Conditions: Metastatic Colorectal Cancer
Keywords: Metastatic Colorectal Cancer
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 10
Healthy volunteers: no

Brief summary:
This is a Phase 1b/2a study investigating the safety and efficacy of Sym004, an investigational medicinal product (IMP), in combination with FOLFIRI (chemotherapy) when administered every second week (Q2W).

Detailed description:
In the Phase 1b (Dose-Escalation) portion of the trial, patients will be sequentially enrolled to dose-escalation cohorts until establishment of the Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D) of Sym004 in combination with FOLFIRI.

The Phase 2a (Dose-Expansion) portion of the trial is expected to begin after establishing the RP2D.

Note: In January 2017, the trial was terminated during Phase 1b and enrollment was prematurely discontinued. The primary objective changed to assess the safety of the treatment combination; collection of data for secondary and exploratory objectives was omitted.

Arms:
arm 1: Phase 1b, Dose-Escalation: Dose Level 1 arm 2: Phase 1b, Dose-Escalation: Dose Level -1 arm 3: Phase 2a, Dose-Expansion: Sym004 in the RP2D in combination with FOLFIRI

Interventions: intervention 1: Sym004 intervention 2: FOLFIRI
Intervention descriptions: intervention 1: Sym004 is a 1:1 mixture of 2 monoclonal antibodies (mAbs), which bind specifically to 2 non-overlapping epitopes of the epidermal growth factor receptor (EGFR). intervention 2: The standard FOLFIRI regimen consists of Irinotecan (180 mg/m\^2 IV, infused over 60-90 minutes) concurrently with Folinic Acid (400 mg/m\^2 IV, infused over 120 minutes) followed by 5-FU (400 mg/m\^2 IV bolus, then 2400 mg/m\^2 infused over 46 hours).

Protocol document:
Prot_000.pdf: 
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Clinical Trial Protocol 
Trial ID: Sym004-09 
Version 4.0 
 
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CLINICAL TRIAL PROTOCOL 
Trial Title: 
An Open-label, Multi-Center Phase 1b/2a Trial Investigating 
Different Doses of Sym004 in Combination with FOLFIRI in 
Patients with Metastatic Colorectal Cancer Progressing after 
First-Line Therapy 
Short Title: 
Sym004 in Combination with FOLFIRI in Metastatic 
Colorectal Cancer Patients 
Sponsor: 
Symphogen A/S 
 
 
 
Sponsor’s Medical 
Expert: 
 
 
Coordinating 
Investigator: 
 
 
 
 
 
Trial ID: 
Sym004-09 
Trial Phase: 
Phase 1b/2a 
EudraCT number: 
2015-003047-19 
IND Number: 
105953 
Protocol Version/Date: 
4.0 / 22-Feb-2017 (Amendment 3) 
Previous Protocol 
Versions/Dates: 
3.0 / 05-Aug-2016 (Amendment 2) 
2.0 / 09-Nov-2015 (Amendment 1) 
1.0 / 26-Aug-2015 
List of Responsible 
Person/ Contact 
Listing 
 
Lists of Investigators responsible for conducting the trial, 
medically qualified physicians responsible for all trial site 
related medical decisions (if other than the Investigators), 
Monitors, clinical laboratories and other medical and/or 


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technical departments and/or institutions involved in the trial 
are provided as separate documents. 
GCP Statement: The trial will be conducted in compliance with this Clinical Trial Protocol, 
ICH E6 GCP (1) and applicable regulations. 
This confidential document is the property of Symphogen A/S. No unpublished information 
contained herein may be passed on, reproduced, published or used without prior written 
approval from Symphogen A/S. Access to this document must be restricted to relevant 
parties. 


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Signature Page 
Sponsor 
I hereby approve the Clinical Trial Protocol as suitable and appropriate for use. 
 
 
 
 
 
 
 
 
Symphogen A/S 
 
 
 
 
 
 
 
Symphogen A/S 
 
 
 
 
 
 
 
 
Symphogen A/S 
 
 
 
 
 
 
 
Symphogen A/S 
 
 
 


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Signature Page 
Principal Investigator 
 
I, the undersigned, am responsible for the conduct of the trial at this site and agree; 
 To assume responsibility for the proper conduct of the clinical trial at this Investigational 
Site 
 Not to implement any changes to the Clinical Trial Protocol without agreement from the 
Sponsor and prior review and written approval from the Ethics Committee, except where 
necessary to eliminate an immediate hazard to the patient 
 That I am aware of, and will comply with “Good Clinical Practice” (ICH GCP) 
(CPMP/ICH/135/95) and all applicable regulatory requirements 
 That all site staff to which I have delegated tasks for this clinical trial, are adequately 
informed about the investigational product(s) and of their trial-related duties and 
functions as described in the Clinical Trial Protocol 
 
________________________________ 
 
____________________ 
Signature 
 
 
 
 
 
Date of Signature 
 
Name: 
Academic degree: 
Function:  
Institution:  
 
 
 


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TABLE OF CONTENTS 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................ 11 
2 
SYNOPSIS ............................................................................................................. 14 
3 
BACKGROUND AND RATIONALE .................................................................. 19 
3.1 
Disease and Treatment ........................................................................................... 19 
3.1.1 
Metastatic Colorectal Cancer ................................................................................. 19 
3.1.2 
Current Treatment of Metastatic Colorectal Cancer Disease ................................. 19 
3.2 
Investigational Medicinal Product ......................................................................... 19 
3.2.1 
Sym004................................................................................................................... 19 
3.2.2 
Mechanism of Action ............................................................................................. 20 
3.2.3 
Summary of Non-clinical Findings ........................................................................ 20 
3.2.4 
Summary of Clinical Findings ............................................................................... 20 
3.2.4.1 
Safety ...................................................................................................................... 20 
3.2.4.2 
Pharmacokinetics ................................................................................................... 22 
3.2.4.3 
Pharmacodynamic Effects ...................................................................................... 22 
3.2.4.4 
Antitumor Effects ................................................................................................... 22 
3.3 
Trial Rationale ........................................................................................................ 23 
3.4 
Dose Rationale ....................................................................................................... 24 
3.5 
Overall Benefit/Risk ............................................................................................... 24 
4 
TRIAL OBJECTIVES AND ENDPOINTS ........................................................... 26 
4.1 
Dose-Escalation (Phase 1b) .................................................................................... 26 
4.1.1 
Primary Objective .................................................................................................. 26 
4.1.2 
Secondary Objectives ............................................................................................. 26 
4.2 
Dose-Expansion (Phase 2a) .................................................................................... 26 
4.2.1 
Primary Objective .................................................................................................. 26 
4.2.2 
Secondary Objectives ............................................................................................. 26 
4.3 
Exploratory Studies ................................................................................................ 26 
4.4 
Trial Endpoints ....................................................................................................... 27 
4.4.1 
Primary Endpoint of Dose-Escalation (Phase 1b) .................................................. 27 
4.4.2 
Primary Endpoint of Dose-Expansion Phase (Phase 2a) ....................................... 27 
4.4.3 
Secondary Endpoints of Dose-Escalation and Dose-Expansion Phases ................ 27 
4.4.3.1 
Safety ...................................................................................................................... 27 
4.4.3.2 
Anti-tumor Response.............................................................................................. 27 
4.4.3.3 
Pharmacokinetic Assessment (Dose-Escalation only) ........................................... 28 
4.4.3.4 
Pharmacodynamic and Biomarker Assessment ..................................................... 28 
5 
TRIAL DESIGN .................................................................................................... 29 
5.1 
Overall Design and Plan ......................................................................................... 29 
5.2 
Discussion of Trial Design ..................................................................................... 31 
5.2.1 
Rationale for Trial Design ...................................................................................... 31 
5.2.2 
Rationale for Trial Population ................................................................................ 31 
5.2.3 
Rationale for Starting Dose and Route of Administration ..................................... 31 
5.2.4 
Rationale for Dose-Escalation and Dose-Expansion ............................................. 31 


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5.3 
Schedule of Events ................................................................................................. 31 
5.3.1 
Screening ................................................................................................................ 32 
5.3.2 
Screening-Failures .................................................................................................. 33 
5.3.3 
Treatment ............................................................................................................... 33 
5.3.4 
End of Treatment and One Month Follow-up Visit ............................................... 34 
5.3.5 
Flow Chart – Schedule of Assessments ................................................................. 34 
5.4 
Recruitment Period ................................................................................................. 37 
5.5 
Number of Patients ................................................................................................. 37 
5.6 
End of Trial ............................................................................................................ 37 
5.7 
Independent Evaluation Committees ..................................................................... 37 
6 
PATIENT SELECTION AND WITHDRAWAL .................................................. 38 
6.1 
Inclusion Criteria All Cohorts ................................................................................ 38 
6.2 
Exclusion Criteria All Cohorts ............................................................................... 38 
6.3 
Withdrawal from Trial Treatment .......................................................................... 41 
6.3.1 
Withdrawal from Treatment with Sym004 and/or FOLFIRI ................................. 42 
6.3.2 
Withdrawal from Trial ........................................................................................... 43 
6.4 
Replacement of Patients ......................................................................................... 43 
6.4.1 
Dose-Escalation Phase ........................................................................................... 43 
6.4.2 
Dose-Expansion Phase ........................................................................................... 43 
7 
TREATMENT ........................................................................................................ 44 
7.1 
Investigational Medical Product/Sym004 .............................................................. 44 
7.1.1 
Identity of the Investigational Medicinal Product/Sym004 ................................... 44 
7.1.2 
Packaging and Labeling of Sym004....................................................................... 44 
7.1.3 
Handling, Storage and Preparation of Sym004 ...................................................... 44 
7.1.4 
Administration of Sym004 ..................................................................................... 45 
7.1.4.1 
Treatment Schedule ................................................................................................ 45 
7.1.4.2 
Dose-Escalation Phase ........................................................................................... 45 
7.1.4.3 
Dose-Escalation Decision Points ........................................................................... 46 
7.1.4.4 
Dose-Expansion Phase ........................................................................................... 47 
7.1.4.5 
Infusion Rate for Administration of Sym004 ......................................................... 47 
7.1.4.6 
Patient Monitoring During and After Infusion of Sym004 .................................... 48 
7.1.4.7 
Infusion-Related Reactions to Sym004 .................................................................. 48 
7.1.4.8 
Handling of Infusion-Related Reactions ................................................................ 49 
7.1.5 
Dose-Adjustments and Delays of Sym004............................................................. 49 
7.1.5.1 
Sym004 Dose-Adjustments for Body Weight ........................................................ 50 
7.1.5.2 
Sym004 Dose-Modifications for Skin Toxicity ..................................................... 50 
7.1.5.3 
Sym004 Dose-Modifications for Events other than Grade 3 Skin Toxicity .......... 51 
7.2 
Other Drugs to be used in the Trial ........................................................................ 51 
7.2.1 
FOLFIRI ................................................................................................................. 51 
7.2.1.1 
FOLFIRI Delays and Dose-Reduction ................................................................... 52 
7.2.2 
Order of Sym004 and FOLFIRI Administration .................................................... 53 
7.2.3 
Prophylactic Treatment .......................................................................................... 53 
7.2.3.1 
Prophylactic Treatment for Infusion Reactions ..................................................... 53 


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7.2.3.2 
Prophylactic Treatment for Gastrointestinal Toxicities ......................................... 53 
7.2.3.3 
Prophylactic Treatment for Skin Toxicity .............................................................. 54 
7.2.4 
Treatment of Skin Toxicity .................................................................................... 55 
7.2.5 
Treatment of Hypomagnesemia ............................................................................. 61 
7.3 
Blinding .................................................................................................................. 61 
7.4 
Drug Accountability and Compliance Check......................................................... 61 
7.5 
Concomitant Medication/Therapy.......................................................................... 62 
7.5.1 
Allowed Concomitant Medication/Therapy and Procedures during the Trial ....... 62 
7.5.2 
Prohibited Concomitant Medication/Therapy and Procedures during the Trial .... 62 
7.6 
Medical Care of Patients after End of Trial Participation ...................................... 63 
8 
TRIAL ASSESSMENTS ....................................................................................... 64 
8.1 
Baseline Characteristics / Eligibility Assessments................................................. 64 
8.1.1 
Signing of Informed Consent ................................................................................. 64 
8.1.2 
Demographics......................................................................................................... 64 
8.1.3 
Medical History ...................................................................................................... 64 
8.1.4 
Tumor Characteristics and Extent of Disease ........................................................ 64 
8.1.5 
Prior Cancer Treatments......................................................................................... 64 
8.2 
Safety Assessments ................................................................................................ 65 
8.2.1 
Medication Survey ................................................................................................. 65 
8.2.2 
Adverse Event Survey ............................................................................................ 65 
8.2.3 
Dose-Limiting Toxicities Evaluation (Dose-Escalation Only) .............................. 65 
8.2.4 
Vital Signs and Body Weight ................................................................................. 65 
8.2.5 
Performance Status ................................................................................................. 65 
8.2.6 
Physical Examination ............................................................................................. 66 
8.2.7 
Dermatological Assessment ................................................................................... 66 
8.2.8 
Electrocardiogram .................................................................................................. 66 
8.2.9 
Laboratory Assessments and Pregnancy Test ........................................................ 67 
8.2.9.1 
Hematology Panel .................................................................................................. 67 
8.2.9.2 
Biochemistry Panel ................................................................................................ 68 
8.2.9.3 
Coagulation Panel .................................................................................................. 68 
8.2.9.4 
Urinalysis ............................................................................................................... 69 
8.2.9.5 
Pregnancy Test ....................................................................................................... 69 
8.3 
Disease Assessments .............................................................................................. 69 
8.3.1 
Tumor Marker Evaluation ...................................................................................... 69 
8.3.2 
Disease Status Evaluation using CT or MRI .......................................................... 70 
8.4 
Pharmacokinetic Assessments (Dose-Escalation Only) [Omitted as of 
Amendment 3] ........................................................................................................ 71 
8.5 
Anti-Drug Antibody Testing (Omitted as of Amendment 3) ................................. 71 
8.6 
Biomarker Tumor, Blood and Urine Sample (Omitted as of Amendment 3) ........ 72 
8.6.1 
Archival Tumor Sample Collection (Omitted as of Amendment 3) ...................... 72 
8.6.2 
Fresh Tumor Biopsy Collection (Omitted as of Amendment 3) ............................ 72 
8.6.3 
Blood and Urine Sample Collection (Omitted as of Amendment 3) ..................... 73 
8.7 
Handling of Biological Samples ............................................................................ 73 


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8.8 
Follow-up Assessments .......................................................................................... 73 
8.9 
Appropriateness of Measurements ......................................................................... 73 
9 
ADVERSE EVENTS ............................................................................................. 74 
9.1 
Definitions of Adverse Events ............................................................................... 74 
9.1.1 
Adverse Event ........................................................................................................ 74 
9.1.2 
Adverse Events of Medical Interest ....................................................................... 74 
9.1.3 
Expected Adverse Events ....................................................................................... 74 
9.1.4 
Serious Adverse Event ........................................................................................... 75 
9.2 
Adverse Event Recording and Reporting Instructions ........................................... 76 
9.2.1 
Adverse Event Recording Period ........................................................................... 76 
9.2.2 
Diagnosis ................................................................................................................ 76 
9.2.3 
Intensity .................................................................................................................. 76 
9.2.4 
Relationship to Investigational Medicinal Product/Sym004 and FOLFIRI ........... 77 
9.2.5 
Outcome ................................................................................................................. 77 
9.2.6 
Follow-up of Adverse Events ................................................................................. 78 
9.3 
Serious Adverse Event Recording and Reporting .................................................. 78 
9.4 
Safety Reporting to Health Authorities, Independent Ethics 
Committees/Institutional Review Boards and Investigators .................................. 79 
9.5 
Dose-Limiting Toxicities ....................................................................................... 79 
9.5.1 
Definition of Dose-Limiting Toxicities.................................................................. 79 
9.5.2 
Observation Period for Dose-Limiting Toxicities .................................................. 80 
9.5.3 
Reporting of Dose-Limiting Toxicities .................................................................. 80 
9.6 
Reporting of Infusion-related Reactions ................................................................ 80 
9.7 
Pregnancy ............................................................................................................... 80 
10 
STATISTICS .......................................................................................................... 82 
10.1 
Sample Size Determination .................................................................................... 82 
10.2 
Analysis Populations .............................................................................................. 82 
10.3 
Primary Endpoint and Analysis.............................................................................. 83 
10.3.1 
Dose Escalation Phase ............................................................................................ 83 
10.3.2 
Dose Expansion Phase ........................................................................................... 83 
10.4 
Secondary Endpoints and Analyses ....................................................................... 83 
10.4.1 
Safety Endpoints and Analyses .............................................................................. 83 
10.4.1.1 Adverse Events ....................................................................................................... 83 
10.4.1.2 Clinical Laboratory Values .................................................................................... 84 
10.4.1.3 Other Assessments Related to Safety ..................................................................... 84 
10.4.2 
Efficacy Endpoints and Analyses ........................................................................... 84 
10.4.2.1 Other Efficacy Assessments ................................................................................... 85 
10.4.3 
Pharmacokinetic Endpoint and Analyses (Omitted as of Amendment 3) .............. 85 
10.4.4 
Pharmacodynamics Endpoints and Analyses (Omitted as of Amendment 3) ........ 86 
10.5 
Interim Analysis ..................................................................................................... 86 
10.6 
Data Collection and Analysis beyond Primary Analysis ....................................... 86 
10.7 
Deviations from the Statistical Plan ....................................................................... 87 
11 
ETHICS .................................................................................................................. 88 


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11.1 
Independent Ethics Committee or Institutional Review Board .............................. 88 
11.2 
Patient Information and Informed Consent ............................................................ 88 
11.3 
Compliance Reference Documents ........................................................................ 88 
12 
SAFETY SURVEILLANCE SET-UP ................................................................... 89 
12.1 
Independent Safety Monitoring Committee ........................................................... 89 
12.2 
Other Safety Surveillance Activities ...................................................................... 89 
13 
MONITORING AND QUALITY ASSURANCE ................................................. 91 
13.1 
Compliance with Good Clinical Practice ............................................................... 91 
13.2 
Source Documentation ........................................................................................... 91 
13.3 
Monitoring .............................................................................................................. 91 
13.4 
Audits and Inspections ........................................................................................... 91 
14 
DATA HANDLING AND RECORD KEEPING .................................................. 93 
14.1 
Data Protection ....................................................................................................... 93 
14.2 
Data Transactions and Access ................................................................................ 93 
14.3 
Case Report Form................................................................................................... 93 
14.4 
Data Processing ...................................................................................................... 93 
14.5 
Retention of Trial Documents at Site ..................................................................... 94 
15 
REGISTRATION AND COMMUNICATION OF RESULTS ............................. 95 
15.1 
Use of Information ................................................................................................. 95 
15.2 
Registration and Publication .................................................................................. 95 
16 
INSURANCE AND LIABILITY .......................................................................... 96 
17 
CHANGES TO THE FINAL CLINICAL TRIAL PROTOCOL .......................... 97 
18 
PREMATURE TERMINATION OF THE TRIAL OR A TRIAL SITE .............. 98 
18.1 
Premature Termination of the Trial ........................................................................ 98 
18.2 
Premature Termination of a Trial Site.................................................................... 98 
19 
REFERENCES ....................................................................................................... 99 
20 
APPENDICES ...................................................................................................... 101 
21 
SUMMARY OF CHANGES ............................................................................... 109 
21.1 
Protocol Amendment 1 dated 09-Nov-2015 ........................................................ 109 
21.2 
Protocol Amendment 2 dated 05-Aug-2016 ........................................................ 111 
21.3 
Protocol Amendment 3 dated 22-Feb-2017 ......................................................... 119 
 
LIST OF FIGURES 
Figure 1 Overall Trial Design ............................................................................................... 29 
LIST OF APPENDICES 
Appendix 1 
Response Evaluation Criteria in Solid Tumors (RECIST v1.1) ................. 101 
Appendix 2 
FOLFIRI Guidelines for Dose Modifications and Delays .......................... 106 
 
LIST OF TABLES 
Table 1 
Overall Trial Plan ................................................................................................... 32 


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Table 2 
Flow Chart – Schedule of Assessments ................................................................. 35 
Table 3 
Description of Investigational Medicinal Product/Sym004 ................................... 44 
Table 4 
Infusion Rate for Administration of Sym004 ......................................................... 47 
Table 5 
Infusion-Related Reactions Management Guidelines ............................................ 49 
Table 6 
Sym004 Dose-Reduction for Grade 3 Skin Toxicity ............................................. 51 
Table 7 
FOLFIRI Dose-Reductions .................................................................................... 52 
Table 8 
Mandatory Prophylaxis for Diarrhea...................................................................... 54 
Table 9 
Mandatory Prophylaxis for Skin Toxicities ........................................................... 54 
Table 10 Treatment of Rash .................................................................................................. 56 
Table 11 Treatment of Xerosis .............................................................................................. 57 
Table 12 Treatment of Paronychia ........................................................................................ 58 
Table 13 Treatment of Pruritus ............................................................................................. 59 
Table 14 Treatment of Photosensitivity ................................................................................ 60 
Table 15 Treatment of Fissures ............................................................................................. 61 
Table 16 Schedule of Safety Blood and Urine Samples ....................................................... 67 
Table 17 Schedule of Pharmacokinetic Assessments ........................................................... 71 
Table 18 Timelines for Reporting Serious Adverse Events and Follow-up.......................... 78 
Table 19 PK Endpoints Definitions and Derivations ............................................................ 85 
Table 20 Response Criteria for Evaluation of Target Lesions ............................................ 104 
Table 21 Response Criteria for Evaluation of Non-target Lesions ..................................... 104 
Table 22 Overall Response Status for Patients with Baseline Measurable Disease ........... 104 
Table 23 Best Overall Response when Confirmation of CR and PR Required .................. 105 
Table 24 Protocol Amendment 1 dated 09-Nov-2015 ........................................................ 109 
Table 25 Protocol Amendment 2 dated 05-Aug-2016 ........................................................ 112 
Table 26 Protocol Amendment 3 dated 22-Feb-2017 ......................................................... 120 
 
 
 
 
 


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1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
ADA  
Anti-Drug Antibodies 
ADCC  
Antibody-Dependent Cellular Cytotoxicity  
AE 
 
Adverse Event 
ALP 
 
Alkaline Phosphatase 
ALT 
 
Alanine Aminotransferase 
ANC  
Absolute Neutrofil Count 
AST   
Aspartate Aminotransferase 
BMI 
 
Body Mass Index 
BUN  
Blood Urea Nitrogen 
CA19-9 
Carbohydrate Antigen 19-9 
CDC  
Complement-Dependent Cytotoxicity 
CEA  
Carcinoembryonic Antigen  
CHF  
Congestive Heart Failure 
CI 
 
Confidence Interval 
CK 
 
Creatine Kinase 
CNS  
Central Nervous System 
CR 
 
Complete Response 
CRC  
Colorectal Cancer 
CT 
 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTP 
 
Clinical Trial Protocol 
CTR 
 
Clinical Trial Report 
DLT 
 
Dose-Limiting Toxicity 
ECOG  
Eastern Cooperative Oncology Group 
CRF 
 
Case Report Form 
EGFR  
Epidermal Growth Factor Receptor 
EOI 
 
End of Infusion 
EOT 
 
End of Treatment 
FAS 
 
Full Analysis Set 
FFPE  
Formalin Fixed Paraffin Embedded 
FUP 
 
Follow-up 
GCP  
Good Clinical Practice 
GGT  
Gamma-Glutamyl Transpeptidase 
HA 
 
Health Authority 
hCG 
 
Human Chorionic Gonadotropin 
HIV 
 
Human Immunodeficiency Virus 
IB 
 
Investigator’s Brochure 
ICH 
 
International Conference on Harmonisation 
ICMJE  
International Committee of Medical Journal Editors 


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ISMC  
Independent Safety Monitoring Committee 
IEC 
 
Independent Ethics Committee 
IMP 
 
Investigational Medicinal Product 
INR 
 
International Normalized Ratio 
IRB 
 
Institutional Review Board 
IRR 
 
Infusion-Related Reaction 
ISF 
 
Investigator Site File 
iv 
 
Intravenous 
KRAS  
Kirsten Rat Sarcoma 
LVEF  
Left Ventricular Ejection Fraction 
mAb  
Monoclonal Antibody 
mAb992 
Monoclonal Antibody 992 (futuximab) 
mAb1024 
Monoclonal Antibody 1024 (modotuximab) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
 
Magnetic Resonance Image/Imaging 
MTD  
Maximum Tolerated Dose 
NCI-CTCAE National Cancer Institute-Common Terminology Criteria for Adverse Events 
NE 
 
Not Evaluable 
NRAS  
Neuroblastoma Rat Sarcoma 
NSCLC 
Non-Small Cell Lung Carcinoma  
OR 
 
Objective Response 
PD 
 
Progressive Disease 
PK 
 
Pharmacokinetic(s) 
PO 
 
Per Os  
PR 
 
Partial Response 
PS 
 
Performance Status 
PSA 
 
Prostate-Specific Antigen 
PT 
 
Prothrombin Time 
PTT 
 
Partial Thromboplastin Time 
QID 
 
Four Times Per Day 
RAS  
Rat Sarcoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D  
Recommended Phase 2 Dose 
RTK  
Receptor Tyrosine Kinases 
SAE 
 
Serious Adverse Event 
SAP 
 
Statistical Analysis Plan 
SCCHN 
Squamous Cell Carcinoma of the Head and Neck  
SD 
 
Stable Disease 
SOC  
System Organ Class 
SOI 
 
Start of Infusion 


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SOP 
 
Standard Operating Procedure(s) 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TdP 
 
Torsade de Pointes 
TEAE  
Treatment Emergent Adverse Events 
TID 
 
Three Times Per Day 
TNM  
Tumor, Node, Metastasis  
ULN  
Upper Limit of Normal 
WT 
 
Wild Type 
 
PHARMACOKINETIC TERMS 
AUC  
Area under the concentration-time curve 
AUCNorm 0-336h Dose-normalized area under the concentration-time curve from end of 
infusion to 336 hours 
CL 
 
Clearance 
Cmax 
 
Maximum concentration 
Ctrough  
Trough Concentration 
T½ 
 
Elimination half-life 
Tmax 
 
Time of maximum concentration 
V 
 
Volume of distribution 
 
OTHER TERMS 
Baseline 
The value measured at Day 1 of Cycle 1, before initiation of Sym004. For 
variables/assessments not scheduled to be performed at that time point or that 
are missing at baseline, the baseline value is the value from the screening 
period measured closest to Day 1 of Cycle 1  
FA 
Folinic Acid 
5-FU 
Fluorouracil 
FOLFIRI 
Combination of FOLinic Acid (FA), Fluorouracil (5-FU) and IRInotecan 
(irinotecan) 
FOLFOX  
Combination of FOLinic Acid (FA), Fluorouracil (5-FU) and OXaliplatin 
(oxaliplatin) 
 
 
 


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2 
SYNOPSIS 
Trial Title 
An Open label, Multi-Center Phase 1b/2a Trial Investigating Different Doses of 
Sym004 in Combination with FOLFIRI in Patients with Metastatic Colorectal 
Cancer Progressing after First-Line Therapy 
Trial ID and Phase 
Sym004-09, Phase 1b/2a 
Trial Sites and 
Countries 
Dose-escalation: Approximately 8 investigational trial sites 
Dose-expansion: 10 to 15 investigational trial sites  
Expected countries: USA and countries within the EU 
Planned Trial 
Period 
The dose-escalation phase of the trial is expected to begin Q4 2015. Patients will be 
sequentially enrolled to dose-escalation cohorts until establishment of the Maximum 
Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D), expectedly Q4 
2016.  
The dose-expansion phase of the trial is expected to begin Q4 2016 with enrollment 
to be completed Q2-Q3 2017. 
Objectives 
Primary Objective of Dose-Escalation Phase (Phase 1b): 
To determine the MTD and/or RP2D of Sym004 when administered by intravenous 
(iv) infusion every second week in combination with a standard dosing regimen of 
FOLFIRI (folinic acid, 5-flurouracil, irinotecan) to patients with locally advanced or 
metastatic colorectal cancer (CRC). 
 
Primary Objective of Dose-Expansion Phase (Phase 2a): 
To evaluate the antineoplastic effect of Sym004 when administered at the RP2D in 
combination with FOLFIRI to patients with locally advanced or metastatic CRC.   
 
As of Amendment 3: Due to the premature discontinuation of the enrollment of the 
trial, the primary, secondary, and exploratory objectives are no longer applicable. 
Clinical safety-related evaluations will continue to be conducted.  
Endpoints 
The Primary Endpoint of the Dose-Escalation Phase is the occurrence of Dose-
Limiting Toxicities (DLT) observed during Cycle 1 of Sym004 administration in 
combination with FOLFIRI. 
 
The Primary Endpoint of the Dose-Expansion Phase is confirmed objective 
antitumor response. 
 
As of Amendment 3: Due to the premature discontinuation of the enrollment of the 
trial, only the clinical safety-related evaluations will continue to be conducted. 
Design and Plan 
Screening Period: After providing informed consent, the eligibility of patients will 
be established according to the protocol-defined inclusion and exclusion criteria. 
Once all screening procedures have been completed and eligibility has been 
confirmed, a blood and urine sample will be taken for biomarker analysis. 
Furthermore, if an archived tumor tissue biopsy sample for central evaluation of Rat 
Sarcoma (RAS) mutations is not available, the patient will have a tumor biopsy 
performed. 
 
Eligible patients will be enrolled into the trial and enter the treatment period. 
 
Treatment Period: During the dose-escalation phase, patients will be assigned 
consecutively to the next available open treatment cohort and will receive Sym004 
in combination with FOLFIRI. Dose escalation will continue in patient cohorts until 
determination of the MTD. If the MTD is not formally reached, the Independent 


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Safety Monitoring Committee (ISMC) will together with the Sponsor declare the 
RP2D based on the available safety data. 
 
Once the RP2D has been identified, all subsequent patients will be enrolled into the 
dose-expansion cohort and will receive the RP2D dose of Sym004 in combination 
with FOLFIRI. 
 
Sym004 and FOLFIRI are both initiated on Day 1 of Cycle 1 (in the following 
C1/D1). 
 
Patients in the trial will receive iv infusions every second week of Sym004 in 
combination with a defined FOLFIRI regimen until occurrence of any of the 
following: Unacceptable toxicity or other conditions preventing further 
administration, Progressive Disease (PD), termination of the trial, or patient’s 
decision to withdraw. Patients may discontinue treatment (Sym004 and FOLFIRI) 
simultaneously; may discontinue Sym004 before discontinuing FOLFIRI; or may 
discontinue FOLFIRI before discontinuing Sym004. 
 
The visit schedule for the treatment period will apply until both Sym004 and 
FOLFIRI have been discontinued. 
 
End of Treatment/Follow-up: Once both Sym004 and FOLFIRI have been 
discontinued, an End of Treatment Visit (EOT) will be performed within 10 days 
from the decision to withdraw treatment. 
 
A follow-up visit will be performed 1 month after the last administration of 
Sym004/FOLFIRI (i.e. only after both treatments have been discontinued). This One 
Month Follow-up (1M FUP) visit, will constitute the end of trial participation for the 
patient. 
 
As of Amendment 3: This amendment to the clinical trial protocol (CTP) is based 
on a Sponsor decision to discontinue the development of Sym004 in combination 
with FOLFIRI. As a result, enrollment has stopped and a reduction in the total scope 
of non-safety related assessments being conducted under this CTP will be 
implemented. 
 
Patients who are actively being treated with Sym004 alone or in combination with 
FOLFIRI may continue therapy until unacceptable toxicity or other conditions 
preventing further administration, progressive disease (PD), or patient’s decision to 
withdraw. Patients no longer receiving Sym004 alone or in combination with 
FOLFIRI should be discontinued from study participation. 
 
Patients will continue to be followed and assessed for clinical safety-related 
concerns throughout their respective treatment periods and at minimum for 30 days 
after the last administration of Sym004. 
Number of Patients 
In total, 50 patients are planned to be treated with Sym004 in combination with 
FOLFIRI. 
The number of patients treated during the dose-escalation phase will depend upon 
the observed tolerability of Sym004 in combination with FOLFIRI.  Up to 
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phase. Enrollment in the dose-expansion phase will continue until a total of 50 
patients have been enrolled in dose-escalation and dose-expansion phases combined. 
Diagnosis and Main 
Inclusion and 
Exclusion Criteria 
Patients with locally advanced or metastatic CRC, wild type KRAS/NRAS (exon 2, 
3, 4) will be enrolled. 
 
Main Inclusion Criteria include: 
 
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 
 
Failed* prior adjuvant therapy or prior therapy for treatment for locally 
advanced or metastatic disease with first-line combination therapy of 
oxaliplatin and a fluoropyrimidine, with or without bevacizumab.   
*Failure is defined as radiologic progression 
 
Eligible for FOLFIRI 
 
Measurable disease according to RECIST v1.1 
 
Main Exclusion Criteria include: 
 
Prior therapy with anti-EGFR antibodies, anti-EGFR small molecule 
inhibitors or irinotecan (CPT-11)  
 
Discontinuation of prior therapy with oxaliplatin and a fluoropyrimidine 
due to diarrhea ≥ Grade 3 
 
Any antineoplastic agent (standard or investigational) within 4 weeks prior 
to first administration of trial treatments 
 
Significant gastrointestinal abnormalities, as per defined criteria 
 
Significant cardiovascular disease, as per defined criteria 
 
Abnormal hematologic, renal or hepatic function, as per defined criteria 
Investigational 
Medicinal Product, 
Dose(s) and 
Treatment Schedule 
The Investigational Medicinal Product (IMP) is Sym004. 
Sym004 is a 1:1 mixture of 2 monoclonal Antibodies (mAbs), which bind 
specifically to 2 non-overlapping epitopes of the Epidermal Growth Factor Receptor 
(EGFR). 
 
In this trial, Sym004 is administered in combination with a standard dosing regimen 
of FOLFIRI. Both therapies/regimens will be administered every second week by iv 
infusion (Day 1 and Day 15 of each 28 day cycle, ± 2 days). 
 
Dose-Escalation 
During the dose-escalation phase of the trial, the following 3 dose levels of Sym004 
will potentially be evaluated in combination with FOLFIRI: 
 
Dose Level 1: Sym004 12 mg/kg + FOLFIRI 
 
Dose Level 2: Sym004 15 mg/kg + FOLFIRI 
 
Dose Level 3: Sym004 18 mg/kg + FOLFIRI 
If the toxicity profile of Dose Level 1 indicates that this dose is not tolerated,  
successive lower dose levels will be explored: 
 
Dose Level -1: Sym004 9 mg/kg + FOLFIRI  
 
Dose Level -2: Sym004 9 mg/kg (loading dose) + FOLFIRI followed by 6 
mg/kg + FOLFIRI 
 
Dose Level -3: Sym004 6 mg/kg + FOLFIRI 
 
If Sym004 at 9 mg/kg + FOLFIRI (Dose-Level -1) has not exceeded the MTD and is 
well tolerated during Cycle 1, but overall tolerability is judged to be insufficient to 
accept this dose level as the RP2D, then Dose Level -2 may be explored. 
 


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If Sym004 at 9 mg/kg + FOLFIRI (Dose-Level -1) during Cycle 1 has not exceeded 
the MTD, but tolerability is judged to be insufficient to accept this dose level as the 
RP2D, then Dose-Level -3 may be explored. 
 
If the toxicity profile of lower doses where mandatory diarrhea prophylaxis is 
utilized indicates that the dose is well tolerated, further evaluation of Dose Level 1, 
and potentially Dose Levels 2 and 3 may take place after approval by the ISMC. 
 
Dose-Expansion 
Once the RP2D has been determined during the dose-escalation phase, the 
enrollment into the dose-expansion phase will commence. All patients enrolled to 
this phase will be treated at the established RP2D of Sym004 in combination with 
FOLFIRI. 
Criteria for 
Evaluation 
All assessments are repeated throughout the trial at protocol specified intervals, 
unless otherwise stated. 
 
Safety Assessments 
 
Medication survey 
 
(Serious) Adverse Event ([S]AE) survey 
 
DLT evaluation (dose escalation only) during Cycle 1 with a final 
assessment 14 (±2) days after the last dose of Cycle 1 or on the scheduled 
first day of Cycle 2, prior to dosing 
 
Vital signs and body weight 
 
Eastern Cooperative Oncology Group (ECOG) performance status 
 
Physical Examination 
 
Dermatological Examination 
 
Electrocardiogram (ECG) 
 
Safety blood samples 
 
Urinalysis 
 
Pregnancy test 
 
Disease Assessments 
 
(Archival) tumor tissue sample is requested at Screening after confirmation 
of eligibility 
 
Tumor marker evaluation 
 
Disease status evaluation by Computed Tomography (CT) or Magnetic 
Resonance Imaging (MRI) 
 
Additional Assessments* 
 
Pharmacokinetic (PK) Sampling* 
 
Anti-Drug Antibody (ADA) Testing* 
 
Biomarker blood and urine sample* 
*Omitted with Amendment 3 
Statistical Methods 
and Sample Size 
Calculation 
The primary endpoint of the dose-escalation phase is the occurrence of DLTs 
observed during Cycle 1 on each of the Sym004 dose levels given in combination 
with FOLFIRI. The number of enrolled patients will depend on the observed DLTs 
independently in each cohort. Based on a 3 + 3 design, it is planned to enroll 
between 9 and 18 patients during dose-escalation. 
 


