Clinical trial NCT03549338
Conditions: Metastatic Colorectal Cancer Colorectal Cancer Metastatic Carcinoma
Keywords: Metastatic Colorectal Cancer Colorectal Cancer Carcinoma Sym004 futuximab modotuximab
Sponsor: Symphogen A/S
Start date: 2018-11-29; Completion date: 2019-03-09
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2, randomized, open-label, 3-arm trial in the ratio of 1:1:1 to either Sym004 (Arm A) versus each of its component monoclonal antibodies (mAbs), futuximab (Arm B) or modotuximab (Arm C), in genomically-selected patients with chemotherapy-refractory metastatic colorectal carcinoma (mCRC) and acquired resistance to anti-epidermal growth factor receptor (anti-EGFR) mAb therapy. The study is designed to evaluate the relative antitumor activity of each agent as assessed by imaging studies performed after 8 weeks of treatment.

Detailed description:
Following consent and prior to randomization, genomic analysis will be conducted on blood samples obtained from each potential patient. Triple-negative (TN) results as defined in trial eligibility criteria will be required for initial eligibility. Patients with TNmCRC will continue in the screening process. Once deemed fully eligible, patients will be randomized to Arm A, Arm B, or Arm C.

Dosing cycles of 28 days will continue until documented disease progression (PD) or another criterion for discontinuation is met. Antitumor activity will be assessed at the end of every 2 cycles (every 8 weeks \[Q8W\]). At the End of Cycle 2 (EOC2) tumor assessment:

* Patients assigned to Arm A (Sym004) with a documented objective response (OR) or stable disease (SD) will continue to receive Sym004; patients at the EOC2 with documented PD will be discontinued from study
* Patients assigned to Arm B (futuximab) or Arm C (modotuximab) with a documented OR or SD will be crossed-over to receive Sym004; patients with documented PD at the EOC2 (or prior to the EOC2) will be offered the opportunity to crossover to receive Sym004 or will be discontinued from study

To be considered evaluable for antitumor activity assessment, patients must have completed 2 cycles of dosing inclusive of EOC2 disease imaging studies and must have received any amount of their assigned investigational medicinal product (IMP) during that period, or have PD documented by imaging studies prior to the EOC2. Non-evaluable patients and patients discontinuing from study prior to the EOC2 for reasons other than documented PD will not be replaced.

Note: In December 2018, the decision was made to terminate the trial and enrollment was prematurely discontinued. The primary, secondary, and exploratory objectives are no longer applicable. Only clinical safety-related evaluations will be conducted.

Arms: arm 1: Sym004 will be given as a loading dose of 9 mg/kg on Cycle 1 Day 1 (C1D1), followed by weekly doses of 6 mg/kg beginning C1D8.

For patients that crossover from Arm B and Arm C, Sym004 will be given at the dose level that contains the corresponding dose level of the respective individual antibody (futuximab or modotuximab) prior to crossover. arm 2: Futuximab will be given as a loading dose of 4.5 mg/kg on C1D1, followed by weekly doses of 3 mg/kg beginning C1D8. At the End of Cycle 2 (EOC2), ongoing patients will crossover to Sym004; crossover may occur prior to the EOC2 in the event of early radiographic documentation of progressive disease (PD). arm 3: Modotuximab will be given as a loading dose of 4.5 mg/kg on C1D1, followed by weekly doses of 3 mg/kg beginning C1D8. At the EOC2, ongoing patients will crossover to Sym004; crossover may occur prior to the EOC2 in the event of early radiographic documentation of PD.
Interventions: intervention 1: Sym004 intervention 2: Futuximab intervention 3: Modotuximab
Intervention descriptions: intervention 1: Sym004 is a 1:1 mixture of two recombinant mAbs (futuximab and modotuximab) which bind specifically to non-overlapping epitopes located in the extracellular domain (ECD) of the EGFR. intervention 2: Futuximab is one of two mAb components that constitute Sym004. intervention 3: Modotuximab is one of two mAb components that constitute Sym004.

Protocol documents:
Prot_000.pdf: 
Symphogen 
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Trial ID: Sym004-13 
Version 6.0 
 
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CLINICAL TRIAL PROTOCOL 
 
Trial Title: 
A Phase 2, Randomized, Open-Label, Multicenter, Three-Arm 
Trial of Sym004 versus each of its Component Monoclonal 
Antibodies, Futuximab and Modotuximab, in Patients with 
Chemotherapy-Refractory Metastatic Colorectal Carcinoma and 
Acquired Resistance to Anti-EGFR Monoclonal Antibody Therapy  
 
Short Title: 
Sym004 versus Futuximab or Modotuximab in Patients with mCRC  
 
Sponsor: 
Symphogen A/S 
 
 
 
 
Sponsor’s Medical 
Expert: 
 
 
 
Coordinating  
Investigator: 
 
 
 
 
 
Trial ID: 
Sym004-13 
 
 
Trial Phase: 
Phase 2 
 
 
IND Number: 
105953 
 
 
EudraCT Number: 
2018-000618-39 
 
 
Protocol Version/Date: 
6.0 / 18-Jan-2019 (Amendment 5) 
 
 
Previous Protocol 
Versions/Dates: 
5.0 / 02-Aug-2018 (Amendment 4) 
4.0 / 08-May-2018 (Amendment 3) 
3.0 / 08-Mar-2018 (Amendment 2) 
2.0 / 02-Jan-2018 (Amendment 1) 
1.0 / 27-Oct-2017  
 
 
 


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Sponsor Declarations 
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. 
The trial will be conducted in compliance with this clinical trial protocol, International Council 
for Harmonisation (ICH) of Technical Requirements for Pharmaceuticals for Human Use 
E6(R2): Guideline for Good Clinical Practice (GCP) (EMA/CHMP/ICH/135/1995), the 
Declaration of Helsinki, and applicable regulations. 
The Sponsor has appointed a Coordinating Investigator for the trial. This Coordinating 
Investigator will provide input to the trial design and act as overall coordinator for Investigators 
across all sites. The Coordinating Investigator will furthermore sign off the Clinical Trial Report 
(CTR) on behalf of all Investigators. 
Lists of Investigators responsible for conducting the trial, medically qualified physicians 
responsible for all site-related medical decisions (if other than the Investigators), monitors, 
clinical laboratories, and other medical and/or technical departments and/or institutions involved 
in the trial are provided as separate documents. 
 


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Principal Investigator Signature Page 
 
