 15 
4.4.3.7 Non confirmed ORR ............................................................. 16 
4.4.4 
Subgroup Analyses ............................................................... 16 
4.4.4.1 Demographic and baseline prognostic 
characteristics .................................................................................... 16 
4.4.4.2 Ang2 baseline biomarker assessment .................................. 16 
4.5 
Pharmacokinetic and Pharmacodynamic 
Analyses ................................................................................ 17 
4.5.1 
Pharmacokinetic analysis ...................................................... 17 
4.5.2 
PK/PD Modeling .................................................................... 18 
4.5.3 
Tumor Growth Kinetics .......................................................... 18 
4.6 
Safety Analyses ..................................................................... 18 
4.6.1 
Exposure of Study Medication ............................................... 18 
4.6.2 
Adverse Events ..................................................................... 18 
4.6.3 
Laboratory Data ..................................................................... 19 
4.6.4 
Vital Signs .............................................................................. 19 
4.6.5 
ECG Data Analysis ................................................................ 19 
4.6.6 
Concomitant Medications ...................................................... 19 
4.7 
Biomarker .............................................................................. 20 
4.8 
Missing Data .......................................................................... 20 
4.9 
Interim Analyses .................................................................... 20 
5. 
REFERENCES ........................................................................................... 21 
 
 
LIST OF TABLES 
Table 1 
Analysis Timings ......................................................................... 10 
 
 
LIST OF APPENDICES 
Appendix 1 
 Protocol Synopsis ...................................................................... 22 
Appendix 2 
 Schedule of Assessments .......................................................... 23 
Appendix 3 
 {Additional Items to Be Appended} ............................................ 24 


RO5520985—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP29262 
5 
1. 
BACKGROUND 
Study BP29262 is a phase II multicenter, randomized, parallel groups, double-blind 
study of RO5520985 to evaluate the efficacy and safety of RO5520985 plus mFOLFOX-
6 versus bevacizumab plus mFOLFOX-6 in patients with previously untreated mCRC.  
The target population consists of adult patients with metastatic colorectal cancer who 
have not previously been treated with chemotherapy for metastatic disease and who are 
not candidates for potentially curative resection.  
The study consists of two parts: Part I (Safety Run-in) open label single arm and Part II 
(Randomization Phase) randomized, parallel groups, double-blind study. A safety 
evaluation will be performed before starting Part II of the study. Upon completion of the 
safety run in and selection of the recommended Phase II dose (RP2D), a total of 190 
patients will be enrolled in Part II of the study.  
The primary objective of Study BP29262 is to estimate the efficacy of RO5520985 in 
combination with oxaliplatin, folinic acid, and 5 fluorouracil (mFOLFOX-6) vs. 
bevacizumab in combination with mFOLFOX-6, as measured by progression-free 
survival (PFS).  
During Part II of the study an interim analysis for futility is planned after approximately 30 
progression-free (PFS) events. Administrative interim analysis, based on efficacy, will 
also be performed during Part II of the study after approximately 30 events and again 
after 50 events.  
A safety Internal Monitoring Committee (sIMC) will conduct a safety analysis prior to 
initiation of Part II and an efficacy Internal Data Monitoring Committee (eIMC) will 
oversee the futility and administrative interim analyses during Part II. The sMC and the 
eIMC will operate according to pre-specified agreements.  The efficacy and the safety 
IMC Agreements define the roles and responsibilities of the IMCs including membership, 
scope, timing of meetings, and communication plan. Details of the interim analysis are 
described in the interim analysis plan. 
This SAP applies to Part II of the study only and describes the final analysis plan for the 
primary and secondary endpoint. 
 
2. 
STUDY DESIGN 
Upon completion of the safety run-in part with selection of the RP2D of RO5520985 in 
combination with mFOLFOX-6 by the IMC, eligible patients will be randomized in a ratio 
of 1:1 to receive either mFOLFOX-6 +RO5520985 (experimental arm) or mFOLFOX-6 + 


RO5520985—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP29262 
6 
bevacizumab (control arm). Patients will prospectively be stratified by region (United 
States vs. Rest of World [RoW]) and number of metastatic sites (1 vs. >1).   
Patients randomized to the experimental arm will receive the fixed dose of RO5520985 
IV on Day 1 of each Cycle on a Q2W schedule as recommended by the IMC based on 
Part I safety data review. Patients randomized to the control arm will receive 
bevacizumab at a dose of 5 mg/kg IV on Day 1 of each Cycle on a Q2W schedule. The 
weight at screening will be used for dose calculation for each patient. Recalculation of 
dosage is not required if weight changes. 
Study treatment will be given in cycles repeated every 14 days and will consist of 
induction and maintenance therapy. 
Induction therapy: up to 8 cycles of mFOLFOX-6 plus either bevacizumab or 
RO5520985. Patients may switch to maintenance therapy earlier if oxaliplatin cannot be 
tolerated.  
Maintenance therapy: following induction therapy, oxaliplatin administration will be 
discontinued and patients receive 5-FU/folinic acid plus either RO5520985 (experimental 
arm) or bevacizumab (control arm) as maintenance therapy for a maximum period of 24 
months (calculated from start of maintenance therapy), if treatment is not stopped earlier 
due to disease progression, unacceptable toxicity, investigator decision or consent 
withdrawal. If patients stop chemotherapy either in part or in whole, then they should 
continue on RO5520985 treatment or bevacizumab for a maximum of 24 months. Details 
of the induction and maintenance therapy can be found in section 3.1.1.2 of study 
protocol. 
Tumor assessments should be performed every 8 weeks until documented disease 
progression. Should a patient discontinue from treatment for any reason other than 
progression, an End of Study CT/MRI is to be performed only if it has not been done ≤ 
28 days prior. 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. 
If a patient discontinues therapy for reasons other than progression, the patient will be 
followed by regular CT assessments until documentation of progressive disease, 
initiation of another anticancer therapy, withdrawal of consent, or death 
All patients who discontinue from the treatment phase will be followed for subsequent 
anticancer therapy and survival (e.g., by phone call) approximately every 3 months after 
end of study visit (EoS) Visit until death, loss to follow-up, or study termination by Roche, 
whichever occurs first unless the patient requests to be withdrawn from study survival 
follow-up.. 