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In the dose-expansion phase of the trial, the primary endpoint is confirmed objective 
antitumor response to the combination of Sym004 and FOLFIRI. The number of 
patients planned to be included in this part of the trial is 32-41 patients depending on 
the number of patients enrolled in the dose-escalation phase.  
 
The planned number of patients to be enrolled is not based on a formal sample size 
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3 
BACKGROUND AND RATIONALE 
3.1 
Disease and Treatment 
3.1.1 Metastatic Colorectal Cancer 
In 2012, the worldwide incidence of Colorectal Cancer (CRC) was estimated to be over 1.36 
million (2). Curative surgical treatment is only possible in the early stages of the disease 
(Stage I/II) and if the malignancy has not spread beyond the regional lymph nodes (Stage 
III).  Five-year survival for patients with Stage I CRC is approximately 90%.  Survival 
decreases with increasing stage of disease, and the five-year survival of patients with Stage 
IV CRC, the patient population targeted in this trial, diminishes to approximately 12% (3). 
3.1.2 Current Treatment of Metastatic Colorectal Cancer Disease 
Metastatic CRC (mCRC) is treated with a variety of regimens of combination chemotherapy 
and targeted agents, including monoclonal Antibodies (mAbs) targeting the Epidermal 
Growth Factor Receptor (EGFR) (3-8). The approved anti-EGFR antibodies, cetuximab and 
panitumumab, have been shown to be active in first-, second-, and third-line therapy of CRC 
(3-8). Cetuximab and panitumumab have been shown to have single agent activity (7,8), and 
to increase the effectiveness of regimens including 5-Fluorouracil (5-FU), folinic acid, and 
irinotecan (e.g., FOLFIRI) in the first- and second-line treatment of CRC (3-8). Despite the 
clearly documented activity of anti-EGFR antibodies, many patients are refractory to these 
agents prior to beginning therapy, and patients who initially respond ultimately progress 
while on therapy. These findings led to exploration as to why patients responded so 
differently. Further analysis of these and other trials, documented that efficacy was only 
demonstrable in patients whose CRC expressed the Wild Type (WT) Kirsten Rat Sarcoma 
(KRAS) genotype, whereas patients with evidence of specific mutations in KRAS, exon 2, 3 
and 4, and Neuroblastoma Rat Sarcoma (NRAS), exon 2, 3 and 4, in their tumors do not 
respond to treatment with anti-EGFR antibodies (7,8). Administration of anti-EGFR mAbs 
appears to have a deleterious effect in the latter population (7,8). Other factors have also been 
implicated in innate and acquired resistance to treatment with anti-EGFR antibodies. 
3.2 
Investigational Medicinal Product 
3.2.1 Sym004 
The Investigational Medicinal Product (IMP) tested in this trial is Sym004.  
Sym004 is a 1:1 mixture of 2 recombinant, human-mouse chimeric, immunoglobulin G1 
(IgG1) antibodies (referred to as mAb992 [futuximab] and mAb1024 [modotuximab]), which 
bind specifically to 2 non-overlapping epitopes of the EGFR.  
Sym004 is a clear, colorless liquid to be administered as an intravenous (iv) infusion through 
a peripheral line or indwelling catheter. 


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3.2.2 Mechanism of Action  
Sym004 binds to non-overlapping epitopes on domain III of the EGFR (9,10). The binding of 
Sym004 induces a distinct mechanism of action that is dependent on the presence of both 
antibodies.  Sym004 induces highly efficient internalization of EGFR on cancer cells, and 
degradation of the internalized receptor protein that leads to down-regulation of EGFR and 
subsequent inhibition of cancer cell growth (9). There is considerable in vitro and in vivo 
evidence suggesting that Sym004 is superior to existing, marketed anti-EGFR antibodies 
(cetuximab and panitumumab) in a wide range of cancer models (9-11).  Furthermore, 
Sym004 has demonstrable activity in cancer cells with acquired resistance to cetuximab (11). 
3.2.3 Summary of Non-clinical Findings 
A series of in vitro and in vivo studies were performed with Sym004 to support clinical trials 
in humans (9-12). The ability of Sym004 to inhibit the proliferation and motility of cancer 
cells was investigated in vitro in a range of human cancer cell lines, and compared to 
cetuximab as a reference anti-EGFR antibody (9,10). The effect of Sym004 on cells with 
acquired resistance to cetuximab was also investigated in several human cancer cell lines 
(11). Mechanistic studies of Sym004 action were performed using a panel of human cancer 
cell lines; testing included: Assessment of inhibition of ligand binding, EGFR activation, 
downstream signaling, EGFR internalization, and EGFR degradation (9). Sym004-mediated 
secondary effector functions, such as Antibody-Dependent Cellular Cytotoxicity (ADCC) 
and Complement-Dependent Cytotoxicity (CDC), were investigated using 51chromium-
release assays and human cancer cell lines. The studies showed that Sym004 is superior at 
inhibiting EGFR activity compared to cetuximab and/or panitumumab, used as reference 
antibodies, in vitro through a mechanism of action (i.e., downregulation and degradation of 
the EGFR) that is dependent on the binding of both antibodies (9,11). 
The activity of Sym004 was also investigated in vivo in several xenograft tumor models in 
mice, and was compared to cetuximab and/or panitumumab in these studies.  In all models, 
Sym004 was either superior to or as efficient as these reference antibodies (9-11). 
Toxicology studies in cynomolgus monkeys showed a toxicity profile consistent with other 
anti-EGFR antibodies, including documentation of dermatological and gastrointestinal 
toxicities (12). 
3.2.4 Summary of Clinical Findings 
Several clinical trials have been completed with Sym004, and other trials are ongoing or 
being initiated.   
3.2.4.1 Safety 
As of 30 Sep 2014, more than 175 patients with solid tumors, including but not limited to 
patients with recurrent/metastatic Squamous Cell Carcinoma of the Head and Neck 
(SCCHN), mCRC, and Non-Small Cell Lung Carcinoma (NSCLC), have been exposed to 
Sym004 in weekly doses of up to 12 mg/kg, and in every second week doses of up to 18 


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mg/kg. Analyses of Adverse Events (AEs) from the initial 2 clinical trials Sym004-01, a 
Phase 1 dose-escalation trial evaluating safety, tolerability, Pharmacokinetic (PK) and 
pharmacodynamic effects of Sym004, and Sym004-02, a phase 2 evaluation of patients with 
SCCHN who were refractory to anti-EGFR antibody therapy, have been performed.  For 
EMR trial 200637-001, a trial of 2 regimens of Sym004 vs. chemotherapy in patients with 
CRC refractory to prior therapy with anti-EGFR mAbs, AE data are available for dose levels 
of 6 mg/kg (3 patients), as well as 9 + 6 mg/kg and 12 mg/kg weekly (6 patients each).  For 
other ongoing clinical trials (Sym004-01 (Part F), EMR 200637-002, and EMR 200637-003), 
only data on Serious Adverse Events (SAEs) are available.  
Skin toxicities, hypomagnesemia, and Infusion-Related Reactions (IRRs) are frequently 
observed after administration of anti-EGFR antibodies, and these toxicities were observed in 
patients receiving Sym004.  Detailed data on these and other AEs are presented in the 
Investigator’s Brochure (IB).  
Anti-EGFR-related skin toxicities (including rash, pruritus, skin fissures, dry skin, erythema, 
and paronychia) have been observed in more than 90% of patients in the completed and 
ongoing clinical trials of Sym004.  In patients who had previously received anti-EGFR mAb 
therapy, Grade 3 skin toxicities were reported frequently; and were noted in 33.3% and 
41.2% of patients at dose levels of 12 mg/kg or 18 mg/kg, respectively, when Sym004 was 
administered every 2 weeks.   
Mucositis was observed in up to 40% of patients, but only 1 patient experienced Grade 3 
severity. Diarrhea has been reported in up to 59% of patients, with ≤ 10% of patients having 
experienced Grade 3 diarrhea.  Diarrhea was reported in 53.8% and 34.5% of patients 
receiving doses of 9 and 12 mg/kg weekly, respectively, and in 33.3% and 58.8% of patients 
at an every second week dose of 12 or 18 mg/kg, respectively.  Nausea was reported in 
33.3% and 11.8% of patients on an every second week dose of 12 or 18 mg/kg. Vomiting 
was reported in 25.0% and 5.9% of patients at an every second week dose of 12 or 18 mg/kg, 
respectively. 
Electrolyte disturbances (in particular hypomagnesemia) often associated with anti-EGFR 
mAbs, were also frequently observed in the completed and ongoing trials of Sym004.  In 
clinical trials for which all AE data are available, hypomagnesemia was reported in from 53.8 
to 76.5% of patients. Hypomagnesemia was observed in 66.7% (≥ Grade 3; 25.0%) and 
76.5% (≥ Grade 3; 35.3%) of patients receiving doses of 12 and 18 mg/kg every 2 weeks, 
respectively.  Hypocalcemia was observed in 37.9% of patients receiving Sym004 at a dose 
of 12 mg/kg weekly, with 3 (10.3%) patients experiencing hypocalcemia ≥ Grade 3. At the 
other dose levels, hypocalcemia occurred in < 10 % of those treated, and Grade 3 events were 
not observed.  In the Sym004-01 and the Sym004-02 clinical trials, hypomagnesemia 
represented the majority of SAEs that were considered to be related to Sym004 therapy.  
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IRRs have also been observed. In all ongoing clinical trials, premedication with 
glucocorticosteroids and antihistamines prior to the first Sym004 infusions is required. Prior 
to the implementation of mandatory premedication, 1 serious IRR occurred.   
Additional data on the safety and tolerability of Sym004, including data on SAEs, are 
provided in detail in the IB. Safety information regarding FOLFIRI (folinic acid [leucovorin], 
5-fluorouracil, irinotecan) should be referenced from the local packaging inserts.  
3.2.4.2 Pharmacokinetics 
PK analyses have been performed on patients participating in the Phase 1 trial (Sym004-01) 
and the Phase 2 trial in patients with SCCHN (Sym004-02).  In the Phase 1 trial, serum levels 
of Sym004 increased in a dose-dependent manner from 0.4 to 12 mg/kg during the dose-
escalation phase.  Doses of < 3 mg/kg were rapidly cleared from the circulation.  A dose-
dependent, non-linear increase in serum elimination half-life (T½) was observed. The 
geometric mean T½ was approximately 3 days after doses of 12 mg/kg and 5 days after doses 
of 18 mg/kg. The 2 antibodies constituting Sym004 displayed similar serum elimination 
profiles (13, IB). 
Data from the Sym004-01 and Sym004-02 trial also documented that the two antibodies 
constituting Sym004 were present in serum close to a 1:1 ratio at each visit throughout the 
trial.  All of the patients were exposed to detectable levels of Sym004 throughout the dosing 
periods evaluated.  The calculated T½  increased from the first to the fourth infusion of 
Sym004, with comparable increases in the calculated Area Under the Concentration-time 
curve (AUC).  The observed increase in exposure was considered to be consistent with 
down-regulation of the antibody target, the EGFR, after repeated doses of Sym004 (IB). 
More complete PK analyses and population PK data are included in the IB. 
3.2.4.3 Pharmacodynamic Effects 
Tumor and skin biopsies obtained before the first and planned fifth infusions of Sym004 in 
trial Sym004-01. A decrease in membranous EGFR expression and decreases in the 
proliferation marker, Ki67, were observed in both tumor and skin biopsies (13). These data 
provided clinical proof that Sym004 at the doses administered distributed to tumor, inhibited 
the intended target, and suppressed a known marker of tumor growth. 
3.2.4.4 Antitumor Effects 
As a part of the Phase 1 Sym004 dose-escalation trial (Sym004-01), antitumor activity was 
documented in patients with mCRC resistant to anti-EGFR antibody therapy (13).  Five of 
the 39 documented refractory patients (13%) with adequate imaging studies achieved a 
partial response (PR).  These responses were confirmed by independent radiologic review.  A 
PR or disease stabilization, Stable Disease (SD), was documented in 67% of patients with 
available assessments.  An exploratory analysis revealed that the responders to Sym004 were 
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evidence of MET amplification.  One of the responder’s tumors expressed an EGFR mutation 
(EGFRS492R) at baseline, a marker that is associated with resistance to cetuximab. 
3.3 
Trial Rationale 
Although the use of anti-EGFR mAbs is well established in the treatment of mCRC, only a 
minority of patients with advanced disease respond to the approved antibodies alone or in 
combination with chemotherapy (3-8). Patients who do respond initially, ultimately become 
resistant to combined therapies, including the currently approved anti-EGFR mAbs.  The 
overall magnitude of clinical effects observed with anti-EGFR antibodies alone or in 
combination has been limited, and patients who develop resistance have few treatment 
options (3-8). The distinct mechanism of action of Sym004 (9), compared to available anti-
EGFR mAbs, as well as the promising nonclinical and clinical data documenting activity in 
models (9-11) and patients with mCRC refractory to prior anti-EGFR antibody therapy (13), 
provide strong support for the trial of Sym004 in combination with FOLFIRI therapy in 
patients with CRC, who have progressed following first-line therapy, but have not received 
prior therapy with an EGFR inhibitor. 
Following treatment with EGFR inhibitors, such as cetuximab and panitumumab, tumors 
may develop resistance to the treatment. Varieties of trials have documented alterations in 
tumor cells that may be involved in acquired resistance to anti-EGFR therapies (14). One 
reported mechanism of resistance is based on increased production of EGFR ligands (15).  
Sym004 may be able to overcome this resistance mechanism by eliciting a more pronounced 
down-regulation of the expression of EGFR (9-11,13) than observed with the approved 
monoclonal anti-EGFR antibodies. This hypothesis is supported by the demonstration of 
clinical activity in patients considered to be resistant to anti-EGFR mAbs, with an observed 
response rate after treatment with Sym004 in a range otherwise expected for cetuximab and 
panitumumab in patients who have not received an anti-EGFR mAb (13). 
Based on the above-cited data, this Phase 1b/2a trial is designed to first evaluate the safety 
and tolerability of Sym004 in combination with FOLFIRI in order to determine the 
Maximum Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D). Upon 
delineation of the RP2D, additional patients who have failed first-line therapy for CRC will 
receive the combination to assess the antitumor activity of this regimen. The preliminary data 
suggesting both a different mechanism of action as well as activity of Sym004 in patients 
with CRC refractory to cetuximab, provides a rationale for improved activity in earlier lines 
of therapy in patients without acquired resistance to anti-EGFR antibodies. 
As of Amendment 3: This amendment to the clinical trial protocol (CTP) is based on a 
Sponsor decision to discontinue the development of Sym004 in combination with FOLFIRI. 
As a result, enrollment has stopped and a reduction in the total scope of non-safety related 
assessments being conducted under this CTP will be implemented.   
Patients who are actively being treated with Sym004 alone or in combination with FOLFIRI 
may continue therapy until unacceptable toxicity or other conditions preventing further 
administration, progressive disease (PD), or patient’s decision to withdraw. Patients no 


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longer receiving Sym004 alone or in combination with FOLFIRI should be discontinued 
from study participation. Refer to Section 7.6. 
Patients will continue to be followed and assessed for clinical safety-related concerns 
throughout their respective treatment periods and at minimum for 30 days after the last 
administration of Sym004. 
3.4 
Dose Rationale 
The starting dose of Sym004 in the trial is based upon prior demonstration that a dose of 12 
mg/kg administered weekly was determined to be the RP2D on this schedule although no 
MTD was formally reached. The safety and tolerability of this dose level on both a weekly 
and every second week schedules are outlined above and greater detail is available in the IB.  
In addition, preliminary antitumor activity in patients with mCRC and acquired resistance to 
available anti-EGFR mAbs was observed after administration of weekly doses of Sym004 of 
9 mg/kg or 12 mg/kg (13). Doses of 12 mg/kg and 18 mg/kg have furthermore been tolerated 
on an every second week schedule (16). 
3.5 
Overall Benefit/Risk 
As previously discussed, Sym004 has been documented to be active in preclinical studies 
using cetuximab-resistant tumors, as well as in preliminary clinical trials in mCRC and 
SCCHN patients with acquired resistance to anti-EGFR mAbs (13,17). The activity of 
Sym004, in patients refractory to therapy with mAbs targeting the EGFR, was similar to the 
single agent activity seen with these agents in treatment-naïve mCRC patients. 
In previous trials, Sym004 showed an acceptable safety profile. The safety profile was 
similar to that of other anti-EGFR antibodies, although for both skin toxicities and 
hypomagnesemia the percentage of patients with grade 3 skin toxicities and grade 3/4 
hypomagnesemia appeared to be higher (13,17).   
The continued unmet need for alternative treatments for mCRC, the available data on the 
safety, and preliminary data on antitumor activity of Sym004 (13), have been considered in 
evaluating the risk-benefit relationship in the planning of the trial. Based on the preclinical 
and clinical data available to date, the conduct of the trial is considered justifiable using the 
doses and dosage regimens of the IMP as specified in this Clinical Trial Protocol (CTP). In 
this trial, as applicable, there will be an ongoing assessment of the risk-benefit ratio with 
periodic evaluation of the results including review by external experts in CRC familiar with 
the use of anti-EGFR antibodies. The trial will be discontinued in the event of any new 
findings that indicate a relevant deterioration of the risk-benefit relationship that would 
render continuation of the trial unjustifiable. 
In order to mitigate potential risks, the trial is designed to allow for dose de-escalation if the 
safety and tolerability of the initial dose exceeds the MTD. If the dose is safe and well 
tolerated, dose-escalation may proceed to establish a RP2D. The potential to slow infusions, 
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Sym004 in the event of specific AEs are outlined.  In addition, steps to prevent infusion 
reactions and measures to intervene in the event of electrolyte imbalances and cutaneous 
toxicities are specified. Furthermore, prophylactic treatment for FOLFIRI induced diarrhea 
and vomiting according to institutional standards is required. 
The trial will be conducted in accordance with the CTP, the principles of the Declaration of 
Helsinki (18), ICH E6 GCP (1), and other laws in the countries where the trial takes place.  
 
 
 


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4 
TRIAL OBJECTIVES AND ENDPOINTS 
4.1 
Dose-Escalation (Phase 1b) 
As of Amendment 3: Due to the premature discontinuation of the enrollment of the trial, the 
primary, secondary, and exploratory objectives are no longer applicable. Clinical safety-
related evaluations will continue to be conducted. 
4.1.1 Primary Objective 
To determine the MTD and/or RP2D of Sym004 when administered by iv infusion every 
second week in combination with a standard dosing regimen of FOLFIRI (Folinic Acid [FA; 
leucovorin], 5-fluorouracil [5-FU], irinotecan) to patients with locally advanced or metastatic 
CRC.   
4.1.2 Secondary Objectives 
 
To determine the safety and tolerability of Sym004 when administered in 
combination with a standard dosing regimen of FOLFIRI 
 
Evaluation of the immunogenicity of Sym004 
 
Characterization of the PK profile of Sym004  
 
Preliminary evaluation of the antineoplastic effect of Sym004 plus FOLFIRI as 
assessed by the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) 
(Appendix 1)  
4.2 
Dose-Expansion (Phase 2a) 
4.2.1 Primary Objective 
To evaluate the antineoplastic effect of Sym004 when administered at the RP2D in 
combination with a standard dosing regimen of FOLFIRI to patients with locally advanced or 
metastatic CRC.   
4.2.2 Secondary Objectives 
 
Further evaluation of the safety and tolerability of Sym004 when administered at 
the RP2D in combination with FOLFIRI 
 
Continued evaluation of the immunogenicity of Sym004 
4.3 
Exploratory Studies 
 
Evaluation of the utility of pharmacodynamic biomarkers of Sym004 action, and 
estimation, if feasible, of the magnitude and duration of biological activity.   


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4.4 
Trial Endpoints 
As of Amendment 3: Due to the premature discontinuation of the enrollment of the trial, 
only the clinical safety-related evaluations will continue to be conducted. 
4.4.1 Primary Endpoint of Dose-Escalation (Phase 1b) 
The primary endpoint of the dose-escalation phase is the occurrence of Dose-Limiting 
Toxicities (DLT) observed during Cycle 1 of Sym004 administration in combination with 
FOLFIRI. 
4.4.2 Primary Endpoint of Dose-Expansion Phase (Phase 2a) 
The primary endpoint of the dose-expansion phase is confirmed objective antitumor 
response. 
4.4.3 Secondary Endpoints of Dose-Escalation and Dose-Expansion Phases 
4.4.3.1 Safety 
 
Nature, incidence and severity of AEs measured from baseline to end of trial 
participation  
NOTE: Adverse Events are graded by the Investigator according to the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE v.4.03, in the following referred to as CTCAE)   
 
AEs leading to dose-reductions, dose delays and permanent treatment cessation 
 
Changes in safety laboratory values from baseline to end of trial participation 
 
Changes in vital signs and physical examinations from baseline to end of trial 
participation 
 
Occurrence of anti-drug antibodies (ADA) to Sym004 measured in serum at 
selected timepoints from baseline to end of trial participation 
4.4.3.2 Anti-tumor Response 
 
Documented Objective Response (OR), defined as documented Partial Response 
(PR) or Complete Response (CR) 
 
Duration of OR from time of first PR or CR to progressive disease (PD) 
 
Changes in sum of diameters of target lesions from baseline to end of trial 
participation 
 
Stable Disease (SD) for > 4 months 
 
Time to documented disease progression, death, patient withdrawal or end of trial 
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4.4.3.3 Pharmacokinetic Assessment (Dose-Escalation only) 
 PK endpoints, derived from the concentration-time curves of Sym004, mAb992 and 
mAb1024, respectively after the first and fourth infusion of Sym004: 
AUCNorm, 0-336h Dose-normalized area under the concentration-time curve from End 
of Infusion (EOI) to 336 hours 
AUC0-336h 
Area under the concentration-time curve from EOI to 336 hours 
Cmax 
Maximum concentration 
Tmax 
Time to reach maximum concentration 
Ctrough 
Trough concentration 
T½ 
Elimination half-life 
CL 
Clearance 
V 
Volume of distribution 
 
4.4.3.4 Pharmacodynamic and Biomarker Assessment 
 
Urine and peripheral blood collection for assessment of biomarkers related to the 
EGFR pathway 
 
Other potential biomarkers to be determined (i.e. genes, gene transcripts and 
proteins of the receptor tyrosine kinases (RTKs)) 
 
 


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5 
TRIAL DESIGN 
5.1 
Overall Design and Plan 
This is an open-label, multicenter, phase 1b/2a trial with an initial dose-escalation phase 
followed by a dose-expansion phase. The trial design is shown in Figure 1. 
Figure 1 
Overall Trial Design 
 
Abbreviations: N, number of patients; RP2D, Recommended Phase 2 Dose 
 
The trial will be conducted in USA and countries within the EU.  
Approximately 8 investigational trial sites, hereafter called “trial sites”, will participate in the 
dose-escalation phase to determine MTD, safety and tolerability of multiple dose levels of 
Sym004 administered every second week in combination with a standard dosing regimen of 
FOLFIRI. Patients will be allocated in sequence to 1 of up to 5 dose levels of Sym004, based 
on tolerability. The RP2D will be based on the MTD evaluation as well as other toxicities 
observed in the study, and may include tolerability observed in Cycle 1 and subsequent 
RP2D 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Period 
Treatment Period (N=50) 
Sym004 in combination with FOLFIRI 
End of Treatment Visit (EOT) 
One Month Follow-up Visit (1M FUP) 
 
 
 
Expansion 
Cohort 
Sym004 at RP2D 
+ FOLFIRI 
 
 
 
Dose-Escalation  
Dose-Expansion 
Dose Level 1: 12 mg/kg Sym004 + FOLFIRI 
Dose Level 2: 
15 mg/kg Sym004   
+ FOLFIRI 
Dose Level -1: 
9 mg/kg Sym004 + FOLFIRI 
Dose Level 3: 
18 mg/kg Sym004   
+ FOLFIRI 
Dose Level -2: 
9 mg/kg 
Sym004 
(loading dose) 
+ FOLFIRI, 
followed by  
6 mg/kg 
Sym004 + 
FOLFIRI 
Dose Level -3: 
6 mg/kg 
Sym004 + 
FOLFIRI 


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cycles as well as PK and other data. The MTD and RP2D may or may not be the same, and 
the RP2D may be selected based on overall tolerability without defining the MTD. 
Approximately 10 to 15 trial sites will participate in the dose-expansion phase to investigate 
the antitumor activity of Sym004 at the RP2D determined in combination with FOLFIRI and 
to further assess the safety and pharmacodynamics effects of this regimen. 
Screening Period: After providing informed consent, the eligibility of patients will be 
established according to the protocol-defined inclusion and exclusion criteria (Section 6.1 
and Section 6.2, respectively). Once all screening procedures have been completed and 
eligibility has been confirmed, a blood and urine sample will be taken for biomarker analysis. 
Furthermore, if an archived tumor tissue biopsy sample for central evaluation of biomarkers 
and Rat Sarcoma (RAS) mutations (KRAS and NRAS, exons 2, 3, and 4) is not available, the 
patient will have a tumor biopsy taken. 
Eligible patients will be enrolled into the trial and enter the treatment period. 
Treatment Period: During the dose-escalation phase, patients will be assigned 
consecutively to the next available open treatment cohort and the dose of Sym004 to be 
administered will be confirmed in writing by Sponsor or designee on an allocation form. Full 
details of the dosing regimens for Sym004 are provided in Section 7.1.4. Once the RP2D has 
been identified, all subsequent patients will be enrolled into the dose-expansion cohort and 
will receive the RP2D dose of Sym004 in combination with FOLFIRI. 
Patients in the trial will receive iv infusions every second week of Sym004 in combination 
with a standard dosing regimen of FOLFIRI (Section 7.2.1) until occurrence of any of the 
following: Unacceptable toxicity or other conditions preventing further administration, PD, 
termination of the trial, or patient’s decision to withdraw. Patients may discontinue treatment 
(Sym004 and FOLFIRI) simultaneously; may discontinue Sym004 before discontinuing 
FOLFIRI; or may discontinue FOLFIRI before discontinuing Sym004. 
The visit schedule for the treatment period will apply until both Sym004 and FOLFIRI have 
been discontinued (Table 2). 
As of Amendment 3: The visit schedule for the treatment period will apply until Sym004 
has been discontinued. 
End of Treatment/Follow-up: Once both Sym004 and FOLFIRI have been discontinued, an 
End of Treatment (EOT) Visit will be performed within 10 days from the decision to 
withdraw treatment. 
A follow-up visit will be performed 1 month after the last administration of 
Sym004/FOLFIRI (i.e. only after both treatments have been discontinued). This One Month 
Follow-up (1M FUP) visit will constitute the end of trial participation for the patient. 
As of Amendment 3: Once Sym004 has been discontinued, an EOT Visit will be performed 
within 10 days from the decision to withdraw treatment, and a follow-up visit will be 
performed 1 month after the last administration of Sym004. 


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5.2 
Discussion of Trial Design 
5.2.1 Rationale for Trial Design 
FOLFIRI is a standard chemotherapeutic regimen used in the treatment of patients with 
mCRC in either the first- or second-line settings. Cetuximab, a chimeric antibody targeting 
the EGFR, had modest single agent activity in patients with advanced CRC, but increased 
efficacy was observed when combined with standard combination chemotherapy regimens 
used to treat this malignancy.  Similar data are available for panitumumab, a human mAb 
targeting the EGFR.  Given the activity and novel mode of action of Sym004 demonstrated in 
nonclinical studies and as single agent in early phase clinical trials, further clinical trials are 
warranted to explore Sym004 in combination with regimens commonly utilized in the 
treatment of CRC patients. 
5.2.2 Rationale for Trial Population 
Antibodies to EGFR have been approved alone and in combination with chemotherapy for 
the treatment of patients with CRC.  The agents are active in only a subset of patients and 
resistance develops in those who respond initially. Sym004 has been shown to have activity 
in patients refractory to therapy with anti-EGFR antibodies in prior clinical trials (13,17), 
thus further trials in CRC patients who have not received prior anti-EGFR therapy are 
warranted. 
5.2.3 Rationale for Starting Dose and Route of Administration 
The rationale for the starting dose, route of administration and duration of infusion is based 
upon the safety and tolerability of Sym004 documented in completed and ongoing trials.  
Intravenous dosing with Sym004 was utilized in nonclinical toxicology studies, and in prior 
trials of Sym004. Intravenous dosing is the route utilized for the majority of mAbs used in 
the treatment of patients with malignancies including previously approved mAbs to EGFR.  
The starting dose of 12 mg/kg is based upon the safety and tolerability of this dose level 
administered every week or every second week. 
5.2.4 Rationale for Dose-Escalation and Dose-Expansion  
The dose-escalation (or de-escalation) in cohorts is based on prior experience with Sym004 
in Phase 1 and 2 completed and ongoing trials. The standard 3 + 3 design is being used to 
determine safety and tolerability within cohorts and to make decisions regarding the dose 
assigned to the next group. The dose expansion group will provide information on the 
antitumor activity as well as additional information on the safety and tolerability of the 
combination of Sym004 and FOLFIRI.  These data will facilitate decision-making with 
regard to the implementation of future trials of Sym004 in patients with CRC. 
5.3 
Schedule of Events 
The overall trial plan is introduced in Table 1 and further defined in the below sections. 


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Table 1 Overall Trial Plan 
Screening Period 
Screening 
14 days within first dose of Sym004 + FOLFIRI 
Treatment Period 
Treatment Allocation 
The allocated dose of Sym004 will depend upon cohort assignment of 
Sym004 and will be confirmed by the Sponsor or designee on an 
allocation form 
FOLFIRI is given as a standard dosing regimen to all patients 
Sym004 + FOLFIRI 
The trial treatments will consist of Sym004 in combination with 
FOLFIRI. 
Sym004 and FOLFIRI are both initiated on C1/D1 and will be 
administered every second week by iv infusion (Day 1 and Day 15 of 
each 28 day cycle [± 2 days]). The Sym004 infusion will be delivered 
first. The FOLFIRI regimen administration will commence no sooner 
than 1 hour following completion of Sym004 administration. 
Discontinuation of 
Sym004 and/or 
FOLFIRI* 
Treatment will continue in cycles of 28 days (± 2 days) until 
unacceptable toxicity or other conditions preventing further treatment, 
PD, termination of the trial or patient’s decision to withdraw.  
Sym004 and FOLFIRI may be discontinued simultaneously or one may 
be discontinued before the other. 
The schedule for the treatment period will apply from the initiation of 
Sym004 and FOLFIRI until both Sym004 and FOLFIRI have been 
discontinued. 
End of Treatment  
End of Treatment  
(EOT)* 
Within 10 days after the decision to discontinue Sym004 and FOLFIRI 
(or the last of the two), an EOT Visit must be performed 
Follow-up 
One Month Follow-up 
(1M FUP)* 
Follow-up continues until 1 month (28 + 7 days) after the last dose of 
Sym004/FOLFIRI. At that time, a 1M FUP Visit must be performed. 
This 1M FUP visit constitutes the end of trial participation for the 
patient. 
Abbreviations (in alphabetical order): C1/D1, Day 1 of Cycle 1; EOT, End of trial treatment Visit (Sym004 and 
FOLFIRI); 1M FUP, One Month Follow-up Visit  
*As of Amendment 3: The schedule for the treatment period will apply from the initiation of Sym004 and FOLFIRI 
until Sym004 has been discontinued. An EOT Visit will be performed within 10 days from the decision to withdraw 
treatment with Sym004, and a follow-up visit will be performed 1 month after the last administration of Sym004.  
5.3.1 Screening  
When the trial site identifies a patient suitable for screening, the Sponsor or designee should 
be contacted to ensure that a cohort is open for inclusion. Once confirmed, the patient may be 
approached for informed consent. Screening activities may begin only once written informed 
consent has been obtained. 
All patients giving informed consent to participate in the trial will receive a unique patient 
number. This number is composed of a four-digit prefix, which identifies the site, and a 
three-digit number, allocated sequentially starting from 001 for the first patient screened at 
the site, 002 for the second patient screened etc. 


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The trial site staff must complete an allocation form, stating at minimum the allocated patient 
number and date of birth, along with the planned dates of screening and the day of first 
scheduled Sym004 and FOLFIRI administration (Cycle 1/Day 1, in the following C1/D1). 
The planned date of C1/D1 will need to be agreed upon in collaboration with the Sponsor or 
designee for the dose-escalation cohorts, in order to ensure adequate time between dosing of 
the first patient and dosing of subsequent patients in each cohort. The completed allocation 
form will then be sent to the Sponsor or designee prior to or on the day of Screening. 
All screening activities must be performed within 14 days prior to C1/D1, unless otherwise 
specified. A Computed Tomography (CT) scan or Magnetic Resonance Imaging (MRI) 
performed within 28 days prior to C1/D1 may be used for evaluation of eligibility, provided 
that the scan has been performed according to protocol requirements. In the event a tumor 
biopsy is required for eligibility, informed consent may be obtained outside the 14-day 
screening period prior to C1/D1 to allow adequate turnaround time for receipt of results.   
Individual screening assessments may be repeated prior to C1/D1, if justified and 
documented by the Investigator.  
Once eligibility has been confirmed in accordance with the inclusion and exclusion criteria, 
the allocation form will be fully completed and signed by the Investigator and resent to the 
Sponsor or designee. A copy of the fully executed allocation form will be returned to the trial 
site for archiving. This form documents the allocated dose of Sym004. 
5.3.2 Screening-Failures 
A patient found not eligible for the trial after giving informed consent is considered a 
screening-failure. The allocation form must be completed and sent to the Sponsor or designee 
to confirm the outcome of the screening process. 
Re-screening of a patient is allowed.  
5.3.3 Treatment  
On the day of the first scheduled Sym004 infusion, C1/D1, and prior to the start of infusion 
(SOI), the Investigator must assess whether any changes have occurred in the clinical state of 
the patient since screening which would exclude the patient from the trial.  
The trial treatment will consist of Sym004 in combination with FOLFIRI. Both therapies will 
be administered every second week by iv infusion (Day 1 and Day 15 of each 28 day cycle, ± 
2 days). Sym004 will be administered first, followed by FOLFIRI, with a minimum interval 
of 1 hour between Sym004 End of Infusion (EOI) and FOLFIRI SOI. 
The dose of Sym004 to be administered will be according to the cohort to which the patient 
is allocated and will be documented on an allocation form.  
There will be no intra-patient dose-escalation.  


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In the event of toxicity due to Sym004, FOLFIRI or the Sym004/FOLFIRI combination, the 
dose of either Sym004 or a component of the FOLFIRI regimen may be reduced, as 
described in Section 7.1.5 and 7.2.1.1. 
Treatment will continue until unacceptable toxicity or other conditions preventing further 
treatment, PD, termination of the trial, or patient’s decision to withdraw.  
An individual patient may discontinue treatments (Sym004 and FOLFIRI) simultaneously; 
may discontinue Sym004 treatment before discontinuing FOLFIRI; or may discontinue 
FOLFIRI before discontinuing Sym004 treatment.   
The visit schedule for the treatment period will apply until both Sym004 and all components 
of FOLFIRI have been discontinued. 
As of Amendment 3: The visit schedule for the treatment period will apply until Sym004 
has been discontinued. 
5.3.4 End of Treatment and One Month Follow-up Visit 
An EOT Visit will be performed for all patients within 10 days after the decision to 
discontinue treatment with all trial medications (i.e. only once both Sym004 and FOLFIRI 
have been discontinued). 
The patient will return for follow-up 1 month (28+7 days) after the last dose of 
Sym004/FOLFIRI, whichever is last (i.e. only once both Sym004 and FOLFIRI have been 
discontinued). This will be the 1M FUP Visit. 
As of Amendment 3: An EOT Visit will be performed for all patients within 10 days after 
the decision to discontinue treatment with Sym004. The patient will return for follow-up 1 
month after the last administration of Sym004. 
5.3.5 Flow Chart – Schedule of Assessments 
A complete schedule of assessments is provided in the trial flow chart in Table 2. 
All efforts should be made to perform assessments as close as possible to the scheduled time 
points. Visit windows are included in the flow chart. 
 