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 appropriate Health Authority (as 
indicated) and the Institutional Review Board/ Ethics Committee, except where necessary 
to eliminate an immediate hazard to the patients 
 That I am aware of, and will comply with “Good Clinical Practice” (ICH E6(R2) GCP) 
(EMA/CHMP/ICH/135/1995), the Declaration of Helsinki, and all applicable regulatory 
requirements 
 That all site staff to which I have delegated tasks for this clinical trial, are appropriately 
selected and 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 
LIST OF ABBREVIATIONS AND EXPANDED TERMS .........................................................11 
1 
SYNOPSIS .............................................................................................................................15 
2 
SCIENTIFIC BACKGROUND AND RATIONALE ...........................................................25 
2.1 
Background ........................................................................................................................25 
2.1.1 
Metastatic Colorectal Carcinoma ....................................................................................25 
2.1.2 
Current Treatment of Metastatic Colorectal Carcinoma .................................................25 
2.1.2.1 
Therapy with anti-EGFR Monoclonal Antibodies ........................................................25 
2.1.2.2 
Resistance to Anti-EGFR Antibodies ...........................................................................25 
2.1.3 
Target Patient Population ................................................................................................26 
2.1.3.1 
Current Recommendation for Treatment of mCRC with anti-EGFR mAbs.................26 
2.1.3.2 
Prior Results with Sym004: Genomic Selection of a Responsive Patient Subset ........27 
2.2 
Overview of the Product: Sym004 .....................................................................................28 
2.2.1 
Description of Sym004 ....................................................................................................28 
2.2.2 
Mechanism of Action of Sym004 and the Individual Antibodies ...................................28 
2.3 
Summary of Nonclinical Studies .......................................................................................28 
2.4 
Clinical Experience ............................................................................................................29 
2.4.1 
Safety ...............................................................................................................................29 
2.4.2 
Pharmacokinetics .............................................................................................................31 
2.4.3 
Pharmacodynamic Effects ...............................................................................................32 
2.4.4 
Antitumor Effects ............................................................................................................32 
2.5 
Trial Rationale ...................................................................................................................32 
2.6 
Dose Rationale ...................................................................................................................33 
2.7 
Summary of Overall Benefit and Risk ...............................................................................33 
3 
TRIAL OBJECTIVES AND DESIGN ..................................................................................35 
3.1 
Objectives ..........................................................................................................................35 
3.1.1 
Primary Objective ............................................................................................................35 
3.1.2 
Secondary Objective ........................................................................................................35 
3.1.3 
Exploratory Objective .....................................................................................................35 
3.2 
Trial Design Summary .......................................................................................................35 
4 
PATIENT SELECTION ........................................................................................................40 
4.1 
Number of Patients ............................................................................................................40 
4.1.1 
Investigational Sites .........................................................................................................40 
4.1.2 
Planned Sample Size .......................................................................................................40 
4.2 
Criteria for Inclusion ..........................................................................................................40 
4.3 
Criteria for Exclusion .........................................................................................................42 
4.3.1 
Patients to be Excluded ...................................................................................................42 
4.3.2 
Drugs and Other Treatments to be Excluded ..................................................................45 
5 
INVESTIGATIONAL MEDICINAL PRODUCT AND COMPARATORS ........................47 
5.1 
Investigational Medicinal Products....................................................................................47 
5.1.1 
Formulations ....................................................................................................................47 
5.1.2 
Formulation Excipients ...................................................................................................47 
5.2 
Storage and Handling of IMPs ...........................................................................................47 
5.3 
Stability of IMPs ................................................................................................................48 
5.4 
Labeling of IMPs ...............................................................................................................48 


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5.5 
Packaging of IMPs .............................................................................................................48 
5.6 
Administration of IMPs .....................................................................................................48 
5.7 
Dose Calculation ................................................................................................................49 
5.8 
Dose Preparation ................................................................................................................49 
5.9 
Accountability ....................................................................................................................50 
5.9.1 
Disposition of Used IMPs ...............................................................................................50 
5.9.2 
Unused IMPs ...................................................................................................................50 
5.9.3 
Destruction of IMPs ........................................................................................................50 
6 
EXPERIMENTAL PLAN .....................................................................................................51 
6.1 
Design Elements ................................................................................................................51 
6.2 
Projected Recruitment Period and Duration of this Trial ..................................................51 
6.2.1 
Recruitment Period ..........................................................................................................51 
6.2.2 
Trial Duration ..................................................................................................................51 
6.2.3 
Trial Closure ....................................................................................................................51 
6.3 
Patient Prescreening, Screening and Randomization.........................................................52 
6.3.1 
Prescreening for Mutation Status ....................................................................................52 
6.3.2 
Screening for Trial Eligibility .........................................................................................52 
6.3.3 
Submission of Patient Eligibility Information .................................................................52 
6.3.4 
Eligibility Confirmation ..................................................................................................52 
6.3.5 
Randomization .................................................................................................................53 
6.3.6 
Patient Identification Code Assignment ..........................................................................53 
6.3.7 
Screen Failures ................................................................................................................53 
6.4 
Requirements for Patient Observation ...............................................................................53 
6.5 
Drug Treatment Regimen ..................................................................................................54 
6.5.1 
Study Start Day ................................................................................................................54 
6.5.2 
Patient Availability ..........................................................................................................54 
6.5.3 
IMP Assignments ............................................................................................................54 
6.5.4 
Administration Details .....................................................................................................54 
6.5.4.1 
Dose ..............................................................................................................................54 
6.5.4.2 
Route of Administration ................................................................................................55 
6.5.4.3 
Diluent ...........................................................................................................................55 
6.5.4.4 
Volume of Infusion .......................................................................................................56 
6.5.4.5 
Duration of Infusion ......................................................................................................56 
6.5.4.6 
Schedule ........................................................................................................................56 
6.5.4.7 
Premedication for Infusion-Related Reactions .............................................................57 
6.5.4.8 
Premedication for Dermatologic AEs ...........................................................................57 
6.5.4.9 
Premedication for Other AEs ........................................................................................57 
6.6 
Cycle 1 ...............................................................................................................................57 
6.7 
Continued Treatment .........................................................................................................57 
6.7.1 
Retreatment Guidelines ...................................................................................................57 
6.7.2 
Cycle 2 .............................................................................................................................58 
6.7.3 
Treatment after Cycle 2 ...................................................................................................58 
6.8 
Duration of Study Follow-Up ............................................................................................59 
6.9 
Concurrent Treatments and Supportive Care .....................................................................59 
7 
STUDY ASSESSMENTS .....................................................................................................61 
7.1 
Consent and Medical History.............................................................................................62 


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7.1.1 
Signing of Informed Consent ..........................................................................................62 
7.1.2 
Assessment of Eligibility .................................................................................................62 
7.1.3 
Demography ....................................................................................................................62 
7.1.4 
Past Medical History .......................................................................................................62 
7.1.5 
History of mCRC .............................................................................................................62 
7.2 
Safety Assessments ............................................................................................................62 
7.2.1 
Medication and Procedure Surveys .................................................................................63 
7.2.2 
Adverse Event Reporting ................................................................................................63 
7.2.3 
Performance Status Evaluation ........................................................................................63 
7.2.4 
Vital Signs .......................................................................................................................64 
7.2.5 
Physical Examination ......................................................................................................64 
7.2.6 
Dermatologic Examination ..............................................................................................64 
7.2.7 
Laboratory Assessments and Pregnancy Test (Local Laboratory) ..................................65 
7.2.7.1 
Hematology Panel .........................................................................................................65 
7.2.7.2 
Biochemistry Panel .......................................................................................................66 
7.2.7.3 
Serum Magnesium, Calcium, and Potassium ................................................................66 
7.2.7.4 
Coagulation Panel .........................................................................................................66 
7.2.7.5 
Urinalysis ......................................................................................................................67 
7.2.7.6 
Pregnancy Testing .........................................................................................................67 
7.2.8 
Electrocardiogram (ECG) ................................................................................................67 
7.3 
Specialty Assessments .......................................................................................................68 
7.3.1 
Immunogenicity Assessment (Specialty Laboratory) .....................................................69 
7.3.2 
Exploratory Pharmacokinetic Assessment (Specialty Laboratory) .................................70 
7.3.3 
Genomic Analysis in Peripheral Blood (Specialty Laboratory) ......................................71 
7.3.4 
Pharmacodynamic Analyses (Specialty Laboratory) ......................................................71 
7.3.4.1 
Peripheral Blood............................................................................................................72 
7.3.4.2 
Skin Biopsies .................................................................................................................72 
7.3.4.3 
Tumor Biopsies .............................................................................................................72 
7.4 
Disease Assessments ..........................................................................................................73 
7.4.1 
Diagnostic Imaging for Tumor Measurements (Local Assessment) ...............................73 
7.4.2 
Response Assessment (Local Assessment) .....................................................................74 
8 
MANAGEMENT OF TOXICITY .........................................................................................75 
8.1 
Premedication ....................................................................................................................75 
8.1.1 
Premedication for Infusion-Related Reactions ................................................................75 
8.1.1.1 
Infusion-Related Reactions ...........................................................................................75 
8.1.1.2 
Premedication for Infusion-Related Reactions .............................................................76 
8.1.1.3 
Premedication for Infusion-Related Reactions (Following an IRR) .............................76 
8.1.2 
Premedication for Dermatologic Toxicity .......................................................................76 
8.1.3 
Premedication for other IMP-Related Toxicities ............................................................77 
8.1.4 
Institution of Mandatory Premedications ........................................................................77 
8.2 
Dose Modification Options ................................................................................................77 
8.2.1 
Prolongation of Infusion Duration ...................................................................................77 
8.2.1.1 
Instructions for Infusion Prolongation ..........................................................................77 
8.2.1.2 
Treatment Following Infusion Prolongation .................................................................78 
8.2.2 
Dose Delay ......................................................................................................................78 
8.2.2.1 
Delay Between Dosing ..................................................................................................78 