RO5520985—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP29262 
7 
. 
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Appendix 2. 
2.2 
OUTCOME MEASURES 
For those patients who discontinue study treatment before progression, all assessments 
conducted before start of new therapy (including surgery with curative or de-bulking 
intent or radiotherapy) will be accounted for the evaluation even if they were performed 
after stopping study treatment. 
 
2.2.1 
Primary Efficacy Outcome Measures 
• 
The primary efficacy endpoint of this study is PFS on study. PFS on study is defined 
as the time between randomization and the date of first documented disease 
progression or death from any cause on study, whichever occurs first. Progression 
will be based on tumor assessment made by the Investigator according to RECIST 
1.1 criteria (Appendix 8 of the protocol). Death on study is defined as death from 
any cause within 30 days of the last study treatment. Patients without an event on 
study will be censored at the date of the last tumor assessment when the patient 
was known to be progression free either during follow up or during study treatment. 
Patients without any post baseline assessments or with all post baseline 
assessments having unknown result/response but known to be alive at the clinical 
cut off for the analysis will be censored at the date of randomization plus 1 day. 
• 
In addition, a more generic definition of PFS will be employed, similar to the primary 
PFS analysis, with the difference that deaths regardless of whether or not the event 
occurred within 30 days of the last study treatment will be taken into account. As 
sensitivity analysis PFS is defined as the time between randomization and the date 
of first documented disease progression or death from any cause, whichever occurs 
first. Progression will be based on tumor assessments made by the Investigator 
according to RECIST 1.1 criteria. Patients without an event on study will be 
censored at the date of the last tumor assessment when the patient was known to 
be progression free either during follow up or during study treatment. Patients 
without any post baseline assessments or with all post baseline assessments 
having unknown result/response but known to be alive at the clinical cut-off for the 
analysis will be censored at the date of randomization plus 1 day. 
• 
For sensitivity analysis a more restrictive definition of PFS on study will be employed, 
same as for the primary PFS analysis with the difference that only assessments or 
death that occurred within 30 days of the last study treatment will be taken in 
account. As sensitivity analysis PFS on study is defined as the time between 
randomization and the date of first documented disease progression or death from 
any cause, whichever occurs first. Progression will be based on tumor assessments 
made by the Investigator according to RECIST 1.1 criteria. Patients without an event 


RO5520985—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP29262 
8 
on study will be censored at the date of the last tumor assessment when the patient 
was known to be progression free either during study treatment or during follow up 
but within the 30 days from last study treatment. Patients without any post baseline 
assessments or with all post baseline assessments having unknown result/response 
but known to be alive at the clinical cut-off for the analysis will be censored at the 
date of randomization plus 1 day. 
 
 
2.2.2 
Secondary Efficacy Outcome Measures 
• 
Objective Response Rate (ORR). Objective response rate (ORR) is determined as 
the rate of patients with an objective tumor response (complete [CR] or partial 
response [PR]). Objective response (OR) is defined as a complete or partial 
response as determined by the Investigator using RECIST v1.1 on two consecutive 
occasions at least 4 weeks apart. Patients without a post-baseline tumor 
assessment will be regarded as non-responders.  
• 
Duration of Objective Response (OR). For patients with an OR, duration of OR is 
defined as the time from the initial response (CR or PR) to disease progression, or 
death from any cause on study.  This will only be calculated for patients who have a 
best overall response of CR or PR. Methods for handling censoring and for analysis 
are the same as those described for PFS on study.  
• 
For sensitivity analysis a more generic definition of Duration of Objective Response 
(OR). will be employed, same as for the above OR analysis with the difference that 
deaths will be included regardless of whether or not the event occurred within 30 
days of the last study treatment. As sensitivity analysis OR is defined as the time 
from the initial response (CR or PR) to the date of first documented disease 
progression or death from any cause, whichever occurs first. Progression will be 
based on tumor assessment made by the Investigator according to RECIST 1.1 
criteria. This will only be calculated for patients who have a best overall response of 
CR or PR. Methods for handling censoring and for analysis are the same as those 
described for PFS. 
• 
Overall Survival (OS). OS is defined as the time from randomization until death from 
any cause. All deaths will be included, regardless whether they occur on study or 
following treatment discontinuation. For patients who have not died, OS will be 
censored at the last date known to be alive. Patients without any post baseline 
information will be censored at the time of randomization.  
• 
Depth of response. Depth of response defined as best percentage change from 
baseline in tumor shrinkage will also be assessed. 
 