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Table 2 Flow Chart – Schedule of Assessments 
Pre-Treatment Phase 
Treatment Phase1 
Post-Treatment Phase 
Cycle Number 
Screening 
Cycle 1 
Cycle 2, 4, 6 etc. 
Cycle 3, 5, 7 etc. 
EOT 
1M FUP 
Day within Cycle 
Visit Window (± days) 
D-14 to D-1 
D1 
 
D8 
(±2) 
D15 
(±2) 
D22 
(±2) 
D1 
 
D15 
(±2) 
D1 
 
D15 
(±2) 
≤ 10 d from 
the decision of 
trial treatment 
withdrawal 
1 month after 
last dose of 
trial treatment 
(28+7d) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Baseline Characteristics/Eligibility2 
X 
X 
 
 
 
 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
Medication Survey 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(S)AE Survey and Reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DLT Evaluation (dose-escalation only)3 
 
X 
X 
X 
X 
C2/D1 
 
 
 
 
 
Vital Signs and Body Weight 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
Physical Examination  
X 
X 
 
 
 
X 
 
X 
 
X 
X 
Dermatological Examination 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
ECG4 
X 
 
 
 
 
 
 
 
 
X 
 
Safety blood samples5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis5 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
X 
 
Disease Assessments 
 
(Archival) Tumor Biopsy Collection6,7  
X 
 
 
 
 
 
 
 
 
 
 
Tumor Marker Evaluation8 
X 
 
 
 
 
 
End of C 
 
 
X 
X 
Disease Status Evaluation by CT/ MRI9,10 
X 
 
 
 
 
 
End of C 
 
 
X 
X 
*Additional Assessments 
 
 
 
 
 
 
 
 
 
 
 
*PK Samples (dose-escalation only)11 
 
X 
 
X 
 
X 
X 
X 
 
X 
X 
*ADA Sample 
 
X 
 
 
 
 
 
X 
 
X 
X 
*Biomarker Blood and Urine Sample12 
X 
 
 
 
 
 
End of C2 
 
 
X 
 
Trial Treatment 
 
 
 
 
 
 
 
 
 
 
 
Skin Toxicity Prophylaxis and TX13 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Infusion Reaction Prophylaxis 14 
 
X 
 
X 
 
 
 
 
 
 
 
Sym004 Infusion 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
Gastrointestinal Toxicity Prophylaxis 15 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
FOLFIRI Infusion 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
Post-Infusion Monitoring 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
Abbreviations (in alphabetical order): ADA, anti-drug antibody; C, Cycle; CT, computed tomography scan; D/d, day(s); DLT, dose-limiting toxicity; EOT, End of trial treatment 
Visit (Sym004 and FOLFIRI); ECG, electrocardiography; ECOG PS, Eastern Cooperative Oncology Group performance status; MRI, magnetic resonance imaging; 1M FUP, One 
Month Follow-up Visit; PK, pharmacokinetic; (S)AE, (serious) adverse event; TX, therapy 
*Omitted with Amendment 3  
 


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1) 
The treatment phase continues until the patient is withdrawn from Sym004 (As of Amendment 3) 
2) 
Screening assessments include demographics, medical history, tumor histology, mutation status, extent of disease, prior anti-cancer treatment etc. 
3) 
Applicable for dose-escalation only: DLTs are reported during Cycle 1 with final assessment on scheduled first day of Cycle 2, prior to dosing  
4) 
In addition to the scheduled EGCs, an ECG should be performed in the event of ≥ Grade 3 hypomagnesemia and if otherwise clinically indicated. Furthermore, in the 
event of QT prolongation, an ECG is to be performed prior to the next dose of Sym004 
5) 
Local laboratory results must be available and assessed no later than 2 days prior to each Sym004/FOLFIRI infusion. Refer to Table 16 for further details 
6)   
Sample is to be taken only after patient eligibility has been confirmed 
7)   
A tumor biopsy must be performed, if archived tumor tissue is not available for central evaluation of biomarkers, RAS mutations (KRAS and NRAS, exon 2, 3, 4). 
8) 
Tumor Marker, Carcinoembryonic Antigen (CEA), completed at EOT if > 3 weeks since previous evaluation; at 1M FUP (if PD was not documented before or at EOT) 
9) 
CT or MRI imaging schedule and conditions, applying to all cohorts: 
 
The first CT/MRI assessment for response is done at the end of Cycle 2 and thereafter repeated at the end of every second cycle.  
 
In the event of suspected PD, a CT/MRI is to be performed as soon as possible  
 
In the event of CR/PR, a confirmatory CT/MRI is to be performed no earlier than 28 days after the first assessment of CR/PR   
10) 
A CT/MRI at EOT should only be performed if the previous CT/MRI has been performed > 3 weeks before; a CT/MRI scan at 1M FUP should only be performed if no 
CT/MRI documents disease progression before or at EOT 
11)  
*Applicable for dose-escalation only: Extended PK sampling for PK profiling will be done for Day 1 (C1/D1) and in relation to the 4th Sym004 infusion (scheduled for 
C2/D15). For all other visits with PK sampling, blood samples are taken prior to and at the end of each infusion. Refer to Table 17 for further details 
12) 
*A biomarker blood and urine sample is taken during screening after patient eligibility has been confirmed. Sampling is repeated at the end of Cycle 2, or upon PD 
whichever occurs first, and at EOT 
13) 
Prophylactic treatment with an oral antibiotic and a topical steroid until end of Cycle 2 followed by comprehensive treatment of skin toxicities 
14)  
Prior to the first 2 infusions with Sym004 patients will receive glucocorticoid therapy and an antihistamine. For infusion following Cycle 1, pre-medication is at the 
Investigators discretion  
15) 
Patients will receive prophylactic treatment for nausea and vomiting according to institutional standards, and all patients will be treated with loperamide in an effort to 
prevent diarrhea during Cycle 1. Prophylaxis with loperamide may be continued beyond Cycle 1 at the Investigator’s discretion. 
*Omitted with Amendment 3 


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5.4 
Recruitment Period 
The dose-escalation phase of the trial is expected to begin Q4 2015. Patients will be 
sequentially enrolled to dose-escalation cohorts until selection of the RP2D, expected by Q4 
2016.  
The dose-expansion phase of the trial is expected to begin Q4 2016 with enrollment to be 
completed Q2-Q3 2017. 
5.5 
Number of Patients 
In total, 50* patients are planned to be treated with Sym004 in combination with FOLFIRI. 
The number of patients treated during the dose-escalation phase will depend upon the 
observed tolerability of Sym004 in combination with FOLFIRI.  Up to approximately 18 
patients are expected to be treated during the dose-escalation phase. Enrollment in the dose-
expansion phase will continue until a total of 50 patients have been enrolled in dose-
escalation and dose-expansion phases combined. 
For details regarding the sample size considerations please refer to Section 10.1. 
*As of Amendment 3: Accrual to this trial has stopped and the total planned number of 
patients will not be enrolled. 
5.6 
End of Trial 
The end of trial will be reached at the latest 1 month (28 +7 days) after the last patient has 
been withdrawn from trial treatments.   
5.7 
Independent Evaluation Committees 
An Independent Safety Monitoring Committee (ISMC) will be established for the trial. The 
composition and role of the ISMC is described in Section 12.1. 
 
 
 


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6 
PATIENT SELECTION AND WITHDRAWAL 
Questions regarding patient eligibility must be addressed and resolved by the Investigator in 
consultation with the Sponsor or designee prior to enrollment. 
6.1 
Inclusion Criteria All Cohorts 
For inclusion in the trial, all of the following criteria must be fulfilled: 
1. 
Written informed consent given before any trial-specific procedure 
2. 
Male or female, at least 18 years of age at the time of informed consent 
3. 
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 
4. 
Life expectancy > 3 months assessed during Screening 
5. 
Histologically or cytologically confirmed, locally advanced or metastatic CRC that 
is documented to be without KRAS or NRAS gene mutations (i.e. tumors must 
express the KRAS and NRAS wild type (WT), exon 2, 3 and 4). 
6. 
Failed* prior adjuvant therapy or prior therapy for treatment for locally advanced 
or metastatic disease with first-line combination therapy of oxaliplatin and a 
fluoropyrimidine, with or without bevacizumab.  
*Failure is defined as radiologic progression 
7. 
Eligible for FOLFIRI  
8. 
Archival tumor tissue available for confirmation of RAS mutation evaluation. If 
tumor tissue is not available, patients must be willing to undergo a tumor biopsy 
and must have a tumor that is safely accessible for biopsy 
9. 
Measurable disease according to RECIST v1.1 (Appendix 1)  
NOTE: Measurable disease is defined as 1 or more target lesions assessed by Computed 
Tomography (CT) or Magnetic Resonance Imaging (MRI). A tumor lesion situated in a 
previously irradiated area is considered measurable only if subsequent disease progression has 
been documented in the lesion 
10. Disease that is currently not amenable to surgical intervention due to either 
medical contraindications or non-resectability of the tumor  
11. If female and of childbearing potential, a negative pregnancy test 
12. Not of childbearing potential or agrees to use a medically effective method, as per 
institutional standards, of contraception during the trial and for 3 months after the 
last dose of trial drug 
6.2 
Exclusion Criteria All Cohorts 
Patients meeting any of the following criteria will not be permitted to enter the trial:  


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1. 
Prior therapy with anti-EGFR antibodies, anti-EGFR small molecule inhibitors or 
irinotecan (CPT-11) 
2. 
Any antineoplastic agent (standard or investigational) within 4 weeks prior to 
C1/D1  
3. 
Radiotherapy against target lesions within 4 weeks prior to C1/D1 
NOTE: Radiotherapy for pain control against non-target lesions is allowed, as long as it does 
not influence bone marrow function 
4. 
Discontinuation of prior therapy with oxaliplatin and a fluoropyrimidine due to 
diarrhea ≥ Grade 3 
5. 
Immunosuppressive or systemic hormonal therapy within 2 weeks prior to C1/D1 
with the exception of the following allowed therapies: 
a. 
Hormonal therapy (e.g., Megace) for appetite stimulation 
b. 
Nasal, ophthalmic, inhaled, and topical glucocorticoid preparations 
c. 
Oral replacement glucocorticoid therapy for adrenal insufficiency 
d. 
Low-dose maintenance steroid/hormonal therapy for other conditions 
(excluding steroid tapers for brain edema/metastases/radiation) 
e. 
Hormonal contraceptive therapy  
6. 
Prophylactic use of hematopoietic growth factors within 1 week prior to C1/D1 
7. 
Active second malignancy or history of another malignancy within the last 5 years, 
with the exception of: 
a. 
Treated, non-melanoma skin cancers 
b. 
Treated carcinoma in situ of the breast or cervix 
c. 
Controlled, superficial carcinoma of the urinary bladder 
d. 
T1a or b carcinoma of the prostate treated according to local standard of care, 
with Prostate-Specific Antigen (PSA) within normal limits for the institution 
8. 
Known Central Nervous System (CNS) or leptomeningeal metastases not 
controlled by prior surgery or radiotherapy, or symptoms suggesting CNS 
involvement for which treatment is required 
NOTE: Patients with treated CNS metastases will be eligible if they are asymptomatic, do not 
require corticosteroids or anticonvulsants, and have confirmation of at least stable brain 
disease status as assessed by 2 imaging studies performed at least 4 weeks apart with the most 
recent study performed within 12 weeks prior to first trial drug administration 
9. 
Inadequate recovery from an acute toxicity associated with any prior antineoplastic 
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NOTE: Patients with any persistent chronic toxicity of Grade 1 in severity, and persistent 
Grade 2 alopecia and/or neuropathy secondary to prior oxaliplatin therapy, will be considered 
eligible for enrollment 
10. Major surgical procedure within 4 weeks prior to C1/D1 or inadequate recovery 
from any prior surgical procedure 
11. Non-healing wounds on any part of the body 
12. Patients with underlying conditions which may affect or be affected by the 
administration of agents in the FOLFIRI regimen. This includes 
a. 
Gilbert-Meulengracht syndrome 
b. 
Dihydropyrimidine dehydrogenase deficiency 
13. Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism, 
within 4 weeks prior to C1/D1; any prior thrombosis must be adequately treated 
and stable 
14. Active uncontrolled bleeding or a known bleeding diathesis 
15. Significant gastrointestinal abnormalities, including: 
a. 
History of inflammatory bowel disease 
b. 
Diarrhea ≥ Grade 2 within 2 weeks prior to C1/D1 
c. 
Requirement for intravenous alimentation 
d. 
Prior surgical procedures affecting absorption 
e. 
Active peptic ulcer disease 
16. Patients with a significant cardiovascular disease or condition, including: 
a. 
Congestive heart failure (CHF) currently requiring therapy 
b. 
Class III or IV cardiovascular disease according to the New York Heart 
Association's (NYHA) Functional Criteria (19) 
c. 
Need for antiarrhythmic medical therapy for a ventricular arrhythmia 
d. 
Severe conduction disturbance (e.g., 3rd degree heart block) 
e. 
Unstable angina pectoris (last episode at least 6 months prior to C1/D1   
f. 
Uncontrolled hypertension (per the Investigator's discretion) 
g. 
Myocardial infarction within 6 months prior to C1/D1 
17. Abnormal hematologic, renal or hepatic function as defined by the following 
criteria: 


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a. 
Absolute neutrophil count (ANC)  < 1.5 ×109/L (1500/mm3) 
b. 
Hemoglobin ≤ 9 g/dL 
c. 
Platelet count < 100 ×109/L (100,000/mm3)  
d. 
Serum creatinine > 1.5 × upper limit of normal (ULN) for the institution 
e. 
Aspartate aminotransferase (AST) > 5 × ULN for the institution 
f. 
Alanine aminotransferase (ALT) > 5 × ULN for the institution 
g. 
Total bilirubin > 1.5 × ULN for the institution 
h. 
Prothrombin Time (PT) as assessed by International Normalized Ratio (INR) 
> 1.5 × ULN for the institution 
i. 
Partial Thromboplastin Time (PTT) > 1.5 × ULN for the institution 
18. Known history of Human Immunodeficiency Virus (HIV) infection  
19. Known active hepatitis B or C virus infection 
20. Any of the following within 2 weeks prior to C1/D1: 
a. 
Any serious or uncontrolled infection 
b. 
Any infection requiring parenteral antibiotics 
c. 
Unexplained fever > 38.0 °C 
21. Known or suspected hypersensitivity to any of the excipients of the Sym004 drug 
product 
22. Any other life-threatening illness, significant organ system dysfunction, or 
clinically significant laboratory abnormality, which in the opinion of the 
Investigator, would either compromise the patient’s safety or interfere with the 
evaluation of the safety of the trial drug 
23. Any kind of disorder that compromises the ability of the patient to give written 
informed consent and/or to comply with trial procedures or is unwilling or unable 
to comply with trial requirements at the discretion of the Investigator  
24. Breast feeding, or plans by the patient (or the patient’s partner) to become 
pregnant during treatment or within 3 months after the end of treatment 
6.3 
Withdrawal from Trial Treatment 
Sym004 and FOLFIRI may be discontinued simultaneously; Sym004 treatment may be 
discontinued before discontinuing FOLFIRI; or FOLFIRI may be discontinued before 
discontinuing Sym004 treatment.  


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Further, if 5-FU/FA treatment is discontinued, irinotecan/Sym004 may be administered. If 
irinotecan administration is discontinued, 5-FU/FA/Sym004 administration may be 
continued.  
The visit schedule for the treatment period will apply until Sym004 and all components of 
FOLFIRI have been discontinued. Once this has occurred, an EOT Visit will be performed 
within 10 days after the decision to discontinue the last of the two; Sym004 and/or FOLFIRI. 
After EOT, the patient will continue to be followed until 1 month (28 +7 days) after the last 
dose of Sym004/FOLFIRI, when the 1M FUP Visit must be completed. 
As of Amendment 3: The visit schedule for the treatment period will apply until Sym004 
has been discontinued. An EOT Visit will be performed within 10 days from the decision to 
withdraw treatment with Sym004, and a follow-up visit will be performed 1 month after the 
last administration of Sym004. 
6.3.1 Withdrawal from Treatment with Sym004 and/or FOLFIRI 
The patient must be withdrawn from treatment with Sym004 and/or FOLFIRI in the event of 
any of the following: 
 
A DLT considered by the Investigator to require treatment discontinuation (See 
Section 9.5) (dose-escalation cohorts only) 
 
Occurrence of an AE considered by the Investigator to require treatment 
discontinuation 
 
CTCAE Grade 4 skin toxicity (applies to Sym004 only) 
 
FOLFIRI-related toxicity not controlled by dose-reduction guidelines are outlined 
in Table 7 in Section 7.2.1.1 and Appendix 2 
 
PD, verified by CT/MRI according to RECIST v1.1 (Appendix 1) 
 
Treatment failure not meeting the criteria for PD, but considered by the 
Investigator to require treatment discontinuation 
 
Requirement for a significant surgical procedure  
NOTE: Patients requiring a minor surgical procedure (e.g., port placement, skin abscess drainage) 
may continue at the Investigator’s discretion following discussion with the Sponsor or designee.  A 
brief interruption in therapy may be considered 
 
An intercurrent illness which, in the opinion of the Investigator, would prevent 
completion of trial-related evaluations 
 
The Investigator judges it necessary due to medical reasons 
 
Use of prohibited concomitant medication, as defined in Section 7.5.2 
 
Pregnancy 


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 
Significant deviation from the protocol or eligibility criteria.  Such patients will be 
considered protocol violations and may be discontinued from treatment after 
discussion with the Sponsor 
 
Noncompliance with trial procedures may require discontinuation after discussion 
with the Sponsor 
 
Patient withdrawal of consent and election to discontinue treatment. (Patients may 
leave the trial at any time for any reason if they wish to do so, without any 
consequences) 
 
Termination of the trial by the Sponsor 
6.3.2 Withdrawal from Trial 
The patient must be withdrawn from trial in the event of any of the following: 
 
The patient withdraws consent to participate 
 
The Investigator judges it necessary due to medical reasons 
The EOT and the 1M FUP visits should be performed to the extent possible and the 
Investigator should ensure any SAE is followed as described in Section 9.3. 
6.4 
Replacement of Patients 
6.4.1 Dose-Escalation Phase 
Patients who do not complete Cycle 1 as defined in Section 9.5.2, for reasons other than 
DLTs, can be replaced.  
Data from these patients will be included in the safety analysis, but will not contribute to the 
determination of the MTD. 
6.4.2 Dose-Expansion Phase 
It is not planned to replace any patients in the dose-expansion phase. 
 
 


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7 
TREATMENT 
7.1 
Investigational Medical Product/Sym004 
The IMP in this trial is Sym004. Sym004 will be administered in combination with FOLFIRI. 
7.1.1 Identity of the Investigational Medicinal Product/Sym004 
Sym004 is a 1:1 mixture of 2 humanized mAbs directed against the EGFR. 
Sym004 IMP is a 5.0 mg/mL solution provided in clear glass vials with a nominal fill volume 
of 30 mL. The closure system for the IMP vials consists of FluroTec®-coated 
chlorobutyl/butyl rubber stoppers, secured with caps with flip-off seals. The materials used 
are of pharmacopeial quality and are considered suitable for storage of sterile injectable 
solutions. Please refer to Table 3 for a full list of ingredients. 
Table 3 Description of Investigational Medicinal Product/Sym004 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.1.2 Packaging and Labeling of Sym004 
Sym004 IMP will be provided as 30 mL clear glass vials, Type 1. 
Labeling will be in accordance with Annex 13 of the European Union Good Manufacturing 
Practice regulation (20) and applicable local regulatory requirements. 
7.1.3 Handling, Storage and Preparation of Sym004 
All handling, storage, and preparation of IMP should take place at the trial site pharmacy. 
The Investigator is responsible for informing the pharmacy of the dose of Sym004 to be 
administered to a given patient, taking into account the patient’s body weight.  
Sym004 will be diluted in saline in an infusion bag prior to administration; the volume of 
saline will depend on the Sym004 dose: 250 mL for doses of 4.5 to 6 mg/kg, 500 mL for 
doses of 9 to 18 mg/kg. The infusion must be completed within 12 hours of preparation of the 
infusion bag. 
A detailed pharmacy guide, specifying handling, storage, and preparation of Sym004, will be 
provided to the trial sites.  


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7.1.4 Administration of Sym004 
7.1.4.1 Treatment Schedule  
This is a non-randomized, open-label trial. All patients will be allocated to the IMP, Sym004, 
in combination with FOLFIRI. The dose of Sym004 will vary depending upon cohort 
assignment. 
All patients will be given iv infusions of Sym004, administered every second week (Day 1 
and Day 15 of each 28 day cycle ±2 days) through a peripheral line or indwelling catheter, 
and with the use of an infusion pump and an inline filter. 
Sym004 is dosed according to the body weight. The allocated dose level will be confirmed in 
writing by Sponsor or designee on the allocation form.  
For all Sym004 infusions, a complete dosing history will be recorded, i.e.: 
 
Total dose and volume administered 
 
Start and stop time of infusion 
 
Infusion interruption or termination and reason for such actions  
7.1.4.2 Dose-Escalation Phase 
During the dose-escalation phase of the trial, the following dose levels of Sym004 will 
potentially be evaluated in combination with FOLFIRI: 
 
Dose Level 1: Sym004 12 mg/kg + FOLFIRI 
 
Dose Level 2: Sym004 15 mg/kg + FOLFIRI 
 
Dose Level 3: Sym004 18 mg/kg + FOLFIRI 
If the toxicity profile of Dose Level 1 indicates that this dose is not tolerated, successive 
lower dose levels will be explored: 
 
Dose Level -1: Sym004 9 mg/kg + FOLFIRI 
 
Dose Level -2: Sym004 9 mg/kg (loading dose) + FOLFIRI followed by 6 mg/kg 
+ FOLFIRI  
 
Dose Level -3: Sym004 6 mg/kg + FOLFIRI 
If Sym004 at 9 mg/kg + FOLFIRI (Dose-Level -1) has not exceeded the MTD and is well 
tolerated during Cycle 1, but overall tolerability is judged to be insufficient to accept this 
dose level as the RP2D, then Dose Level -2 may be explored. 
If Sym004 at 9 mg/kg + FOLFIRI (Dose-Level -1) during Cycle 1 has not exceeded the 
MTD, but tolerability is judged to be insufficient to accept this dose level as the RP2D, then 
Dose-Level -3 may be explored. 


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If the toxicity profile of lower doses where mandatory diarrhea prophylaxis is utilized 
indicates that the dose is well tolerated, further evaluation of Dose Level 1, and potentially 
Dose Levels 2 and 3 may take place after approval by the ISMC.  
Cohorts will be filled sequentially. Patients will be allocated to the next available treatment 
slot within the current or next cohort, as appropriate and depending on the ongoing 
observation of DLTs and other safety parameters. 
7.1.4.3 Dose-Escalation Decision Points 
In the dose-escalation 3 + 3 design, at least 3 patients will be treated per dose level.  
Enrollment will be staggered between the first and second patient in each new cohort. The 
first patient in a 3-patient cohort must have completed and tolerated Cycle 1 (at minimum 2 
full doses of both Sym004 and FOLFIRI plus 14 days of follow-up [±2 days]) in order to 
allow for review of clinical and laboratory assessments. Thereafter patients within a cohort 
may be added concurrently.  
Progression from a current dose level to the next, will only proceed following evaluation of 
tolerability at the current dose level. Thus, dosing of the first patient at Dose Level 2 will 
commence only once Dose Level 1 has been found to be tolerable, and dosing in Dose Level 
3 will only commence once Dose Level 2 has been found to be tolerable according to the 
dose-escalation decision points below: 
 
If no DLTs are encountered in any of the first 3 patients completing Cycle 1 within 
a dose level, dose-escalation may continue to the next level 
 
If 1 of 3 patients within a dose level experiences a DLT, 3 more patients will be 
enrolled at the same dose level. If no DLTs are encountered in the 3 additional 
patients, dose-escalation may continue to the next level when all patients have 
completed Cycle 1 
 
If  ≥ 2 patients within a dose level (of up to 6 patients) experience a DLT, then that 
dose will be considered to have exceeded the MTD and the dose level just below 
this dose level will be considered to be the MTD 
NOTE: Should ≥ 2 of 6 patients at Dose Level 1 experience a DLT, then the dose will be reduced 
to Dose Level -1. Furthermore, if ≥ 2 of 6 patients at Dose Level -1 experience a DLT, then the 
dose will be reduced to Dose Level -3. 
 
Once the ISMC declares the potential MTD, this MTD dose level will be 
completed to a total of 6 patients, if not already done. In order to confirm the 
MTD, ≤ 1 patient of 6 within the dose level may have experienced a DLT 
 
If no DLT’s are encountered in any of the first 3 patients at Dose Level 3, 3 more 
patients will be enrolled at this dose level. If < 1 patient experiences a DLT, dose-
escalation will end without formally having reached the MTD. The ISMC will 
together with the Sponsor declare the RP2D based on the available safety data 


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Each patient enrolled will receive doses of Sym004 at the allocated dose, unless dose-
reduction is necessary as specified in Section 7.1.5. There will be no intra-patient dose-
escalation.   
7.1.4.4 Dose-Expansion Phase 
Once the RP2D has been determined during the dose-escalation phase, the enrollment into 
the dose-expansion phase will commence. All patients enrolled to this phase will be treated at 
the established RP2D of Sym004 in combination with FOLFIRI.  
7.1.4.5 Infusion Rate for Administration of Sym004 
For the first 2 Sym004 infusions (Cycle 1), the infusion rate should be increased every 30 
minutes to a maximum of 400mL per hour according to the schedule shown in Table 4. Thus, 
a maximum of 19.2 mg Sym004 will be delivered per minute per kg body weight (based on 
an 80 kg patient). 
Table 4 Infusion Rate for Administration of Sym004 
 
Dose Level 4.5 mg/kg 
Volume 250 mL, body weight 80 kg, 1.4 mg/mL 
Time - min 
mL/hr 
mL/30min 
mg/30min 
mg/min 
0-30 
100 
50 
72 
2.4 
31-60 
150 
75 
108 
3.6 
61-90 
250 
125 
180 
6.0 
Total 
 
250 mL 
 
 
 
 
Dose Level 6 mg/kg 
Volume 250 mL, body weight 80 kg, 1.9 mg/mL 
Time - min 
mL/hr 
mL/30min 
mg/30min 
mg/min 
0-30 
100 
50 
96 
3.2 
31-60 
150 
75 
144 
4.8 
61-90 
250 
125 
240 
8.0 
Total 
 
250 mL 
 
 
 
 
Dose Level 9 mg/kg 
Volume 500 mL, body weight 80 kg, 1.4 mg/mL 
Time - min 
mL/hr 
mL/30min 
mg/30min 
mg/min 
0-30 
100 
50 
72 
2.4 
31-60 
200 
100 
144 
4.8 
61-90 
300 
150 
216 
7.2 
91-120 
400 
200 
288 
9.6 
Total 
 
500 mL 
 
 
 
 
 


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Dose Level 12 mg/kg 
Volume 500 mL, body weight 80 kg, 1.9 mg/mL 
Time - min 
mL/hr 
mL/30min 
mg/30min 
mg/min 
0-30 
100 
50 
96 
3.2 
31-60 
200 
100 
192 
6.4 
61-90 
300 
150 
288 
9.6 
91-120 
400 
200 
384 
12.8 
Total 
 
500 mL 
 
 
 
 
Dose Level 15 mg/kg 
Volume 500 mL, body weight 80 kg, 2.4 mg/mL 
Time - min 
mL/hr 
mL/30min 
mg/30min 
mg/min 
0-30 
100 
50 
120 
4.0 
31-60 
200 
100 
240 
8.0 
61-90 
300 
150 
360 
12.0 
91-120 
400 
200 
480 
16.0 
Total 
 
500 mL 
 
 
 
 
Dose Level 18 mg/kg 
Volume 500 mL, body weight 80 kg, 2.9 mg/mL 
Time - min 
mL/hr 
mL/30min 
mg/30min 
mg/min 
0-30 
100 
50 
144 
4.8 
31-60 
200 
100 
288 
9.6 
61-90 
300 
150 
432 
14.4 
91-120 
400 
200 
576 
19.2 
Total 
 
500 mL 
 
 
Abbreviations (in alphabetical order): hr, hour; min, minute 
 
For all subsequent infusions, the infusion rate will be according to the trial site standard 
practices for iv administration of mAbs and no faster than the highest safest rate administered 
during Cycle 1. 
7.1.4.6 Patient Monitoring During and After Infusion of Sym004 
Patients will be treated on an outpatient basis.  
Sym004 infusions should be administered under the close supervision of an experienced 
physician in an environment where full resuscitation facilities are immediately available. At 
the end of each infusion, the iv line must remain in place for at least 1 hour to allow 
administration of iv drugs, if necessary. 
Patients will be carefully observed for a minimum of 2 hours following completion of the 
first administration of Sym004 and a minimum of 1 hour following completion of subsequent 
administrations. 
7.1.4.7 Infusion-Related Reactions to Sym004 


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An Infusion-Related Reaction (IRR) is defined as an AE occurring during the Sym004 
infusion and up to 2 hours (or longer, if considered by the Investigator to be an IRR) after the 
EOI, which is assessed by the Investigator to be related to the infusion of Sym004.  
7.1.4.8 Handling of Infusion-Related Reactions 
If an IRR occurs, it should be classified according to CTCAE and the management guidelines 
shown in Table 5 should be followed. 
Table 5 Infusion-Related Reactions Management Guidelines 
CTCAE Grade 
Management/Treatment 
Grade 1 
Mild transient reaction; 
infusion interruption not 
indicated; 
intervention not indicated 
• 
Continue infusion 
• 
Monitor closely 
Grade 2 
Therapy or infusion interruption 
indicated but responds promptly 
to symptomatic treatment (e.g. 
antihistamines, NSAIDs, 
narcotics, iv fluids); 
prophylactic medications 
indicated for ≤ 24 h 
 
• 
Interrupt Sym004 infusion for a minimum of 30 minutes. 
• 
Administer symptomatic treatment (e.g. antihistamines, NSAIDs, 
etc.) 
• 
Use supportive treatment (e.g. bronchodilator, oxygen, etc.), if 
necessary 
• 
When symptoms have resolved and the patient is clinically stable, 
restart infusion at half the previous rate (when the IRR occurred) and 
monitor vital signs closely during the entire infusion  
• 
If the vital signs remain stable and symptoms do not recur, the 
infusion rate can be increased at the discretion of the Investigator 
• 
Monitor closely 
• 
If symptoms reoccur, stop the infusion, institute remedial therapy, 
monitor closely and evaluate whether the patient can continue the 
trial 
Grade 3 
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
clinical sequelae 
• 
Discontinue Sym004 infusion 
• 
Administer symptomatic and supportive treatment (e.g. 
bronchodilator, antihistamine, glucocorticoid, iv fluid, oxygen, etc.) 
as needed 
• 
Either withdraw the patient from treatment or continue subsequent 
treatments at a reduced dose 
• 
Premedication should be reinstituted if previously discontinued 
Grade 4 
Life-threatening consequences; 
urgent intervention indicated 
• 
Stop Sym004 infusion 
• 
Administer necessary life-support measures as needed 
• 
Withdraw the patient from treatment  
Abbreviations (in alphabetical order): CTCAE, The National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events, Version 4.03; h, hours; IRR, Infusion-related Reaction; iv, intravenous; NSAID, nonsteroidal anti-
inflammatory drug 
7.1.5 Dose-Adjustments and Delays of Sym004 
The dose of Sym004 in mg/kg, assigned to the individual patient, will be confirmed by the 
Sponsor or designee prior to C1/D1.  


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Based on the body weight of the patient, the site will calculate the nominal dose of Sym004 
to be administered in mg.  
Weight changes (≥ ± 10%) for a patient during trial will require recalculation of the dose 
(Section 7.1.5.1). 
Furthermore, dose delays of Sym004 and intra-patient dose-reduction(s) may also be required 
upon occurrence of Grade 3 anti-EGFR-associated skin toxicity (Section 7.1.5.2) and other 
safety events (Section 7.1.5.3). Dose adjustments should be discussed with the Sponsor or 
designee prior to implementation. 
If Sym004 administration is delayed, subsequent dosing will be resumed in combination with 
a scheduled FOLFIRI administration. 
7.1.5.1 Sym004 Dose-Adjustments for Body Weight 
Sym004 is dosed in mg/kg and the dose to be administered will be calculated based on the 
actual body weight of the patient. The dose calculated may be used for subsequent infusions, 
unless body weight changes ≥ ± 10% from screening, in which case the dose must be 
adjusted according to the change in body weight. Adjustment may be made in the event of 
lesser incremental changes in weight at the site’s discretion. 
7.1.5.2 Sym004 Dose-Modifications for Skin Toxicity 
The infusion of Sym004 must be paused in the event of a Grade 3 skin toxicity, by delaying 
the dose of Sym004 resulting in a period of approximately 28 days between 2 Sym004 
administrations. 
If Sym004 is paused, all per protocol scheduled assessments must be done and FOLFIRI will 
be administered according to the planned schedule and Section 7.2.1.  
Sym004 dosing will subsequently be resumed in combination with a scheduled FOLFIRI 
administration and according to specific instructions on dose-delays and dose-reductions 
provided in Table 6.   
 