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8.2.2.2 
Retreatment Following Dose Delay ..............................................................................78 
8.2.3 
Dose Reduction ...............................................................................................................78 
8.2.3.1 
Dose Reduction Schedule .............................................................................................78 
8.2.4 
Reescalation/Rechallenge Following Dose Reduction ....................................................79 
9 
DISCONTINUING PATIENTS FROM STUDY TREATMENT ........................................80 
9.1 
Criteria for Treatment Discontinuation ..............................................................................80 
9.2 
Replacements .....................................................................................................................81 
9.3 
Criteria for Premature Discontinuation of the Trial ...........................................................81 
10 ADVERSE EVENTS .............................................................................................................83 
10.1 
Definitions of Adverse Events ...........................................................................................83 
10.1.1 
Adverse Event .................................................................................................................83 
10.1.2 
Events Not to be Considered as Adverse Events .............................................................83 
10.1.3 
Adverse Events of Medical Interest ................................................................................83 
10.1.4 
Serious Adverse Events ...................................................................................................83 
10.1.5 
Events That Do Not Meet the Definition of Serious Adverse Events .............................84 
10.2 
Adverse Event Recording and Reporting ..........................................................................84 
10.2.1 
Information to be Provided for Each AE .........................................................................85 
10.2.2 
Required Follow-up for AEs ...........................................................................................86 
10.3 
Serious Adverse Event Recording and Reporting .............................................................86 
10.3.1 
Timeframes for Reporting to the Sponsor .......................................................................86 
10.3.2 
Safety Reporting to Health Authorities, IRBs/ECs, and Investigators ............................87 
10.4 
Pregnancy ...........................................................................................................................87 
11 PRECAUTIONS WHEN DOSING .......................................................................................88 
11.1 
Precautions Regarding Procreation ....................................................................................88 
11.2 
Infusion-Related Reactions ................................................................................................88 
11.3 
Dermatologic AEs ..............................................................................................................88 
11.4 
Hypomagnesemia, Hypocalcemia, and Hypokalemia .......................................................89 
11.5 
Additional Precautions .......................................................................................................89 
12 SAFETY SURVEILLANCE DURING STUDY ..................................................................90 
12.1 
Safety Review ....................................................................................................................90 
12.2 
Other Safety Surveillance Activities ..................................................................................90 
12.3 
Study Safety Committee ....................................................................................................91 
13 REGULATORY AND ETHICAL CONSIDERATIONS .....................................................92 
13.1 
Conditions of Testing .........................................................................................................92 
13.2 
Institutional Review ...........................................................................................................92 
13.3 
Informed Consent...............................................................................................................92 
13.4 
Conditions for Modifying or Terminating the Study .........................................................93 
13.4.1 
Modification of the Study Protocol .................................................................................93 
13.4.2 
Modification of the Informed Consent Form ..................................................................94 
13.4.3 
Conditions for Termination of the Study or a Study Site ................................................94 
13.5 
Trial Registration ...............................................................................................................95 
13.6 
Insurance and Liability ......................................................................................................95 
14 INVESTIGATOR RESPONSIBILITIES ..............................................................................96 
14.1 
Medical Supervision ..........................................................................................................96 
14.2 
Confidentiality ...................................................................................................................96 
14.3 
Use of Information .............................................................................................................96 


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14.4 
Publications ........................................................................................................................97 
14.5 
Patient Screening Log ........................................................................................................97 
14.6 
Drug Dispensing Inventory ................................................................................................97 
14.7 
Handling and Disposal of IMP ..........................................................................................98 
14.8 
Recording of Data ..............................................................................................................98 
14.9 
Source Document Requirements ........................................................................................98 
14.10 Laboratory Reports ............................................................................................................99 
14.11 Record Retention ...............................................................................................................99 
14.12 Monitoring of the Study .....................................................................................................99 
14.13 Patient Confidentiality .....................................................................................................100 
14.14 Financing and Insurance ..................................................................................................100 
15 HANDLING AND PROCESSING OF DATA ...................................................................101 
15.1 
Data Handling ..................................................................................................................101 
15.2 
Data Review During this Study .......................................................................................101 
15.3 
Data Processing ................................................................................................................101 
15.4 
Clinical Trial Report ........................................................................................................101 
15.5 
Compliance with the General Data Protection Regulation ..............................................101 
16 STATISTICAL ANALYSIS ...............................................................................................103 
16.1 
Statistical Analysis Plan ...................................................................................................103 
16.2 
Sample Size Considerations .............................................................................................103 
16.3 
Analysis Sets ....................................................................................................................103 
16.4 
Trial Endpoints.................................................................................................................104 
16.4.1 
Primary Efficacy Endpoint (omitted as of Amendment 5) ............................................104 
16.4.2 
Exploratory Endpoints and Analyses (omitted as of Amendment 5) ............................104 
16.4.2.1 Pharmacokinetic Endpoints .........................................................................................104 
16.4.2.2 Modeling of Pharmacokinetic and Pharmacodynamic Data .......................................105 
16.5 
Statistical Analysis ...........................................................................................................105 
16.5.1 
General Specifications ...................................................................................................105 
16.5.2 
Patient Disposition and Baseline Characteristics ..........................................................105 
16.5.2.1 Patient Disposition ......................................................................................................105 
16.5.2.2 Baseline and Disease Characteristics ..........................................................................105 
16.5.3 
Exposure ........................................................................................................................106 
16.6 
Primary Analysis ..............................................................................................................106 
16.6.1 
Efficacy Analysis ...........................................................................................................106 
16.7 
Secondary Analysis ..........................................................................................................106 
16.7.1 
Safety Analysis ..............................................................................................................106 
16.8 
Exploratory Analysis .......................................................................................................106 
16.8.1 
Exploratory Biomarker and Pharmacodynamic Analyses .............................................107 
16.9 
Deviations from the Preplanned Statistical Analyses ......................................................107 
16.10 Interim Analysis ...............................................................................................................107 
17 REFERENCES ....................................................................................................................108 
18 APPENDICES .....................................................................................................................114 
Appendix 1 Performance Status Evaluation..............................................................................114 
Appendix 2 New York Heart Association Functional Criteria .................................................115 
Appendix 3 Clinical Adverse Events: Grading Scale ...............................................................116 
Appendix 4 Clinical Adverse Events: Determining Relationship to IMP ................................117 


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Appendix 5 Response Evaluation Criteria in Solid Tumors (RECIST v1.1) ............................118 
Appendix 6 Management of Infusion-Related Reactions .........................................................123 
Appendix 7 Management of Dermatologic Adverse Events .....................................................126 
Appendix 8 Management of Hypomagnesemia ........................................................................133 
Appendix 9 Maximum Total Blood Collection Volumes .........................................................134 
Appendix 10 Schedule of Study Activities ...............................................................................135 
19 SUMMARY OF CHANGES ...............................................................................................138 
19.1 
Protocol Amendment 1 dated 02-Jan-2018......................................................................138 
19.2 
Protocol Amendment 2 dated 08-Mar-2018 ....................................................................145 
19.3 
Protocol Amendment 3 dated 08-May-2018....................................................................156 
19.4 
Protocol Amendment 4 dated 02-Aug-2018 ....................................................................161 
19.5 
Protocol Amendment 5 dated 18-Jan-2019......................................................................162 
 