2.2.3 
Exploratory Efficacy Outcome Measures 
• 
Levels of circulating targets by comparing baseline vs. on-treatment values of Ang-2 
and VEGF-A and their differential expression/regulation during RO5520985 versus 
bevacizumab therapy.  


RO5520985—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP29262 
9 
• 
Changes of Placenta Growth Factor (PlGF) from baseline during treatment as 
marker of unspecific endothelial stress response and as potential response towards 
RO5520985  
• 
Assessment of tissue and soluble blood markers potentially related to predicting 
clinical benefit or toxicity of RO5520985 vs. bevacizumab  
• 
An assessment of tumor growth kinetics will be made by comparing post-treatment 
scans with one or more pre-treatment scans not older than 12 weeks prior to C1D1. 
The two pre-treatment scans consist of a pre-study scan and the study baseline 
scan. If not available, tumor growth kinetics will be applied by comparing post-
treatment scans with the baseline scan. OS prediction for comparison between the 2 
arms will be performed. 
• 
Analysis of additional CT parameters including necrotic volume/total tumor volume 
and intensity to assess their potential value as early response prediction markers. 
 
2.2.4 
Pharmacokinetic Efficacy Outcome Measures 
• 
The PK profile of RO5520985 will be characterized with the plasma concentration-
time data following IV administration of RO5520985, and may include the following 
parameters: Cmax, Cmin, Tmax, t1/2, AUC, AUCτ, CL, Vss, accumulation ratio (RA), 
as applicable 
• 
The PK profiles of oxaliplatin (free and total) and 5-FU will be characterized with the 
plasma concentration-time data following IV administration of FOLFOX, and will 
include the following parameters: Cmax, Cmin, Tmax, t1/2, AUC (when applicable) 
• 
Additional PK parameters may be evaluated as appropriate 
 
2.2.5 
Safety Outcome Measures 
• 
Exposure to study drug medication 
• 
Adverse events and adverse events of special interest 
• 
Laboratory data 
• 
Vital sign  
• 
ECG 
• 
Concomitant medication 
• 
 
 
2.3 
DETERMINATION OF SAMPLE SIZE 
Part II of the study will enroll approximately 190 patients, and the primary analysis will be 
performed after approximately 80 investigator assessed PFS events. The emphasis of 
the efficacy analysis will be on estimation of the magnitude of treatment effect rather 
than hypothesis testing. This trial is hypothesis-generating and is designed to be able to 
detect a meaningful benefit of the combination therapy of RO5520985 plus mFOLFOX-6 
versus bevacizumab plus mFOLFOX-6. Based on the sample size of 80 events 
observed in the two treatment arms combined, there is an 80% power to detect a HR of 
0.574 at a one-sided significance level of 0.05. 


RO5520985—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP29262 
10 
Initially 140 patients were planned to be enrolled in the study. The sample size was 
increased to 190 with a subsequent amendment in October 2015. At the cut-off date of 
10 August 2015, the number of observed PFS events (14 events in 10 months) was 
significantly lower than expected. This seemed to indicate that the median progression 
free survival (PFS) for the control arm of bevacizumab plus FOLFOX-6 may be longer 
than the assumed 10 months originally planned for sample size calculation and study 
duration. 
Additionally, as of 10 August 2015, a drop-out rate of approximately 20% of enrolled 
patients for reasons other than PD/death had been observed. It is of note that Adverse 
Events accounted for a drop out of 8% of enrolled patients, whereas 13% were other 
reasons, predominantly physician decisions, but also cases of secondary resectability. 
On 05 June 2015, the sIMC (safety internal monitoring committee) performed a blinded 
safety analysis of study BP29262 and came to the conclusion that the overall observed 
toxicity was acceptable and balanced between both treatment arms, including the 
incidence of drop-outs due to AE. 
To mitigate the potential risk of not achieving the required number of PFS events (n=80) 
for the primary analysis, approximately 50 additional patients were additionally enrolled 
into study BP29262. 
2.4 
ANALYSIS TIMING 
Table 1 
Analysis Timings 
Analysis 
Timing of 
Analysis 
Percent 
Information 
 
 
 
First interim for 
futility 
30 events 
37.5% 
 
 
 
Second interim 
administrative 
50 events 
62.5% 
 
 
 
Final 
80 events 
100% 
 
 
 
 
The primary analysis will occur when approximately 80 PFS events have been observed. 
The clinical cut off is defined as the date at which Roche is informed of the 80th event. At 
the time of PFS analysis OS data will not be sufficiently mature. OS data analysis will be 
performed only at the end of the study.  The study will formally end once the survival 
follow-up is complete or the last patient has completed the EoS Visit or is withdrawn 
from the study prior to that time (whichever occurs last), but may be prematurely 
terminated by the Sponsor. 
The study will not be stopped for evidence of efficacy. Futility and administrative interim 
analysis are described in the Interim Analysis Plan.  