 
 


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Table 6 Sym004 Dose-Reduction for Grade 3 Skin Toxicity 
Skin Toxicity 
Grade 3 
Sym004 
Immediate Action 
Outcome 
Improvement 
Sym004 
First 
occurrence 
Delay dose 
 
Yes, Grade 2 
Reduce by 3 mg/kg 
Yes, Grade ≤1 
Continue at same dose 
No 
Discontinue 
Second 
occurrence 
Delay dose 
 
Yes, Grade 2 
Doses at 9 mg/kg or above: Reduce by 3 mg/kg 
Dose at 6 mg/kg: Reduce by 1.5 mg/kg 
Yes, Grade ≤1 
Continue at same dose 
No 
Discontinue 
Subsequent 
occurrences 
Delay dose 
 
Yes, Grade 2 
Doses at 9 mg/kg or above: Reduce by 3 mg/kg 
Dose at 6 mg/kg: Reduce by 1.5 mg/kg 
Dose at 4.5 mg/kg: Discontinue 
Yes, Grade ≤1 
Continue at same dose 
No 
Discontinue 
 
In case of a Grade 2 skin toxicity, which is locally debilitating for the patient, the guidelines 
outlined in Table 6 above may be followed at the Investigator’s discretion. 
In the occurrence of fissures unresponsive to intensive therapeutic treatment as specified in 
Table 15, the dose of Sym004 should be delayed or reduced. The need for > 2 week dose 
delays or dose-reduction should be discussed with the Sponsor or designee if adequate 
improvement is not seen after the initial delay. 
7.1.5.3 Sym004 Dose-Modifications for Events other than Grade 3 Skin Toxicity 
In the occurrence of hypomagnesemia Grade 4, refractory to iv magnesium-replacement 
therapy as specified in Section 7.2.5, dosing of Sym004 may be delayed or reduced. The 
need for > 2 week dose delays or dose-reduction should be discussed with the Sponsor or 
designee if adequate improvement is not seen after the initial delay. 
Sym004 will not be delayed for FOLFIRI-related toxicities. FOLFIRI dosing will be resumed 
in combination with the next scheduled Sym004 administration once related toxicities have 
resolved.  
7.2 
Other Drugs to be used in the Trial 
7.2.1 FOLFIRI 
The FOLFIRI regimen consists of:  
 
Irinotecan 180 mg/m2 iv, infused over 60-90 minutes, concurrently with 
 
Folinic Acid (FA) 400 mg/m2 iv, infused over 120 minutes, followed by 


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 
5-Fluorouracil (5-FU) 400 mg/m2 iv bolus, then 2400 mg/m2 5-FU infused over 46 
hours 
This regimen is typically repeated every 2 weeks. For the purposes of this trial, FOLFIRI will 
be administered on the same schedule as Sym004 i.e. every second week (Day 1 and Day 15 
of each 28 day cycle, ± 2 days). 
7.2.1.1 FOLFIRI Delays and Dose-Reduction 
On the planned day of treatment, FOLFIRI may be administered only if the following 
treatment criteria are met: 
 
ANC ≥ 1.5 ×109/L (1500/mm3) 
 
Platelet count ≥ 100 ×109/L (100,000/mm3)  
 
FOLFIRI-related gastrointestinal toxicity is ≤ Grade 1 
If any of the above criteria are not met, all components of FOLFIRI dosing will be delayed. 
If FOLFIRI administration is delayed subsequent dosing will be resumed in combination 
with a scheduled Sym004 administration. 
In the event of toxicities other than those listed above, dose-adjustments of the components 
of FOLFIRI should be made independently, based on the toxicity observed. 
Table 7 presents the recommended dose-reductions for each of the components of FOLFIRI 
for which dose-modifications will be allowed. If a dose-reduction exceeding that represented 
by Dose Level -3 is required for any agent, that agent should be discontinued. 
Table 7 FOLFIRI Dose-Reductions 
FOLFIRI 
Component 
Dose Level 
Initial Dose 
-1 
-2 
-3 
Irinotecan 
180 mg/m2 
150 mg/m2 
120 mg/m2 
100 mg/m2 
5-FU Bolus 
400 mg/m2 
200 mg/m2 
0 mg/m2 
0 mg/m2 
5-FU Infusion 
2400 mg/m2 
over 46-48 hours 
2000 mg/m2 
over 46-48 hours 
1600 mg/m2 
over 46-48 hours 
1200 mg/m2 
over 46-48 hours 
Abbreviations: 5-FU, Fluorouracil 
 
FOLFIRI guidelines for dose modifications and delays are provided (refer to Appendix 2). If 
other symptoms not discussed in Appendix 2 occur, the Sponsor or designee should be 
consulted. 
General dosing considerations are as follows:  
 
If 5-FU/FA administration is delayed, irinotecan treatment must also be postponed, 
although Sym004 administration may continue without postponement 


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 
If irinotecan administration is delayed, 5-FU/FA treatment must also be postponed, 
although Sym004 administration may continue without postponement 
 
No dose-reductions will be implemented for FA; however, FA will always be 
withheld when 5-FU is held 
 
In general, if a dose is reduced because of toxicity, it should not be re-escalated to 
the starting level.  However, patients who require dose-reductions during a cycle 
for Grade 2 toxicity may, at the investigator’s discretion, begin the following cycle 
at 1 dose level higher than the final dose level during that cycle 
 
If FOLFIRI is withheld because of toxicity for more than 1 cycle (approximately 
28 days), FOLFIRI will be discontinued; Sym004 may be continued if the toxicity 
resulting in FOLFIRI discontinuation is not considered by the investigator to be 
related to Sym004. 
For hypersensitivity reactions due to infusion of irinotecan or 5-FU, treatment should be 
administered as per institutional guidelines and/or at the discretion of the Investigator. 
7.2.2 Order of Sym004 and FOLFIRI Administration 
Sym004 and FOLFIRI administration will be initiated on Day 1 and Day 15 (± 2 days) of 
each 28 day cycle. The Sym004 infusion will be delivered first. The FOLFIRI regimen 
administration will commence no sooner than 1 hour following completion of Sym004 
administration. 
7.2.3 Prophylactic Treatment 
7.2.3.1 Prophylactic Treatment for Infusion Reactions  
There is an inherent risk for IRRs with the administration of mAbs. A premedication 
schedule will therefore be implemented for all patients treated. 
Prior to the first 2 infusions of Sym004 (i.e. during Cycle 1) all patients will receive:  
 
Glucocorticoid therapy equivalent to 80-100 mg iv methylprednisolone, approx. 
0.5 to 2 hours prior to the start of Sym004 infusion 
 
Antihistamine (H1 antagonist) equivalent to 25-50 mg iv diphenhydramine, 
approx. 0.5 hours prior to the start of Sym004 infusion 
For infusion following the completion of Cycle 1, pre-medication is at the Investigators 
discretion. Premedication should be reinstituted in the event of Grade ≥ 3 IRR. 
7.2.3.2 Prophylactic Treatment for Gastrointestinal Toxicities 
To minimize the risk of gastrointestinal side-effects related to FOLFIRI and/or Sym004, all 
patients will receive: 
 
Prophylaxis for nausea and vomiting according to institutional standards 


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 
Mandatory prophylaxis for diarrhea as shown in Table 8. Loperamide therapy may 
be continued beyond end of Cycle 1 (C1) at the Investigator’s discretion.   
Table 8 Mandatory Prophylaxis for Diarrhea 
Treatment 
Dose 
Start 
Stop 
Loperamide 
4 mg po prior to start of FOLFIRI 
4 mg tid 
C1/D1 
C1/D2 
4 mg tid 
C1/D2 
C1/D3 
2 or 4 mg tid or qid as required 
C1/D4 
End of C1 
Abbreviations: C1/D1, Day 1 of Cycle 1; po, per os; tid, three times per day; qid, four times per day 
1) 
Loperamide may be continued beyond end of Cycle 1 (C1) at the Investigator’s discretion  
2) 
If the patient is experiencing > G2 diarrhea continuation of loperamide therapy at 4 mg on an up to qid 
schedule is permissible. 
3) 
These recommendations do not supersede the recommendations for treatment or prophylaxis of early 
diarrhea due to irinotecan nor do they alter the recommendations for dose reduction of 5-FU or 
irinotecan as specified in Appendix 2.    
7.2.3.3 Prophylactic Treatment for Skin Toxicity 
All patients will receive mandatory prophylactic treatment for skin toxicities and may be 
continued beyond end of Cycle 2 (C2) at the Investigator’s discretion as described in Table 9. 
Table 9 Mandatory Prophylaxis for Skin Toxicities 
Treatment 
Dose 
Start 
Stop 
Alternatives 
SYSTEMIC THERAPY1 
Minocycline 
 
or 
 
Doxycycline 
1 × 100 mg/day 
 
 
 
2 × 100 mg/day 
C1/D1 
End of C22 
In case of 
intolerance: 
 
First generation 
cephalosporins 
 
Amoxicillin 
 
Erythromycin 
 
Limecycline 
TOPICAL THERAPY 
Low potency steroid creams such as 
 
Alclometasone 0.05% 
 
Desonide 0.05 % 
 
Fluocinolone 0.01% 
2 × daily on face and 
chest 
C1/D1 
End of C2 
 
Moisturizer (creams or ointments) 
3 × daily to hands, 
and after hand 
washing using 
fragrance-free soaps 
2 × daily to rest the 
body 
C1/D1 
Continue 
 
Abbreviations: C1/D1, Day 1 of Cycle 1; C2, Cycle 2 
1) 
If infection is suspected (yellow crusts, purulent discharge, painful skin/nares) obtain culture and change to oral 
antibiotic based on sensitivities 
2) 
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7.2.4 Treatment of Skin Toxicity 
Recommendations for management of Grade 1 to 3 Sym004 induced skin toxicities, i.e. rash, 
xerosis, paronychia, pruritus, photosensitivity and fissures, are summarized in Table 10 to 
Table 15 below. 
In the event that a patient experiences any Grade 4 skin toxicity, the patient must be 
withdrawn from Sym004 treatment. 
It is strongly recommended that a dermatologist is consulted in the event of Grade 3 or 4 skin 
toxicity.  
 
 


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Table 10 Treatment of Rash 
CTCAE Grade 
Action with Sym004 
Treatment 
Grade 1 
Papules and/or pustules covering 
< 10% BSA, which may or may 
not be associated with symptoms 
of pruritus or tenderness 
Continue at the same dose 
Topical:  
Face and Chest 
 
Steroid creams of low 
potency (alclometasone 
0.05%, desonide 0.05% 
or fluocinolone 0.01%), 2 
× daily,  
Rest-of-body 
 
Moisturizers, 2 × daily, 
rest of body 
Systemic1: 
 
Minocycline 100 mg/day 
or doxycycline 200 
mg/day at least 4 weeks 
Grade 2 
Papules and/or pustules covering 
10-30% BSA, which may or may 
not be associated with symptoms 
of pruritus or tenderness; 
associated with psychosocial 
impact; limited instrumental ADL 
 
Continue at the same dose 
 
If locally debilitating for the 
patient, consider to follow 
guidelines of dose-delay and dose-
reduction as outlined in Table 6 
Topical:  
 
See Grade 1 
Systemic1: 
 
Minocycline 100 mg/day 
or doxycycline 200 
mg/day for at least 4 
weeks 
 
1 week course of oral 
steroid: 
Methylprednisolone 4 
mg tablets: Day 1: 2-1-1-
2, Day 2: 1-1-1-2, Day 3: 
1-1-1-1, Day 4: 1-1-1, 
Day 5 1-0-1, Day 6: 1 
Grade 3 
Papules and/or pustules covering 
>30% BSA, which may or may 
not be associated with symptoms 
of pruritus or tenderness; limiting 
self-care ADL; associated with 
local superinfection with oral 
antibiotics indicated 
Delay dose of Sym004, continue 
skin treatment and re-asses. Refer 
to Table 6 for further guidelines 
on dose-reduction 
Topical:  
 
See Grade 1 
 
Systemic1: 
 
See Grade 2 
Abbreviations (in alphabetical order): ADL, activities of daily living; BSA, body surface area; CTCAE, The National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 4.03 
1) Alternatives in case of intolerance: First generation cephalosporins, amoxicillin, erythromycin or limecycline. If 
infection is suspected (yellow crusts, purulent discharge, painful skin/nares): Obtain culture and change to oral 
antibiotic based on sensitivities 
 


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Table 11 Treatment of Xerosis 
CTCAE Grade 
Action with Sym004 
Treatment 
Grade 1 
<10% BSA and no associated 
erythema or pruritus 
Continue at the same dose 
Topical: 
Face 
 
Moisturizing cream or 
ointment1, 2 × daily 
And 
 
Body 
 
Ammonium lactate 6-12% 
cream, 2 × daily 
Grade 2 
10-30% BSA associated with 
erythema or pruritus; limited 
instrumental ADL 
 
Continue at the same dose 
 
If locally debilitating for the 
patient, consider to follow 
guidelines of dose-delay and 
dose-reduction as outlined in 
Table 6 
Topical:  
Face 
 
Moisturizing cream or 
ointment1, 2 × daily 
And 
 
Body 
 
Ammonium lactate 12% 
cream or salicylic acid 3-
6% cream or urea 10-20% 
cream, 2 x daily  
Grade 3 
>30% BSA associated with 
pruritus; limited self-care ADL 
Delay dose of Sym004, continue 
skin treatment and re-asses. Refer 
to Table 6 for further guidelines 
on dose-reduction 
Topical:  
Face 
 
Moisturizing cream or 
ointment1, 2 × daily 
And 
 
Body 
 
Ammonium lactate 12% 
cream or salicylic acid 3-
6% cream or urea 10-20% 
cream, 2 × daily;  
and 
 
Eczematous areas: 
Topical steroid (e.g. 
triamcinolone acetonide 
0.025%, desonide 0.05%, 
alclometasone 0.05%, 
fluticasone propionate 
0.05%), 2 × daily 
Abbreviations (in alphabetical order): ADL, activities of daily living; BSA, body surface area; CTCAE, The National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 4.03 
1) 
If prescription is not available, recommendation by pharmacist/dermatologist is acceptable 
 
 


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Table 12 Treatment of Paronychia 
CTCAE Grade 
Action with Sym004 
Treatment 
Grade 1 
Nail fold edema or erythema; 
disruption of the cuticle 
Continue at the same dose 
Topical:  
 
Antibiotics (e.g. 
clindamycin 1%, 
erythromycin 1%) 
and 
 
Vinegar soaks (i.e. 
soaking fingers or toes in 
a 1:1 solution of white 
vinegar in water for 15 
minutes every day 
And 
Systemic: 
 
Bacterial culture, oral 
antibiotic if infection 
confirmed 
Grade 2 
Localized intervention indicated; 
oral intervention indicated (e.g., 
antibiotic, antifungal, antiviral); 
nail fold edema or erythema with 
pain; associated with discharge or 
nail plate separation; limiting 
instrumental ADL 
Continue at the same dose 
 
If locally debilitating for the 
patient, consider to follow 
guidelines of dose-delay and 
dose-reduction as outlined in 
Table 6 
Same as for Grade 1 
 
And 
Topical:  
 
Silver nitrate application 
weekly (needs 
consultation with 
dermatologist or surgeon) 
 
Grade 3 
Surgical intervention or iv 
antibiotics indicated; limiting self-
care ADL 
 
Delay dose of Sym004, continue 
skin treatment and re-asses. Refer 
to Table 6 for further guidelines 
on dose-reduction 
Same as for Grade 1 
 
And 
 
Silver nitrate application 
weekly (needs 
consultation with 
dermatologist or surgeon) 
And 
 
Consider nail avulsion 
(needs consultation with 
dermatologist or surgeon) 
Abbreviations (in alphabetical order): ADL, activities of daily living; BSA, body surface area; CTCAE, The National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 4.03; iv, intravenous 
 
 


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Table 13 Treatment of Pruritus 
CTCAE Grade 
Action with Sym004 
Treatment 
Grade 1 
Mild or localized; topical 
intervention indicated 
Continue at the same dose 
Topical:  
 
Steroid (e.g. 
triamcinolone acetonide 
0.025%, desonide 0.05%, 
alclometasone 0.05%, 
Fluticasone propionate 
0.05%), 2 × daily  
or 
 
Anti-pruritics (e.g. 
pramoxine 1%, doxepin 
5% cream), 2 × daily 
Grade 2 
Intense or widespread; 
intermittent; skin changes from 
scratching (e.g., edema, 
papulation, excoriations, 
lichenification, oozing/crusts); 
oral intervention indicated; 
limiting instrumental ADL 
Continue at the same dose 
 
If locally debilitating for the 
patient, consider to follow 
guidelines of dose-delay and 
dose-reduction as outlined in 
Table 6 
Same as for Grade 1 
And 
Systemic: 
 
Oral antihistamines 
(diphenhydramine 25-50 
mg; hydroxyzine 25 mg; 
fexofenadine 60 mg, 3 × 
daily  
Grade 3 
Intense or widespread; constant; 
limiting self-care, ADL or sleep; 
oral corticosteroid or 
immunosuppressive therapy 
indicated 
Delay dose of Sym004, continue 
skin treatment and re-asses. Refer 
to Table 6 for further guidelines 
on dose-reduction 
Same as for Grade 2 
 
Abbreviations (in alphabetical order): ADL, activities of daily living; BSA, body surface area; CTCAE, The National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 4.03 
 
 


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Table 14 Treatment of Photosensitivity 
CTCAE Grade 
Action with Sym004 
Treatment 
Grade 1 
Painless erythema and erythema 
covering <10% BSA 
Continue at the same dose 
Topical:  
 
Broad spectrum sunscreen 
with an SPF of at least 15; 
need to be applied every 2 
hours or more frequently 
if swimming or perspiring 
And 
Systemic: 
 
Bacterial culture, oral 
antibiotic if infection 
confirmed 
Grade 2 
Tender erythema covering 10-
30% BSA 
 
Continue at the same dose 
 
If locally debilitating for the 
patient, consider to follow 
guidelines of dose-delay and 
dose-reduction as outlined in 
Table 6 
Same as for Grade 1 
And 
Topical:  
 
Corticosteroids (e.g. 
triamcinolone acetonide 
0.025%, desonide 0.05%, 
alclometasone 0.05% 
cream, fluticasone 
propionate 0.05%), 2 × 
daily 
Grade 3 
Erythema covering >30% BSA 
and erythema with blistering; 
photosensitivity; oral 
corticosteroid therapy indicated; 
pain control indicated (e.g. 
narcotics or NSAIDs) 
Delay dose of Sym004, continue 
skin treatment and re-asses. Refer 
to Table 6 for further guidelines 
on dose-reduction 
Same as Grade 2 
 
Abbreviations (in alphabetical order): ADL, activities of daily living; BSA, body surface area; CTCAE, The National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 4.03; NSAID, nonsteroidal anti-
inflammatory drugs; SPF, sun protection factor 
 
 
 


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Prophylaxis of fissures includes careful use of moisturizing creams and/or ointments 3 times 
a day and after handwashing, using only fragrance-free soaps. Should fissures begin to form, 
a stepwise approach outlined in Table 15 should be followed. 
 
Table 15 Treatment of Fissures 
Treatment Step 
Action with Sym004 
Treatment 
Step 1 
Initiated at first occurrence 
No action 
Topical:  
 
Thick moisturizers of 
zink oxide (13-40%) 
cream 
 
Liquid glues of 
cyanoacrylate to seal 
cracks 
Step 2 
If no improvement after 2 weeks 
from initiation of Step 1 
No action 
Topical:  
 
Thick moisturizers of 
zink oxide (13-40%) 
cream under occlusion at 
night 
 
Salicylic acid 6% cream 
or ammonium 
lactate/lactic acid 12% 
Step 3 
If no improvement after 2 weeks 
from initiation of Step 2 
Delay dose of Sym004 and re-
assess. 
Discuss need for dose-reduction 
and/or further dose omissions 
with Sponsor or designee 
Continue local treatment as 
described in Step 2 
7.2.5 Treatment of Hypomagnesemia 
In the event that a patient experiences Grade 3 or 4 hypomagnesemia, treatment with iv 
magnesium sulphate 6-10 g or equivalent should be given at least twice a week until 
magnesium levels are ≤ Grade 1.  
A 12-lead ECG should be performed prior to administration of the next dose of Sym004 for 
monitoring of QT prolongation which may result in Torsade de Pointes (TdP) arrhythmias. In 
the event of TdP arrhythmia or any other life-threatening cardiac arrhythmia, the patient 
should be withdrawn from treatment with Sym004. 
7.3 
Blinding 
Not applicable as this is an open-label trial.  
7.4 
Drug Accountability and Compliance Check 
The Investigator is responsible for ensuring accountability for the IMP, including 
maintenance of IMP accountability records. 


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IMP accountability records will include a full inventory of the IMP including: 
 
Confirmation of IMP delivery to the trial site 
 
Record of each dose dispensed 
 
The return of unused IMP to the Sponsor or designee 
Records will specify dates, quantities, batch numbers, use-by dates and patient numbers, as 
applicable. 
The Investigator, or designee, should maintain records that adequately document: 
 
That the patients were provided the doses specified by the CTP, and 
 
That all IMP provided by the Sponsor was fully reconciled 
7.5 
Concomitant Medication/Therapy 
7.5.1 Allowed Concomitant Medication/Therapy and Procedures during the Trial 
Patients may receive their current concomitant medication and any medication considered 
necessary for the welfare of the patient during trial, except if listed in Section 7.5.2.  
Furthermore, the following medications and procedures are permitted during the trial: 
 
Premedication with standard therapies prior to Sym004 administration to reduce 
the risk of IRRs 
 
Prophylaxis and treatment of Sym004 and FOLFIRI related toxicities 
 
Prophylactic use of blood products and growth factors after Cycle 1. 
Interventional/therapeutic use is allowed at any time 
 
Radiotherapy for pain control against non-target lesions, as long as it does not 
influence bone marrow function 
7.5.2 Prohibited Concomitant Medication/Therapy and Procedures during the Trial 
The following medications and procedures are not allowed from C1/D1, or as specified in the 
inclusion/exclusion criteria, until the EOT Visit: 
 
Anti-cancer treatment, including cytotoxic or cytostatic agents, hormonal therapy 
(except as physiologic hormone replacement), other anti-EGFR antibodies or anti-
EGFR small molecule inhibitors 
 
Radiotherapy against target lesion(s) 
 
Systemic immunosuppressive or systemic hormonal therapy with the exception of 
the following allowed therapies: 


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a. 
Hormonal therapy (e.g., Megace) for appetite stimulation 
b. 
Nasal, ophthalmic, inhaled, and topical glucocorticoid preparations 
c. 
Oral replacement glucocorticoid therapy for adrenal insufficiency 
d. 
Low-dose maintenance steroid/hormonal therapy for other conditions 
(excluding steroid tapers for brain edema/metastases/radiation) 
e. 
Hormonal contraceptive therapy  
 
Prophylactic use of hematopoietic growth factors during Cycle 1 
 
Major surgery that would preclude the patient from complying with the 
requirements of the protocol 
If any one of the above listed medications/procedures becomes necessary during the trial, the 
patient must be withdrawn from Sym004 and FOLFIRI and the EOT Visit should be 
performed. The 1M FUP Visit should then be conducted, no less than 1 month (28 +7 days) 
after withdrawal from trial treatments. 
7.6 
Medical Care of Patients after End of Trial Participation 
After completing participation in this trial, patients will be offered standard of care treatment 
in accordance with generally accepted medical practice and depending on the patient’s 
individual medical need. 
 
 


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8 
TRIAL ASSESSMENTS  
8.1 
Baseline Characteristics / Eligibility Assessments 
8.1.1 Signing of Informed Consent 
Prior to any protocol-related procedure, unless such testing was performed previously as part 
of the routine clinical management of the patient.  
 
Screening 
NOTE: In the event a tumor biopsy is required for eligibility, informed consent may be obtained 
outside the 14-day screening period prior to C1/D1 
8.1.2 Demographics 
To include date of birth, sex, race and ethnicity. 
 
Screening 
8.1.3 Medical History 
To include details of prior and ongoing medical illnesses and conditions and prior surgical 
procedures not related to the primary diagnosis. 
 
Screening 
 
C1/D1 (prior to dosing)  
8.1.4 Tumor Characteristics and Extent of Disease 
To include details of diagnosis and date of initial diagnosis, Tumor Node Metastasis (TNM) 
staging at time of initial diagnosis, tumor histology, current location of metastases, date of 
most recent disease progression and mutation status. 
 
Screening 
8.1.5 Prior Cancer Treatments 
To include details of prior surgical procedures for the primary diagnosis, as well as prior 
radiotherapy, chemotherapy and/or biological targeted therapy, investigational treatments 
and/or procedures.  Include dates of treatments, numbers of cycles, and best response to such 
treatments.  
 
Screening 
 
C1/D1 (prior to dosing) 


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8.2 
Safety Assessments 
To be performed within 14 days of C1/D1 (first dose of Sym004/FOLFIRI), unless otherwise 
specified. 
8.2.1 Medication Survey 
To include details of all medications and/or treatments taken other than Sym004 or FOLFIRI.  
Include generic name or brand name, indication for use, dose and frequency, route of 
administration, start and stop dates or if ongoing at 1M FUP Visit 
 
Starting from the date of Screening 
 
Until the date of the 1M FUP  
8.2.2 Adverse Event Survey 
For details about (S)AEs and (S)AE reporting, refer to Section 9.  
 
Starting from signing the informed consent until the date of the 1M FUP  
NOTE: Patients who sign the informed consent and are subsequently deemed to be screening 
failures will be followed for the occurrence of SAEs/AEs until it is determined they will not be 
participating in the trial 
8.2.3 Dose-Limiting Toxicities Evaluation (Dose-Escalation Only) 
For details about AEs meeting DLT criteria, refer to Section 9.5. 
 
Starting from the first dose of trial drug (C1/D1) 
 
Reported during Cycle 1 with final assessment 14 days (±2) after the second dose 
of Cycle 1 or prior to dosing on the scheduled Day 1 of Cycle 2 (C2/D1) 
8.2.4 Vital Signs and Body Weight 
To include temperature, heart rate, blood pressure, and body weight.   
 
Screening 
 
Day 1 and 15 of each cycle (prior to dosing) 
 
EOT 
 
1 M FUP  
 
As clinically indicated 
8.2.5 Performance Status  
To be assessed by ECOG PS score. 
 
Screening 


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 
Day 1 of each cycle (prior to dosing) 
 
EOT 
 
1 M FUP 
 
As clinically indicated 
8.2.6 Physical Examination  
To include evaluation of: General appearance, head, ears, eyes, nose, throat, neck/thyroid, 
chest, cardiovascular system, abdomen, musculoskeletal system, pulses, lymph nodes, 
neurologic status and mental status. At Screening, include height (without shoes, rounded to 
nearest centimeter). 
 
Screening 
 
Day 1 of each cycle (prior dosing) 
 
EOT 
 
1M FUP 
 
As clinically indicated 
8.2.7 Dermatological Assessment 
To be performed by a physician or qualified designee; complete skin examination  
 
Screening 
 
Day 1 and 15 of each cycle (prior to dosing) 
 
EOT 
 
1M FUP 
 
As clinically indicated 
8.2.8 Electrocardiogram 
To include standard 12-lead ECG. The Investigator, or qualified designee, should document 
the evaluation of the ECG, including specification of any abnormality as clinically significant 
or not clinically significant. 
 
Screening 
 
EOT 
 
In the event of  ≥ Grade 3 hypomagnesemia an ECG is to be scheduled as soon as 
possible 


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 
In the event of QT prolongation an ECG is to be performed prior to the next dose 
of Sym004 
 
As otherwise clinically indicated 
 
In the event of significant electrolyte abnormalities, the evaluation frequency 
should be increased to include additional evaluations between the scheduled 
assessments, as clinically indicated.   
8.2.9 Laboratory Assessments and Pregnancy Test 
All routine laboratory analyses will be performed at a laboratory facility local to the trial site. 
Results should be available to confirm eligibility and prior to each dosing of Sym004 and 
FOLFIRI. 
Sponsor or designee must be provided with a list of trial site laboratory normal ranges for all 
required parameters prior to screening of the first patient at the site. Likewise, any change in 
laboratory normal ranges during the trial should be forwarded to the Sponsor or designee 
promptly during the trial. 
Blood samples will be taken at all visits and analyzed for the following parameters as per 
Table 16 and as clinically indicated: 
Table 16 Schedule of Safety Blood and Urine Samples 
Sample Analysis 
Screening 
Cycle 1 
Cycles 
Thereafter 
EOT 
1M FUP 
Day within Cycle 
 
D1 
D8 
D15 
D22 
D1 
D15 
 
 
Hematology Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
 
X 
 
X 
 
X 
X 
Pregnancy Test 
X 
 
 
 
 
 
 
X 
 
Abbreviations (in alphabetical order): D, day; EOT, End of Treatment Visit; 1M FUP, One Month Follow-up 
Visit 
 
8.2.9.1 Hematology Panel 
To include complete blood count with differential, ANC, and platelet count. 
 
Screening 
 
Cycle 1 
a. 
Day 1 and 15 (prior to dosing) 
b. 
Day 8 and 22 
 
Each cycle thereafter 


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a. 
Day 1 and 15 (prior to dosing) 
 
EOT 
 
1M FUP 
 
As clinically indicated  
In the event of hematologic toxicity, the evaluation frequency should be increased to include 
additional evaluations between scheduled assessments, as clinically indicated. 
8.2.9.2 Biochemistry Panel 
To include, if applicable, sodium, potassium, chloride, bicarbonate or carbon dioxide, Blood 
Urea Nitrogen (BUN), creatinine, glucose, bilirubin [total and direct], AST, ALT, Alkaline 
Phosphatase (ALP), calcium, magnesium, phosphorus, albumin, total protein, uric acid, 
amylase, lipase, and Creatine Kinase (CK).  Clinically significant electrolyte abnormalities 
should be corrected prior to dosing. 
 
Screening 
 
Cycle 1 
a. 
Day 1 and 15 (prior to dosing) 
b. 
Day 8 and 22 
 
Each cycle thereafter 
a. 
Day 1 and 15 (prior to dosing) 
 
EOT 
 
1M FUP 
 
As clinically indicated  
In the event of significant biochemistry analyte abnormalities, the evaluation frequency 
should be increased to include additional evaluations between the scheduled assessments, as 
clinically indicated.  In the event of CK abnormalities, isoenzyme analysis should be 
performed. 
8.2.9.3 Coagulation Panel 
To include PT, PTT and INR. 
 
Screening 
 
Cycle 1 
a. 
Day 1 and 15 (prior to dosing) 
b. 
Day 8 and 22 


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 
Each cycle thereafter 
a. 
Day 1 and 15 (prior to dosing) 
 
EOT 
 
1M FUP 
 
As clinically indicated  
8.2.9.4 Urinalysis 
Multi-parameter chemical test strips are acceptable and should include assessment of: 
Specific gravity, pH, protein, glucose, ketones, leukocyte esterase, nitrite, bilirubin, and 
urobilinogen. 
 
Screening 
 
Cycle 1 
a. 
Day 1 and 15 (prior to dosing) 
 
Day 1 of each cycle thereafter (prior dosing) 
 
EOT 
 
1M FUP 
 
As clinically indicated  
8.2.9.5 Pregnancy Test  
Serum human Chorionic Gonadotropin (β-hCG) at screening, urine β-hCG thereafter, in 
women of childbearing potential. 
 
Screening 
 
EOT 
 
As clinically indicated 
Women are considered of childbearing potential unless they have been hysterectomized, have 
undergone tubal ligation or have been postmenopausal for at least one year. 
8.3 
Disease Assessments 
8.3.1 Tumor Marker Evaluation 
To include Carcinoembryonic Antigen (CEA). Will be performed at a laboratory facility 
local to the trial site. 
 
Screening 
 
End of Cycle 2 and end of every second cycle thereafter, i.e. Cycle 4, 6, 8 etc. 


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NOTE: End of cycle assessments may be conducted at any time during the week prior to Day 1 of 
the next cycle 
 
At least 28 days following an OR (PR, CR) 
 
EOT (if  > 3 weeks since previous evaluation) 
 
1M FUP (if PD was not documented before or at EOT) 
8.3.2 Disease Status Evaluation using CT or MRI 
The anti-tumor activity of Sym004 in combination with FOLFIRI will be assessed by the 
Investigator, or qualified designee, according to RECIST v1.1. Refer to Appendix 1. 
Patients will undergo imaging of the thorax, abdomen, and pelvis by CT or MRI as  
indicated, based on tumor type and prior areas of documented disease. The use of CT or MRI 
must be consistent per patient throughout the trial.  Use of contrast is preferred but is at the 
discretion of the Investigator, as medically indicated.  
 
Screening 
NOTE: A CT/MRI performed within 28 days prior to Day 1 can be used for evaluation of 
eligibility and as baseline scan, provided that the CT/MRI has been performed according to the 
protocol requirements 
 
End of Cycle 2 and end of every second cycle thereafter, i.e. Cycle 4, 6, 8 etc. 
NOTE: End of cycle assessments may be conducted at any time during the week prior to Day 1 of 
the next cycle 
 
Suspected PD (as soon as possible) 
 
At least 28 days following an OR (PR, CR) 
 
EOT (if  > 3 weeks since previous CT/MRI)  
 
At 1M FUP (if PD was not documented before or at EOT) 
If disease progression is documented at any time, no further disease assessments will be 
required.  Patients with documented PD will be discontinued from further treatment with 
Sym004/FOLFIRI so that alternative management of their malignancy may be considered. 
To be assigned a status of confirmed PR or CR, changes in disease status must be confirmed 
by repeat studies performed no less than 28 days (4 weeks) after the criteria for response are 
first met.  In the case of SD, follow-up measurements must have met the SD criteria at least 
once after trial entry at a minimal interval in general no less than 6-8 weeks. 
Imaging data will be stored by the sites and will be available upon request for potential 
review by the Sponsor or an independent radiology reviewer. 
For all imaging time points, the following will be recorded as per RECIST v1.1: Target 
lesions including size, location, and type (nodal/non-nodal); sum of diameters of target 


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lesions; any new lesions noted during trial, including size, location, and type (nodal/non-
nodal); final response assessment at each visit (PD, SD, PR, CR or Not Evaluable [NE]) 
8.4 
Pharmacokinetic Assessments (Dose-Escalation Only) [Omitted as of Amendment 
3] 
PK samples will be taken according to the schedules shown in Table 17 for patients in dose-
escalation only. Per sampling, approximately 5 mL of blood will be obtained from patients to 
measure Sym004 concentration in serum.  
Analysis of PK will be performed at a central laboratory. A detailed laboratory manual 
specifying sample collection, handling, storage and shipment will be provided to the trial 
sites. 
In the event that a collected serum sample is inadequate for PK analysis, the analysis of PK 
can be done using an ADA serum sample from the same time point, if available. 
Table 17 Schedule of Pharmacokinetic Assessments  
 
Cycle 1 
Cycle 2 
Cycles 
Thereafter 
EOT 
1M FUP 
 
 
D1 
D15 
D1 
D15 
D1 
 
 
Sampling Time 
Window 
 
 
 
 
 
 
 
SOI 
- 4 h 
X 
X 
X1 
X1,2 
X1 
 
 
EOI 
+ 10 min 
X 
X 
X 
X 
X 
 
 
EOI + 1 h 
+/- 15 min 
X 
 
 
X 
 
 
 
EOI + 2 h 
+/- 30 min 
X 
 
 
X 
 
 
 
EOI + 4 h 
+/- 30 min 
X 
 
 
X 
 
 
 
EOI + 24 h 
+/- 6 h 
X 
 
 
X 
 
 
 
EOI + 48 h 
+/- 12 h 
X 
 
 
X 
 
 
 
During Visit 
NA 
 
 
 
 
 
X 
X 
Abbreviations (in alphabetical order): D, day; EOI, End of Infusion, EOT, End of Treatment Visit; NA, Not 
Applicable; h, hour; min, minutes; 1M FUP, One Month Follow-up Visit; SOI, Start of Infusion 
1) If Sym004 is paused, only one PK sample should be taken during the visit 
2) If Sym004 is paused, the scheduled extended PK profile samples (i.e. additional timepoints EOI + 1, 2, 4, 24 
and 48 hours) should be postponed until the 4th administration of Sym004 takes place  
8.5 
Anti-Drug Antibody Testing (Omitted as of Amendment 3) 
To assess formation of ADA. All samples must be taken prior to the Sym004 infusion of that 
visit. Per sampling, approximately 5 mL of blood will be obtained for preparation of serum. 
Analysis of ADA and residual serum levels of Sym004 will be performed at a central 
laboratory. A detailed laboratory manual specifying sample collection, handling, storage and 
shipment will be provided to the trial sites. In the event that a collected serum sample is 
inadequate for ADA analysis, the analysis of ADA can be done using a PK serum sample 
from the same time point, if available. 
 
C1/D1 


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 
Prior to every second cycle thereafter, i.e. Cycle 3, 5, 7 etc.  
 
EOT 
 
1M FUP 
8.6 
Biomarker Tumor, Blood and Urine Sample (Omitted as of Amendment 3) 
To be performed only after eligibility has been confirmed. 
8.6.1 Archival Tumor Sample Collection (Omitted as of Amendment 3) 
If available, archived formalin-fixed paraffin-embedded (FFPE) tumor tissue sample from a 
prior surgical procedure or biopsy to be submitted to a central laboratory for evaluation of 
RAS mutations; tissue block or cut/unstained slides are acceptable.  This sample could be 
taken at any time from the time of diagnosis to the time of enrollment into this trial. All 
tumor tissue samples should be reviewed by a pathologist to confirm the presence of tumor 
cells before the tissue sample is sent to the central laboratory for analysis. Unused portions of 
paraffin blocks will be returned to the referring institution if requested.  Procedures for 
handling and shipment will be provided.    
 
Screening 
8.6.2 Fresh Tumor Biopsy Collection (Omitted as of Amendment 3) 
To be performed only if archival FFPE tumor samples (blocks or slides) are not available for 
submission and only after eligibility has been confirmed. 
The patient will have a tumor core biopsy of a locally recurrent or metastatic lesion. This 
procedure will take place after eligibility has been confirmed and prior to first Sym004 
administration. The tumor biopsy must be performed with minimal morbidity to the patient 
by a percutaneous core biopsy needle either with or without the aid of an imaging modality 
chosen at the discretion of the physician performing the biopsy.  
Biopsy specimens will be obtained using standard sterile surgical techniques and formalin-
fixed, paraffin-embedded according to standard laboratory techniques. All tumor tissue 
samples should be reviewed by a pathologist to confirm the presence of tumor cells before 
the tissue sample is sent to the central laboratory for analysis. 
 
Screening (after confirmation of eligibility and only if archival tumor tissue 
sample is not available for central analysis)  
Biomarker testing from collected tumor biopsies (archival FFPE or fresh tumor biopsy) will, 
if amount of tissue allows, in addition to RAS and EGFR, include biomarkers connected to 
EGFR signaling or escape mechanisms observed after EGFR treatment. 


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8.6.3 Blood and Urine Sample Collection (Omitted as of Amendment 3) 
The purpose of the pharmacodynamics biomarker assessments is to develop an approach for 
the identification and validation of genes or proteins that may predict which patients are 
likely to respond to Sym004, and that may change with the possible development of acquired 
resistance to Sym004. Potential biomarkers of interest includes genes, gene transcripts and 
proteins of the Receptor Tyrosine Kinases (RTKs) and molecules of the EGFR signaling 
pathway. 
Analysis of all samples taken for pharmacodynamics assessments will be performed at a 
central laboratory. A detailed laboratory manual specifying sample collection, handling, 
storage and shipment will be provided to the trial sites.  
Patients will have blood samples taken of approximately 20 mL, for preparation of plasma, 
and a urine sample of approximately 100 mL.  
 
Screening 
 
End of Cycle 2 (prior to dosing or upon PD, whichever occurs first) 
NOTE: End of cycle assessments may be conducted at any time during the week 
prior to Day 1 of the next cycle 
 
EOT 
8.7 
Handling of Biological Samples 
All biological samples to be analyzed locally will be collected and handled according to 
institutional practices. 
All biological samples to be analyzed centrally will be collected and handled according to a 
detailed laboratory manual. 
Retention time for biologic specimens will be specified in the laboratory manual. 
8.8 
Follow-up Assessments 
Assessments at the 1M FUP Visit include disease status and subsequent cancer therapy. 
8.9 
Appropriateness of Measurements 
Standardized methods for assessments of efficacy and safety variables will be used.  
 