List of Figures 
Figure 1: Trial Design ....................................................................................................................38 
 
List of Tables 
Table 1: Sym004 Adverse Events ≥ 10% ......................................................................................30 
Table 2: Overall Trial Plan ............................................................................................................39 
Table 3: Crossover Dose of Sym004 .............................................................................................59 
Table 4: Schedule of Safety Blood and Urine Analyses ................................................................65 
Table 5: Timepoints for Specialty Assessments (Arm A, Arm B, and Arm C) ............................69 
Table 6: Dose-Reduction of Sym004 .............................................................................................79 
Table 7: Dose-Reduction of Futuximab and Modotuximab ..........................................................79 
Table 8: PK Endpoint, Definitions, and Derivations ...................................................................104 
Table 9: Measures of Performance Status ...................................................................................114 
Table 10: New York Heart Association Functional Criteria .......................................................115 
Table 11: Clinical Adverse Event Grading ..................................................................................116 
Table 12: Clinical Adverse Event Attribution .............................................................................117 
Table 13: Summary of RECIST v1.1 Guidelines ........................................................................118 
Table 14: Premedications for Infusion-Related Reactions ..........................................................123 
Table 15: Grading of Infusion-Related Reactions .......................................................................124 
Table 16: Management of Infusion-Related Reactions ...............................................................125 
Table 17: Mandatory Premedications for Dermatologic AEs......................................................126 
Table 18: Management of Rash – Sym004, Futuximab, or Modotuximab .................................127 
Table 19: Management of Xerosis – Sym004, Futuximab, or Modotuximab .............................128 
Table 20: Management of Paronychia – Sym004, Futuximab, or Modotuximab .......................129 
Table 21: Management of Pruritus – Sym004, Futuximab, or Modotuximab .............................130 
Table 22: Management of Photosensitivity – Sym004, Futuximab, or Modotuximab ................131 
Table 23: Management of Fissures – Sym004, Futuximab, or Modotuximab ............................131 
Table 24: Dose Reduction for Grade 3 Dermatologic AEs - Sym004 .........................................132 
Table 25: Dose Reduction for Grade 3 Dermatologic AEs - Futuximab or Modotuximab .........132 
Table 26: CTCAE Grading of Hypomagnesemia and QTc Prolongation ...................................133 
Table 27: Management of Hypomagnesemia and QTc Prolongation ..........................................133 
Table 28: Maximum Total Blood Collection Volumes ...............................................................134 
Table 29: Schedule of Study Activities .......................................................................................135 


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Table 30: Protocol Amendment 1 ................................................................................................139 
Table 31: Protocol Amendment 2 ................................................................................................147 
Table 32: Protocol Amendment 3 ................................................................................................157 
Table 33: Protocol Amendment 4 ................................................................................................161 
Table 34: Protocol Amendment 5 ................................................................................................163 
 


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LIST OF ABBREVIATIONS AND EXPANDED TERMS  
Abbreviation 
Expanded Term 
1M FUP 
1-Month Follow-up 
4.5/3 mg/kg 
4.5 mg/kg loading dose followed by weekly doses of 3 mg/kg of Futuximab or 
Modotuximab 
5-FU 
5-Fluorouracil 
9/6 mg/kg 
9 mg/kg loading dose followed by weekly doses of 6 mg/kg of Sym004 
ADA 
Anti-Drug Antibody 
ADCC 
Antibody-Dependent Cellular Cytotoxicity 
AE(s) 
Adverse Event(s) 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase  
ANC 
Absolute Neutrophil Count 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase  
AT 
As-Treated (population) 
AUC 
Area Under the Concentration-Time Curve 
β-hCG 
Beta-Human Chorionic Gonadotropin 
BSC 
Best Supportive Care 
C 
Cycle 
C#D# 
Cycle Number (#) Day Number (#) 
CBC 
Complete Blood Count 
CDC 
Complement-Dependent Cytotoxicity 
CEOI 
Concentration at the End of Infusion 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CL 
Clearance 
Cmax 
Maximum Concentration 
CNS 
Central Nervous System 
CR 
Complete Response 
CRC 
Colorectal Carcinoma 
CrCl 
Creatinine Clearance 
CRF 
Case Report Form 
CT 
Computed Tomography 


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Abbreviation 
Expanded Term 
CTCAE v5 
Common Terminology Criteria for Adverse Events (Version 5) 
ctDNA 
Circulating Tumor Deoxyribonucleic Acid 
CTR 
Clinical Trial Report 
Ctrough 
Trough Concentration 
dMMR 
Mismatch Repair-Deficient 
DMP 
Data Management Plan 
DNA 
Deoxyribonucleic Acid 
DVT 
Deep Vein Thrombosis 
EC 
Ethics Committee 
ECD 
Extracellular Domain 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EEA 
European Economic Area 
EGFR 
Epidermal Growth Factor Receptor 
EOC# 
End of Cycle Number (#) 
EOI 
End of Infusion 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FOLFIRI 
5-fluorouracil, folinic acid, and irinotecan 
FOLFOX 
5-fluorouracil, folinic acid, and oxaliplatin 
FSH 
Follicle-Stimulating Hormone 
FUP 
Follow-up 
GCP 
Good Clinical Practice 
hCG 
Human Chorionic Gonadotropin 
HRT 
Hormone Replacement Therapy 
IB 
Investigator’s Brochure 
IC 
Investigator’s Choice 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation  
IgG1 
Immunoglobulin G1 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 


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Abbreviation 
Expanded Term 
IRB 
Institutional Review Board   
IRR 
Infusion-Related Reaction 
IV 
Intravenous 
KRAS 
Kirsten Rat Sarcoma Viral Oncogene Homolog 
mAb 
Monoclonal Antibody 
MAF 
Mutation Allele Frequency 
mCRC 
Metastatic Colorectal Carcinoma 
MRI 
Magnetic Resonance Imaging 
MSI-H 
Microsatellite Instability-High 
NE 
Not Evaluable 
NRAS 
Neuroblastoma RAS Viral Oncogene Homolog 
OR 
Objective Response 
OS 
Overall Survival 
PD 
Progressive Disease 
PD-1 
Programmed Cell Death Protein-1 
PD-L1 
Programmed Death-Ligand 1 
PE 
Pulmonary Embolism 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic(s) 
PR 
Partial Response 
PR Interval 
ECG interval between beginning of the P-wave to beginning of the QRS complex 
PS 
Performance Status 
PSA 
Prostate Specific Antigen 
Q#M 
Every Number (#) Months 
Q#W 
Every Number (#) Weeks 
Q1W 
Once weekly 
QT Interval 
ECG interval between onset of QRS complex to end of the T-wave 
QTc Interval 
QT interval corrected for heart rate 
RAS 
Rat Sarcoma 
RBC 
Red Blood Cell 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors (Version 1.1) 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 


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Abbreviation 
Expanded Term 
SAR 
Suspected Adverse Reaction 
SD 
Stable Disease 
SOI 
Start of Infusion 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1/2  
Serum Elimination Half-Life 
TAS-102 
Trifluridine/Tipiracil 
TdP 
Torsade de Pointes 
TEAE 
Treatment Emergent Adverse Event 
TKI 
Tyrosine Kinase Inhibitor 
TN 
Triple Negative (mCRC) 
ULN 
Upper Limit of Normal 
U.S. 
United States 
UV 
Ultraviolet 
Vd 
Volume of Distribution 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White Blood Cell 
WNL 
Within Normal Limits 
WOCBP 
Woman of Childbearing Potential 
WT 
Wild-Type 
 