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3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION ISSUES 
In part II patients will be randomized in a double-blinded fashion in a ratio of 1:1 to 
receive mFOLFOX-6 + RO5520985 (experimental arm) or mFOLFOX-6 + bevacizumab 
(control arm). Randomization will be performed using a permuted block randomization 
and patients will prospectively be stratified by region (United States vs. RoW) and 
number of metastatic sites (1 vs. > 1).  Randomization will be implemented via IxRS 
system. 
3.2 
DATA MONITORING 
A safety Internal Monitoring Committee (sIMC) will conduct a safety analysis prior to 
initiation of Part II and an efficacy Internal Data Monitoring Committee (eIMC) will 
oversee the futility and administrative interim analyses during Part II. The sMC and the 
eIMC will consist of employees of Roche and will operate according to pre-specified 
agreements. The efficacy and the safety IMC agreements define the roles and 
responsibilities of the IMCs including membership, scope, timing of meetings, and 
communication plan. Details of the interim analysis are described in the interim analysis 
plan. 
4. 
STATISTICAL METHODS 
The analyses outlined in this Statistical Analysis Plan will supersede those specified in 
the protocol,  
For all analysis the clinical cutoff date will be applied for all data and not the snap shot 
date i.e. data occurring after the clinical cutoff date will not be included in the analysis.  
4.1 
ANALYSIS POPULATIONS 
4.1.1 
ITT Population 
The ITT population It will include all patients who were randomized (Part II only) and 
received any amount of study treatment (5-FU/folic acid, oxaliplatin, bevacizumab, or 
RO5520985). Patients will be assigned to the treatment arm to which they were 
randomized. 
4.1.2 
Pharmacokinetic-Evaluable Population 
PK analyses will include all patients who received any amount of study treatment (5-
FU/folinic acid, oxaliplatin, bevacizumab, or RO5520985), the same as the safety 
analysis population.  
Patients may be excluded from the PK analysis population if they significantly violate the 
eligibility criteria, deviate significantly from the protocol or if data are unavailable or 
incomplete which may influence the pharmacokinetic analysis. Excluded cases will be 


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documented together with the reason for exclusion. All decisions on exclusions from the 
analysis will be made prior to database closure. 
4.1.3 
Safety Population 
The safety analysis population will include all patients who receive any amount of study 
treatment (5-FU/folic acid, oxaliplatin, bevacizumab, or RO5520985). Patients will be 
assigned to treatment arm based on the study treatment they actually received: patients 
randomized to bevacizumab will be included in the RO5520985 arm if they received at 
least one dose of RO5520985.  
Patients randomized to RO5520985 or bevacizumab who received only 5-FU/folic acid 
or oxaliplatin but no RO5520985 nor bevacizumab will not be included in the overall 
summaries by treatment arm but will be listed separately.  
4.2 
ANALYSIS OF STUDY CONDUCT 
Descriptive statistics will be used in evaluating the conduct of the study. Enrollment, 
study treatment administration, and discontinuations from the study will be summarized 
by part and treatment arm for all ITT randomized patients. The summaries will include 
the following: 
Total number of cycles and doses of study treatment administered (mFOLFOX-6 , 
RO5520985 or bevacizumab). 
Reasons for discontinuation of stud treatment (mFOLFOX-6 , RO5520985 or 
bevacizumab). 
A summary of the first non-protocol specified cancer therapy by treatment arm (including 
surgery with curative or debulking intent, or radiotherapy) after study discontinuation will 
be provided. 
In addition study enrollment will be summarized by treatment arm for all randomized 
patients. 
A listing of major protocol deviations will be produced.  
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
The following demographic and baseline disease characteristics and cancer history will 
be summarized by treatment arm for all ITT patients: 
Demographic and baseline disease characteristics: 
sex, age, weight, height, BMI, time since first diagnosis, ECOG at baseline, number of  
metastatic sites (1, >1), adjuvant therapy (Y/N), sum of all lesions at baseline, sum of 
target lesion at baseline, primary tumor location (left/right side as per clinical science 


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classification), primary tumor location (all terms), primary tumor in place (Y/N), tumor 
staging, tumor histology grade and type, peritoneal disease (Y/N), RAS and BRAF 
mutation (Y/N/UNK), plasma Ang2 Dx baseline value. 
In addition to the above prior cancer treatment, including surgery and radiotherapy, and 
medical history will also be summarized by treatment arm. 
The baseline value of any variable will be defined as the last available value prior to the 
first administration of study drug. 
 
4.4 
EFFICACY ANALYSIS 
This Phase II trial is designed to make a preliminary evaluation of the efficacy and safety 
of RO5520985 plus mFOLFOX-6 versus bevacizumab plus mFOLFOX-6 in patients with 
previously untreated mCRC. The emphasis of the efficacy analysis will be on estimation 
of the magnitude of treatment effect rather than hypothesis testing.  
4.4.1 
Primary Efficacy Endpoint 
Progression-Free Survival by Investigator Assessment 
The primary endpoints are defined in section 2.2.1. 
Kaplan-Meier methods will be used to estimate median PFS for each treatment arm and 
the 95% CIs for median PFS will be computed using the Brookmeyer and Crowley 
method.  
The stratified Cox proportional hazard model will be used to estimate the hazard ratio 
(i.e., the magnitude of the treatment effect) and the corresponding 95% confidence 
interval. The stratification factors are number of metastatic sites (1 vs.> 1) and 
country/region (USA vs rest of the world).  
P-values of comparing the two treatment arms from stratified and unstratified log-rank 
test will also be presented; however, given that the focus of the study is on estimation of 
treatment P values should not be interpreted as confirmatory testing. Treatment 
comparison will be based on a two sided level 0.05 stratified log rank test on all ITT 
patients. 
Kaplan-Meier curve will be provided for a visual description of the difference over time 
between the two treatment arms. IVRS stratification information data will be used for the 
analysis.  
The reasons for PFS censoring will be summarized.  
For the primary PFS (death on study) the treatment comparison based on a one sided 
level 0.05 stratified log rank test on all ITT patients will also be reported. 