 


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9 
ADVERSE EVENTS 
9.1 
Definitions of Adverse Events 
9.1.1 Adverse Event 
An AE is any untoward medical occurrence in a patient or a clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, symptom, or disease temporally associated with 
the use of an IMP, whether or not considered related to the IMP.  
Please Note: Progression of disease will not be captured as an AE/SAE unless the nature of 
the PD is different than expected (i.e. other diagnoses and/or signs/symptoms that are not 
typical of PD). Events associated with the actual PD will also be captured, as determined by 
the investigator. Additionally, AE occurring simultaneously with PD, but which may not be 
related to the actual PD, will also be captured.  
Causality for the above-mentioned AE will be assessed appropriately as; Related to Study 
Drug, Not Related to Study Drug or Related to Disease Progression. In addition, any AE, 
regardless of causality, that also meets seriousness criteria, will be reported on an SAE Form 
Events not to be considered as Adverse Events 
A pre-existing condition (i.e., a disorder that is present before the AE recording period starts 
and is noted on the medical history/physical examination form) should not be recorded as an 
AE unless the condition worsens or episodes increase in frequency during the AE recording 
period. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be recorded as AEs. A medical condition for which an unscheduled procedure was 
performed, should however be recorded if it meets the definition of an AE. For example, an 
acute appendicitis should be recorded as the AE and not the appendectomy. 
Procedures to support the treatment regimens, such as insertion of central venous catheters 
etc. should not be recorded as AEs, unless the procedures result in complications. 
Events such as lab results reported outside the normal range and determined to be clinically 
insignificant by the Investigator will not be recorded as AEs. 
9.1.2 Adverse Events of Medical Interest 
Not applicable. 
9.1.3 Expected Adverse Events  
Based on pharmacologic action, the following AEs have been observed with Sym004:  


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 
Electrolyte imbalances, including hypomagnesemia, hypocalcemia and 
hypokalemia 
 
Dermatological toxicities, acneiform rash, dry skin, fissuring of the skin and 
secondary skin infections 
 
Infusion reactions of variable severity 
9.1.4 Serious Adverse Event 
An SAE is an AE that meets one or more of the following criteria: 
 
Results in death 
 
Is life-threatening 
NOTE: The term "life-threatening" in this definition refers to an event in which the patient is at 
immediate risk of death at the time of the event; it does not refer to an event which hypothetically 
might cause death if it was more severe 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect 
 
Is medically important  
NOTE: Medical and scientific judgment must be exercised in deciding whether an AE is believed 
to be “medically important”. Medically important events 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 other outcomes listed in the definition above. 
In the case of deaths, the event(s) leading to the death should be recorded and reported as 
SAE(s) with the outcome “Fatal”. The death itself will not be reported as an SAE, unless the 
cause of the death cannot be reported (e.g. in case of unexplained or sudden death).  
Events That Do Not Meet the Definition of a Serious Adverse Event 
Elective surgery or other scheduled hospitalization periods that were planned before the 
patient was included in this trial are not to be recorded as SAEs, unless an outcome is 
considered serious.  
Hospitalization for observation or convenience following the Sym004/FOLFIRI infusions 
without an SAE occurring should not be recorded as an SAE, e.g. if a patient is hospitalized 
merely for observation, or if a patient finalizes the infusion at a time of day requiring a 
convenience overnight stay in the hospital.  
If procedures to support the treatment regimens require hospitalization they should not be 
recorded as SAEs. However, in cases where a procedure results in complications 
requiring/prolonging hospitalization this must be recorded and reported as an SAE. 


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9.2 
Adverse Event Recording and Reporting Instructions 
9.2.1 Adverse Event Recording Period  
All AEs will be recorded from signing the informed consent. The recording period ends at 
the time of the 1M FUP Visit. 
NOTE: Patients who sign the informed consent and are subsequently deemed to be screening failures will 
be followed for the occurrence of SAEs/AEs until it is determined they will not be participating in the trial. 
The Investigator must record all directly observed AEs and all AEs spontaneously reported 
by the patient. A general, open-ended type of question should be used to elicit a response 
from the patient, such as, “Do you have any health problems?” or “Have you had any health 
problems since your last visit?”. 
All AEs that occur in patients during the AE recording period must be recorded/entered on 
the AE section of the Case Report Form (CRF), whether or not the event is assessed as 
related to Sym004. If the AE is serious, the SAE report forms must also be completed and 
submitted (see Section 9.3). 
9.2.2 Diagnosis 
A diagnosis should be recorded if possible. If no diagnosis is available, signs and symptoms 
should be recorded instead. 
9.2.3 Intensity 
The Investigator will use CTCAE version 4.03 to describe the severity of an AE. If the 
severity of an AE is not specifically graded by the CTCAE guidance document, the 
Investigator should use the general definitions of Grades 1 to 5 as per the following, and use 
his/her best medical judgment to describe the severity of the AE: 
 
Grade 1: Mild 
 
Grade 2: Moderate 
 
Grade 3: Severe 
 
Grade 4: Life-threatening or disabling 
 
Grade 5: Death caused by the event 
Changes in severity of AEs will be recorded.  
Generally, an AE of CTCAE Grade 4 or 5 qualifies for SAE reporting to the Sponsor or 
designee. However, a laboratory abnormality of CTCAE Grade 4 does not need to be 
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9.2.4 Relationship to Investigational Medicinal Product/Sym004 and FOLFIRI 
The Investigator must assess the AE as either related or not related to the IMP and/or 
FOLFIRI. Relatedness has to be assessed and recorded within the initial report (CRF and 
SAE report form). 
The causal relationship is an assessment of whether or not the event is related to the use of 
the IMP and/or FOLFIRI. It is not an evaluation of whether or not the event could 
hypothetically occur in the investigational patient population. 
The causal relationship of an AE to the IMP and/or FOLFIRI will be rated as follows: 
Not Related: The AE is not related to the IMP and/or FOLFIRI, which means the event: 
 
Does not follow a reasonable temporal sequence from drug administration  
 
Is readily explained by the patient’s clinical state or by other modes of therapy 
administered to the patient 
 
The AE is clearly NOT related to the IMP and/or FOLFIRI 
Related: The AE is related to the IMP and/or FOLFIRI, which means the event: 
 
Follows a reasonable temporal sequence from drug administration  
 
Abates upon discontinuation of the IMP and/or FOLFIRI (de-challenge)  
 
Is confirmed by reappearance of the reaction on repeat exposure (re-challenge)  
 
Cannot be reasonably explained by the known characteristics of the patient’s 
clinical state  
 
Is not likely to have been produced by the patient’s clinical state or by other modes 
of therapy administered to the patient 
9.2.5 Outcome 
Outcome of the AE must be assessed by the Investigator utilizing one of the following terms: 
 
Recovered 
 
Recovered with sequelae (if recovered with sequelae, specify sequelae) 
 
Not recovered 
 
Fatal 
 
Unknown 
Instructions for reporting changes in an ongoing AE during a patient’s participation in the 
trial are provided in the instructions that accompany the AE CRF pages. 


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9.2.6 Follow-up of Adverse Events 
All AEs should be followed until they are resolved or until the 1M FUP Visit, whichever 
comes first.  
NOTE: Patients who sign Informed Consent and are subsequently deemed to be screening failures will be 
followed for the occurrence of SAEs/AEs until it is determined they will not be participating in the trial. 
9.3 
Serious Adverse Event Recording and Reporting 
All SAEs occurring at any time after the informed consent has been signed and until the 1M 
FUP Visit, must be recorded on the SAE report form and recorded as an SAE in the CRF. 
NOTE: Patients who sign the informed consent and are subsequently deemed to be screening failures will 
be followed for the occurrence of SAEs/AEs until it is determined they will not be participating in the trial. 
In case of an SAE, the Investigator must, within 24 hours of first awareness of the event, 
report the SAE to the Sponsor or designee. Fax numbers and the e-mail address are stated in 
the SAE report form and the SAE report form instruction. 
Timelines for reporting of SAEs and SAE follow-up information are shown in Table 18.  
Table 18 Timelines for Reporting Serious Adverse Events and Follow-up  
 
Initial Report 
Follow-up Report 
Type of event 
Time Frame 
Document 
Time Frame 
Document 
SAE 
24 hours 
SAE report form 
24 hours 
SAE report form 
Abbreviation: SAE, Serious Adverse Event 
 
SAEs, still ongoing after 1M FUP Visit, should be followed on a regular basis according to 
the Investigator’s clinical judgment, until the event has been resolved or until the Investigator 
assesses it as chronic or stable. The Sponsor or designee will pursue sufficient information 
and will return to the trial sites for such information as deemed required. 
If the Investigator becomes aware of an SAE that occurred after the 1M FUP Visit for the 
patient and finds it related to the IMP or trial conduct it must be recorded and reported to the 
Sponsor or designee as an SAE. SAEs occurring after the 1M FUP Visit for a patient will not 
be reported as an SAE in the CRF, i.e. the event will only be recorded in the safety database. 
The Investigator should be aware of local reporting regulations to the Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC). The Sponsor or designee will either 
supply the Investigator with the reports, which should be forwarded to the IRB/IEC, or report 
directly to the IRB/IEC depending on local regulations. 


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9.4 
Safety Reporting to Health Authorities, Independent Ethics 
Committees/Institutional Review Boards and Investigators 
The Sponsor will assess seriousness, causality and expectedness of SAE as reported by 
Investigator. Expectedness of the event is based on the Reference Safety Information 
contained within the IB. The Sponsor or designee is responsible for reporting all relevant 
safety information, including Suspected Unexpected Serious Adverse Reactions (SUSARs), 
New Safety Issues and annual Development Safety Update Reports, to the Health Authorities 
(HAs) and to the IRB/IEC concerned. Where applicable as per local requirements, the 
Investigator will inform the IRB/IEC of the SUSAR. 
The Sponsor or designee will inform all Investigators concerned of relevant information 
about SUSARs. 
SUSARs will be reported within 7 days if fatal or life-threatening, otherwise within 15 days. 
9.5 
Dose-Limiting Toxicities  
9.5.1 Definition of Dose-Limiting Toxicities 
A DLT is defined as any of the following toxicities that occur during the DLT observation 
period, if considered by the Investigator, and confirmed by the ISMC, to be related to 
Sym004 or the Sym004/FOLFIRI combination:   
1. 
Grade 3 non-hematologic toxicity regardless of duration, with the exceptions of:  
a. 
Grade 3 nausea, vomiting, diarrhea, or fatigue lasting ≤ 5 days with best 
supportive care  
b. 
Grade 3 asymptomatic electrolyte abnormalities1  
2. 
Any Grade 4 non-hematologic toxicity 
3. 
Neutropenia that is: 
a. 
Grade 3 or 4, associated with fever (ANC < 1000 per mm3; temperature > 
38.5ºC), and requiring antibiotic therapy  
b. 
Grade 4 and sustained (i.e., ANC < 500 per mm3, duration > 5 days) 
4. 
Thrombocytopenia that is Grade 4 (platelets < 25,000 per mm3) 
5. 
Inability to complete Cycle 1 at the initial assigned doses of Sym004 and 
FOLFIIRI due to > Grade 3 toxicity 
6. 
Treatment delays > 2 weeks from the scheduled “next doses” due to > Grade 3 
toxicity 
1 In addition to the scheduled ECGs (at screening and EOT), an ECG should be performed as soon as possible in the event of 
≥ Grade 3 hypomagnesemia, and as otherwise clinically indicated. Furthermore, in the event of QT prolongation, an ECG is 
to be performed prior to the next dose of Sym004.  See Section 7.2.5 for further details regarding procedures to address this 
expected AE. 


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Section 12.1 outlines the responsibilities of the ISMC with respect to DLTs.  
9.5.2 Observation Period for Dose-Limiting Toxicities 
Throughout the dose-escalation phase, the decision to dose-escalate is based on close 
monitoring of safety during the observation period for DLTs, defined as Cycle 1, i.e. the 
initial 28 day period (± 2 days) from first treatment of Sym004 in combination with 
FOLFIRI. 
A minimum of 2 infusions of Sym004 in combination with FOLFIRI (full doses) must have 
been administered for a patient to have completed and tolerated the DLT observation period.  
9.5.3 Reporting of Dose-Limiting Toxicities 
All presumed DLTs must be reported to the Sponsor or designee within 24 hours after the 
Investigator or designee have become aware of the event. In addition, serious DLTs must be 
reported in an expedited manner according to the procedure for SAEs, as outlined above. 
9.6 
Reporting of Infusion-related Reactions 
The definition of an IRR is included in Section 7.1.4.7. 
All IRRs must be reported in the CRF as an AE with the term “Infusion-related Reaction” 
followed by a specification of symptoms (e.g. “Infusion-related Reaction with dyspnea and 
flushing”).   
In addition, serious IRRs must be reported in an expedited manner according to the 
procedure for SAEs, as outlined above. 
9.7 
Pregnancy 
If any trial patient becomes pregnant during the course of the trial, the patient must be 
discontinued from Sym004 and FOLFIRI immediately and the pregnancy must be reported to 
the Sponsor or designee according to the same timelines as an SAE. While pregnancy is not 
considered an AE, all pregnancies are tracked as SAEs within the safety database in order to 
follow-up on exposure to the fetus/infant.  
Pregnancies reported in female partners of male trial patients must also be data-based; 
therefore, a pregnant partner must provide informed consent before information can be 
collected. 
All pregnancies must be followed up every third month to determine outcome (including 
premature termination) and status of mother and child. Pregnancy complications and elective 
terminations for medical reasons must be reported as AEs or SAEs as appropriate (trial 
patients only). Elective terminations for non-medical reasons should not be reported as AEs. 
Spontaneous abortion must be reported as an SAE. 


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Any SAE occurring in association with a pregnancy brought to the Investigator’s attention 
after the patient has completed the trial and considered by the Investigator as possibly related 
to the IMP, must be promptly reported to the Sponsor or designee. 
All pregnancy information including follow-up information must be reported in a designated 
pregnancy form provided by the Sponsor or designee. 
 
 


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10 STATISTICS 
10.1 Sample Size Determination 
The primary endpoint of the dose-escalation phase is the occurrence of DLTs on each of the 
Sym004 dose levels given in combination with FOLFIRI. The number of enrolled patients 
will depend on the extent of observed DLTs independently in each cohort. Please, refer to 
Section 7.1.4.2 and 7.1.4.3 for a description of planned dose levels and decision tree for 
dose-escalation. Based on a 3 + 3 design, it is planned to enroll between 9 and 18 patients 
during dose-escalation. 
In the dose-expansion phase of the trial, the primary endpoint is confirmed objective 
antitumor response to the combination of Sym004 and FOLFIRI. The number of patients 
planned to be included in this part of the trial is 32-41 patients depending on the number of 
patients enrolled in the dose-escalation phase.  
In a Phase III study of patients with CRC treated with a second line regimen including 
panitumumab plus FOLIFIRI, the response rate reported was 35% or 36% (21, 22). In one 
phase II study of CRC patients treated with cetuximab plus FOLFIRI as a second line 
regimen, a response rate of 32% was observed (23). The results from these studies were 
utilized as references to consider an increment in response rate that would support further 
studies to evaluate the potential efficacy of the combination of Sym004 and FOLFIRI.  
If between 32 and 41 patients are included in the dose-expansion phase of the trial, the lower 
90% exact confidence bound of a 47% observed response rate is at least 32%. 
10.2 Analysis Populations 
Three analysis sets will be defined in accordance with the consolidated ICH E6 GCP 
guidelines (1).  
The Full Analysis Set (FAS) will comprise all enrolled patients who have received at least 
one dose of IMP. The FAS will be used for evaluation of safety and PD endpoints. The 
patients in the FAS will contribute to the analyses as allocated to treatment. 
The DLT analysis set will comprise all patients in the FAS. Patients who did not complete 
Cycle 1 (i.e. minimum 2 infusions of Sym004 in combination with FOLFIRI [full dose]) for 
reasons other than drug toxicity will be excluded from the DLT analysis set. The DLT 
analysis set will be used for evaluation of DLTs. 
The PK analysis set will comprise all enrolled and exposed patients in the dose-escalation 
with at least one evaluable PK profile. For a PK profile to be evaluable at least 3 
measurements after Cmax and with a negative slope on the concentration-time curve are 
required. 
The PK analysis set will be used for evaluation of PK. For the evaluation, patients, full 
profiles, or single measurements can be excluded from the analyses. The decision to exclude 
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10.3 Primary Endpoint and Analysis 
10.3.1 Dose Escalation Phase 
The primary objective of the dose-escalation phase is to determine the MTD of Sym004, 
assessed by the occurrence of DLTs during the DLT observation period for each of the 
Sym004 dose levels given in combination with FOLFIRI. 
All DLT events (if any) will be listed by dose cohort and patient. A summary table of DLTs 
by System Organ Class (SOC) and preferred term will be presented for each dose cohort, if 
applicable. The summaries will include number of DLTs and number and percentages of 
patients who experienced a DLT. The definition of a DLT is included in Section 9.5.1. The 
MTD is defined as the highest dose with a maximum of 1 out of 6 patients experiencing a 
DLT. The MTD might not be found. 
10.3.2 Dose Expansion Phase 
The primary objective of the dose-expansion phase is to evaluate the antineoplastic effect of 
Sym004. This will be evaluated by confirmed OR (i.e. documented PR or CR). 
Number and percentages of patients in the FAS with confirmed OR will be presented 
including corresponding 95% exact Confidence Intervals (CI). 
10.4 Secondary Endpoints and Analyses 
All statistical analyses of the secondary endpoints for both phases will be performed after 
completion of the dose expansion phase of the trial.  
10.4.1 Safety Endpoints and Analyses 
The safety endpoints are presented below and will all be presented for the FAS by trial phase. 
Safety data will only be presented descriptively, and no formal statistical analyses will be 
performed. 
10.4.1.1 Adverse Events 
The AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
current version. AEs will be regarded as treatment emergent AEs (TEAEs) if they occur after 
first treatment. Non-treatment emergent AEs (Non-TEAEs) are defined as AEs collected 
before dosing. TEAEs will be presented by SOC and preferred term unless stated otherwise. 
The frequencies of TEAEs will be presented including number and percentages of patients 
having experienced an event and the total number of events.  
AEs including SAEs are reported from signing the informed consent until the end of trial 
participation. SAEs reported outside the required reporting window are only entered into the 
safety database and will be described separately in the report.  
NOTE: Patients who sign the informed consent and are subsequently deemed to be screening failures will 
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All AEs will be listed. The TEAEs will be presented using summary tables by trial phase 
including: 
 
AEs, in total and sorted by frequency  
 
AEs by relationship 
 
AEs by CTCAE Grade and max CTCAE Grade  
 
Skin toxicity AEs defined as AEs within a predefined set of preferred terms (list to 
be included in the Statistical Analysis Plan [SAP]) 
 
AEs of Medical Interest 
 
SAEs, in total, and by relationship 
 
AEs leading to withdrawal from treatment 
 
AEs leading to trial drug interruption or dose reduced  
 
Fatal AEs 
10.4.1.2 Clinical Laboratory Values 
Biochemistry, hematology and coagulation parameters will be presented using box plots by 
visits and by cohort and trial phase. In addition, individual patient biochemistry, hematology 
and coagulation parameters during the trial will be presented graphically using longitudinal 
plots. Urinalysis parameters will be summarized using descriptive statistics. 
Laboratory values outside normal range by flagged and all laboratory values will be listed 
including CTCAE grading of abnormal values. 
10.4.1.3 Other Assessments Related to Safety 
Change in vital signs from baseline to end of trial participation will be summarized by visit, 
cohort and trial phase. Normal and abnormal findings in physical examination and ECG 
measurements will be presented in shift tables by visit, cohort and trial phase. 
Skin examination will be summarized by visit, cohort and trial phase.  
ECOG PS, body weight and ADA results will be listed. 
10.4.2 Efficacy Endpoints and Analyses 
The following anti-tumor response endpoints will be measured 
 
Documented OR (dose-escalation) 
 
Duration of OR from time of first PR or CR to PD 
 
Changes in sum of diameters of target lesions from baseline to end of trial 
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 
SD for > 4 months 
 
Time to documented PD, death, patient withdrawal or end of trial participation, 
whichever comes first 
All secondary efficacy endpoint will be presented using the FAS.  
Best overall response by RECIST v1.1 will be summarized by trial phase and dose cohort by 
means of counts and percentages for the categories CR, PR, SD, PD and NE. 
Number and percentages of patients with documented OR in the dose-escalation phase will 
be presented including corresponding 95% exact CI. All documented ORs (dose-escalation 
and dose-expansion phase) will be listed including duration of OR.  
Duration of SD is calculated from baseline till first measurement of PD. The number and 
percentages of patients with SD for more than 4 months will be presented by trial phase. 
Time to documented PD, death, patient withdrawal or end of trial participation, whichever 
comes first, will be presented using Kaplan-Meier plots by trial phase. The median survival 
time including 95% CI. 
10.4.2.1 Other Efficacy Assessments 
CEA will be assessed at Screening, at the end of every even cycle thereafter, and at EOT and 
1MFU, if applicable. CEA will be presented using descriptive statistics. 
10.4.3 Pharmacokinetic Endpoint and Analyses (Omitted as of Amendment 3) 
The PK endpoints will be derived based on the concentration time curves of Sym004, 
mAb992 and mAb1024, respectively after the first and fourth infusion of Sym004 in the 
dose-escalation phase, regardless of delays in treatment. Refer to Table 19. 
Table 19 PK Endpoints Definitions and Derivations 
Symbol 
Definition and derivation 
AUC0-336h, sym004, AUC0-336h, mAb992, AUC0-336h, mAb1024  Area under the concentration-time curve from 
time zero (end of infusion) up to 336 hours. 
AUC0-336h will be calculated using the linear 
trapezoidal method and interpolated in case of 
measurements after 336 hours, or extrapolated 
using terminal rate constant and the last 
quantifiable concentration, Cz 
AUCnorm, 0-336h, sym004, AUCnorm, 0-336h, mAb992, AUCnorm, 
0-336h, mAb1024 
Dose normalized area under the concentration-
time curve from time zero (end of infusion) up to 
336 hours, calculated as AUC0-336h divided by the 
dose infused 
λz, sym004, λz, mAb992, λz, mAb1024 
Terminal rate constant (negative of the slope of an 
ln-linear regression of the un-weighted data 
considering the terminal phase of the 
concentration-time curve ≥ LOQ). Λz is not an 
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Symbol 
Definition and derivation 
CL sym004, CLmAb992, CL mAb1024 
Clearance (Dose/AUC0-336h)  
Vzsym004, VzmAb992, Vz mAb1024 
Volume of distribution during the terminal phase 
(CL/ λz). Formula is used for both profiles as 
steady state is not reached. 
Cmax, sym004, Cmax, mAb992, Cmax, mAb1024 
Maximum concentration 
Ctrough, sym004, Ctrough, mAb992, Ctrough, mAb1024 
Concentration measured pre-infusion 
Tmax, sym004, Tmax, mAb992, Tmax, mAb1024 
Time of maximum concentration 
T½, sym004, T½, mAb992, T½, mAb1024 
Terminal half-life, calculated as ln(2)/ λz 
 
Cmax, CTrough and Tmax will be derived from observed data while AUC0-336h, AUCnorm, 0-336h,  
CL, Vz, and T½ will be estimated using non-compartmental methods and actual time points. 
Individual curves of serum concentration versus time of Sym004, mAb992, and mAb1024, 
respectively will be presented on log- and linear scale for all patients who have received at 
least one infusion of Sym004, one plot for each profile after Sym004 administration (the first 
and fourth infusion) and one plot on linear scale for the whole period of time including 
trough serum concentrations only. In addition, mean concentration time curves will be 
presented on linear scale using nominal time point by cohort. Furthermore, the PK endpoints 
will be summarized by cohort and listed. 
10.4.4 Pharmacodynamics Endpoints and Analyses (Omitted as of Amendment 3) 
Potential biomarkers includes genes, gene transcripts and proteins of RTKs and molecules of 
the EGFR signaling pathway. All biomarkers will be listed. 
Exploratory analysis using the biomarkers might be performed. 
10.5 Interim Analysis 
In the dose escalation phase clinical safety data will be assessed when the first patient in a 3-
patient cohort has completed and tolerated Cycle 1, when 3 patients have completed and 
tolerated Cycle 1, and if the cohort is expanded when 6 patients have completed and tolerated 
Cycle 1. 
An ISMC will be established to review all relevant safety and toxicity data of available 
patients. Please refer to Section 12. 
Based on an overall evaluation of the dose-escalation phase, a dose for the second phase of 
the trial will be recommended by the ISMC, i.e. the RP2D. The RP2D might not necessarily 
be either the MTD or the highest administered dose.  
10.6 Data Collection and Analysis beyond Primary Analysis 
As of Amendment 3: After the trial has closed enrollment and all DLT evaluation is 
completed, the Sponsor may reduce trial data collection to information needed for safety 
reporting required by the FDA and/or other regulatory authorities, as well as efficacy and 
safety follow-up data considered necessary by the Sponsor. 


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10.7 Deviations from the Statistical Plan 
Any deviation(s) from the original analysis plan will be described in a CTP Amendment 
and/or in a SAP and/or in the final CTR, as appropriate. 
 
 


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11 ETHICS 
11.1 Independent Ethics Committee or Institutional Review Board  
An IEC/IRB will review the CTP and any amendments and advertisements used for 
recruitment, as well as the informed consent documents, their updates (if any), and any other 
written materials given to the patients. The CTR will include a list of all IECs/IRBs to which 
the CTP has been submitted and the name of the committee chair. 
11.2 Patient Information and Informed Consent 
The Investigator or his/her designee must obtain written informed consent from each patient 
before any trial related procedures are performed. Each patient must receive full patient 
information before giving consent. The patient information must contain full and adequate 
verbal and written information regarding the objective and procedures of the trial and the 
possible risks involved. 
Before signing the informed consent form the patient must be given sufficient time to 
consider his/her possible participation. Each patient must also be informed about his/her right 
to withdraw from the trial at any time. 
Each patient must sign the informed consent form; the patient receives a copy of the signed 
form and the original is retained in the Investigator Site File (ISF). The informed consent 
form must be signed and dated both by the patient and by the Investigator providing the 
information to the patient. 
11.3 Compliance Reference Documents 
The trial will be conducted in accordance with the CTP, the principles of the Declaration of 
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12 SAFETY SURVEILLANCE SET-UP 
12.1 Independent Safety Monitoring Committee 
An ISMC will be established for the trial. Functions and responsibilities of the ISMC are 
described in an ISMC charter. 
Throughout dose-escalation, the ISMC will review all reported AEs and SAEs on an ongoing 
basis and will decide by consensus on the following: 
 
Agreement with the Investigator assessment of a medical event for a patient 
meeting the DLT definition 
 
Dose-escalation 
 
Dose-deescalation 
 
Dose level expansion (i.e. another 3 patients to be included on a given dose level) 
 
Suspension of enrollment 
 
Declaration of the MTD 
 
Declaration of the R2PD 
NOTE: All reported AEs, including those occurring after the end of the DLT observation period, will be 
considered for decision-making by the ISMC. 
Throughout the trial, the ISMC will monitor the overall safety of the trial and provide 
appropriate recommendations to the Sponsor regarding trial continuation, protocol 
modifications or trial suspension. 
The conclusion of the ISMC meeting will be provided verbally to the Sponsor immediately 
after each meeting followed by signed written minutes within a few days. 
Any safety related ISMC recommendation that may result in protocol changes will be 
reported to the HAs and IECs/IRBs. A letter of trial continuation after each ISMC meeting 
will be supplied to IECs/IRBs only if required. 
12.2 Other Safety Surveillance Activities 
A Medical Monitor is assigned to review and evaluate relevant clinical/safety information 
concerning the clinical trial. The responsibilities of the Medical Monitor include, but are not 
limited to 
 
Evaluation of medical terminology coding and trending of AEs in conjunction with 
the Drug Safety physician 
 
Performing surveillance on potential safety signals in conjunction with the Drug 
Safety physician 


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 
Evaluating abnormal laboratory values 
 
Providing medical support to the Sponsor in answering questions related to the 
trial protocol 
 
Updating the ISMC on trial status at scheduled meetings 
A Drug Safety physician is assigned to review, assess and approve all SAE cases and 
associated reports. This physician will also perform the following: 
 
Assess for safety signals and trends in conjunction with the Medical Monitor 
 
Assist with questions regarding coding of SAEs 
 
Discussing with the Sponsor Chief Medical Officer, any cases which may present 
a concern with regard to a signal or safety issue. 
 
 


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13 MONITORING AND QUALITY ASSURANCE 
13.1 Compliance with Good Clinical Practice 
The responsibilities of the Sponsor, the Monitor and the Investigator are defined in ICH E6 
GCP (1), and applicable regulatory requirements in the country where the trial takes place. 
The Investigator is responsible for adhering to the ICH-GCP responsibilities of the 
Investigators, and for dispensing IMP only in accordance with this CTP or a signed 
amendment, and for its storage and safe handling throughout the trial.  
13.2 Source Documentation 
Each trial site will permit authorized representatives of the Sponsor and relevant authorities 
to examine (and when required by applicable law, to copy) clinical records for the purposes 
of quality assurance reviews, audits and evaluation of the trial safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to: 
Hospital records, clinical and office charts, laboratory notes, memoranda, patients’ written 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, and 
patient files and records kept at the pharmacy, at the laboratories, and medico-technical 
departments involved in the clinical trial. 
The Investigator must maintain source documentations for each patient in the trial and all 
information in the CRF must be traceable to these source documents in the patient’s file. 
Data not requiring a separate written record will be defined before trial start and will be 
recorded directly in the CRF, which will be documented as being the source data. 
13.3 Monitoring 
Monitoring visits to the trial sites will be made periodically during the trial to ensure that the 
CTP is followed. The Investigator must give the Sponsor and/or their representatives access 
to all relevant source documents to confirm consistency with the CRF entries and SAEs. 
Source Data Verification will be conducted according to Sponsor or designee Standard 
Operating Procedures (SOPs) and requirements will be specified in a trial specific monitoring 
plan.  
It is important that the Investigator and their relevant personnel are available during 
monitoring visits and possible audits and that sufficient time is devoted to the process. 
13.4 Audits and Inspections 
Independent audits and inspections of clinical program activities may be performed at any 
time, before, during and/or after the trial. The Investigator and trial staff is responsible for 


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maintaining a comprehensive and accurate filing system of all trial-related documentation 
that will be suitable for inspection at any time by the Sponsor, its designees, and/or HAs. In 
signing this CTP, the Investigator understands and agrees to give direct access to the 
necessary documentation and files. 
The Sponsor must be notified immediately if HA inspections are announced. For any 
response forwarded to the authorities that involves a Symphogen sponsored trial, Symphogen 
must be involved in this correspondence. 
 
 


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14 DATA HANDLING AND RECORD KEEPING 
Data will be handled according to good data management practices, all applicable data 
protection regulations and comply with ICH E6 GCP (1).  
14.1 Data Protection  
The Investigator, Sponsor and Sponsor designee(s) will ensure that the confidentiality of the 
patients’ data is preserved. Each participating site will maintain appropriate medical and 
research records for this trial, in compliance with ICH E6 GCP (1) and regulatory and 
institutional requirements for the protection of confidentiality of patients. 
14.2 Data Transactions and Access 
The trial data and any trial document transferred to the Sponsor or designee will not contain 
patient names or other confidential personal data. Patients will be identified using the 
assigned trial specific patient numbers. 
When data are transferred to the Sponsor or designee, access will be limited to relevant 
persons. 
Documents that are not for collection by the Sponsor, e.g. patient identification list and the 
signed informed consent forms, will be maintained by the Investigator in confidence. 
14.3 Case Report Form  
The Investigator or designee will be responsible for entering trial data in the CRF provided. It 
is the responsibility of the Investigator to ensure the accuracy of the data entered in the CRF. 
All collected data will be entered into a validated database.  
14.4 Data Processing 
The process of entering or uploading of data from trial sites will assure the accuracy of data 
entry into the database and include a validation at data entry time (real time validation). Entry 
or electronic transfer of other data than those directly from trial sites (e.g. imports of 
laboratory results) will follow the Sponsor requirements for data flow and transfer. 
The Sponsor or designee will be responsible for data processing in accordance with the 
applicable data management SOPs.  
The Sponsor will ensure that any data management vendor performs the agreed checks on the 
data quality and manages the query process following their appropriate SOPs in alignment 
with the requirements as outlined in the relevant Sponsor SOP. 
Conduct of medical terminology coding against agreed dictionaries (i.e. MedDRA, 
WHOdrug and others) forms part of data quality review and database lock. Coding lists will 
be reviewed and approved by the Sponsor. 


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Reconciliation of SAEs entered both in the clinical database and in the safety database will 
be performed before database lock.  
All semantically created data will be converted into a CDISC data model.  
Database lock will occur once quality control procedure, and quality assurance procedures (if 
applicable) have been completed. PDF files of the CRFs will be provided to the investigators 
at the completion of the trial.  
14.5 Retention of Trial Documents at Site 
The Investigator at each trial site must make arrangements to store the essential trial 
documents (including the ISF) after the end of trial according to ICH E6 GCP (1) and local 
requirements. 
In addition, the Investigator is responsible for archiving all relevant source documents so that 
the trial data can be compared against source data after completion of the trial, e.g. in case of 
inspection from authorities. 
The Investigator is required to ensure the continued storage of the documents, even if the 
Investigator should leave the clinic/practice or retire before the end of the required storage 
period. 
 
 


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15 REGISTRATION AND COMMUNICATION OF RESULTS 
15.1 Use of Information 
All unpublished information relating to this trial and the IMP is considered confidential by 
the Sponsor and shall remain the sole property of the Sponsor. The Investigator must accept 
that the Sponsor may use information from this trial in connection with the development of 
the IMP, and therefore, may disclose it as required to Investigators, to government licensing 
authorities, to HAs of other government, stock exchange market and commercial partners. 
15.2 Registration and Publication 
The trial will be registered in one or more public trial registries and results will be reported 
according to current legislation. The trial results will be posted in the same clinical trial 
registries as the initial registrations in accordance with the latest International Committee of 
Medical Journal Editors (ICMJE) recommendations (URL: www.icmje.org). 
The Sponsor acknowledges the Investigators’ rights to publish the full results of the trial, 
regardless of the outcome, in accordance with the latest ICMJE recommendations. 
The Coordinating Investigator will together with the Sponsor decide on the publication 
strategy and has the right to publish and present the results and methods as first author of 
multicenter publications. Co-authorship will be decided by the Sponsor and the Coordinating 
Investigator and will be limited to a number of persons who have contributed substantially to 
the trial. The Sponsor will have representation in the list of authors. 
Publication is subject to the following conditions: 
 
No publication before the completion of the trial at all participating trial sites 
without preceding written approval from the Sponsor 
 
Publications shall not disclose any Sponsor confidential information and property 
(not including the trial results) 
 
The Sponsor reserves the right to review results communications prior to public 
release and can embargo communications regarding trial results for a period that is 
less than or equal to 60 days. The Sponsor cannot require changes to the 
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16 INSURANCE AND LIABILITY 
The Sponsor will take out Human Clinical Trials Insurance for its legal liability in 
accordance with laws and regulations, and with limits customary or required by law in the 
territory in question. 
 
 


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17 CHANGES TO THE FINAL CLINICAL TRIAL PROTOCOL 
Changes to the CTP will not be implemented without agreement from the Sponsor and prior 
review and written approval from the Ethics Committee, except where necessary to eliminate 
an immediate hazard to the patient. No protocol waivers will be allowed.  
 