 
 


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1 
SYNOPSIS  
CLINICAL TRIAL PROTOCOL 
Trial Title 
A Phase 2, Randomized, Open-Label, Multicenter, Three-Arm Trial of Sym004 versus each of its 
Component Monoclonal Antibodies, Futuximab and Modotuximab, in Patients with Chemotherapy-
Refractory Metastatic Colorectal Carcinoma and Acquired Resistance to Anti-EGFR Monoclonal 
Antibody Therapy   
Trial ID  
Sym004-13 
Trial Phase  
Phase 2 
INVESTIGATIONAL MEDICINAL PRODUCTS  
Investigational 
Medicinal Products 
Sym004 is a mixture of 2 recombinant, human-mouse chimeric, immunoglobulin G1 (IgG1) 
monoclonal antibodies (mAbs) (futuximab and modotuximab) targeting 2 non-overlapping epitopes 
of the Epidermal Growth Factor Receptor (EGFR). 
The Investigational Medicinal Products (IMPs) in this trial are Sym004 (a mixture of futuximab and 
modotuximab), the drug product futuximab, and the drug product modotuximab.   
Supplies 
Labeled IMP supplies will be provided by the Sponsor as liquid formulations for intravenous (IV) 
infusion.   
Sym004:  Single-use clear glass vials contain: 
 
A nominal fill volume of 20 mL  
 
At a concentration of 25 mg/mL for a total vial content of 500 mg 
Futuximab: Single-use clear glass vials contain: 
 
A nominal fill volume of 10 mL  
 
At a concentration of 25 mg/mL for a total vial content of 250 mg  
Modotuximab: Single-use clear glass vials contain: 
 
A nominal fill volume of 10 mL  
 
At a concentration of 25 mg/mL for a total vial content of 250 mg 
TRIAL OBJECTIVES 
Primary Objective 
As of Amendment 5: Due to the Sponsor’s decision to discontinue the trial for administrative reasons (effective 
20Dec2018), the primary, secondary, and exploratory objectives as detailed below are no longer applicable. Only 
clinical safety-related evaluations will be conducted.  
To evaluate the relative contribution of futuximab and modotuximab to the antitumor activity of 
Sym004 following 8 weeks of treatment in genomically-selected patients with chemotherapy 
refractory metastatic colorectal carcinoma (mCRC) and acquired resistance to anti-EGFR mAb 
therapy.  
Note:  Antitumor activity will be assessed by changes in tumor measurements (as determined according to 
Response Evaluation Criteria in Solid Tumors Version 1.1 [RECIST v1.1]). 
Secondary Objective 
To evaluate the safety profile of a weekly dosing regimen of Sym004 versus single agent futuximab 
or single agent modotuximab. 
Exploratory Objective 
To evaluate potential predictive and/or prognostic biomarkers of response to treatment (peripheral 
blood, skin biopsies, and tumor biopsies to be collected). Tumor biopsies will be used to establish 
primary tumor and non-tumor cell lines, and patient-derived xenograft models. 
TRIAL DESIGN 
Design Summary 
As of Amendment 5: This amendment to the clinical trial protocol is based on the Sponsor’s decision to 
discontinue the trial for administrative reasons, effective 20Dec2018; the intent to discontinue the trial was 
communicated to all active sites on this date.  As a result, the original trial design as described below is no longer 
applicable, future accrual has been halted, and a reduction in the scope of non-safety-related assessments being 
conducted under this protocol has been implemented.   


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Patients consented as of the trial discontinuation date, and determined to meet study eligibility criteria, may be 
treated with IMP and may continue therapy until the occurrence of one of the following: unacceptable toxicity or 
other conditions preventing further administration, documented progressive disease (PD), or the patient’s decision 
to withdraw. 
Treated patients will be followed and assessed for only clinical safety-related concerns throughout their treatment 
period and at minimum for 30 days after the last administration of IMP.   
The pre-Amendment 5 trial design was as follows: 
This is a Phase 2, open-label, three-Arm trial with randomization in the ratio of 1:1:1 to either 
Sym004 (Arm A) versus futuximab (Arm B) or modotuximab (Arm C) in genomically-selected 
patients with chemotherapy-refractory mCRC and acquired resistance to anti-EGFR mAb therapy. 
The study is designed to evaluate the relative antitumor activity of each agent as assessed by imaging 
studies performed after 8 weeks of treatment (i.e., at the end of Cycle 2 [EOC2]).   
Following consent and prior to randomization, genomic analysis of RAS, BRAF V600, and EGFR-
ECD mutation status will be conducted on blood samples obtained from each potential patient. 
Triple-negative (TN) results as defined in trial eligibility criteria will be required for initial eligibility. 
Patients with TNmCRC will continue in the screening process. Once deemed fully eligible, patients 
will be randomized to Arm A, Arm B, or Arm C. 
 
Patients randomized to Arm A will receive Sym004 by the IV route, at a loading dose of 9 mg/kg 
on Cycle 1 Day 1 (C1D1) followed by weekly doses of 6 mg/kg beginning on C1D8 (total of 4 
doses per 28-day cycle).  
 
Patients randomized to Arm B or Arm C will receive futuximab or modotuximab, respectively, 
by the IV route, at a loading dose of 4.5 mg/kg on C1D1 followed by weekly doses of 3 mg/kg 
beginning on C1D8 (total of 4 doses per 28-day cycle).  
Dosing cycles of 28 days (+ 2 days) will continue until documented disease progression or another 
criterion for discontinuation is met. Antitumor activity will be assessed at the end of every 2 cycles 
(every 8 weeks [Q8W]).   
At the EOC2 tumor assessment: 
 
Patients assigned to Arm A (Sym004) with a documented objective response (OR) or Stable 
Disease (SD) will continue to receive Sym004; patients with documented progressive disease 
(PD) at the EOC2 will be discontinued from study 
 
Patients assigned to Arm B (futuximab) or Arm C (modotuximab) with a documented OR or SD 
will be crossed-over to receive Sym004; patients with documented PD at the EOC2 (or prior to 
the EOC2) will be offered the opportunity to crossover to receive Sym004 or will be 
discontinued from study 
To be considered evaluable for antitumor activity assessment, patients must have completed 2 cycles 
of dosing inclusive of EOC2 disease imaging studies (i.e., computed tomography [CT]/magnetic 
resonance imaging [MRI]) and must have received any amount of their assigned IMP during that 
period, or have PD documented by imaging studies prior to the EOC2. Non-evaluable patients and 
patients discontinuing from study prior to the EOC2 for reasons other than documented PD will not 
be replaced (every effort will be made to obtain imaging studies at the time of discontinuation).  
Site Investigators will evaluate patients for eligibility and submit relevant information. Designated 
Eligibility Reviewers and the Sponsor’s Medical Monitor(s) (or designee) will review patient 
eligibility information provided, confirm eligibility, and authorize patients for randomization.   
Clinical and laboratory safety data will be reviewed on an ongoing basis throughout the trial. A Study 
Safety Committee will be established and will be comprised of participating Investigator(s) and the 
Sponsor’s Medical Representative(s).  If indicated, Study Safety Committee teleconferences will be 
held to discuss ongoing patient status and any emerging safety concerns. 
PATIENT SELECTION 
Investigational Sites 
As of Amendment 5: As of the trial discontinuation date (20Dec2018), a single center in the United States had 
consented and screened patients. Two (2) of 5 patients screened were determined to be eligible for participation 


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and both were enrolled in the study.  The total number of sites planned will not be participating. 
This is a multicenter, multinational trial  
 