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4.4.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include OS, ORR confirmed, duration of objective 
response, depth of response and 6 months and 12 months PFS rate as defined in 
section 2.2.2. All the key secondary endpoints will be tested at two sided 0.05 levels and 
will not have adjustment for multiplicity. The p values from these analyses should be 
interpreted accordingly and should not be interpreted as confirmatory testing. 
Objective Response Rate (ORR) 
An estimate of the objective response rate and 95% confidence intervals (Casella 1986) 
will be calculated for each treatment arm. The difference in objective response rate 
between the two treatment arms and its confidence intervals (Wald, 95% CI) will be 
calculated as well. 
Duration of Objective Response (OR) 
Methods for handling censoring and for analysis are the same as those described for 
PFS. Kaplan-Meier curve will be provided for a visual description of the difference in 
duration of response over time between the two treatment arms. Descriptive summaries 
of duration of response by treatment arm will be produced. These descriptive summaries 
will consist of the Kaplan-Meier estimates of median duration of response and the 
unstratified HR and its 95% CI computed using the Brookmeyer and Crowley method. 
No adjustments will be made to account for the non random nature of this comparison 
Overall Survival (OS) 
Analysis methods are the same as those described for the PFS endpoint.  
4.4.3 
Sensitivity Analyses 
4.4.3.1 
Unstratified Analysis for Progression-Free Survival 
As the primary analysis of progression-free survival is stratified, the unstratified analysis 
to compare the difference in progression-free survival between the two treatment arms, 
using a two-sided unstratified log-rank test at the 0.05 alpha level, will serve as a 
sensitivity analysis to check the robustness of the results. 
The hazard ratio λRO / λBev will be estimated using an unstratified Cox regression 
model. 
4.4.3.2 
PFS including death outside the 30 days window 
As sensitivity analysis the analysis described in Section 4.4.1 will be applied to the more 
generic definition of PFS that also includes deaths occurring more than 30 days after last 
study treatment as defined in section 2.2.1. 


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4.4.3.3 
PFS on study 
As sensitivity analysis the analysis described in Section 4.4.1 will be applied to the more 
restrictive definition of PFS on study that includes only assessments occurring within 30 
days after last study treatment as defined in section 2.2.1 
4.4.3.4 
Censoring pattern evaluation  
Censoring reasons will be summarized and time to censoring will be evaluated across 
the two arms. Deaths occurring more than 30 days after last study treatment as 
described in section 2.2.1 will be considered as a PFS event.  
Kaplan-Meier curve will be provided for a visual description of the difference in censoring 
over time between the two treatment arms. Descriptive summaries of median censoring 
time by treatment arm will be produced. These descriptive summaries will consist of the 
Kaplan-Meier estimates of median time to censoring and the unstratified HR and its 95% 
CI computed using the Brookmeyer and Crowley method.  
4.4.3.5 
Time to surgery evaluation 
A summary of time to surgery with debulking or curative intent (mean median and range) 
will be provided.  
4.4.3.6 
Prognostic factors assessment 
In order to further assess the effect of important prognostic variables on PFS, including 
Ang2 VEGF biomarker (see also section 4.4.4.2), a non-stratified Cox proportional 
hazard model will be fitted and methods like shrinkage for covariate selection may be 
applied to the following terms for best model selection:  
• 
Treatment arm  
• 
Age as continuous variable 
• 
RAS mutation status as categorical (mutant, vs wild type),  
• 
Primary tumor location as categorical (left vs right), 
• 
Primary tumor in place (yes vs no)  
• 
Time since first diagnosis as continuous variable in days,  
• 
ECOG at baseline as categorical variable,  
• 
Number of metastatic sites as categorical variable (1, >1) 
• 
Biomarker Ang2 levels at baseline as categorical variable (high vs low) 
(dichotomized at median)   
• 
Biomarker VegfA levels at baseline as categorical variable (high vs low, median 
cut off)  
• 
Treatment by biomarker group  
 
This analysis will only be applied to the generic definition of PFS (including all death 
irrespective of the 30 days window) as described in section 2.2.1  


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The effect of the biomarker as continuous variable may also be explored instead of the 
categorical biomarker high/low classification.  
Missing values will be imputed as described in section 4.8 
 
4.4.3.7 
Non confirmed ORR 
As sensitivity analysis not confirmed responses will also be summarized by treatment 
arm. 
4.4.4 
Subgroup Analyses 
4.4.4.1 
Demographic and baseline prognostic characteristics  
The effects of demographic and baseline prognostic characteristics on PFS will be 
explored for all ITT patients. It is expected that accrual in the subgroups defined by 
these baseline characteristics will not be large enough for definitive treatment 
comparisons to be made among these subgroups. 
• 
Race (white ,  non white) 
• 
Region (USA , rest of the world) 
• 
Number of metastatic sites (1 or >1)  
• 
Baseline ECOG performance status 
• 
Tumor location (left , right)  
• 
RAS mutation status (mutant, vs wild type)  
• 
Primary tumor location (left ,right) 
• 
Primary tumor in place (yes, no)  
• 
Age as categorical () 
• 
Baseline target lesion size, mm (median) (≥ median, < median)  
• 
Adjuvant treatment (Yes vs. No)Baseline Serum CEA (<=5 vs. >5 mg/dl)) 
• 
Age (<= 65 vs. >65 years) 
• 
Baseline Ang2 (high vs low) 
 