 


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18 PREMATURE TERMINATION OF THE TRIAL OR A TRIAL SITE 
18.1 Premature Termination of the Trial 
If the Sponsor, the Coordinating Investigator or the ISMC discovers conditions arising during 
the trial, which indicates that the trial should be halted, the trial can be terminated after 
appropriate consultation between the Sponsor, the ISMC and the Coordinating Investigator. 
The CA and IEC/IRB will be notified in writing. The reason will be stated. 
Conditions that may warrant termination of the trial include, but are not limited to the 
following: 
 
The discovery of an unexpected and significant or unacceptable risk to the patients 
enrolled in the trial 
 
The discovery of lack of efficacy 
 
Failure of the Investigators to enter patients at an acceptable rate in the trial as a 
whole 
 
A decision on the part of the Sponsor to suspend or discontinue development of 
the IMP 
18.2 Premature Termination of a Trial Site 
The Sponsor can also decide to prematurely terminate single trial sites. Conditions that may 
warrant termination include, but are not limited to the following: 
 
Insufficient adherence to CTP requirements 
 
Failure to enter patients at an acceptable rate 
 
 


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19 REFERENCES 
1. 
ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice 
E6(R1). 10-Jun-1996 
2. 
Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0,Cancer 
incidence and mortality worldwide: IARC CancerBase No. 11 [Internet]. Lyon, 
France: International Agency for Research on Cancer; 2013. 
<http://globocan.iarc.fr> 
3. 
Brenner H, Kloor M, and Pox CP. Colorectal Cancer. Lancet. 2014;383:1490-1502 
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Van Cutsem E, Nordlinger B, and Cervantes A. Advanced colorectal cancer: 
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Davies JM and Goldberg RM. Treatment of metastatic colorectal cancer. Seminars 
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Wolpin BM and Mayer RJ. Systemic treatment of colorectal cancer. Gastroenterol. 
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Kirstein MM, Lange A, Prenzler A, et al. Targeted therapies in metastatic 
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8. 
National Comprehensive Cancer Network. Clinical practice guidelines in 
oncology: Colon cancer. NCCN.org. Version 3.2015  
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Pedersen MW, Jacobsen HJ, Koefoed K, et al. Sym004: a novel synergistic anti-
epidermal growth factor receptor antibody mixture with superior anticancer 
efficacy. Cancer Res. 2010;70(2):588-597 
10. Koefoed K, Steinaa L, Soderberg JN, et al. Rational identification of an optimal 
antibody mixture for targeting the epidermal growth factor receptor. mAbs. 
2011;3(6):584-595 
11. Iida M, Brand TM, Starr MM, et al. Sym004, a novel EGFR antibody mixture, can 
overcome acquired resistance to cetuximab. Neoplasia. 2013;15(10);1196-1206 
12. Skartved NJO, Jacobsen HJ, Pedersen MW, et al. Preclinical pharmacokinetics and 
safety of Sym004: a synergistic antibody mixture directed against epidermal 
growth factor receptor. Clin Cancer Res. 2011;17(18):5962-5972 
13. Dienstmann R, Patnaik A, Garcia-Carbonero R, et al. Safety and activity of the 
first-in-class Sym004 anti-EGFR antibody mixture in patients with refractory 
colorectal cancer. Cancer Discov. 2015;5(6):1-12 


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14. Misale S, Di Nicolantonio F, Sartore-Bianchi A, et al. Resistance to anti-EGFR 
therapy in colorectal cancer: from heterogeneity to convergent evolution. Cancer 
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15. Rajput A, Koterba AP, Kreisberg JI, et al. A novel mechanism of resistance to 
epidermal growth factor receptor antagonism in vivo. Cancer Res. 2007;67(2):665-
673 
16. Argilés G, Dienstmann R, Viñuales MB, et al. Phase 1 study of biweekly (Q2W) 
anti-EGFR monoclonal antibody (mAb) mixture Sym004 in patients (pts) with 
metastatic colorectal cancer (mCRC) resistant to previous anti-EGFR treatment. 
2014 ASCO Annual Meeting, General Poster Session, Gastrointestinal 
(Colorectal) Cancer. http://meetinglibrary.asco.org/content/127412-144 
17. Machiels J-P, Specenier P, Krauβ J, et al. A proof of concept trial of the anti-
EGFR antibody mixture Sym004 in patients with squamous cell carcinoma of the 
head and neck. Cancer Chemother Pharmacol. 2015;76(1):13-20 
18. World Medical Association Declaration of Helsinki: Ethical Principles for Medical 
Research Involving Human Subjects. JAMA. 2013;310(20):2191-2194 
19. American Heart Association. Classification of Functional Capacity and Objective 
Assessment. 
http://my.americanheart.org/professional/StatementsGuidelines/ByPublicationDate
/PreviousYears/Classification-of-Functional-Capacity-and-Objective-
Assessment_UCM_423811_Article.jsp 
20. Annex 13 to Volume 4 EU Guidelines to Good Manufacturing Practice Medicinal 
Products for Human and Veterinary Use. 03 February 2010 
21. Peeters M, Price TJ, Cervantes A, e al. Final results from a randomized phase 3 
study of FOLFIRI +/- panitumumab for second-line treatment of metastatic 
colorectal cancer. Annals of Oncology. 2014;25:107-116 
22. Peeters M, Oliner KS, Price TJ, et al. Analysis of KRAS/NRAS Mutations in a 
Phase 3 Study of Panitumumab with FOLFIRI compared with FOLFIRI alone as 
second-line treatment for metastatic colorectal cancer. Cancer Research. 
2015;21:5469-5479 
23. Iwamoto S, Hazama S, Kato HS, et al. Multicenter phase II study of second-line 
Cetuximab plus Folinic Acid/5-Fluorouracil/Irinotecan (FOLFIRI) in KRAS wild-
type metastatic colorectal cancer: The FLIER Study. Anticancer Research. 
2014;34:1967-1974 
 
 


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20 APPENDICES 
Appendix 1 
Response Evaluation Criteria in Solid Tumors (RECIST v1.1) 
For details, see Eisenhauer EA, Therasse P, Bogaerts J, et al (2009). New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 45:228-247. 
 
Measurability of tumor at baseline 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
Measurable: 
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 notes below on “Baseline documentation of target 
and non-target lesions” for information on lymph node measurement. 
Non-measurable: 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with 10 to < 15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
Special considerations regarding lesion measurability: 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment: 
 
 


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Bone lesions 
 
Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions. However, these techniques can be used to 
confirm the presence or disappearance of bone lesions 
 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above 
 
Blastic bone lesions are non-measurable 
Cystic lesions 
 
Lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts 
 
“Cystic lesions” thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions 
Lesions with prior local treatment 
 
Tumor lesions situated in a previously irradiated area, or 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 
 
Specifications 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 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam.  
 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥10 mm diameter as assessed using calipers (e.g., skin nodules). 


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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 
 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when 
progression is an important endpoint, since CT is more sensitive than X-ray, 
particularly in identifying new lesions. However, lesions on chest X-ray may be 
considered measurable if they are clearly defined and surrounded by aerated lung 
 
CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment. This guideline has defined measurability 
of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or 
less. When CT scans have slice thickness greater than 5 mm, the minimum size for 
a measurable lesion should be twice the slice thickness. MRI is also acceptable in 
certain situations (e.g., for body scans) 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement 
 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials 
where recurrence following CR or surgical resection is an endpoint 
 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response 
 
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 confirmation 
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 SD in 
order to differentiate between response (or SD) and progressive disease 
 
Tumor response evaluation 
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 defined by the presence of at 
least one measurable lesion. Response criteria are listed in Table 20 and Table 21. 


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Table 20 Response Criteria for Evaluation of 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 
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 
 
Table 21 Response Criteria for Evaluation of Non-target Lesions 
 
Evaluation of Non-target Lesions 
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) 
Progressive Disease (PD) 
Unequivocal progression of existing non-target lesions.  
(NOTE: the appearance of one or more new lesions is also considered 
progression) 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits 
 
Evaluation of Best Overall Response 
It is assumed that at each protocol specified time point, a response assessment occurs.  
Table 22 provides a summary of the overall response status calculation at each time point for 
patients who have measurable disease at baseline. 
Table 22 Overall Response Status for Patients with Baseline Measurable Disease 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviation: CR, complete response; NE, non-evaluable; PD, progressive disease; PR, partial response; SD, stable disease 


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The best overall response is determined once all the data for the patient is known. 
Best response determination in trials where confirmation of CR or PR IS NOT required:  
Best response in these trials is defined as the best response across all time points (for 
example, a patient who has SD at first assessment, PR at second assessment, and PD on last 
assessment has a best overall response of PR). When SD is believed to be best response, it 
must also meet the protocol specified minimum time from baseline. If the minimum time is 
not met when SD is otherwise the best time point response, the patient’s best response 
depends on the subsequent assessments. For example, a patient who has SD at first 
assessment, PD at second and does not meet minimum duration for SD, will have a best 
response of PD. The same patient lost to follow-up after the first SD assessment would be 
considered non-evaluable. 
Best response determination in trials where confirmation of CR or PR IS required:  
Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point as specified in the protocol (generally 4 weeks later). In this 
circumstance, the best overall response can be interpreted as shown in Table 23. 
 
Table 23 Best Overall Response when Confirmation of CR and PR Required 
Overall Response 
First Time Point 
Overall Response 
Subsequent Time Point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR1 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
NE 
NE 
NE 
Abbreviation: CR, complete response; NE, non-evaluable; PD, progressive disease; PR, partial response; SD, stable disease 
1) 
If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not 
CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best 
response is PR. 


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Appendix 2 
FOLFIRI Guidelines for Dose Modifications and Delays 
The following sections include guidelines for dose modifications and delays associated with 
specific symptoms.  
 
Neutropenia or Thrombocytopenia 
The following guidelines are based on the worst grade of neutropenia or thrombocytopenia 
observed during a 2-week dosing period (Please note: For the purposes of this trial, two 
consecutive 2-week dosing periods equals 1 cycle): 
 
Grade 2 neutropenia or thrombocytopenia: 5-FU and irinotecan may be resumed at 
the previous dose levels for the next administration, provided ANC >1.5 x 103/µL 
(1.5 x 109/L) and platelets >100 x 103/µL (100 x 109/L).  If hematologic criteria 
are not met, doses of 5 FU and irinotecan should be reduced for the next 
administration. 
 
Grade 3 or 4 neutropenia or thrombocytopenia: Interrupt or skip 5-FU and 
irinotecan. Skipped doses are not to be made up. For subsequent administrations, 
5-FU and irinotecan should continue at 1 dose level lower. 
 
Febrile neutropenia (ANC <1.0 x 103/µL [1.0 x 109/L] and fever >38.5°C): 
Interrupt or skip 5-FU and irinotecan.  If fever resolves, neutropenia resolves to 
ANC >1.5 x 103/µL (1.5 x 109/L), and platelets are >100 x 103/µL (100 x 109/L), 
5-FU and irinotecan should continue at 1 dose level lower for the next 
administration.  Skipped doses are not to be made up. 
If a dose delay is required due to any grade of neutropenia or thrombocytopenia, prophylactic 
use of granulocyte colony-stimulating factor (G-CSF)/granulocyte macrophage colony 
stimulating factor (GM-CSF) prior to the next administration of FOLFIRI is permitted at 
investigator discretion, provided that G-CSF/GM-CSF administration is completed ≥48 hours 
prior to administration of FOLFIRI. 
 
Diarrhea 
Lacrimation, rhinorrhea, miosis, diaphoresis, hot flashes, flushing, abdominal cramping, 
diarrhea, or other symptoms of early cholinergic syndrome may occur during or shortly after 
receiving irinotecan.  Atropine, 0.25 to 1.0 mg IV or subcutaneously, may be used (unless 
clinically contraindicated) to treat these symptoms at the discretion of the treating physician.  
In patients with troublesome or recurrent symptoms, prophylactic administration of atropine 
shortly before irinotecan therapy may be considered.  Additional antidiarrheal measures may 
be used at the discretion of the treating physician.  Combination anticholinergic medications 
containing barbiturates or other agents (e.g., Donnatal®) should not be used because these 
may affect irinotecan metabolism.  Anticholinergics should be used with caution in patients 
with potential contraindications (e.g., obstructive uropathy, glaucoma, tachycardia). 


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Late diarrhea (developing more than 24 hours after irinotecan) should be managed with 
loperamide. Refer to Table 8 for mandatory prophylaxis for diarrhea. 
Dose modifications in this section are based on the worst grade of diarrhea experienced 
during a 2-week dosing period: 
 
Grade 2: For the next administration, 5-FU should be continued at 1 dose level 
lower, provided diarrhea has recovered to Grade <1.  For recurrent Grade 2 
diarrhea, both 5-FU and irinotecan should be continued at 1 dose level lower for 
the next administration. 
 
Grade 3: Interrupt or skip 5 FU and irinotecan.  If diarrhea resolves to Grade <1 
during the current 2-week dosing period, 5-FU and irinotecan administration may 
be resumed at 1 dose level lower for the next administration.  Skipped doses are 
not to be made up.  For subsequent administrations, 5 FU and irinotecan should 
continue at the reduced dose levels. 
 
Grade 4: Interrupt or skip 5-FU and irinotecan.  If Grade 4 diarrhea does not 
resolve to Grade <1 during the current 2-week dosing period, 5-FU and irinotecan 
administration should be held for another 2-week period (approximately 28 days) 
until resolution to Grade <1; when treatment resumes, the doses of 5-FU and 
irinotecan should be reduced by 2 dose levels. 
 
Mucositis 
The following guidelines are based on the worst grade of mucositis observed during a 2-week 
dosing period: 
 
Grade 2: If mucositis resolves to Grade <1 during the current 2-week dosing 
period, 5-FU may be continued at the same dose level or may be resumed at 1 dose 
level lower during the next administration.  For recurrent Grade 2 mucositis, the 
dose of 5-FU should be reduced by an additional dose level. 
 
Grade 3: If mucositis resolves to Grade <1 during the current 2-week dosing 
period, 5-FU may be resumed at 1 dose level lower for the next administration.  If 
mucositis does not resolve to Grade <1 during the current 2-week dosing period, 5 
FU administration should be held for another 2-week dosing period 
(approximately 28 days) until resolution to Grade <1; when treatment resumes, the 
dose of 5-FU should be reduced by 2 dose levels. 
 
Grade 4: Interrupt or skip 5-FU and irinotecan. 5-FU administration should be held 
for a maximum of 1 cycle (approximately 28 days) until resolution to Grade <1; 
when treatment resumes, the dose of 5-FU should be reduced by 2 dose levels. 
 
Nausea/Vomiting 


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The following guidelines are based on the worst grade of nausea and vomiting occurring 
during a 2-week dosing period.  Dose reductions should occur only if symptoms persist 
despite 2 treatments with adequate (combination) antiemetic treatment.  Note that the 
irinotecan prescribing information recommends that patients receive premedication with anti-
emetic agents. 
 
Grade 3: Reduce irinotecan 1 dose level for the next administration. Continue 
irinotecan at the reduced dose level for subsequent administrations. 
 
Grade 4: Reduce 5-FU and irinotecan 1 dose level for the next administration.  
Continue both 5 FU and irinotecan at the reduced dose levels for subsequent 
administrations. 
 
Skin Toxicity 
Dose modifications in this section are based on the worst grade of skin toxicity experienced 
during a 2-week dosing period.  For Grade 3 or 4 skin toxicity, interrupt or skip 5 FU. 5-FU 
should be held for a maximum of 1 cycle (approximately 28 days) until resolution to Grade 
≤1; when treatment resumes, the dose of 5-FU should be reduced by 2 dose levels. 
 
Cardiac Toxicity 
In the event of Grade ≥2 cardiac toxicity attributable to 5-FU, treatment with 5-FU should be 
discontinued. 
 
Other Nonhematologic Toxicity 
For Grade ≥3 nonhematologic toxicities not described above, withhold treatment with 
FOLFIRI and monitor toxicity at least weekly.  If toxicity resolves to Grade ≤1 within 2 
weeks, treatment may be resumed with 5-FU and irinotecan at 1 dose level lower.  For Grade 
3 toxicities associated primarily with laboratory abnormalities only (for example, elevation of 
ALT, AST, hyperlipasemia, hyperamylasemia, hypophosphatemia without clinical or other 
evidence of pancreatitis or other hepatic dysfunction), study treatment may continue without 
interruption at the discretion of the investigator. 
 
Neurocerebellar Toxicity 
In the event of neurocerebellar toxicity, treatment with 5-FU should be discontinued. 


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21 SUMMARY OF CHANGES 
21.1 Protocol Amendment 1 dated 09-Nov-2015 
1. 
Increase the blood volume collected for the biomarker  
2. 
Change timing for collecting AEs/SAEs 
3. 
Correction and clarification of inconsistencies and minor typographical errors 
The objective of the present amendment is to increase the volume of blood for biomarker 
analysis from 5mL to 20mL per blood sample collection. The blood sample is collected from 
patients at screening, end of cycle 2 or upon disease progression (whichever occurs first), and 
at the end of trial. A larger volume of blood, and subsequent plasma, is needed for biomarker 
analysis when using Next-Generation Sequencing (NGS). 
Timing for collection of AEs and SAEs is being extended. This will allow total safety 
surveillance to include analysis of unanticipated problems having to do with overall trial 
conduct. This would include any adverse effects that may occur from protocol-specific 
investigations at screening.   
Minor typographical errors and inconsistencies have been corrected.  
With reference to “Detailed Guidance on the request to the competent authorities for 
authorization of a clinical trial on a medicinal product for human use, the notification of 
substantial amendments and the declaration of the end of trial (CT-1)” paragraph, this 
amendment is considered substantial as it has an impact on the conduct or management of the 
trial.  
Refer to Table 24 for the changes in Protocol Amendment 1.  
Table 24 Protocol Amendment 1 dated 09-Nov-2015 
SECTION 
CHANGE 
ORIGINAL TEXT  
NEW TEXT 
Section: 1 
Heading: List of 
Abbreviations and 
Definitions of Terms 
Addition 
 
TEAE: Treatment 
Emergent Adverse 
Events 
Section: 5.3.5 
Heading: Table 2 
Flow Chart – Schedule 
of Assessments 
Day within Cycle Visit 
Window (± days) 
Correction 
 
Cycle 2, 4, 6 etc. 
D1 (±2) 
 
Cycle 3, 5, 7 etc. 
D1 (±2) 
Cycle 2, 4, 6 etc. 
D1 (±2) 
 
Cycle 3, 5, 7 etc. 
D1 (±2) 
 
Section: 5.3.5 
Heading: Table 2 
Flow Chart – Schedule 
of Assessments 
(S)AE Survey and 
Reporting 
Addition 
(S)AE survey and 
Reporting collected from 
C1D1 
(S)AE survey and 
Reporting collected from 
C1D1 Screening 
 


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SECTION 
CHANGE 
ORIGINAL TEXT  
NEW TEXT 
Section: 7.1.5.1 
Heading: Sym004 Dose-
Adjustments for Body 
Weight 
Sentence: 2 
Clarification 
 
The dose calculated may 
be used for subsequent 
infusions, unless body 
weight changes ≥ ± 5% 
The dose calculated may 
be used for subsequent 
infusions, unless body  
weight changes ≥ ± 5% 
from screening 
Section: 8.2.2 
Heading: Adverse Event 
Survey 
Bullet point: 1 
Addition 
Starting from the first 
dose of Sym004 (C1/D1) 
Starting from the first 
dose of Sym004 (C1/D1) 
signing the informed 
consent 
Section: 8.2.6 
Heading: Physical 
Examination 
Sentence: 1 
Correction 
To be performed by a 
physician. To include 
evaluation of 
To be performed by a 
physician. To include 
evaluation of 
Section: 8.6 
Heading: Biomarker 
Blood and Urine Sample 
Paragraph 3 
Sentence 1 
Correction 
 
Patients will have blood 
samples taken of 
approximately of 5 mL 
Patients will have blood 
samples taken of 
approximately of 5 20 
mL 
Section:  9.2.1 
Heading: Adverse Event 
Recording Period 
Sentence: 1 
Addition 
All AEs will be recorded 
from the initiation of 
Sym004 dosing 
All AEs will be recorded 
from the initiation of 
Sym004 dosing signing 
the informed consent 
Section:  9.3 
Heading: Serious 
Adverse Event 
Recording and Reporting 
Sentence: 1 
Addition 
All SAEs occurring at 
any time after the first 
dose of Sym004 
All SAEs occurring at 
any time after the first 
dose of Sym004 
informed consent has 
been signed 
Section:  10.4.1.1 
Heading: Adverse 
Events 
Paragraph: 1 
Sentence: 1 and 2 
Addition 
 
The AEs will be coded 
using Medical 
Dictionary for 
Regulatory Activities 
(MedDRA) current 
version and presented by 
SOC and preferred term 
unless stated otherwise. 
The frequencies of AEs 
will be presented 
including number and 
percentages of patients 
having experienced an 
event and the total 
number of events. 
 
The AEs will be coded 
using Medical 
Dictionary for 
Regulatory Activities 
(MedDRA) current 
version. AEs will be 
regarded as treatment 
emergent AEs (TEAEs) 
if they occur after first 
treatment. Non-treatment 
emergent AEs (Non-
TEAEs) are defined as 
AEs collected before 
dosing. And TEAEs will 
be presented by SOC and 
preferred term unless 
stated otherwise. The 
frequencies of TEAEs 
will be presented 
including number and 
percentages of patients 
having experienced an 


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SECTION 
CHANGE 
ORIGINAL TEXT  
NEW TEXT 
event and the total 
number of events. 
Section:  10.4.1.1 
Heading: Adverse 
Events 
Paragraph: 2 
Sentence: 1 
Addition 
 
AEs including SAEs are 
reported from first 
treatment until the end of 
trial participation 
AEs including SAEs are 
reported from first 
treatment signing the 
informed consent until 
the end of trial 
participation 
Section 10.4.1.1 
Heading: Adverse 
Events 
Paragraph: 3 
Sentence: 1  
Addition 
All AEs will be listed. 
The AEs will be 
presented using 
summary tables by trial 
phase including: 
All AEs will be listed. 
The TEAEs will be 
presented using 
summary tables by trial 
phase including: 
Amended text are struck through with a single line and new text is written in italics 
 
21.2 Protocol Amendment 2 dated 05-Aug-2016 
1. 
Added additional dose levels to facilitate further exploration of the safety and 
tolerability of Sym004 
2. 
Initiated mandatory prophylaxis for diarrhea in Cycle 1 with potential to continue 
in later cohorts 
3. 
Modified the inclusion and exclusion criteria section to allow enrollment of 
patients who progressed > 3 months after last dose and to allow enrollment of 
patients treated with drugs that potentially could cause QT prolongation  
4. 
Removed Sym004 dose-adjustment for obese patients 
5. 
Clarification of biomarker testing from collected tumor biopsies and revision of 
the tumor marker section to only collect CEA 
6. 
Modified the statistical section to clarify the number of patients required and 
added relevant references 
7. 
Specified grading of adverse events when there are changes in severity   
The objective of Amendment 2 is to add additional dose levels to facilitate further 
exploration of the safety and tolerance of lower doses of Sym004 in combination with 
FOLFIRI, if necessary.  
Because of the safety and tolerability observed in patients entered in the initial cohort (Dose 
Level 1: 12 mg/kg Sym004 + FOLFIRI), mandatory prophylaxis for diarrhea has been added 
for all patients during Cycle 1, with the potential to continue based on the Investigator’s 
discretion.  
Sym004 dose adjustment for obese patients has been removed until there is sufficient data to 
support it. Symphogen is in the process of completing a population pharmacokinetics model 
based on data from completed studies.  


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Clarified that the RP2D will be based on the MTD, toxicities observed during Cycle 1 and 
subsequent cycles, as well as PK and other relevant data.  
Minor modifications, clarifications, and specifications have been added, and minor 
typographical errors and inconsistencies have been corrected. 
Refer to Table 25 for the changes in Protocol Amendment 2. 
 
Table 25 Protocol Amendment 2 dated 05-Aug-2016 
SECTION 
ORIGINAL TEXT 
NEW TEXT 
2. Synopsis 
 
Diagnosis and Main 
Inclusion and 
Exclusion Criteria  
 
 
Main Inclusion Criteria include: 
Failed* treatment for locally advanced 
or metastatic disease with first-line 
combination therapy of oxaliplatin and a 
fluoropyrimidine, with or without 
bevacizumab, during treatment or < 3 
months after the last dose of first-line 
therapy and within < 3 months of 
C1/D1. 
Patients who discontinued first-line 
therapy due to toxicity may be enrolled 
provided progression occurred < 6 
months after the last dose of the first-line 
therapy regimen. 
or  
Failed* adjuvant therapy with 
combination therapy of oxaliplatin and a 
fluoropyrimidine during treatment or 
within < 6 months after the last dose of 
oxaliplatin and within < 6 months of 
C1/D1. 
 
Main Inclusion Criteria include: 
Failed* prior treatment for locally 
advanced or metastatic disease with first-
line combination therapy of oxaliplatin 
and a fluoropyrimidine, with or without 
bevacizumab. 
Patients who discontinued first-line 
therapy due to toxicity and who 
subsequently progressed may be 
enrolled. 
or  
Failed* adjuvant therapy with 
combination therapy of oxaliplatin and a 
fluoropyrimidine. 
 
 
Main Exclusion Criteria include: 
 Discontinuation of prior therapy with 
oxaliplatin and a fluoropyrimidine 
due to diarrhea ≥ Grade 3 
2. Synopsis 
 
Investigational 
Medicinal Product, 
Dose(s) and 
Treatment Schedule 
If the toxicity profile of Dose Level 1 
indicates that this dose is not tolerated, a 
successive lower dose levels will be 
explored: 
• Dose Level -1: Sym004 9 mg/kg + 
FOLFIRI 
If the toxicity profile of Dose Level 1 
indicates that this dose is not tolerated,  
successive lower dose levels will be 
explored: 
 
Dose Level -1: Sym004 9 
mg/kg + FOLFIRI  
 
Dose Level -2: Sym004 9 
mg/kg (loading dose) + 
FOLFIRI followed by 6 mg/kg 
+ FOLFIRI 
 
Dose Level -3: Sym004 6 
mg/kg + FOLFIRI 
 
If Sym004 at 9 mg/kg + FOLFIRI 
(Dose-Level -1) has not exceeded the 
MTD and is well tolerated during Cycle 
1, but overall tolerability is judged to be 


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insufficient to accept this dose level as 
the RP2D, then Dose Level -2 may be 
explored. 
 
If Sym004 at 9 mg/kg + FOLFIRI 
(Dose-Level -1) during Cycle 1 has not 
exceeded the MTD, but tolerability is 
judged to be insufficient to accept this 
dose level as the RP2D, then Dose-Level 
-3 may be explored 
 
If the toxicity profile of lower doses 
where mandatory diarrhea prophylaxis is 
utilized indicates that the dose is well 
tolerated, further evaluation of Dose 
Level 1, and potentially Dose Levels 2 
and 3 may take place after approval by 
the ISMC. 
 
3.2.1 Sym004 
Each mAb is manufactured by Chinese 
Hamster Ovary cells (referred to as CHO 
cells), transfected with an expression 
vector coding for both the antibody light 
chains and heavy chains. 
Removed 
5.1 Overall Design 
and Plan 
Patients will be allocated in sequence to 
1 of up to 3 dose levels of Sym004. The 
MTD is expected to be found and a 
RP2D will be declared. The MTD and 
RP2D may or may not be the same. 
Patients will be allocated in sequence to 
1 of up to 5 dose levels of Sym004, 
based on tolerability. The RP2D will be 
based on the MTD evaluation as well as 
other toxicities observed in the study, 
and may include tolerability observed in 
Cycle 1 and subsequent cycles as well as 
PK and other data. The MTD and RP2D 
may or may not be the same, and the 
RP2D may be selected based on overall 
tolerability without defining the MTD. 
5.3.1 Screening 
Not applicable 
In the event a tumor biopsy is required 
for eligibility, informed consent may be 
obtained outside the 14-day screening 
period prior to C1/D1 to allow adequate 
turnaround time for receipt of results. 
5.3.5 Flow Chart – 
Schedule of 
Assessments  
(Table 2 footnotes) 
5. Local laboratory results must be 
available and assessed prior to each 
Sym004/FOLFIRI infusion. 
 
8. Tumor Marker, Carcinoembryonic 
Antigen (CEA), and/or Carbohydrate 
Antigen 19-9 (CA 19-9). 
 
15. Patients will receive prophylactic 
treatment for FOLFIRI induced diarrhea 
5. Local laboratory results must be 
available and assessed no later than 2 
days prior to each Sym004/FOLFIRI 
infusion. 
 
8. Tumor Marker, Carcinoembryonic 
Antigen (CEA). 
 
15. Patients will receive prophylactic 
treatment for nausea and vomiting 


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and vomiting according to institutional 
standards.  
 
according to institutional standards, and 
all patients will be treated with 
loperamide in an effort to prevent 
diarrhea during Cycle 1. Prophylaxis 
with loperamide may be continued 
beyond Cycle 1 at the Investigator’s 
discretion.  
6.1 Inclusion Criteria 
All Cohorts 
6.  Failed* treatment for locally 
advanced or metastatic disease with 
first-line combination therapy of 
oxaliplatin and a fluoropyrimidine, 
with or without bevacizumab, during 
treatment or < 3 months after the last 
dose of first-line therapy and within < 
3 months of C1/D1.  
Patients who discontinued first-line 
therapy due to toxicity may be 
enrolled provided progression 
occurred < 6 months after the last 
dose of the first-line therapy regimen. 
or  
Failed* adjuvant therapy with 
combination therapy of oxaliplatin 
and a fluoropyrimidine during 
treatment or within < 6 months after 
the last dose of oxaliplatin and within 
< 6 months of C1/D1. 
6.  Failed* prior adjuvant therapy or 
prior treatment for locally advanced 
or metastatic disease with first-line 
combination therapy of oxaliplatin 
and a fluoropyrimidine, with or 
without bevacizumab. 
 
6.2 Exclusion 
Criteria All Cohorts 
Not applicable 
 
 
 
6. Drugs with the potential to cause QT 
prolongation within 2 weeks prior to 
C1/D1 
 
13. Active thrombosis, or a history of 
deep vein thrombosis or pulmonary 
embolism within 6 months prior to 
C1/D1 
4. Discontinuation of prior therapy with 
oxaliplatin and a fluoropyrimidine due to 
diarrhea ≥ Grade 3 
 
Removed 
 
 
 
13. Active thrombosis, or a history of 
deep vein thrombosis or pulmonary 
embolism, within 4 weeks prior to 
C1/D1; any prior thrombosis must be 
adequately treated and stable 
7.1.4.2 Dose-
Escalation Phase 
 
 
 
 
 
 
 
 
If the toxicity profile of Dose Level 1 
indicates that this dose is not tolerated, a 
successive lower dose level will be 
explored: 
• Dose Level -1: Sym004 9 mg/kg + 
FOLFIRI 
If the toxicity profile of Dose Level 1 
indicates that this dose is not tolerated, 
successive lower dose levels will be 
explored: 
• Dose Level -1: Sym004 9 mg/kg + 
FOLFIRI  
• Dose Level -2: Sym004 9 mg/kg 
(loading dose) + FOLFIRI followed by 6 
mg/kg + FOLFIRI 


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• Dose Level -3: Sym004 6 mg/kg + 
FOLFIRI 
 
If Sym004 at 9 mg/kg + FOLFIRI 
(Dose-Level -1) has not exceeded the 
MTD and is well tolerated during Cycle 
1, but overall tolerability is judged to be 
insufficient to accept this dose level as 
the RP2D, then Dose Level -2 may be 
explored. 
 
If Sym004 at 9 mg/kg + FOLFIRI 
(Dose-Level -1) during Cycle 1 has not 
exceeded the MTD, but tolerability is 
judged to be insufficient to accept this 
dose level as the RP2D, then Dose-Level 
-3 may be explored 
 
If the toxicity profile of lower doses 
where mandatory diarrhea prophylaxis is 
utilized indicates that the dose is well 
tolerated, further evaluation of Dose 
Level 1, and potentially Dose Levels 2 
and 3 may take place after approval by 
the ISMC. 
 
7.1.4.3 Dose-
Escalation Decision 
Points 
 
NOTE: Should ≥ 2 of 6 patients at Dose 
Level 1 experience a DLT, then the dose 
will be de-escalated to Dose Level -1. 
 
NOTE: Should ≥ 2 of 6 patients at Dose 
Level 1 experience a DLT, then the dose 
will be reduced to Dose Level -1. 
Furthermore, if ≥ 2 of 6 patients at Dose 
Level -1 experience a DLT, then the 
dose will be reduced to Dose Level -3. 
7.1.4.8 Handling of 
Infusion-Related 
Reactions 
 
Table 5: Infusion-
Related Reactions 
Management 
Guidelines 
 
Grade 2:  
Stop Sym004 infusion 
 
 
Grade 3: 
Stop Sym004 infusion 
 
Withdraw the patient from treatment  
 
 
 
 
Grade 2: 
Interrupt Sym004 infusion for a 
minimum of 30 minutes 
 
Grade 3: 
Discontinue Sym004 infusion 
 
Either withdraw the patient from 
treatment or continue subsequent 
treatments at a reduced dose 
 
Premedication should be reinstituted if 
previously discontinued 
 
7.1.5 Dose-
Adjustments and 
Delays of Sym004 
Weight changes (≥ ± 5%) for a patient 
during trial will require recalculation of 
the dose (Section 7.1.5.1). 
Weight changes (≥ ± 10%) for a patient 
during trial will require recalculation of 
the dose (Section 7.1.5.1). 


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Dose-adjustments are required for obese 
patients (Section 7.1.5.2). 
Furthermore, dose omissions of Sym004 
and intra-patient dose-reduction(s) may 
also be required upon occurrence of 
Grade 3 anti-EGFR-associated skin 
toxicity (Section 7.1.5.3) and other 
safety events (Section 7.1.5.4). 
 
 
Removed 
 
Furthermore, dose delays of Sym004 and 
intra-patient dose-reduction(s) may also 
be required upon occurrence of Grade 3 
anti-EGFR-associated skin toxicity 
(Section 7.1.5.2) and other safety events 
(Section 7.1.5.3). Dose adjustments 
should be discussed with the Sponsor or 
designee prior to implementation. 
If Sym004 administration is delayed, 
subsequent dosing will be resumed in 
combination with a scheduled FOLFIRI 
administration. 
7.1.5.1 Sym004 
Dose-Adjustments 
for Body Weight 
 
The dose calculated may be used for 
subsequent infusions, unless body 
weight changes ≥ ± 5% from screening, 
in which case the dose must be adjusted 
according to the change in body weight. 
 
The dose calculated may be used for 
subsequent infusions, unless body 
weight changes ≥ ± 10% from screening, 
in which case the dose must be adjusted 
according to the change in body weight. 
Adjustment may be made in the event of 
lesser incremental changes in weight at 
the site’s discretion. 
 
7.1.5.2 Sym004 
Dose-Adjustments 
for Obese Patients 
 
If the Body Mass Index (BMI) of a 
patient exceeds 30 kg/m2, the dose of 
Sym004 must be adjusted according to 
the following algorithm: 
Adjusted dose (mg) = 30 (kg/m2) × 
height2 (m2) × planned dose (mg/kg) 
 
Example:  
Planned dose: 12 mg/kg  
Patient metrics: Weight 90.0 kg, height 
of 1.62 m, giving a BMI = Body weight 
(kg) / height2 (m2) = 90 kg / 1.622 m2 = 
34.3 kg/m2 
The adjusted dose to be administered 
according to the algorithm provided is: 
30 kg/m2 × (1.62 m)2 × 12 mg/kg = 
944.8 mg 
Entire section removed 
7.2.3.2 Prophylactic 
Treatment for 
Gastrointestinal 
Toxicities 
To minimize the risk of side-effects 
related to FOLFIRI, all patients will 
receive: 
• Prophylactic treatment for diarrhea and 
vomiting according to institutional 
standards 
To minimize the risk of gastrointestinal 
side-effects related to FOLFIRI and/or 
Sym004, all patients will receive: 
• Prophylaxis for nausea and vomiting 
according to institutional standards 
• Mandatory prophylaxis for diarrhea as 
shown in Table 8. Loperamide therapy 


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may be continued beyond end of Cycle 1 
(C1) at the Investigator’s discretion. 
 
7.5.2 Prohibited 
Concomitant 
Medication/Therapy 
and Procedures 
during the Trial 
Drugs with the potential to cause QT 
prolongation 
Removed 
 
8.1.1 Signing of 
Informed Consent 
Not applicable 
NOTE: In the event a tumor biopsy is 
required for eligibility, informed consent 
may be obtained outside the 14-day 
screening period prior to C1/D1 
 
8.2.2 Adverse Event 
Survey 
Not applicable 
NOTE: Patients who sign the informed 
consent and are subsequently deemed to 
be screening failures will be followed for 
the occurrence of SAEs/AEs until it is 
determined they will not be participating 
in the trial 
8.2.7 Dermatological 
Assessment 
To be performed by a physician; 
complete skin examination 
To be performed by a physician or 
qualified designee; complete skin 
examination 
 
8.2.8 
Electrocardiogram 
Not applicable 
In the event of significant electrolyte 
abnormalities, the evaluation frequency 
should be increased to include additional 
evaluations between the scheduled 
assessments, as clinically indicated.   
 
8.3.1 Tumor Marker 
Evaluation 
To include Carcinoembryonic Antigen 
(CEA) and/or Carbohydrate Antigen 19-
9 (CA19-9). Will be performed at a 
laboratory facility local to the trial site 
To include Carcinoembryonic Antigen 
(CEA). Will be performed at a 
laboratory facility local to the trial site 
 
8.3.2 Disease Status 
Evaluation using CT 
or MRI 
Patients will undergo imaging of the 
thorax and abdomen by CT or MRI. 
Patients will undergo imaging of the 
thorax, abdomen, and pelvis by CT or 
MRI as indicated, based on tumor type 
and prior areas of documented disease. 
 
8.6.2 Fresh Tumor 
Biopsy Collection 
Not applicable 
Biomarker testing from collected tumor 
biopsies (archival FFPE or fresh tumor 
biopsy) will, if amount allows, in 
addition to RAS and EGFR, include 
biomarkers connected to EGFR 
signaling or escape mechanisms 
observed after EGFR treatment. 
 
9.1.1 Adverse Event 
Not applicable 
Events such as lab results reported 
outside the normal range and determined 
to be clinically insignificant by the 
Investigator will not be recorded as AEs. 