Number of Sites: Approximately 20 sites may participate based on anticipated accrual 
 
Number of Countries: Approximately 4-6 countries in North America and Europe   
Planned Sample Size 
As of Amendment 5: Effective 20Dec2018, accrual to this trial has been halted; the total planned number of 
patients planned will not be enrolled.   
Up to approximately 54 evaluable patients (18 evaluable patients per Arm)  
Key Eligibility 
Criteria  
 
 
As of Amendment 5: Effective 20Dec2018, accrual to this trial has been halted; however, patients consented prior 
to the effective date will be required to meet the following eligibility criteria:   
Patients to be Included (patients must meet all the following criteria) 
1. 
Male or female patients, ≥ 18 years   
2. 
Patients with histologically- or cytologically-confirmed mCRC  
3. 
Patients with microsatellite instability-high (MSI-H) / mismatch repair-deficient (dMMR) 
tumors must have received prior therapy with pembrolizumab, nivolumab, or other programmed 
cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway blocker, and must 
have progressed on that therapy. 
4. 
Patients meeting the protocol definition of TNmCRC assessed in the screening blood test 
(ctDNA): 
a. 
Without RAS (KRAS and NRAS) MAF ≥ 20% for mutations in the following codons: 
o 
Exon 2: codon 12, 13  
o 
Exon 3: codon 59, 61  
o 
Exon 4: codon 117, 146 
b. 
Without BRAF V600E mutation at any mutation allele frequency (MAF) 
c. 
Without EGFR-ECD V441D, V441G, S464L, G465E, G465R, S492R mutations at any 
MAF 
Note:  Centralized genomic analysis to be performed; peripheral blood to be collected for assessment of 
circulating tumor DNA (ctDNA) by Guardant360®.   
5. 
Patients with mCRC currently not amenable to surgical intervention due to either medical 
contraindications or non-resectability of the tumor 
6. 
Patients with measurable disease according to RECIST v1.1, and willingness to undergo a total 
of 2 biopsies of a primary or metastatic tumor site(s) considered safely accessible for biopsy   
7. 
Patients must have received at least 2 prior regimens of standard chemotherapy for mCRC and 
must have been refractory to or failed (includes intolerance to) those regimens.  Prior standard 
chemotherapy may not have included TAS-102 or regorafenib but must have included all the 
following agents (where approved in the country). 
a. 
Fluoropyrimidines, irinotecan, oxaliplatin 
b. 
An anti-vascular endothelial growth factor (VEGF) pathway inhibitor approved for 
treatment of mCRC 
c. 
At least one anti-EGFR mAb approved for the treatment of mCRC   
Note:  Patients who have withdrawn from standard therapy(ies) due to unacceptable toxicity warranting 
discontinuation of treatment and precluding retreatment with the same agent prior to progression of 
disease will be eligible to enter the study 
Patients who received adjuvant chemotherapy and had documented recurrence (by imaging studies) 
during or within 6 calendar months of completion of the adjuvant chemotherapy are permitted to 
count the adjuvant therapy as one regimen of chemotherapy 
8. 
Patients with “acquired” resistance to commercially available anti-EGFR mAbs approved for the 
treatment of mCRC must have: 
a. 
Received treatment with an anti-EGFR for ≥16 weeks  
b. 
PD documented by imaging or clinical findings < 6 calendar months after cessation of 
previous anti-EGFR mAb treatment 
c. 
No more than 6 calendar months from last dose of previous anti-EGFR mAb treatment to 
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9. 
Patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 
1 
10. Patients who are either not of childbearing potential or who agree to use a highly effective 
method of contraception.   
11. Patients with the ability to understand and give written informed consent 
Patients to be Excluded (patients must not meet any of the following criteria 
1. 
Women who are pregnant or lactating or intending to become pregnant before, during, or within 
3 months after the last dose of IMP.     
2. 
Patients with a prior history of any of the following mutations in their tumor at the time of any 
previous assessment: 
a. 
RAS (KRAS and NRAS) mutations in the following codons: 
o 
Exon 2: codon 12, 13  
o 
Exon 3: codon 59, 61  
o 
Exon 4: codon 117, 146 
b. 
BRAF V600E mutation  
c. 
EGFR-ECD V441D, V441G, S464L, G465E, G465R, S492R mutations  
3. 
Patients with known, untreated central nervous system (CNS) or leptomeningeal metastases, or 
spinal cord compression; patients with any of these not controlled by prior surgery or 
radiotherapy, or patients with symptoms suggesting CNS involvement for which treatment is 
required   
4. 
Patients with an active second malignancy or history of another malignancy within the last 5 
years (see protocol for exceptions) 
5. Patients with any of the following hematologic abnormalities at baseline: 
a. 
Hemoglobin < 9 g/dL 
b. 
Absolute neutrophil count (ANC) < 1,500 per mm3 
c. 
Platelet count < 100,000 per mm3  
6. 
Patients with any of the following serum chemistry abnormalities at baseline: 
a. 
Total bilirubin > 2.0 × the upper limit of normal (ULN) for the institution  
b. 
Alkaline phosphatase (ALP) > 2.5 × the ULN for the institution (> 5 × ULN if due to 
hepatic involvement by tumor) 
c. 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × the ULN for 
the institution (> 5 × ULN if due to hepatic involvement by tumor)  
d. 
Creatinine clearance [CrCl] < 30 mL/min as calculated by the Cockroft-Gault formula  
e. 
Magnesium < 1.2 mg/dL  
7. 
Patients with: 
a. 
Active thrombosis, or a history of deep vein thrombosis (DVT) or pulmonary embolism 
(PE) within 4 weeks prior to first administration of IMP unless adequately treated and 
considered by the Investigator to be stable  
b. 
Active uncontrolled bleeding or a known bleeding diathesis 
8. 
Patients with a known clinically significant cardiovascular disease or condition, as specified in 
the protocol 
9. 
Patients with non-healing wounds on any part of the body 
10. Patients with significant gastrointestinal abnormality, including: 
a. 
Diarrhea > Grade 1 at the time of randomization 
b. 
Requirement for IV alimentation 
11. Patients with skin rash > Grade 1 from prior anti-EGFR therapy at the time of randomization 
12. Patients with any unresolved > Grade 1 toxicity associated with any prior antineoplastic therapy 
with the exception of persistent Grade 2 alopecia, decreased hemoglobin, peripheral neuropathy, 
and/or end-organ failure being adequately managed by hormone replacement therapy  
13. Patients with a known or suspected hypersensitivity to any of the excipients of formulated 
IMP(s) 
Drugs and Other Treatments to be Excluded (patients must not be receiving any of the following) 
1. 
Prior treatment with TAS-102 or regorafenib 