Descriptive summaries of PFS will be produced for each level of the categorical 
variables listed above for each treatment arm. These descriptive summaries will consist 
of the Kaplan-Meier estimates of median time to event and the unstratified HR and its 
95% CI. Number of patients and events in each subgroup will be summarized. 
This analysis will only be applied to the generic definition of PFS as described in section 
2.2.1  
4.4.4.2 
Ang2 baseline biomarker assessment 
In addition to the analysis already specified in the ITT population, and in order to guide 
decisions on total ang2 plasma levels as a potential biomarker to predict treatment 


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response to RO5520985, a subgroup analysis based on patients’ baseline ang2 plasma 
concentration (diagnostic assay) will also be performed. Patients will be grouped as 
Ang2 “high” or “low” based on their baseline total ang2 plasma concentrations levels with 
the median as the pre-specified cutoff point.  
The subgroup analysis will be performed in the safety population..  
The generic definition of PFS will be used for this analysis. 
In each subgroup, the primary efficacy endpoint of PFS (including death irrespective of 
the 30 day time window period as described in section 2.2.1) will be compared between 
the two treatment arms (RO5520985 plus mFOLFOX6 vs. bevacizumab plus 
mFOLFOX6) and within each treatment arm between subgroups (high Ang2 vs low 
Ang2).  
Kaplan-Meier methods will be used to estimate median PFS for each treatment arm or 
biomarker subgroup and the 95% CIs for median PFS will be computed using the 
Brookmeyer and Crowley method. The stratified Cox proportional hazard model will be 
used to estimate the hazard ratio (i.e., the magnitude of the treatment within each 
subgroup or between subgroup within each treatment) and the corresponding 95% 
confidence interval. The stratification factors are number of metastatic sites (1 vs.> 1) 
and country/region (USA vs rest of the world).  
The reasons for PFS censoring with each group and treatment will be summarized. 
Assessment of the effect of different cut off from the median on the unstratified PFS HR 
will also be conducted.  
Biomarker data will also be plotted against other known important factors and 
stratification factors by treatment arm. 
 
4.5 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
4.5.1 
Pharmacokinetic analysis 
All pharmacokinetic parameters will be presented by listings and descriptive summary 
statistics separately by group or cohorts. Individual and mean plasma RO5520985, 
oxaliplatin (free and total), and 5-FU concentration versus time data will be tabulated and 
plotted. The plasma pharmacokinetics of RO5520985, oxaliplatin, and 5-FU may be 
summarized by estimating total exposure (area under the curve [AUC]), maximum 
concentration, total clearance, volume of distribution at steady−state, and terminal half-
life (when applicable). These parameters will be tabulated and summarized (arithmetic 
mean, standard deviation, geometric mean, coefficient of variation, median, minimum, 
and maximum). Interpatient variability and drug accumulation will be evaluated. 


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Additional PK analyses will be conducted as appropriate. 
4.5.2 
PK/PD Modeling 
Exploratory graphical analyses of exposure-efficacy relationships may be produced for 
selected efficacy, PD and/or safety measurements if feasible. A PK/PD modeling 
approach may be considered in order to further explore the exposure-response 
relationship of selected response variables. 
4.5.3 
Tumor Growth Kinetics 
An exploratory assessment of tumor growth kinetic will be made by comparing post 
treatment scans with pretreatment scans. The tumor growth kinetic methodology will be 
applied to predict overall survival in the two arms.  
When available a pre-study scan (not older than 12 weeks prior to C1D1) and a study 
baseline scan will allow estimation of tumor growth rate before start of treatment and this 
will then be compared to the growth/shrinkage rate after start of treatment. 
If only a limited number of patients had pre-study scan available, the tumor growth 
kinetic will be assessed by comparing post treatment scans to the baseline scan. 
 Data will be explored using linear and/or exponential models, as appropriate, using non 
linear mixed effect modelling software. Further details are provided in the appendix 3. 
4.6 
SAFETY ANALYSES 
Safety analyses will be performed for all patients in the safety analysis population. All 
safety parameters will be analyzed using descriptive statistics, summarized and 
presented in tables. 
4.6.1 
Exposure of Study Medication 
 Summaries of treatment administration will include the following: 
 
• 
Total number of infusions for RO5520985 /Bevacizumab 
• 
Number of infusions not administered or dose reduction for RO5520985 
/Bevacizumab 
• 
Total number of cycles received for mFOLFOX6 
• 
Number of cycles not administered or dose reduction for each of the mFOLFOX6 
regimen components. 
4.6.2 
Adverse Events 
The original terms recorded on the eCRF by the Investigator for adverse events will be 
standardized by the Sponsor; for classification purposes, preferred terms will be 
assigned by the Sponsor to the original terms entered on the eCRF, using the most up-
to-date version of the Medical Dictionary for Regulatory Activities (MedDRA) terminology 