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9.2.1 Adverse Event 
Reporting Period 
Not applicable 
NOTE: Patients who sign the informed 
consent and are subsequently deemed to 
be screening failures will be followed for 
the occurrence of SAEs/AEs until it is 
determined they will not be participating 
in the trial. 
9.2.3 Intensity 
The grade assigned by the Investigator 
should be the most severe that occurred 
during the AE period. 
Changes in severity of AEs will be 
recorded. 
9.2.6 Follow-up of 
Adverse Events 
Not applicable 
NOTE: Patients who sign the informed 
consent and are subsequently deemed to 
be screening failures will be followed for 
the occurrence of SAEs/AEs until it is 
determined they will not be participating 
in the trial. 
9.3 Serious Adverse 
Event Recording and 
Reporting 
Not applicable 
NOTE: Patients who sign the informed 
consent and are subsequently deemed to 
be screening failures will be followed for 
the occurrence of SAEs/AEs until it is 
determined they will not be participating 
in the trial. 
9.5.1 Definition of 
Dose-limiting 
Toxicities 
a. Grade 3 nausea, vomiting, diarrhea, or 
fatigue lasting ≤ 2 days with best 
supportive care 
 
b. Grade 3 asymptomatic electrolyte 
abnormalities lasting ≤ 3 days that are 
not considered clinically relevant by the 
Investigator and that resolve with 
medical therapy 
a. Grade 3 nausea, vomiting, diarrhea, or 
fatigue lasting ≤ 5 days with best 
supportive care 
 
b. Grade 3 asymptomatic electrolyte 
abnormalities1  
 
1In addition to the scheduled ECGs (at 
screening and EOT), an ECG should be 
performed as soon as possible in the 
event of ≥ Grade 3 hypomagnesemia, 
and as otherwise clinically indicated. 
Furthermore, in the event of QT 
prolongation, an ECG is to be performed 
prior to the next dose of Sym004. See 
Section 7.2.5 for further details 
regarding procedures to address this 
expected AE. 
9.5.3 Reporting of 
Dose-Limiting 
Toxicities 
All presumed DLTs must be reported in 
the eCRF within 24 hours after the 
Investigator or designee have become 
aware of the event. 
All presumed DLTs must be reported to 
the Sponsor or designee within 24 hours 
after the Investigator or designee have 
become aware of the event. 
10.1 Sample Size 
Determination 
The planned number of patients to be 
enrolled is not based on a formal sample 
size calculation. In trial Sym004-01 a 
total of 3 out of 91 patients had 
confirmed objective tumor response. 
In a Phase III study of patients with CRC 
treated with a second line regimen 
including panitumumab plus FOLIFIRI, 
the response rate reported was 35% or 
36% (22, 23). In one phase II study of 


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Based on this it is expected to observe 1-
2 patients with confirmed CR or PR in 
the current trial. 
CRC patients treated with cetuximab 
plus FOLFIRI as a second line regimen, 
a response rate of 32% was observed 
(24). The results from these studies were 
utilized as references to consider an 
increment in response rate that would 
support further studies to evaluate the 
potential efficacy of the combination of 
Sym004 and FOLFIRI. 
 
If between 32 and 41 patients are 
included in the dose-expansion phase of 
the trial, the lower 90% exact confidence 
bound of a 47% observed response rate 
is at least 32%.  
10.4.1.1 Adverse 
Events 
Not applicable 
NOTE: Patients who sign the informed 
consent and are subsequently deemed to 
be screening failures will be followed for 
the occurrence of SAEs/AEs until it is 
determined they will not be participating 
in the trial. 
10.4.2.1 Other 
Efficacy 
Assessments 
CEA and/or CA19-9 will be assessed at 
Screening, at the end of every even cycle 
thereafter, and at EOT and 1MFU, if 
applicable. CEA and CA19-9 will be 
presented using descriptive statistics. 
CEA will be assessed at Screening, at 
the end of every even cycle thereafter, 
and at EOT and 1MFU, if applicable. 
CEA will be presented using descriptive 
statistics. 
Appendix 2: 
FOLFIRI Guidelines 
for Dose 
Modifications and 
Delays 
 
Mucositis 
Grade 2: If mucositis resolves to Grade 
<1 during the current 2-week dosing 
period, 5-FU should be continued at the 
dose level lower during the next 
administration.   
Grade 2: If mucositis resolves to Grade 
<1 during the current 2-week dosing 
period, 5-FU may be continued at the 
same dose level or may be resumed at 1 
dose level lower during the next 
administration.   
 
21.3 Protocol Amendment 3 dated 22-Feb-2017 
The objectives of Amendment 3 are to stop the enrollment of the trial and to change the total 
scope of assessments being conducted as a result of a Sponsor decision to discontinue the 
development of Sym004 in combination with FOLFIRI.  
1. Explanation included for prematurely discontinuing trial enrollment. 
2. Changed the visit schedule for treatment and follow-up to apply only until Sym004 
has been discontinued. 
3. Omitted collection of non-safety related assessments and modified the statistical 
section to further reduce the collection of data to information needed for safety 
reporting required by authorities. 
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Refer to Table 26 for the changes in Protocol Amendment 3. 
Table 26 Protocol Amendment 3 dated 22-Feb-2017 
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2. Synopsis: Trial 
Sites and Countries 
 
5.1 Overall Design 
and Plan 
Dose-escalation: 2-3 investigational trial 
sites 
 
Dose-escalation: Approximately 8 
investigational trial sites 
 
2. Synopsis: 
Objectives 
 
4.1 Dose-Escalation 
(Phase 1b) 
Not applicable 
As of Amendment 3: Due to the 
premature discontinuation of the 
enrollment of the trial, the primary, 
secondary, and exploratory objectives 
are no longer applicable. Clinical safety-
related evaluations will continue to be 
conducted. 
2. Synopsis: 
Endpoints 
 
4.4 Trial Endpoints 
Not applicable 
As of Amendment 3: Due to the 
premature discontinuation of the 
enrollment of the trial, only the clinical 
safety-related evaluations will continue 
to be conducted. 
2. Synopsis: Design 
and Plan 
 
3.3 Trial Rationale 
Not applicable 
As of Amendment 3: This amendment 
to the clinical trial protocol (CTP) is 
based on a Sponsor decision to 
discontinue the development of Sym004 
in combination with FOLFIRI. As a 
result, enrollment has stopped and a 
reduction in the total scope of non-safety 
related assessments being conducted 
under this CTP will be implemented. 
 
Patients who are actively being treated 
with Sym004 alone or in combination 
with FOLFIRI may continue therapy 
until unacceptable toxicity or other 
conditions preventing further 
administration, progressive disease (PD), 
or patient’s decision to withdraw. 
Patients no longer receiving Sym004 
alone or in combination with FOLFIRI 
should be discontinued from study 
participation. 
 
Patients will continue to be followed and 
assessed for clinical safety-related 
concerns throughout their respective 
treatment periods and at minimum for 30 
days after the last administration of 
Sym004. 


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2. Synopsis: Criteria 
for Evaluation 
Additional Assessments 
 
Pharmacokinetic (PK) 
Sampling 
 
Anti-Drug Antibody (ADA) 
Testing 
 
Biomarker blood and urine 
sample 
 
Additional Assessments 
 
Pharmacokinetic (PK) 
Sampling* 
 
Anti-Drug Antibody (ADA) 
Testing* 
 
Biomarker blood and urine 
sample* 
*Omitted with Amendment 3 
5.1 Overall Design 
and Plan: Treatment 
Period 
 
5.3.3 Treatment 
Not applicable 
As of Amendment 3: The visit schedule 
for the treatment period will apply until 
Sym004 has been discontinued. 
5.1 Overall Design 
and Plan: End of 
Treatment/Follow-up 
 
Not applicable 
As of Amendment 3: Once Sym004 has 
been discontinued, an EOT Visit will be 
performed within 10 days from the 
decision to withdraw treatment, and a 
follow-up visit will be performed 1 
month after the last administration of 
Sym004. 
5.3 Schedule of 
Events: Table 1 
Not applicable 
As of Amendment 3: The schedule for 
the treatment period will apply from the 
initiation of Sym004 and FOLFIRI until 
Sym004 has been discontinued. An EOT 
Visit will be performed within 10 days 
from the decision to withdraw treatment 
with Sym004, and a follow-up visit will 
be performed 1 month after the last 
administration of Sym004.  
5.3.4 End of 
Treatment and One 
Month Follow-up 
Visit 
Not applicable 
As of Amendment 3: An EOT Visit will 
be performed for all patients within 10 
days after the decision to discontinue 
treatment with Sym004. The patient will 
return for follow-up 1 month after the 
last administration of Sym004. 
5.3.5 Flow Chart – 
Schedule of 
Assessments 
Additional Assessments: 
PK Samples (dose-escalation only) 
ADA Sample 
Biomarker Blood and Urine Sample 
 
Footnote 1: The treatment phase 
continues until the patient is withdrawn 
from trial treatments (i.e. Sym004 and 
all components of FOLFIRI) 
*Additional Assessments: 
*PK Samples (dose-escalation only) 
*ADA Sample 
*Biomarker Blood and Urine Sample 
*Omitted with Amendment 3 
 
Footnote 1: The treatment phase 
continues until the patient is withdrawn 
from Sym004 (As of Amendment 3) 
 
5.5 Number of 
Patients 
Not applicable 
*As of Amendment 3: Accrual to this 
trial has stopped and the total planned 
number of patients will not be enrolled. 
6.3 Withdrawal from 
Trial Treatment 
Not applicable 
As of Amendment 3: The visit schedule 
for the treatment period will apply until 


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Sym004 has been discontinued. An EOT 
Visit will be performed within 10 days 
from the decision to withdraw treatment 
with Sym004, and a follow-up visit will 
be performed 1 month after the last 
administration of Sym004. 
8.2.9.2 Biochemistry 
Panel 
To include sodium, potassium, 
chloride… 
To include, if applicable, sodium, 
potassium, chloride… 
8.4 Pharmacokinetic 
Assessments (Dose-
Escalation Only) 
 
8.5 Anti-Drug 
Antibody Testing 
 
8.6 Biomarker 
Tumor, Blood and 
Urine Sample 
(inclusive of 8.6.1 
through 8.6.3) 
Entire section text 
Sections are omitted as of Amendment 3 
9.1.1 Adverse Event 
Please Note: Progression of disease will 
be captured as an AE. 
Please Note: Progression of disease will 
not be captured as an AE/SAE unless the 
nature of the PD is different than 
expected (i.e. other diagnoses and/or 
signs/symptoms that are not typical of 
PD). 
10.4.3 
Pharmacokinetic 
Endpoint and 
Analyses 
 
10.4.4 
Pharmacodynamics 
Endpoints and 
Analyses 
Entire section text 
Sections are omitted as of Amendment 3 
10.6 Data Collection 
and Analysis beyond 
Primary Analysis 
Not applicable 
As of Amendment 3: After the trial has 
closed enrollment and all DLT 
evaluation is completed, Sponsor may 
reduce trial data collection to 
information needed for safety reporting 
required by the FDA and/or other 
regulatory authorities, as well as efficacy 
and safety follow-up data considered 
necessary by the Sponsor. 
 

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2 4 F E B 2 0 1 7  
 
N ot A p plic a bl e – First V ersi o n  
1. 0  
3 0 M A R 2 0 1 7  
 
U p d at es m a d e aft er S y m p h o g e n’s r e vi e w.  
1. 1  
0 7 J U N E2 0 1 7  
 
U p d at es m a d e t o t h e S A P t ext a n d s h ells as 
f oll o ws:  
1.  U p d at e d t h e d efi niti o n of 
d er m at ol o gic t oxicit y i n t h e S A P 
t ext. 
2.  A d d e d a listi n g a n d c o u nt of T E A Es 
of h y p o m a g n es a e mi a t o t h e o v er all 
A E s u m m ar y t a bl e.  
3.  A d d e d a listi n g of F OL FI RI ex p os ur e 
v ari a bl es.  
 
 


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 4 of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
T A BL E O F C O N T E N T S  
1.1.  I N T R O D U C TI O N
I N T R O D U C TI O N ................................
................................................................
................................................................
..........................................................
.......................... 8  
2.2.  T RI AL O BJ E C TI V ES
T RI AL O BJ E C TI V ES ................................
................................................................
................................................................
.......................................................
....................... 8  
2. 1.  
E x pl or at or y O bj ecti v es  ................................................................................................................................8  
3.3.  S T U D Y D ESI G N
S T U D Y D ESI G N ................................
................................................................
................................................................
............................................................
............................ 8  
3. 1.  
G e n er al D escri pti o n  .....................................................................................................................................8  
3. 2.  
Sc h e d ul e of E v e nts .......................................................................................................................................9  
3. 3.  
C h a n g es t o A n al ysis fr o m Pr ot oc ol  ..............................................................................................................9  
4.4.  PL A N N E D A N AL YS ES
PL A N N E D A N AL YS ES  ................................
................................................................
................................................................
...................................................
................... 9  
5.5.  A N AL YSIS S E TS
A N AL YSIS S E TS  ................................
................................................................
................................................................
............................................................
............................ 9  
5. 1.  
F ull A n al ysis s et ( F A S)  ..................................................................................................................................9  
5. 2.  
M a xi m u m T ol er a bl e D os e ( M T D) a n al ysis S et  ............................................................................................ 1 0  
6.6.  G E N E R AL C O NSI D E R A TI O
G E N E R AL C O NSI D E R A TI O NSNS  ................................
................................................................
................................................................
.....................................
..... 1 01 0  
6. 1.  
R ef er e nc e St art D at e a n d D at a C ut -off D at e  .............................................................................................. 1 0  
6. 2.  
b as eli n e  ..................................................................................................................................................... 1 0  
6. 3.  
U nsc h e d ul e d Visits a n d E arl y T er mi n ati o n D at a  ........................................................................................ 1 0  
6. 4.  
Wi n d o wi n g C o n v e nti o ns  ............................................................................................................................ 1 1  
6. 5.  
St atistic al T ests  .......................................................................................................................................... 1 1  
6. 6.  
C o m m o n C alc ul ati o ns  ................................................................................................................................ 1 1  
6. 7.  
S oft w ar e V ersi o n  ....................................................................................................................................... 1 1  


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 5 of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
7.7.  S T A TIS TI C AL C O NSI D E R
S T A TIS TI C AL C O NSI D E R A TI O NS
A TI O NS  ................................
................................................................
................................................................
................................ 1 11 1  
8.8.  O U T P U T P R ES E N T A TI O NS
O U T P U T P R ES E N T A TI O NS  ................................
................................................................
................................................................
.........................................
......... 1 11 1  
9.9.  D IS P OSI TI O N A N D WI T H D
IS P OSI TI O N A N D WI T H DR A W ALS
R A W ALS  ................................
................................................................
...........................................................
........................... 1 11 1  
1 0.
1 0.  
D E M O G R A P HI C A N D O T H E
D E M O G R A P HI C A N D O T H E R B AS ELI N E C H A R A C T E R
R B AS ELI N E C H A R A C T E R IS TI CS
IS TI CS ................................
....................................................
.................... 1 21 2  
1 0. 1.  
D eri v ati o ns  ............................................................................................................................................ 1 3  
1 1.
1 1.  
S U R GI C AL, M E DI C AL A N
S U R GI C AL, M E DI C AL A N D DIS E AS E HIS T O R Y
D DIS E AS E HIS T O R Y  ................................
................................................................
.........................................
......... 1 31 3  
1 2.
1 2.  
M E DI C A TI O NS
M E DI C A TI O NS  ................................
................................................................
................................................................
.......................................................
....................... 1 31 3  
1 2. 1.  
Pri or A nti -c a nc er T h er a pi es ................................................................................................................... 1 3  
1 2. 2.  
C o nc o mit a nt M e dic ati o ns a n d T h er a pi es  ............................................................................................... 1 3  
1 3.
1 3.  
T RI AL T R E A T M E N T E X P O
T RI AL T R E A T M E N T E X P O S U R E A N D C O M PLI A N C E
S U R E A N D C O M PLI A N C E ................................
................................................................
................................ 1 41 4  
1 3. 1.  
D eri v ati o ns  ............................................................................................................................................ 1 4  
1 3. 1. 1.  
N u m b er of i nf usi o ns of tri al tr e at m e nt r ec ei v e d  ......................................................................................1 4  
1 3. 1. 2.  
Tr e at m e nt d ur ati o n ( w e e ks)  .....................................................................................................................1 4  
1 3. 1. 3.  
Ex p os ur e d ur ati o n ( W e e ks)  ......................................................................................................................1 5  
1 3. 1. 4.  
D os e r ec ei v e d ( m g/ k g or m g/ m 2) .............................................................................................................1 5  
1 3. 1. 5.  
C u m ul ati v e d os e ( m g/ k g or m g/ m 2) .........................................................................................................1 5  
1 3. 1. 6.  
D os e i nt e nsit y ( m g/ k g/ 2 w e e ks or m g/ m 2/ 2 w e eks) ................................................................................1 5  
1 3. 1. 7.  
R el ati v e D os e i nt e nsit y ( %)  .......................................................................................................................1 6  
1 3. 1. 8.  
N u m b er of d os e r e d ucti o ns  ......................................................................................................................1 6  
1 3. 1. 9.  
N u m b er of d os e i nt err u pti o ns  ..................................................................................................................1 7  
1 4.
1 4.  
E N D P OI N T E V AL U A TI O N
E N D P OI N T E V AL U A TI O N  ................................
................................................................
................................................................
.......................................
....... 1 71 7  
1 4. 1.  
Pri m ar y E n d p oi nt A n al ys es  .................................................................................................................... 1 7  
1 4. 2.  
S ec o n d ar y E n d p oi nt A n al ys es  ................................................................................................................ 1 7  
1 4. 3.  
Ot h er E n d p oi nt A n al ys es  ....................................................................................................................... 1 8  
1 5.
1 5.  
S AF E T Y O U T C O M ES
S AF E T Y O U T C O M ES  ................................
................................................................
................................................................
...............................................
............... 1 81 8  


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 6 of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1 5. 1.  
A d v ers e E v e nts  ...................................................................................................................................... 1 8  
1 5. 1. 1.  
All T E A Es  ...................................................................................................................................................1 8  
1 5. 1. 1. 1.  
S ev erit y  .............................................................................................................................................1 8  
1 5. 1. 1. 2.  
R el ati o ns hi p t o Tri al tr e at m e nt  ........................................................................................................1 9  
1 5. 1. 2.  
T E A Es L e a di n g t o D os e R e d ucti o n of Tri al Tr e at m e nt  ..............................................................................1 9  
1 5. 1. 3.  
T E A Es L e a di n g t o I nt err u pti o n of Tri al Tr e at m e nt  ....................................................................................1 9  
1 5. 1. 4.  
T E A Es L e a di n g t o Tri al Tr e at m e nt Wit h dr a w al  .........................................................................................1 9  
1 5. 1. 5.  
T E A Es L e a di n g t o Tri al T er mi n ati o n  ..........................................................................................................1 9  
1 5. 1. 6.  
S eri o us A d v ers e E v e nts  .............................................................................................................................1 9  
1 5. 1. 7.  
A d v ers e E v e nts L e a di n g t o D e at h  .............................................................................................................1 9  
1 5. 1. 8.  
I nf usi o n R el at e d R e acti o ns (I R Rs) .............................................................................................................2 0  
1 5. 1. 9.  
D er m at ol o gic T oxiciti es  ............................................................................................................................2 0  
1 5. 1. 1 0.  
N o n -S eri o us T E A Es wit h a Fr e q u e nc y of > = 5 %  ....................................................................................2 0  
1 5. 2.  
D e at hs  ................................................................................................................................................... 2 0  
1 5. 3.  
L a b or at or y E v al u ati o ns  .......................................................................................................................... 2 0  
1 5. 4.  
E C G E v al u ati o ns  ..................................................................................................................................... 2 1  
1 5. 5.  
Vit al Si g ns  .............................................................................................................................................. 2 1  
1 5. 6.  
Ot h er S af et y Ass ess m e nts  ..................................................................................................................... 2 1  
1 5. 6. 1.  
E ast er n C o o p er ati v e O nc ol o g y Gr o u p P erf or m a nc e St at us ( E C O G P S)  ....................................................2 1  
1 5. 6. 2.  
Pr ot oc ol D evi ati o ns  ..................................................................................................................................2 1  
1 6.
1 6.  
D A T A N O T S U M M A RI Z E D 
D A T A N O T S U M M A RI Z E D O R P R ES E N T E D
O R P R ES E N T E D  ................................
................................................................
.............................................
............. 2 22 2  
1 7.
1 7.  
R EF E R E N C ES
R EF E R E N C ES ................................
................................................................
................................................................
..........................................................
.......................... 2 22 2  
A P P E N DI X 1.
A P P E N DI X 1.  P R O G R A M MI N G C O N V E N TI
P R O G R A M MI N G C O N V E N TI O NS F O R O U T P U TS
O NS F O R O U T P U TS  ................................
......................................................
...................... 2 32 3  
 O ut p ut C o n v e nti o ns ......................................................................................................................... 2 3  
D at es & Ti m es  ....................................................................................................................................................... 2 3  
S p elli n g F or m a t ..................................................................................................................................................... 2 3  
Pr es e nt ati o n of Tr e at m e nt Gr o u ps  ....................................................................................................................... 2 3  
Listi n gs .................................................................................................................................................................. 2 3  
A P P E N DI X 2.
A P P E N DI X 2.  P A R TI AL D A T E C O N V E N T
P A R TI AL D A T E C O N V E N T I O NS
I O NS ................................
................................................................
.................................................
................. 2 42 4  


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 7 of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
Al g orit h m f or Tr e at m e nt E m er g e nc e of A d v ers e E v e nts:  ...................................................................................... 2 4  
Al g orit h m f or Pri or / C o nc o mit a nt M e dic ati o ns:  ................................................................................................... 2 6  
 
 


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 8 of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1.  IN T R O D U C TI O N  
T his d oc u m e nt d escri b es t h e r ul es a n d c o n v e nti o ns t o b e us e d i n t h e pr es e nt ati o n of s af et y d at a c oll ect e d u p t o 
t h e c ut-off d at e of 1 5 t h M a y 2 0 1 7, f or Pr ot oc ol S y m 0 0 4 -0 9 . T his d oc u m e nt  d escri b es t h e d at a t o b e s u m m ariz e d  
a n d pr es e nt e d i n t h e a b br e vi at e d cli nic al tri al r e p ort ( C T R) .  
T his st atistic al a n al ysis pl a n ( S A P) is b as e d o n v ersi o n  V 3. 0 of t h e cli nic al tri al pr ot oc ol ( C T P) , d at e d 0 5 A U G 2 0 1 6.  
H o w e v er, b as e d o n a s p o ns or d ecisi o n t o disc o nti n u e t h e tri al, o nl y t w o d os es  ( 1 2 m g/ k g a n d 9 m g/ k g) of 
S y m 0 0 4 i n c o m bi n ati o n wit h F OL FI RI will n o w b e i n v esti g at e d . N o f urt h er s u bj ects ar e t o b e r ecr uit e d or e nr oll e d 
i n t h e tri al a n d t h e D os e Ex p a nsi o n ( P h as e  2 a) p art of t h e tri al  will n ot b e c o n d uct e d. T h er ef or e t h e ori gi n al tri al 
o bj ecti v es d et ail e d i n V ersi o n 3. 0 of t h e C T P will n ot b e f ull y d oc u m e nt e d i n t his S A P.  
2.  T RI AL  O BJ E C TI V E S 
T h e ori gi n al pri m ar y o bj ecti v e f or t h e D os e -Esc al ati o n ( P h as e 1 b) p art of t h is tri al w as t o d et er mi n e t h e 
m axi m u m t ol er at e d d os e ( M T D) a n d/ or t h e r ec o m m e n d e d p h as e 2 d os e ( R P 2 D)  of S y m 0 0 4 w h e n a d mi n ist er e d 
b y i ntr a v e n o us (I V)  i nf usi o n e v er y s ec o n d w e ek i n c o m bi n ati o n wit h a st a n d ar d d osi n g r e gi m e n of F OL FI RI ( F oli nic 
Aci d [ F A; l e uc o v ori n], 5 -fl u or o ur acil ( 5-F U), I ri n ot ec a n) t o s u bj ects wit h l oc all y a d v a nc e d or m et ast atic c ol or ect al 
c a nc er ( C R C).  
As t h e tri al will b e disc o nti n u e d t h e o bj ecti v e of t h e tri al is n o w t o ass ess t h e s af et y of S y m 0 0 4 w h e n 
a d mi nist er e d i n c o m bi n ati o n wit h a st a n d ar d d osi n g r e gi m e n of F OL FI RI.  
2. 1.   E X P L O R A T O R Y O BJ E C TI V E S  
T h er e will n ot b e a n y ex pl or at or y o bj ecti v es.  
3.  S T U D Y D E SI G N  
3. 1.  G E N E R AL D E S C RI P TI O N  
T his w a s a n o p e n-l a b el, m ultic e ntr e , p h as e 1 b tri al wit h a n i niti al d os e-esc al ati o n p h as e f oll o w e d b y a d os e -
ex p a nsi o n p h as e.  
T h e tri al  w as  t o b e c o n d uct e d i n t h e U S A a n d c o u ntri es wit hi n t h e E U.  
A p pr oxi m at el y 2 t o 3 i n v esti g ati o n al tri al sit es w er e t o  p artici p at e i n t h e d os e -esc al ati o n p h as e t o d et er mi n e t h e 
M T D of S y m 0 0 4 a d mi nist er e d ev er y s ec o n d w e ek i n c o m bi n ati o n wit h a st a n d ar d d osi n g r e gi m e n of F OL FI RI. 
S u bj ects  w er e t o  b e all oc at e d i n s e q u e nc e t o 1 of u p t o 5 d os e l e v els of S y m 0 0 4, b as e d o n t ol er a bilit y.  
T e n s u bj ects  at 6 i n v esti g ati o n al sit es  i n S p ai n a n d U S A w er e e nr oll e d i n t h e D os e Esc al ati o n ( P h as e 1 b) p art of 
t h e tri al at t h e ti m e th e d ecisi o n w as t a k e n t o disc o nti n u e t h e tri al. T h e pri m ar y st atistic al a n al ysis ti mi n g a n d 


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 9 of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
d at a b as e will b e b as e d u p o n  a s p o ns or d et er mi n e d d at a c ut -off, w hic h is s et u p t o i ncl u d e s uffici e nt s af et y d at a 
( at le ast 3 m o nt hs aft er t h e l ast s u bj ect’s  first dos e), w hil e all o wi n g s u bj ect s i n r es p o ns e or st a bl e dis e as e t o 
c o nti n u e b e n efiti n g fr o m t h eir st u d y tr e at m e nts.    
3. 2.  S C H E D UL E O F E V E N T S  
Sc h e d ul e of e v e nts c a n b e f o u n d i n S ecti o n  5. 3 a n d  T a bl e 1  of t h e C T P . 
3. 3.  C H A N G E S T O A N AL Y SI S F R O M P R O T O C OL  
•  
T h e tri al h as b e e n st o p p e d e arl y, p h as e 2 a of t his tri al h as b e e n c a nc ell e d.  
•  
O nl y  s u m m ari es a n d listi n gs r e q uir e d f or a n a b br evi at e d C T R will b e g e n er at e d , b as e d o n t h e f ull 
a n al ysis s et ( F A S ) u nl ess ot h er wis e st at e d.  
•  
N o effic ac y a n al ysis will b e c arri e d o ut. 
•  
T h e D os e Li miti n g T oxicit y ( DL T) a n al ysis s et h as b e e n r e n a m e d a n d t h e d efi niti o n u p d at e d t o b e t h e 
M axi m u m T ol er a bl e D os e ( M T D) a n al ysis s et.  
 
4.  P L A N N E D A N AL Y S E S  
T h e fi n al pl a n n e d a n al ys es  i d e ntifi e d i n t his S A P will b e p erf or m e d b y 
 Bi ost atistics  foll o wi n g t h e 
a ut h oriz ati o n of t h e S A P a n d d at a b as e  ( D B) l oc k, w hic h will i ncl u d e all tri al d at a c oll ect e d u p t o t h e c ut -off d at e 
of t h e 1 5 t h M a y 2 0 1 7.  N o f or m al st atistic al t ests will  b e  c arri e d o ut o n  t his tri al. 
5.  A N AL Y SI S S E T S  
5. 1.  F ULL A N AL Y SI S S E T  ( F A S) 
T h e F ull A n al ysis S et ( F A S) will c o m pris e  all s u bj ects w h o r ec ei v e d at l e ast o n e d os e of tri al tr e at m e nt. S u bj ects 
will b e s u m m ariz e d acc or di n g t o t h e tr e at m e nt t h ey r ec ei v e d.  
All o ut p uts  will b e pr es e nt e d o n t h e F A S  u nl ess ot h er wis e i n dic at e d.  
5. 2.  M A XI M U M T OL E R A BL E D O S E ( M T D) A N AL Y SI S S E T  
T h e M axi m u m T ol er a bl e D os e (M T D ) A n al ysis S et  will  b e  c o m pris ed of all s u bj ects i n t h e F A S w h o c o m pl et e d 


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 1 0  of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
Cycl e 1 (i. e. mi ni m u m 2 i nf usi o ns of S y m 0 0 4 i n c o m bi n ati o n wit h F OL FI RI [f ull d os e])  or w h o h a v e d os e li miti n g 
t oxiciti es ( DL Ts) i n c ycl e 1. S u bj ects w h o disc o nti n u e st u d y tr e at m e nt  f or r e as o ns ot h er t h a n DL T  will b e excl u d e d 
fr o m t h e M T D  A n al ysis S et . As per  t h e pr ot oc ol, t h es e s u bj ect s w er e  t o b e r e pl ac e d.  
T h e M T D  a n al ysis s et will b e us e d f or e v al u ati o n of DL Ts.  
6.  G E N E R AL C O N SI D E R A TI O N S   
6. 1.  R E F E R E N C E S T A R T D A T E A N D D A T A C U T -O F F D A T E  
R ef er e nc e st art d at e is d efi n e d as t h e first d a y of tri al tr e at m e nt ( D a y 1)  f or e ac h s u bj ect. 
T h e d at a c ut -off d at e f or t h e pri m ar y a n al ysis is t h e 1 5 t h M a y 2 0 1 7. O nl y o bs er v ati o ns wit h a n ass ess m e nt d at e or 
st art d at e t h at is pri or t o or e q u al t o t h e d at e of d at a c ut-off will b e i ncl u d e d i n t h e  a n al ysis d at a m o d el ( A D a M)  
d at as ets a n d st atistic al o ut p uts. If h o w ev er, t h er e ar e  a d v ers e e v e nt  ( A E) or c o nc o m it a nt m e dic ati o n st o p d at es 
t h at ar e aft er t h e c ut-off d at e a n d ar e a v ail a bl e i n t h e d at a b as e at t h e ti m e of D B l oc k (f or A Es or m e dic ati o ns 
t h at st art e d pri or/ e q u al t o t h e c ut-off d at e), t h es e will b e pr es e nt e d i n listi n gs.  
6. 2.  B A S ELI N E  
U nl ess ot h er wis e s p eci fi e d, b as eli n e is d efi n e d as t h e l ast n o n-missi n g m e as ur e m e nt t a k e n pri or t o r ef er e nc e 
st art d at e (i ncl u di n g u nsc h e d ul e d ass ess m e nts). I n t h e c as e w h er e t h e l ast n o n -missi n g m e as ur e m e nt a n d t h e 
r ef er e nc e st art d at e c oi nci d e, a n d t h er e is n o evi d e nc e t o s u g g est t h at t h e ass ess m e nts w er e c o m pl et e d aft er 
d osi n g, t h at m e as ur e m e nt will b e c o nsi d er e d as b as eli n e.   
6. 3.  U N S C H E D UL E D V I SI T S A N D E A RL Y T E R MI N A TI O N D A T A  
U nsc h e d ul e d m e as ur e m e nts  will n ot b e i ncl u d e d i n b y -visit su m m ari es, b ut will c o ntri b ut e t o t h e b est/ w or st 
c as e v al u e w h er e  r e q uir e d.  
E arl y t er mi n ati o n d at a ( E n d of tr e at m e nt visit) will b e pr es e nt e d as p er t h e  assi g n e d  visit l a b els.  
Listi n gs will i ncl u d e sc h e d ul e d , u nsc h e d ul e d , r et est a n d e arl y t er mi n ati o n d at a . 
6. 4.  W I N D O WI N G C O N V E N TI O N S   
N o visit wi n d o wi n g wi ll b e p erf or m e d f or t his tri al. 


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 1 1  of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
6. 5.  S T A TI S TI C AL T E S T S  
N o st atistic al t ests will b e p erf or m e d f or t his tri al.  
6. 6.  C O M M O N C AL C UL A TI O N S  
F or q u a ntit ati v e m e as ur e m e nts, c h a n g e fr o m b as eli n e  (if r e q uir e d) will b e c alc ul at e d as:   
•  
T est V al u e at Visit X – B as eli n e V al u e  
6. 7.  S O F T W A R E V E R SI O N  
All a n al ys es will b e c o n d uct e d usi n g S A S v ersi o n 9. 2 or hi g h er.   
7.  S T A TI S TI C AL C O N SI D E R A TI O N S  
N ot a p plic a bl e f or t his tri al.  
8.  O U T P U T P R E S E N T A TI O N S  
A p p e n dix 1 s h o ws t h e c o n v e nti o ns f or pr es e nt ati o n of d at a i n o ut p uts.  
T h e t e m pl at es pr o vi d e d wit h t his S A P d escri b e t h e pr es e nt ati o ns f or t his tri al a n d t h er ef or e t h e f or m at a n d 
c o nt e nt of t h e s u m m ar y t a bl es a n d listi n gs t o b e pr o vi d e d b y 
 Bi ost atistics. 
If t h er e ar e missi n g d at a i n a s u m m ar y t a bl e, t h e n u m b er of s u bj ects wit h missi n g d at a will b e i ncl u d e d i n 
br ac k ets aft er t h e N f or e ac h tr e at m e nt ar m, i. e. 5 0 ( 2). P erc e nt a g es will b e b as e d o n t h e t ot al n u m b er i n t h e 
c orr es p o n di n g a n al ysis s et, u nl ess ot h er wis e i n dic at e d, h e nc e a n y s u bj ect(s) wit h missi n g d at a ar e i ncl u d e d i n t h e 
d e n o m i n at or.  
9.  D I S P O SI TI O N A N D W I T H D R A W AL S 
All s u bj ects w h o pr o vi d e i nf or m e d c o ns e nt will b e acc o u nt e d f or i n t his tri al.  
S u bj ect dis p ositi o n a n d tri al disc o nti n u ati o ns  will b e s u m m ariz e d i n a t a bl e w hic h will i ncl u d e t h e f oll o wi n g:  
1.  
N u m b er of s u bj ects scr e e n e d (i. e., s u bj ects w h o g a v e i nf or m e d c o ns e nt). 
2.  
N u m b er ( %) of s u bj ects all oc at e d t o tr e at m e nt  
3.  
N u m b er ( %) of s u bj ects tr e at e d ( F A S). 