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2. 
Any antineoplastic agent for the primary malignancy (standard or investigational) without 
delayed toxicity within 4 weeks prior to first administration of IMP and during study, with 
exceptions as specified in the protocol: 
3. 
Any other investigational treatments within 4 weeks prior to and during study; includes 
participation in any medical device or other therapeutic intervention clinical trials    
4. 
Radiotherapy:  
a. 
For lesions to be used as target lesions, within 4 weeks prior to first administration of IMP 
unless disease progression has been documented in the lesion post-radiotherapy, and 
during study 
b. 
For non-target lesions within 1 week prior to first administration of IMP   
5. 
Immunosuppressive or systemic hormonal therapy (> 10 mg daily prednisone equivalent) within 
2 weeks prior to first administration of IMP and during study; allowed therapies are specified in 
the protocol.  
EXPERIMENTAL PLAN 
Randomization  
As of Amendment 5: As of the trial discontinuation date (20Dec2018), 5 patients had provided written consent 
for trial participation; following screening, 2 were determined to be eligible. The first patient was deemed eligible 
prior to the trial discontinuation date and was randomized to Arm B (futuximab). The second patient was deemed 
eligible after the trial discontinuation date and although randomized to Arm B (futuximab), per Sponsor decision 
was enrolled to Arm A to receive Sym004. The pre-Amendment 5 randomization plan detailed below will not be 
followed.  
Randomization to Arm A (Sym004) versus Arm B (futuximab) or Arm C (modotuximab) will take 
place once a consented patient has completed all the necessary Screening procedures (within the 14-
day screening window) and is authorized as eligible for study entry. C1D1 dosing is to occur on the 
day of randomization or within 3 days (72 hours) after randomization. 
IMP ADMINISTRATION 
Doses to be 
Administered 
As of Amendment 5: Two (2) patients screened and determined to be eligible have been treated with IMP. The 
first patient deemed eligible prior to the trial discontinuation date (20Dec2018) was randomized to Arm B 
(futuximab) and crossed over to Arm A (Sym004) at the EOC1 per Sponsor decision; the second patient deemed 
eligible after the trial discontinuation date was randomized to Arm B (futuximab), however per Sponsor decision 
was enrolled to Arm A to receive Sym004. 
With this amendment, the doses of IMP to be delivered remain unchanged; however, the pre-Amendment 5 
crossover dose plan as detailed below is no longer in effect. 
Sym004  
 
Loading dose of 9 mg/kg on C1D1 
 
Thereafter, weekly doses (+ 2 days) of 6 mg/kg, beginning on C1D8 
Futuximab and modotuximab, each  
 
Loading dose of 4.5 mg/kg on C1D1 
 
Thereafter, weekly doses (+ 2 days) of 3 mg/kg, beginning on C1D8 
Changes in Dose to be Administered 
Each patient will continue to be treated with IMP at that same dose level, unless dose reduction is 
necessary due to the occurrence of an adverse event(s) (AEs) warranting such action.  
Crossover Dose of Sym004 
At the EOC2, ongoing patients from Arm B and Arm C will be crossed-over from futuximab or 
modotuximab to Sym004; crossover may occur prior to the EOC2 in the event of early radiographic 
documentation of PD 
Upon crossover, Sym004 will be administered at the dose level that contains the corresponding dose 
level of the individual antibody futuximab or modotuximab as was previously being administered 
(prior to crossover). Therefore, patients receiving futuximab or modotuximab at the dose of 3 mg/kg 
or the reduced dose of 1.5 mg/kg will crossover to receive Sym004 at the dose of 6 or 3 mg/kg, 
respectively.  


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Sym004 treatment may be initiated at least one week after the latest dose of futuximab or 
modotuximab, unless AEs prevent this according to the protocol retreatment criteria. Dosing of 
Sym004 may continue until further PD is observed 
Route of 
Administration 
IV infusions via central or peripheral indwelling venous access catheter, utilizing a controlled 
infusion device 
Infusion Materials 
Infusion set containing a 0.22 micron in-line filter   
Infusion Volume  
Arm A (9/6 mg/kg) 
 
500 mL for 9 mg/kg infusions  
 
250 mL for ≤ 6 mg/kg infusions  
Arm B and Arm C (4.5/3 mg/kg) 
 
500 ml for 4.5 mg/kg infusions 
 
250 ml for ≤ 3 mg/kg infusions  
Diluent and Delivery 
Commercially available sterile 0.9 % Sodium Chloride Injection, USP or local equivalent solution for 
IV infusion    
Infusion Duration 
Arm A 
 
Initial infusion (9 mg/kg in 500 mL) to be administered over 1 hour (+10 min). The maximum 
infusion rate of 500 mL/hour should not be exceeded throughout administration. 
 
Subsequent infusions (≤ 6 mg/kg in 250 mL) to be delivered over 30 minutes (+ 10 min), with a 
maximum infusion rate of 500 mL/hour.   
Arm B and Arm C 
 
Initial infusion (4.5 mg/kg in 500 mL) to be administered over 1 hour (+10 min). The maximum 
infusion rate of 500 mL/hour should not be exceeded throughout administration. 
 
Subsequent infusions (≤ 3 mg/kg in 250 mL) may be delivered over 30 minutes (+10 min), with 
a maximum infusion rate of 500 mL/hour.   
Schedule 
Once weekly (+ 2 days) on Day 1, 8, 15, and 22 of each 28-day cycle (4 weeks [28 days] equals 1 
dosing cycle).   
Observation 
Requirements 
Patients will be treated and followed on an outpatient basis. All patients: 
 
Will be observed for a minimum of 2 hours following completion of the first administration of 
IMP on C1D1 and a minimum of 1 hour following completion of subsequent infusions of IMP 
(C1D8 and thereafter).   
 
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. 
Premedication  
Premedication for Infusion-Related Reactions (IRRs) 
Premedication for prophylaxis of IRRs will be mandatory prior to each dose of IMP. All patients will 
be premedicated with standard therapies that include a glucocorticoid and an H1 antagonist. Where 
indicated, consideration may be given to include an H2 antagonist and/or acetaminophen. 
Recommended premedication doses are provided. 
Premedication for Dermatologic AEs 
To minimize the risk of dermatologic AEs, all patients will receive at minimum during Cycle 1 and 2 
minocycline or doxycycline, and will apply topical therapy to the face and chest with a low potency 
steroid cream, and moisturizing creams/ointments to the hands and body. Use of fragrance-free soaps 
will be encouraged throughout the treatment period.  
CONTINUED TREATMENT 
Continued Treatment  
 
 
Upon completion of Cycle 1, in the absence of unacceptable toxicity or documented PD, patients may 
continue to receive additional cycles of IMP provided protocol-specified retreatment guidelines are 
met.   
Cycle 2 
Administration will be at the same dose (unless dose reduction is necessary) and infusion duration 
established for the patient during the previous cycle, and on the same weekly schedule.   


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Treatment after  
Cycle 2 
As of Amendment 5: Due to the Sponsor’s decision to discontinue the trial (effective 20Dec2018), the frequency 
of disease status evaluations will be per either institutional guidelines or Investigator discretion.  Enrolled patients 
(2 total) have been either crossed over to receive or are receiving Sym004, and may continue to receive Sym004 
until confirmation of PD. The pre-Amendment 5 plan for continued treatment after Cycle 2 as detailed below will 
not be followed. 
 
Disease assessment and tumor measurements will be conducted at the EOC2. Patients in Arm A, in 
the absence of PD, may continue to receive additional cycles of Sym004. Patients in Arm B or Arm 
C, in the absence of PD, will be crossed-over to receive Sym004; patients with PD will be offered the 
opportunity to crossover to receive Sym004 (until further PD is observed).  
TOXICITY MANAGEMENT 
AE Management 
 
Dose Delay 
AEs that do not meet the protocol discontinuation criteria, but nevertheless warrant dose 
modification, may be managed by temporary dose delay to allow for amelioration of the toxicity. 
Dose Reduction 
In the event of Grade 3 treatment-related AEs that are self-limiting or can be managed by supportive 
care or other therapy, the patient may continue in the study if there is evidence of response, disease 
stabilization, or other clinical benefit, but must do so at a reduced dose of IMP. Patients may not be 
retreated until retreatment criteria are met. Once a patient has undergone dose reduction for any 
reason, the patient will continue to be treated at the reduced dose throughout the remainder of their 
time on study treatment. 
Infusion-Related 
Reactions 
 
 
 
 
Instructions for the grading and management of IRRs are provided.  In all cases the Investigator 
should use best clinical judgment in managing such reactions.    
 
For Grade 3 reactions, the infusion will be STOPPED. The patient will be either discontinued 
from treatment or must receive subsequent treatments at a reduced dose and at a prolonged 
infusion rate. 
 