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for adverse events and diseases. AEs will be graded according to the most up-to-date 
version of NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE). 
Adverse events will be listed and summarized by MedDRA system organ class and 
preferred term. Toxicity grade, seriousness and relationship to study treatment will be 
presented, as well as summaries of deaths, AEs leading to death and premature 
withdrawal from study treatment... 
Glossary of adverse events, medication and procedures and  
4.6.3 
Laboratory Data 
All clinical laboratory data will be stored on the database in the units in which they were 
reported. Patients’ listings and summary statistics at each assessment time will be 
presented using the International System of Units (SI units; Système International 
d’Unités). Laboratory data not reported in SI units will be converted to SI units before 
processing. Laboratory test values will be presented by individual listings with flagging of 
values outside the normal ranges.  
For laboratory data, summary tables of change from baseline over time based on SI 
(Standard International) units will be displayed. Shifts in toxicity grade from baseline to 
the worst grade observed during treatment will be presented for selected laboratory 
parameters.  
Additional figures/tables/listings may be produced as deemed appropriate. 
For standard reference ranges and transformation of data and definition of laboratory 
abnormalities refer to section 6.5.2 of the protocol. 
4.6.4 
Vital Signs 
Vital signs data will be presented by individual listings with flagging of values outside the 
normal ranges and flagging of marked abnormalities. In addition, tabular summaries will 
be used, as appropriate. Additional figures/tables/listings may be produced as deemed 
appropriate. 
4.6.5 
ECG Data Analysis 
ECG data will be presented by individual listings with flagging of values outside the 
normal ranges and flagging of marked abnormalities. In addition, tabular summaries will 
be used, as appropriate. 
4.6.6 
Concomitant Medications 
The original terms recorded on the patients’ eCRF by the Investigator for concomitant 
medications will be standardized by the sponsor. For classification purposes, preferred 
terms will be assigned by the Sponsor to the original terms entered on the eCRF, using 
the most up-to-date version of the d the International Non-proprietary Name (INN) Drug 


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Terms and Procedures Dictionary for treatments and surgical and medical procedures. 
Concomitant medications will be presented in listings and summary tables by treatment 
arm. . 
4.7 
BIOMARKER  
Exploratory biomarker parameters may be presented by listings and descriptive 
summary statistics separately by treatment arms. 
All analyses of PD and exploratory biomarkers will be based on the safety analysis 
population, in other words, any patients who received any amount of study treatment (5-
FU/folic acid, oxaliplatin, bevacizumab, or RO5520985). 
For the analysis of PD biomarkers the primary evaluation will be based on the observed 
change from baseline. Both actual values and estimated parameters will be presented in 
summary tables and graphically. 
To assess predictability of a biomarker, the association between clinical outcome and 
the biomarker level or changes thereof will be explored. Details of the biomarker analysis 
will be provided within the biomarker analysis plan.  
Analysis of Ang 2 biomarker data at baseline are provided in section 4.4.4.2. 
Exploratory PKPD analysis may be performed  for selected biomarker if appropriate. 
4.8 
MISSING DATA 
In case of incomplete RECIST assessment’s or death dates if the day is missing, but the 
month and year are available, then the day will be imputed as the first day of the month. 
No imputation will be done for missing month or year. For biomarker analysis values 
below the limit of quantitation (BLQ) will be imputed as half of the BLQ value. Details of 
the BLQ values employed for each biomarker are stored in the output specification 
document within the DAP module 2. For the categorization of patients in high or low 
biomarker subgroup any patient for which the biomarker value at baseline is missing 
because outside the upper range of quantitation of the assay will be considered as been 
in the high subgroup. 
 
4.9 
INTERIM ANALYSES 
No stopping for efficacy is planned. For interim analysis details please refer to the 
interim analysis plan.  


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5. 
REFERENCES 
 


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Appendix 1  
Protocol Synopsis 


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Appendix 2  
Schedule of Assessments 


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Appendix 3  
Tumor growth kinetic analysis 
Tumor kinetics (TK) model 
 
A non-linear mixed-effect model describing the time dynamics of tumor size (sum of 
lesion diameter) as a function of drug exposure will be developed on the basis of the 
data collected in each arm of the current study.  
Adopting a structure which has already been considered in previous analysis of anti-
angiogenic drug effect in mCRC patients [1,2], the following differential equation could 
be considered to describe such a time dynamics: 
 
with y, the tumor size, 
, the tumor size at baseline, 
, the tumor growth rate,  
 the tumor shrinkage rate and 
, the drug exposure level. The tumor 
shrinkage rate is expected to decrease over time (in this equation, exponentially, at a 
rate ). 
Various alternatives models will be considered to describe drug exposure ranging from 
daily dose (K-PD approach) to individual concentration at any time t, as predicted from a 
population PK model.  
This model will be used to extract patient-level tumor kinetics metrics such as time to 
growth (TTG) and relative change in tumor size (TSR) from baseline at first post-
treatment visit (
and 
 respectively) already identified as relevant predictors of 
survival in mCRC (see [1,2] for further details). 
 
Validation of the TK model  
 
In order to validate the TK model (1), it is proposed to leverage historical data from the 
phase III study NO16966 with bevacizumab/FOLFOX4. [3]. 
A tumor kinetics model (similar to the one described in the previous section) will be 
fitted to the NO16966 data collected in the 350 patients treated with combination 
therapy with FOLFOX-4+Bev. From this model, the individual estimates of tumor kinetics 
metrics will be derived. 
A Kolmogorov-Smirnov test (or equivalent) will be used to compare the distributions of 
 and 
 in patients treated with chemotherapy+Bev in studies BP29262 and 
NO16966. 
To sustain this comparison, it will assumed that the effects of FOLFOX-4 and mFOLFOX6 
on the tumor size dynamics are not markedly different [4]. 
 