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 1 2  of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
4.  
N u m b er of s u bj ects e v al u a bl e f or M T D.  
5.  
N u m b er ( %) of s u bj ects all oc at e d t o tr e at m e nt b ut  n ot tr e at e d . 
6 
N u m b er ( %) of s u bj ects  w h o wit h dr e w fr o m S y m 0 0 4 tr e at m e nt  
7. 
N u m b er ( %) of s u bj ects w h o wit h dr e w fr o m F OL FI RI tr e at m e nt  
8. 
N u m b er ( %) of s u bj ects w h o wit h dr e w fr o m b ot h  S y m 0 0 4 a n d F OL FI RI . 
9. 
N u m b er ( %) of s u bj ects o n g oi n g S y m 0 0 4 at D at a C ut -off.  
1 0 . 
N u m b er ( %) of s u bj ects o n g o i n g F OL FI RI at D at a C ut-off.  
1 1. 
N u m b er ( %) of s u bj ects w h o disc o nti n u e d  fr o m tri al (i ncl u di n g r e as o n f or disc o nti n u ati o n). 
P erc e nt a g es f or c at e g or y 2 will b e b as e d o n t h e ‘ N u m b er of s u bj ects scr e e n e d ’.  
P erc e nt a g es f or c at e g ori es 3  - 4 will b e b as e d o n t h e ‘ N u m b er of s u bj ects all oc at e d t o tr e at m e nt ’.  
P erc e nt a g es f or c at e g ori es 5 - 1 1 will b e b as e d o n t h e ‘ N u m b er of s u bj ects tr e at e d  ( F A S)’.  
Tr e at m e nt wit h dr a w als (s u bj ects w h o h a v e disc o nti n u e d fr o m tri al tr e at m e nt)  f or e ac h tri al tr e at me nt r ec ei v e d  
will b e pr es e nt e d o v er all a n d b y r e as o n, f or t h e F A S.  
T h e n u m b er of s u bj ects i n e ac h a n al ysis s et p er c o u ntr y will b e s u m m ariz e d i n a t a bl e als o. 
1 0.  D E M O G R A P HI C A N D  O T H E R B A S ELI N E C H A R A C T E RI S TI C S  
D e m o gr a p hic d at a will b e  pr es e nt e d f or t h e F A S. 
N o  st atistic al t esti n g will b e c arri e d o ut f or d e m o gr a p hic or ot h er b as eli n e c h ar act eristics.  
T h e f oll o wi n g d e m o gr a p hic c h ar act eristics will b e r e p ort e d f or t his tri al:  
•  
A g e ( y e ars)  
•  
S ex  
•  
R ac e  
•  
Et h nicit y  
•  
H ei g ht (c m)  
•  
W ei g ht ( k g)  
•  
B MI ( k g/ m 2) 
•  
B S A ( m 2) 
1 0. 1.  D E RI V A TI O N S  
•  
A g e ( y e ars) = (D at e of i nf or m e d c o ns e nt – d at e of birt h + 1)/ 3 6 5. 2 5  


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 1 3  of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
I n c as e of missi n g d a y or d a y a n d m o nt h, A g e will b e c alc ul at e d usi n g t h e m o nt h a n d/ or y e ar of i nf or m e d c o ns e nt 
mi n us  m o nt h a n d/ or y e ar of birt h.  
1 1.  S U R GI C AL , M E DI C AL  A N D D I S E A S E H I S T O R Y 
S ur gic al, M e dic al a n d Dis e as e  Hist or y i nf or m ati o n will b e pr es e nt e d i n listi n gs  f or t h e F A S. S ur gic al dis e as e hist or y 
will i ncl u d e pri or l oc al tr e at m e nt m o d aliti es a n d pri or c a nc er s ur g eri es.  
M e dic al hist or y will b e c o d e d usi n g M e d D R A , V ersi o n 1 9. 1 or hi g h er.  
1 2.  M E DI C A TI O N S  
1 2. 1.  P RI O R A N TI -C A N C E R T H E R A PI E S  
Pri or a nti -c a nc er r a di ot h er a p y, pri or c a nc er tr e at m e nts a n d pri or a nti -c a nc er dr u g t h er a pi es will b e list e d f or t h e 
F A S . 
1 2. 2.  C O N C O MI T A N T M E DI C A TI O N S A N D T H E R A PI E S  
M e dic ati o ns (i ncl u di n g pr o p hyl actic tr e at m e nts f or ski n t oxicit y a n d pr e m e dic ati o ns f or S y m 0 0 4 a n d F OL FI RI) will 
b e pr es e nt e d i n listi n gs f or t h e F A S  a n d c o d e d usi n g E n h a nc e d W H O D R U G V ersi o n M arc h 2 0 1 5 .  
S e e A p p e n dix 2 f or h a n dli n g of p arti al d at es f or m e dic ati o ns, i n t h e c as e w h er e it is n ot p ossi b l e t o d efi n e a 
m e dic ati o n as pri or, c o nc o mit a nt, or p ost tr e at m e nt, t h e m e dic ati o n will b e cl assifi e d b y t h e w orst c as e; i. e. 
c o nc o mit a nt.  
•  
‘Pri or ’ me dic ati o ns ar e m e dic ati o ns w hic h st art e d a n d st o p p e d pri or t o t h e first d os e of tri al tr e at m e nt.  
•  
‘C o nc o mit a nt ’ me dic ati o ns  ar e m e dic ati o ns w hic h :  
o  
st art e d pri or t o, o n or aft er t h e first d os e of tri al tr e at m e nt a n d st art e d n o l at er t h a n t h e l ast 
d os e of tri al tr e at m e nt,  
o  
A N D e n d e d o n or aft er t h e d at e of first  d os e of tri al tr e at m e nt or w er e o n g oi n g at t h e e n d of 
t h e tri al. 
•  
‘ P ost’ me dic ati o ns ar e m e dic ati o ns w hic h st art e d aft er t h e l ast  d os e of tri al tr e at m e nt . 
1 3.  T RI AL T R E A T M E N T E X P O S U R E A N D C O M PLI A N C E  
A d mi nistr ati o n d et ails of S y m 0 0 4  a n d F OL FI RI dr u gs will b e list e d f or e ac h dr u g r ec ei v e d f or  t he F A S . T h e 
f oll o wi n g list s u m m ariz es t h e c o m pli a nc e a n d ex p os ur e e n d p oi nts t h at ar e t o b e d eri v e d  f or S y m 0 0 4, Iri n otec a n, 


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 1 4  of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
5- F U b ol us a n d 5 -F U i nf usi o n . Tr e at m e nt w as gi v e n e v er y 2 w e eks a n d t h er ef or e t his is n ot e d i n t h e u nits f or 
d os e i nt e nsit y : 
•  
N u m b er of  i nf usi o ns of tri al tr e at m e nt r ec ei v e d 
•  
Tr e at m e nt d ur ati o n ( w e e ks) – i ncl u di n g a n y tr e at m e nt d el a ys 
•  
Ex p os ur e d ur ati o n ( w e e ks ) 
•  
C u m ul ati v e d os e  r ec ei v e d ( m g/ k g or m g/ m 2) 
•  
D os e i nt e nsit y ( m g/ k g/ 2 w e e ks  or m g/ m 2/2 w e eks ) 
•  
R el ati v e d os e i nt e nsit y ( %)  
T h e f oll o wi n g will b e d eri v e d a n d list e d f or S y m 0 0 4 o nl y: 
•  
N u m b er of d os e r e d ucti o ns  
•  
N u m b er of d os e i nt err u pti o ns  
1 3. 1.  D E RI V A TI O N S  
1 3. 1. 1.  
N U M B E R O F I N F U SI O N S O F T RI AL T R E A T M E N T R E C EI V E D 
A n y a d mi nistr ati o n of tri al tr e at m e nt r e g ar dl ess of t h e act u al d os e ( a n y d os e > 0) will b e c o u nt e d as o n e i nf usi o n 
of t h at tr e at m e nt.  
1 3. 1. 2.  
T R E A T M E N T D U R A TI O N (W E E K S ) 
T r e at m e nt d ur ati o n ( w e e ks) will b e c alc ul at e d f or S y m 0 0 4, Iri n ot ec a n, c alci u m f oli n at e a n d 5 -F U b ol us  as:  
(L ast d os e d at e pri or t o d at a c ut off – first d os e d at e + 1 4 )/ 7 d a ys 
 
As t h e 5-F U i nf usi o n is gi v e n o v er 4 6 h o urs, tr e at m e nt d ur ati o n ( w e eks) will b e c alc ul at e d f or 5 -F U i nf usi o n as:  
(L ast d os e d at e pri or t o d at a c ut off – first d os e d at e + 1 3)/ 7 d a ys 
1 3. 1. 3.  
E X P O S U R E D U R A TI O N ( WE E K S) 
Ex p os ur e d ur ati o n ( w e e ks ) will b e c alc ul at e d f or S y m 0 0 4, Iri n ot ec a n, c alci u m f oli n at e, 5-F U b ol us a n d 5 -F U 
i nf usi o n as:  
(L ast d os e d at e pri or t o d at a c ut -off  – first d os e d at e + 1)/ 7 d a ys  


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 1 5  of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1 3. 1. 4.  
D O S E R E C EI V E D  (M G / K G O R M G / M 2) 
T h e d os e of S y m 0 0 4 r ec ei v e d ( m g) at e ac h tr e at m e nt a d mi nistr a ti o n visit will b e c alc ul at e d as f oll o ws: 
 
T ot al d os e ( m g) * T ot al v ol u m e I nf us e d ( mL)  
T ot al v ol u m e pr e p ar e d ( mL)  
 
T h e S y m 0 0 4 d os e i n m g/ k g f or a s u bj ect will b e c alc ul at e d as:  
D os e of S y m 0 0 4 r ec ei v e d ( m g) / B o d y w ei g ht ( k g),  
w h er e w ei g ht r ec or d e d o n t h e d a y of tr e at m e nt a d mi nistr ati o n is t o b e us e d. I n c as e t his w ei g ht is missi n g, t h e 
l at est a v ail a bl e w ei g ht pri or t o t his visit will b e us e d. 
T h e d os e r ec ei v e d ( m g) at e ac h visit f or e ac h F OL FI RI  dr u g  (iri n ot ec a n, C alc i u m F oli n at e a n d 5-Fl u or o ur acil ) will 
b e e q u al t o t h e t ot al pl a n n e d d os e ( m g), if t h e t ot al d os e d eli v er e d w as  1 0 0 % . Ot h er wis e, if < 1 0 0 % of d os e w as  
d eli v er e d t h e n d os e r ec ei v e d ( m g) = t h e a m o u nt of d os e d eli v er e d ( m g).  
 
T h e d os e f or e ac h F OL FI RI dr u g i n m g/ m 2 will b e c alc ul at e d f or a s u bj ect as:  
D os e of dr u g r ec ei v e d ( m g) / B S A  ( m2), 
w h er e w ei g ht r ec or d e d o n t h e d a y of tr e at m e nt a d mi nistr ati o n is t o b e us e d t o d et er mi n e B S A. I n c as e t his 
w ei g ht is missi n g, t h e l at est a v ail a bl e w ei g ht pri or t o t his visit will b e us e d.  
1 3. 1. 5.  
C U M UL A TI V E D O S E (M G / K G O R M G / M 2) 
T h e c u m ul ati v e d os e is d efi n e d t h e s u m of all d os es r ec ei v e d pri or t o d at a c ut -off i n u nits of m g/ k g f or S y m 0 0 4 
a n d m g/ m 2 f or e ac h F OL FI RI dr u g . 
1 3. 1. 6.  
D O S E I N T E N SI T Y  (M G / K G / 2  W E E K S  O R M G / M 2/ 2  W E E K S ) 
T h e d os e i nt e nsit y ( m g/ k g/ 2 w e e k s) f or S y m 0 0 4 is d efi n e d as:  
C u m ul ati v e d os e ( m g/ k g) / (Tr e at m e nt d ur ati o n i n w e eks/ 2)   
 
T h e d os e i nt e nsit y ( m g/ m 2/2 w e e k s) f or e ac h F OL FI RI dr u g  is d efi n e d as:  
C u m ul ati v e d os e ( m g/ m 2) / ( Tr e at m e nt d ur ati o n i n w e eks/ 2) 


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 1 6  of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1 3. 1. 7.  
R EL A TI V E D O S E I N T E N SI T Y ( %) 
T h e r el ati v e d os e i nt e nsit y f or S y m 0 0 4 a n d all F OL FI RI dr u gs is d efi n e d as: 
( D os e i nt e nsit y ( m g/ k g/2 w e e ks ) / Pl a n n e d d os e i nt e nsit y ( m g/ k g/2 w e eks ) o n D a y 1) * 1 0 0 
T h e r el ati v e d os e i nt e nsit y will b e s u m m ariz e d usi n g t h e f oll o wi n g c at e g ori es:  
> 1 1 0 %  
> 1 0 0 % - 1 1 0 %  
> 9 0 % - 1 0 0 %  
> 8 0 % - 9 0 %  
> 7 0 % - 8 0 %  
> 6 0 % - 7 0 %  
< = 6 0 %  
1 3. 1. 8.  
N U M B E R O F D O S E R E D U C T I O N S 
T h e n u m b er of d os e r e d ucti o n will o nl y b e d eri v e d f or S y m 0 0 4 a n d pr es e nt e d i n listi n gs. A s u bj ect will b e 
i d e ntifi e d as h a vi n g a d os e r e d ucti o n if t h e q u esti o n ‘ W as t h e tr e at m e nt pr escri b e d at a r e d uc e d d os e’ is tic k e d 
‘ Y es’ o n t h e e C R F S y m 0 0 4 a d mi nistr ati o n d et ails p a g e a n d t h e s u bj ect r ec ei v e d at l e ast o n e d os e of t his n e wl y 
pr escri b e d d os e. T h e r e as o n f or d os e r e d ucti o n is r ec or d e d o n t his p a g e als o, as eit h er “ A d v ers e e v e nt” , 
“I nf usi o n r el at e d r e acti o n” or “ Ot h er”.  


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 1 7  of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
T he n u m ber of d ose re d ucti o ns per s u bj ect will b y calc ulate d as s h o w n i n t he ta ble bel o w (t he n u m bers i n t he cells 
are t he n u m ber of d ose re d ucti o ns):  
R ec eiv e d at l e ast  
o n e d os e of  
 S u bj ects r a n d o miz e d  
t o 9 m g/ k g  
S u bj ects r a n d o miz e d  
t o 1 2 m g/ k g  
9 m g/ k g  
 
n a  
1  
6 m g/ k g  
 
1  
2  
4. 5 m g/ k g  
 
2  
3  
3 m g/ k g  
 
3  
4  
1. 5 m g/ k g  
 
4  
5  
 
1 3. 1. 9.  
N U M B E R O F D O S E I N T E R R U P TI O N S  
T h e n u m b er of d os e of i nt err u pti o ns will o nl y b e d eri v e d f or S y m 0 0 4 a n d pr es e nt e d i n listi n gs . T h e n u m b er of 
d os e i nt err u pti o ns p er s u bj ect will b e d eri v e d as t h e n u m b er of ti m es t h e q u esti o n ‘ W as i nf usi o n i nt err u pt e d?’ is 
tic k e d ‘Y es ’. 
1 4.  E N D P OI N T E V AL U A TI O N  
N o f or m al a n al ys es ar e pl a n n e d.  
1 4. 1.  P RI M A R Y E N D P OI N T A N AL Y S E S  
T h e pri m ar y e n d p oi nt is  t h e occ urr e nc e of DL T s f or e ac h of t h e S y m 0 0 4 d os e le v els gi v e n i n c o m bi n ati o n wit h 
F OL FI RI.  O nl y DL Ts t h at occ urr e d d uri n g Cycl e 1 of tri al tr e at m e nt (i. e. mi ni m u m 2 i nf usi o ns of S y m 0 0 4 i n 
c o m bi n ati o n wit h F OL FI RI [f ull d os e]) will b e s u m m ariz e d.  
T h e f oll o wi n g i nf or m ati o n r el at i n g t o DL T s as p er i n v esti g at or o pi ni o n  will b e pr es e nt e d  f or t h e M T D a n al ysis s et: 
1.  
N u m b er ( %) of S u bj ects wit h w h o ex p eri e nc e d a  DL T.  
2.  
N u m b er ( %) of S u bj ects wit h DL Ts acc or di n g t o S O C a n d P T.  
P erc e nt a g es h er e will b e b as e d o n n u m b er of s u bj ects  i n e ac h of t h e S y m 0 0 4 d os e l e v els gi v e n i n c o m bi n ati o n 
wit h a F OL FI RI r e gi m e nt.  
1 4. 2.  S E C O N D A R Y E N D P OI N T A N AL Y S E S  
All s ec o n d ar y e n d p oi nts ar e s af et y e n d p oi nts , a n d t h er ef or e  t h es e ar e d et ail e d i n S ecti o n 1 5  of t his S A P . 


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 1 8  of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1 4. 3.  O T H E R E N D P OI N T A N AL Y S E S  
T u m or , s u m of t h e l o n g est di a m et er ( S OL D) a n d dis e as e ass ess m e nt d at a will b e pr es e nt e d i n  listi n gs o nl y.  
1 5.  S A F E T Y O U T C O M E S  
S af et y a n d t ol er a bilit y of tri al tr e at m e nt will b e ass ess e d b y t h e ex a mi n ati o n of A Es, l a b or at or y d at a, E C Gs a n d 
vit al si g ns.  N o f or m al st atistic al c o m p aris o n will b e m a d e b et w e e n tr e at m e nt ar ms a n d s o m e s af et y s u m m ari es 
will b e pr es e nt e d usi n g d escri pti v e st atistics.  
All listi n gs a n d s u m m ari es of s af e t y d at a will b e b as e d o n t h e F A S . 
1 5. 1.  A D V E R S E E V E N T S  
A d v ers e E v e nts ( A Es) will b e c o d e d usi n g M e dic al Dicti o n ar y f or R e g ul at or y Acti viti es ( M e d D R A) c e ntr al c o di n g 
dicti o n ar y, V ersi o n 1 8 or hi g h er.  
Tr e at m e nt e m er g e nt a d v ers e ev e nts ( T E A Es) ar e d efi n e d as A Es t h at st art e d o n or aft er t h e first d os e of tri al 
tr e at m e nt a n d pri or t o t h e l ast d at e of tri al tr e at m e nt + 2 8 d a ys (i ncl usi v e). If a n A E st art e d o n t h e s a m e d at e as 
t h e first a dmi nistr ati o n of S y m 0 0 4 a n d F OL FI R I, t h e n t h e ti mi n g r el at e d t o tri al tr e at m e nt as r ec or d e d o n t h e 
a d v ers e e v e nts p a g e of t h e e C R F will b e t a k e n i nt o acc o u nt w h e n d et er mi ni n g tr e at m e nt e m er g e nc e.  
S e e A p p e n dix 2 f or h a n dli n g of p arti al d at es f or A Es.  I n t h e c as e w h er e it is n ot p ossi bl e t o  d efi n e a n A E as 
tr e at m e nt e m er g e nt or n ot, t h e A E will b e cl assifi e d b y t h e w orst c as e; i. e. tr e at m e nt e m er g e nt.  
A n o v er all s u m m ar y t a bl e f or n u m b er of s u bj ects wit hi n e ac h of t h e c at e g ori es d escri b e d i n t h e s u b -s ecti o ns 
1 5. 1. 1 -1 5. 1. 9 b el o w, will b e pr o vi d e d as s p ecifi e d i n t h e t e m pl at es.  I n a d diti o n t o t h e c at e g ori es d escri b e d i n t h e 
s u bs ecti o ns b el o w, t h e n u m b er of s u bj ects wit h at l e ast o n e s eri o us T E A E r el at e d t o S y m 0 0 4 o nl y  a n d t h e 
n u m b er of s u bj ects w h o ex p eri e nc e at l e ast o n e T E A E of h y p o m a g n es a e mi a , will b e pr es e nt e d i n t h e o v er all A E 
s u m m ar y t a bl e. 
Listi n gs will i ncl u d e T E A Es a n d N o n-T E A Es.  
1 5. 1. 1.  
A LL T E A E S  
I nci d e nc e of T E A Es will b e pr es e nt e d b y S yst e m Or g a n Cl ass ( S O C) a n d Pr ef err e d T er m ( P T) a n d als o br o k e n d o w n 
f urt h er b y w orst gr a d e ( m axi m u m s ev erit y) a n d r el ati o ns hi p t o e ac h tri al tr e at m e nt. A s u m m ar y of tr e at m e nt r el at e d 
T E A E S b y w orst gr a d e > =  3 will b e pr es e nt e d als o.  
1 5. 1. 1. 1.  S ev erit y  
S ev erit y is cl assifi e d acc or di n g t o N CI -C T C A E crit eri a V 4. 0 3 ( Gr a d e 1 ( Mil d), 2 ( M o d er at e), 3 ( S e v er e), 4 (Lif e -
t hr e at e ni n g or dis a bli n g), 5 ( D e at h r el at e d A E)). If a s u bj ect r e p orts a T E A E m or e t h a n o nc e wit hi n t h at S O C/ P T, 


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 1 9  of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
t h e A E wit h t h e w orst gr a d e ( m axi m u m  s ev erit y) will b e us e d i n t h e c orr es p o n di n g s u m m ari es. Missi n g gr a d es 
ar e n ot t o b e i m p ut e d.  
1 5. 1. 1. 2.  R el ati o ns hi p t o T ri al tr e at m e nt 
R el ati o ns hi p,  as i n dic at e d b y t h e I n v esti g at or , is cl ass e d as “ R el at e d” or “ U nr el at e d”. T E A Es wit h a missi n g 
r el ati o ns hi p t o a tri al tr e at m e nt will b e r e g ar d e d as r el at e d t o t h at p artic ul ar tri al tr e at m e nt. If a s u bj ect r e p orts 
t h e s a m e A E m or e t h a n o nc e wit hi n t h at S O C/ P T, t h e A E wit h t h e w orst c as e r el ati o ns hi p t o tri al tr e at m e nt will 
b e us e d i n t h e c orr es p o n di n g r el ati o ns hi p s u m m ari es.  
1 5. 1. 2.  
T E A E S L E A DI N G T O D O S E R E D U C TI O N O F T RI AL T R E A T M E N T  
T E A Es l e a di n g t o  d os e r e d ucti o n of tri al tr e at m e nt ar e t h os e ev e nts wit h a n acti o n t a k e n wit h tri al tr e at m e nt of 
“ D os e R e d uc e d”. T h es e T E A Es will b e list e d o nl y . 
1 5. 1. 3.  
T E A E S L E A DI N G T O IN T E R R U P TI O N O F T RI AL T R E A T M E N T  
T E A Es l e a di n g t o a n i nt err u pti o n of tri al tr e at m e nt ar e t h os e  ev e nts wit h a n acti o n t a k e n wit h tri al tr e at m e nt of 
“ Dr u g I nt err u pt e d”. T h es e T E A Es will b e list e d o nl y . 
1 5. 1. 4.  
T E A E S L E A DI N G T O T RI AL T R E A T M E N T W I T H D R A W AL 
T E A Es l e a di n g t o tri al tr e at m e nt wit h dr a w al ar e t h os e e v e nts wit h a n acti o n t a k e n wit h tri al tr e at m e nt of “ Dr u g 
Wit h dr a w n ”. T h es e T E A Es will b e list e d o nl y . 
1 5. 1. 5.  
T E A E S L E A DI N G T O T RI AL T E R MI N A TI O N  
T E A Es l e a di n g t o tri al  t er mi n ati o n ar e t h os e e v e nts wit h a n  acti o n t a k e n of “L e d t o st u d y t er mi n ati o n” . T h es e 
T E A Es will b e list e d o nl y.  
1 5. 1. 6.  
S E RI O U S A D V E R S E E V E N T S  
S eri o us a d v ers e e v e nts ( S A Es) ar e t h os e e v e nts r ec o r d e d as “S eri o us” o n t h e A d v ers e E v e nts p a g e of t h e ( e) C R F. 
A s u m m ar y of s eri o us T E A Es b y S O C a n d P T will b e pr e p ar e d.  
1 5. 1. 7.  
A D V E R S E E V E N T S L E A DI N G T O D E A T H  
T E A Es l e a di n g t o D e at h ar e t h os e e v e nts w hic h ar e r ec or d e d as  “F at al” o n t h e A d v ers e E v e nts p a g e of t h e ( e) C R F. 
A s u m m ar y of T E A Es l e a di n g t o d e at h b y S O C a n d P T will b e pr e p ar e d .  


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 2 0  of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1 5. 1. 8.  
IN F U SI O N R EL A T E D R E A C TI O N S (I R RS) 
I nf usi o n r el at e d r e acti o ns (I R R S) ar e t h os e ev e nts w hic h h a v e a n a ns w er of “ y es” t o t h e q u esti o n, “Is t his e v e nt 
a n i nf usi o n r el at e d r e acti o n ? ” o n t h e A d v ers e E v e nts p a g e of t h e ( e) C R F. T h es e I R Rs will b e list e d o nl y .  
1 5. 1. 9.  
D E R M A T OL O GI C T O XI CI TI E S  
D er m at ol o gic t oxiciti es i ncl u d e a n y A E t er ms as d escri b e d i n t h e “ D er m at ol o gic T oxicit y” s ecti o ns i n t h e 2 0 1 5 
p ac k a g e i ns erts of c et uxi m a b, p a nit u m u m a b, or n ecit u m u m a b, as w ell as A E t er ms u n d er i nf ecti o us s e q u el a e i n 
c et uxi m a b p ac k a g e i ns ert u nl ess all A Es wit h a s p ecific pr ef err e d t er m ar e u nr el at e d.  A Es wit h 
re p ort e d/ pr ef err e d t er m of “ S ki n t oxicit y” will b e r evi e w e d a n d d et er mi n e o n a c as e -b y -c as e b asis. S y m p h o g e n 
will s p ecify t h e A E t er ms t h at ar e t o b e cl assifi e d as a d er m at ol o gic t oxicit y i n a s pr e a ds h e et a n d pr o vi d e t his t o 
 Bi ost atistics.  
I n v esti g at or r es p o ns es t o t h e q u esti o n “Is t his a d v ers e e v e nt ski n r el at e d ?” will b e pr es e nt e d i n t h e d at a listi n g 
b ut n ot us e d i n t h e d er m at ol o gic t oxiciti es cl assific ati o n t o a v oi d s u bj ecti vit y a n d i nc o nsist e nc y.  
1 5. 1. 1 0.  N O N - SE RI O U S T E A E S WI T H A F R E Q U E N C Y O F > =  5 %  
T E A Es t h at ar e n o n-s eri o us a n d h a v e a fr e q u e nc y, i n a n y of t h e tr e at m e nt ar ms of > = 5 %, will b e s u m m ariz e d 
s e p ar at el y b y S O C a n d P T. 
1 5. 2.  D E A T H S  
T h e n u m b er of d e at hs a n d pri m ar y r e as o n f or d e at h , f or all d e at hs a n d d e at hs wit hi n 3 0 d a ys fr o m t h e l ast d os e 
of tri al tr e at m e nt will b e s u m m ariz e d b as e d o n t h e D e at h e C R F -p a g e  f or t h e F A S. I n a d diti o n a listi n g of d e at hs 
i ncl u di n g d at e of i nf or m e d c o ns e nt, d at es of first a n d l ast tri al tr e at m e nt a d mi nistr ati o n, t h e n u m b er of d a ys 
si nc e l ast a d mi nistr ati o n of tri al tr e at m e nt, pri m ar y r e as o n f or d e at h  a n d w h et h er a n a ut o psy w as p erf or m e d will 
b e pr o vi d e d . 
1 5. 3.  LA B O R A T O R Y E V AL U A TI O N S  
H e m at ol o g y, s er u m c h e mistr y, c o a g ul ati o n, uri n al ysis  a n d t u m or a nti g e n bi o m ar k er  d at a will b e i ncl u d e d i n  
listi n gs. 
N CI -C T C A E gr a d es will b e c alc ul at e d f or h e m at ol o g y, s er u m c h e mistr y, c o a g ul ati o n a n d uri n al ysis  p ar a m et ers 
i ncl u d e d i n V ersi o n 4. 0 3 of t h e crit eri a.  T h es e gr a d es will b e s h o w n i n t h e d at a listi n gs o nl y .   
L a b or at or y v al u es t h at ar e o utsi d e t h e n or m al r a n g e will b e pr es e nt e d as a s e p ar at e listi n g .  


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 2 1  of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1 5. 4.  E C G  E V AL U A TI O N S  
All E C G d at a will b e dis pl a y e d i n listi n gs o nl y.   
1 5. 5.  V I T AL S I G N S 
All vit al si g ns d at a will b e dis pl a y e d i n listi n gs o nl y.   
1 5. 6.  O T H E R S A F E T Y A S S E S S M E N T S  
1 5. 6. 1.  
E A S T E R N C O O P E R A TI V E O N C OL O G Y G R O U P P E R F O R M A N C E S T A T U S ( E C O G P S ) 
E ast er n C o o p er ati v e O nc ol o g y Gr o u p ( E C O G) P S  is ass ess e d o n d a y 1 of e ac h tr e at m e nt c ycl e ( 2 8 ± 2 d a ys ) a n d 
pri or t o S y m 0 0 4 a d mi nistr ati o n.  
All E C O G P S d at a will b e list e d f or t h e F A S.  
1 5. 6. 2.  
P R O T O C OL D E VI A TI O N S  
Pr ot oc ol d evi ati o ns c oll ect e d i n t h e 
 cli nic al tri al m a n a g e m e nt syst e m ( C T M S) will b e pr es e nt e d i n a 
listi n g f or t h e F A S. 
 
 


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 2 2  of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1 6.  D A T A N O T S U M M A RI Z E D  O R P R E S E N T E D  
T h e ot h er v ari a bl es a n d/ or d o m ai ns n ot pr es e nt e d ar e:  
•  
Pr e g n a nc y t est  
•  
S ki n Ex a mi n ati o n ( Y es/ N o a n d D at e)  
•  
S ki n R as h  
•  
T u m o ur bi o psy s a m pl e d at es (c oll ect at scr e e ni n g o nl y)  
T h es e d o m ai ns a n d/ or v ari a bl es will n ot b e s u m m ariz e d or pr es e nt e d, b ut will b e a v ail a bl e i n t h e cli nic al tri al 
d at a b as e a n d S D T M d at as ets  
1 7.  R E F E R E N C E S  
N ot A p plic a bl e  
 
 


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 2 3  of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
A P P E N DI X 1.  P R O G R A M MI N G C O N V E N TI O N S F O R O U T P U T S  
 O U T P U T C O N V E N TI O N S  
O ut p uts will b e pr es e nt e d as p er t h e f or m at/l a y o ut s h o w n i n t h e s h ells.   
D A T E S &  T I M E S 
D e p e n di n g o n d at a a v ail a bl e, d at es a n d ti m es will t a k e t h e f or m D D M M Y Y Y Y: H H: M M. 
S P ELLI N G F O R M A T  
E n glis h U S.   
P R E S E N T A TI O N O F T R E A T M E N T G R O U P S  
F or o ut p uts, tr e at m e nt gr o u ps will b e r e pr es e nt e d as f oll o ws a n d i n t h at or d er:  
Tr e at m e nt Gr o u p  
F or T a bl es a n d Gr a p hs  
F or Listi n gs  
S y m 0 0 4 1 2  m g/ k g  i n 
c o m bi n ati o n wit h F OL FI RI  
S y m 0 0 4 1 2  m g/ k g  + F OL FI RI  
S y m 0 0 4 1 2  m g/ k g  + F OL FI RI  
S y m 0 0 4 9  m g/ k g  i n 
c o m bi n ati o n wit h F OL FI RI  
S y m 0 0 4 9  m g/ k g  + F OL FI RI  
S y m 0 0 4 9 m g/ k g  + F OL FI RI  
L I S TI N G S 
All listi n gs will b e or d er e d b y t h e f oll o wi n g ( u nl ess ot h er wis e i n dic at e d i n t h e t e m pl at e):  
•  
Tr e at m e nt gr o u p,  
•  
S u bj ect I D,  
•  
d at e ( w h er e a p plic a bl e),  
 


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 2 4  of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
A P P E N DI X 2.  P A R TI AL D A T E C O N V E N TI O N S  
I m p ut e d d at es will N O T b e pr es e nt e d i n t h e listin gs.  
A L G O RI T H M F O R T R E A T M E N T E M E R G E N C E O F A D V E R S E E V E N T S : 
S T A R T D A T E  
S T O P D A T E  
A C TI O N  
K n o w n  
K n o w n  
If st art d at e < tri al m e d st art d at e, t h e n n ot T E A E  
If st art d at e > = tri al m e d st art d at e / a n d < = tri al m e d e n d 
d at e + 2 8 d a ys, t h e n T E A E  
 
P arti al  
If st art d at e < tri al m e d st art d at e, t h e n n ot T E A E  
If st art d at e > = tri al m e d st art d at e  a n d < = tri al m e d e n d 
d at e + 2 8 d a ys, t h e n T E A E  
 
Missi n g  
If st art d at e < tri al m e d st art d at e, t h e n n ot T E A E  
If st art d at e > = tri al m e d st art d at e  a n d < = tri al m e d e n d  
d at e + 2 8 d a ys, t h e n T E A E  
 
 
 
P arti al, b ut k n o w n 
c o m p o n e nts s h o w t h at it 
c a n n ot b e o n or aft er tri al 
m e d st art d at e . 
K n o w n  
N ot T E A E  
 
P arti al  
N ot T E A E  
 
Missi n g  
N ot T E A E  
 
 
 
P arti al, c o ul d b e o n or aft er 
tri al m e d st art d at e . 
K n o w n  
If st o p d at e < tri al m e d st art d at e, t h e n n ot T E A E  
If st o p d at e > = tri al m e d st art d at e  a n d < = tri al m e d e n d 
d at e + 2 8 d a ys, t h e n T E A E  
 
P arti al  
I m p ut e st o p d at e as l at est p ossi bl e d at e (i. e. l ast d a y of 
m o nt h if d a y u n k n o w n or 3 1st D ec e m b er if d a y a n d m o nt h 
ar e u n k n o w n), t h e n: 
If st o p d at e < tri al m e d st art d at e, t h e n n ot T E A E  
If st o p d at e > = tri al m e d st art d at e  a n d < = tri al m e d e n d 
d at e + 2 8 d a ys, t h e n T E A E  


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 2 5  of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
S T A R T D A T E  
S T O P D A T E  
A C TI O N  
 
Missi n g  
Ass u m e d T E A E  
 
 
 
Missi n g  
K n o w n  
If st o p d at e < tri al m e d st art d at e, t h e n n ot T E A E  
If st o p d at e > = tri al m e d st art d at e  a n d < = tri al m e d e n d 
d at e + 2 8 d a ys, t h e n T E A E  
 
P arti al  
I m p ut e st o p d at e as l at est p ossi bl e d at e (i. e. l ast d a y of 
m o nt h if d a y u n k n o w n or 3 1st D ec e m b er if d a y a n d m o nt h 
ar e u n k n o w n), t h e n:  
If st o p d at e < tri al m e d st art d at e , t h e n n ot T E A E 
If st o p d at e > = tri al m e d st art d at e  a n d < = tri al m e d e n d 
d at e + 2 8 d a ys, t h e n T E A E  
 
Missi n g  
Ass u m e d T E A E  
 
 
 


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 2 6  of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
A L G O RI T H M F O R P RI O R /  C O N C O MI T A N T M E DI C A TI O N S:  
S T A R T D A T E  
S T O P D A T E  
A C TI O N  
K n o w n  
K n o w n  
If st o p d at e < tri al m e d st art d at e, assi g n as pri or  
If st o p d at e > = tri al m e d st art d at e a n d st art d at e < = e n d of tr e at m e nt, 
assi g n as c o nc o mit a nt  
If st o p d at e > = tri al m e d st art d at e a n d st art d at e > e n d of tr e at m e nt, assi g n 
as p ost tri al  
 
P arti al  
I m p ut e st o p d at e as l at est p ossi bl e d at e (i. e. l ast d a y of m o nt h if d a y 
u n k n o w n or 3 1 st D ec e m b er if d a y a n d m o nt h ar e u n k n o w n), t h e n:  
If st o p d at e < tri al m e d st art d at e , assi g n as pri or  
If st o p d at e > = tri al m e d st art d at e a n d st art d at e < = e n d of tr e at m e nt, 
assi g n as c o nc o mit a nt  
If st o p d at e > = tri al m e d st art d at e a n d st art d at e > e n d of tr e at m e nt, assi g n 
as p ost tr e at m e nt  
 
Missi n g  
If st o p d at e is missi n g c o ul d n ev er b e ass u m e d a pri or m e dic ati o n 
If st art d at e < = e n d of tr e at m e nt, assi g n as c o nc o mit a nt 
If st art d at e > e n d of tr e at m e nt, assi g n as p ost tr e at m ent  
 
 
 
P arti al  
K n o w n  
I m p ut e st art d at e as e arli est p ossi bl e d at e (i. e. first d a y of m o nt h if d a y 
u n k n o w n or 1 st J a n u ar y if d a y a n d m o nt h ar e u n k n o w n), t h e n: 
If st o p d at e < tri al m e d st art d at e, assi g n as pri or  
If st o p d at e > = tri al m e d st art d at e a n d st art d at e < = e n d of tr e at m e nt, 
assi g n as c o nc o mit a nt  
If st o p d at e > = tri al m e d st art d at e a n d st art d at e > e n d of tr e at m e nt, assi g n 
as p ost tr e at m e nt  
 
P arti al  
I m p ut e st art d at e as e arli est p ossi bl e d at e (i. e. first d a y of m o nt h if d a y 
u n k n o w n or 1 st J a n u ar y if d a y a n d m o nt h ar e u n k n o w n) a n d i m p ut e st o p 
d at e as l at est p ossi bl e d at e (i. e. l ast d a y of m o nt h if d a y u n k n o w n or 3 1 st 
D ec e m b er if d a y a n d m o nt h ar e u n k n o w n), t h e n:  
If st o p d at e < tri al m e d st art d at e, assi g n as pri or  
If st o p d ate > = tri al m e d st art d at e a n d st art d at e < = e n d of tr e at m e nt, 
assi g n as c o nc o mit a nt  
If st o p d at e > = tri al m e d st art d at e a n d st art d at e > e n d of tr e at m e nt, assi g n 
as p ost tr e at m e nt  
 
Missi n g  
I m p ut e st art d at e as e arli est p ossi bl e d at e (i. e. first d a y of m o nt h if d a y 
u n k n o w n or 1 st J a n u ar y if d a y a n d m o nt h ar e u n k n o w n), t h e n: 
If st o p d at e is missi n g c o ul d n ev er b e ass u m e d a pri or m e dic ati o n 
If st art d at e < = e n d of tr e at m e nt, assi g n as c o nc o mit a nt 
If st art d at e > e n d of tr e at m e nt, assi g n as p ost tr e at m e nt 
 
 
 


 
S y m p h o g e n A/ SI n s ert C u st o m er N a m e/ L o g o  
St ati sti c al A n al y si s Pl a n: Pr ot o c ol S y m 0 0 4 -0 9  
P a g e 2 7  of 2 7  
 
 
 
V er si o n N u m b er:  
1. 1  
 
 
V er si o n D at e:  
[0 7 J U N E 2 0 1 7 ] 
 
 
 
C o p yri g ht © 
. All ri g ht s r e s er v e d. 
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o 
. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
S T A R T D A T E  
S T O P D A T E  
A C TI O N  
Missi n g  
K n o w n  
If st o p d at e < tri al m e d st art d at e, assi g n as pri or  
If st o p d at e > = tri al m e d st art d at e, assi g n as c o nc o mit a nt  
C a n n ot b e assi g n e d as ‘ p ost tr e at m e nt’  
 
P arti al  
I m p ut e st o p d at e as l at est p ossi bl e d at e (i. e. l ast d a y of m o nt h if d a y 
u n k n o w n or 3 1 st D ec e m b er if d a y a n d m o nt h ar e u n k n o w n), t h e n:  
If st o p d at e < tri al m e d st art d at e, assi g n as pri or  
If st o p d at e > = tri al m e d st art d at e , assi g n as c o nc o mit a nt  
C a n n ot b e assi g n e d as ‘ p ost tr e at m e nt’  
 
Missi n g  
Assi g n as c o nc o mit a nt