Prediction of overall survival 
 
As observed in multiple clinical trials with anti-angiogenic treatments, changes in tumor 
size correlates strongly with OS [5]. Since exposure is explicitly influencing tumor 
shrinkage in model (1), the drug effect is carried over in the survival model throughout 
the estimates of individual tumor kinetics (e.g.  
). Hence, in a survival model 
(1) 


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applied to mCRC patients, tumor kinetics metrics can be used as surrogate marker of the 
drug effect. 
 
In order to predict the overall survival in patients treated with mFOLFOX6+Van or Bev, it 
is proposed again to rely on the NO16966 study where 351 patients were allocated to 
FOLFOX-4+placebo and 350 to FOLFOX-4+bevacizumab and for which survival data is 
available.  
 
A tumor kinetics model (similar to the one described in the previous section) will be 
fitted to the tumor size data collected in these 701 patients. This model will be used to 
extract individual estimates of tumor kinetics metrics. 
Then, a parametric survival model will be developed to describe the distribution of 
survival time in study NO16966. The following tumor kinetics covariates will be tested 
for inclusion in the model: 
, TTG and TSR. In addition, baseline characteristics will also 
be tested for inclusion in the model, such as ECOG performance status, number of 
metastatic sites, alkaline phosphatase level and presence or absence of prior adjuvant 
therapy, as they may impact the death hazard in this patient population.  
Various distributions will be considered to fit the time to survival model, including (but 
not limited to) exponential, log-normal and Weibull. The most suitable distribution is 
selected on the basis of penalized log-likelihood value (the smaller, the better). There is 
no clinical insight involved in the process of selecting the best parametric model. 
 
If deemed suitable for prediction purpose, the survival model developed on the basis of 
the NO16966 data will be used for predicting OS in patients whose tumor kinetics 
correspond to the one observed in the current (BP29262) study. 
To estimate the distribution of the difference in median OS, 1000 replicates of 
independent phase III studies (each of size N=1000) of mFOLFOX6+Bev vs. 
mFOLFOX6+Van (allocation ratio 1:1) were simulated. Each replicate will contribute a 
median OS time in each treatment group. 
For each replicate (i.e. each simulated study) 
- 
model parameters (for TK and OS models respectively) will be sampled from the 
model parameter uncertainty distribution (standard error),  
- 
individual tumor kinetics metrics (
 and 
) will be derived from individual 
tumor kinetics profiles simulated using individual model parameter estimates 
sampled from log-normal distributions (representing inter-individual variability 
in tumor kinetics), 
- 
individual survival times will be drawn from the parametric survival model 
probability density function, 
- 
baseline characteristics (e.g. 
, 
, …) will be generated using non-
parametric bootstrap from the baseline characteristics observed in study 
BP29262, in each treatment arm respectively.  
 


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The distribution of the difference in median OS (∆OS) will be displayed and the 
proportion of simulated studies with ∆OS >5 month will be calculated. This quantity will 
correspond to the predictive power of a phase III study (with N=1000). 
 
Validation of the OS model 
 
In order to validate the OS model (1), it is proposed to leverage literature data, where 1L 
mCRC patients were treated with either FOLFOX-4 or mFOLFOX6, given in combination 
with either Bev or Cetuximab or Panitumumab.. 
 
The Kaplan-Meier curves observed in the CRYSTAL [6,7], OPUS [8], FIRE-3 [9], TRIBE-3 
[10], PRIME [11], PEAK [12], HORIZON-3 [13] and PACCE [14] will be overlaid to the 
simulated curves (described in the previous section) and the one observed in study 
NO16966 in patients treated with FOLFOX-4+Bev. 
The differences observed between the study-specific curves and the simulated ones will 
be assessed by overlaying the KM simulated from the model to the ones reported in 
published trials. 
 
References 
 
[1] Claret et al. 2009 doi:10.1200/JCO.2008.21.0807 
[2] Claret et al. 2013 doi:10.1200/JCO.2012.45.0973 
[3] Saltz et al. 2008 doi:10.1200/JCO.2007.14.9930 
[4] Ohhara et al. 2015 doi:10.2147/OTT.S77190 
[5] Bruno et al. 2014 doi:10.1038/clpt.2014.4 
[6] Van Cutsem et al. 2009 doi:10.1056/NEJMoa0805019 
[7] Van Cutsem et al. 2011 doi:10.1200/JCO.2010.33.5091 
[8] Bokemeyer et al. 2011 doi:10.1093/annonc/mdq632 
[9] Heinemann et al. 2014 doi:10.1016/S1470-2045(14)70330-4 
[10] Loupakis et al. 2014 doi:10.1056/NEJMoa1403108 
[11] Douillard et al. 2010 doi:10.1200/JCO.2009.27.4860 
[12] Schwartzberg et al. 2014 doi:10.1200/JCO.2013.53.2473 
[13] Schmoll et al. 2012  doi:10.1200/JCO.2012.42.5355 
[14] Hecht et al. 2008 doi:10.1200/JCO.2008.19.8135