For Grade 4 reactions, the infusion will be STOPPED and the patient will be permanently 
discontinued from treatment.   
Dermatologic Toxicity  
 
 
 
 
 
Patients will be monitored weekly for evidence of dermatologic AEs.   
Dose delay and/or intrapatient dose-reduction(s) will be required upon occurrence of Grade 3 AEs, 
and may be implemented in the event of a Grade 2 dermatologic reaction that is debilitating for the 
patient.    
Recommendations for management of Grade 1 to 3 dermatologic AEs are provided. Patients must be 
withdrawn from IMP treatment in the event of a Grade 4 dermatologic AE. 
Hypomagnesemia, 
Hypocalcemia, and 
Hypokalemia 
Patients will be monitored weekly for hypomagnesemia, hypocalcemia, and hypokalemia.  
In the event of Grade 3-4 hypomagnesemia, repletion is required as well as predosing 
electrocardiograms (ECGs) to monitor for QTc prolongation. For Grade 4 hypomagnesemia that is 
refractory to IV magnesium-replacement therapy, dosing with Sym004 should be delayed or reduced. 
Full management instructions are provided in the protocol. 
SAFETY MONITORING 
AE Grading 
For reported AEs, the Common Terminology Criteria for Adverse Events (Version 5) (CTCAE v5), 
will be used to grade the severity of the AE. 
Safety Reporting 
Clinical and laboratory safety data will be reviewed on an ongoing basis to make decisions regarding 
the advisability of continuing accrual. To facilitate this, the following will be promptly reported to the 
Sponsor or designee: 
 
Serious adverse event(s) (SAE)s, within 24 hours of Investigator awareness 
 
AEs resulting in permanent discontinuation from study, regardless of seriousness or relationship 
to study drug 
 
IRRs (> Grade 3) 
Safety Monitoring 
Clinical and laboratory safety data will be reviewed on an ongoing basis throughout the trial. A Study 
Safety Committee will be established and will be comprised of participating Investigators(s) and the 


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Sponsor’s Medical Representative(s). If indicated, Study Safety Committee teleconferences will be 
held to discuss ongoing patient status and any emerging safety concerns. 
STUDY ASSESSMENTS 
Efficacy Assessment 
 
 
As of Amendment 5: Due to the Sponsor’s decision to discontinue the trial (effective 20Dec2018), the frequency 
of disease status evaluations will be per either institutional guidelines or Investigator discretion until confirmation 
of PD. The pre-Amendment 5 disease status assessment schedule as detailed below will not be followed. 
Disease Status (Local Assessment) 
 
Diagnostic imaging (CT/MRI) for tumor assessment; EOC2 and every 8 weeks thereafter (Q8W)  
 
Tumor assessment (per RECIST v1.1) for determination of antitumor activity (OR, SD)  
Safety Assessments 
Safety Assessments 
Patients to be monitored throughout the treatment and follow-up periods for occurrence of AEs 
(acute, delayed, and/or cumulative), as well as for changes in clinical status, physical findings 
including dermatologic changes, vital signs (VS), laboratory data, and ECGs. 
ADA, PK,  
Genomic, and 
Pharmacodynamic 
Assessments 
As of Amendment 5: Due to the Sponsor’s decision to discontinue the trial (effective 20Dec2018), only clinical 
safety-related evaluations will be conducted.  ADA and samples for exploratory PK and PD assessments (in 
peripheral blood, skin biopsies, and tumor biopsies) will not be collected. Genomic samples for eligibility 
assessment were obtained at prescreening and analyzed; however post-dosing genomic samples will not be 
collected. 
  
The pre-Amendment 5 specialty assessment plan was as follows: 
 
Immunogenicity (Specialty Lab) 
Serum sampling to assess the potential for anti-drug antibody (ADA) formation.  
 
Exploratory Pharmacokinetics (Specialty Lab) 
Serum sampling to support determination of the AUCinf, AUC0-168h, T½, CL, CLss, Vd, Ctrough 
(start of infusion [SOI]) and Cmax (end of infusion [EOI]) concentrations. Data will also enable 
population pharmacokinetic (PK) modeling for further PK characterization. 
 
Genomic Analyses (Specialty Lab) 
Peripheral blood sampling for ctDNA bioanalyses 
 
Pharmacodynamic Analyses (Specialty Lab) 
Peripheral blood, skin biopsies, and tumor biopsies for potential predictive and/or prognostic 
biomarker assessment  
DISCONTINUATION AND FOLLOW-UP 
Key Treatment 
Discontinuation 
Criteria 
Patients are to be discontinued from treatment in the event of any of the following: 
1. 
PD: Confirmed radiologically (and evaluated according to RECIST v1.1) (patients receiving 
futuximab or modotuximab may opt to crossover and receive Sym004) 
2. 
Clinical Progression: Treatment failure not meeting the criteria for PD, but considered by the 
Investigator to require treatment discontinuation (patients receiving futuximab or modotuximab 
may opt to crossover and receive Sym004) 
3. AEs, including: 
 
Hepatotoxicity characterized by Hy’s Law criteria (see protocol) 
 
Any of the following AEs:   
o 
Need for more than 2 dose reductions (Arm A), or more than 1 dose reduction (Arm B 
or Arm C)  
o 
Grade 4 IRR 
o 
Grade 4 EGFR-associated dermatologic AE  
o 
Torsade de pointes arrhythmia or other life-threatening arrhythmias  
 
Any other AE or SAE considered by the Investigator to require treatment discontinuation  
4. Physician Decision  
Replacements 
After randomization to the study, no patients will be replaced. Patients not evaluable (NE) for 
antitumor activity assessment, as defined, or patients discontinuing from study prior to the EOC2 due 


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to either documented PD or for reasons other than documented PD, will not be replaced.   
Follow-up 
All follow-up (FUP) visits and assessments, as described, should be conducted to the fullest extent 
possible. 
 
End of Treatment (EOT) evaluations to be conducted within ~ 7 to 10 days following the decision 
to discontinue the patient from treatment  
 
1 Month FUP evaluations to be conducted ~ 30 days (+ 7 days) following the last dose of IMP   
 
Long-Term FUP for Safety: If an observed toxicity thought to be related to IMP has not resolved 
by the 1M FUP evaluation, an additional follow-up AE assessment will be conducted, if feasible, 
to confirm that the event has either resolved, returned to baseline status, or been adequately 
explained.*   
*Documentation may be obtained by telephone, e-mail, or submitted in writing.  An in-person visit will not be 
required. 
ANALYSIS PLAN 
Statistical Methods  
As of Amendment 5: Due to the Sponsor’s decision to discontinue the trial (effective 20Dec2018), only clinical 
safety-related analyses will be conducted.  Planned efficacy analyses as detailed below will not be performed. 
 
Analysis Sets 
 As-Treated (AT) Analysis Set: This analysis set includes all patients who took part of any dose of 
study treatment, will be used as basis for the evaluation of antitumor effects and safety analyses.  
All analyses using this population will be based on the treatment actually received.  
 PK Analysis Set*: All patients in the AT analysis set who receive any amount of their assigned 
dose of the IMPs (i.e., Sym004, futuximab, or modotuximab), and have a measurable 
concentration of at least one of the IMPs for at least one timepoint after the first dose, with no 
significant protocol deviations that may impact the data. 
*As of Amendment 5: PK analysis will not be performed, therefore the PK analysis set is no longer 
applicable. 
 
Primary Efficacy Analysis 
Percentage change from baseline in the sum of the diameter of tumors designated as target lesions 
(per RECIST v1.1), as documented at the EOC2 tumor assessment will be calculated and plotted by 
treatment Arm using Waterfall plots. Percent of patients with on-study tumor shrinkage will be 
presented along with the associated 95% confidence intervals (CI). Magnitude of tumor shrinkage 
will also be summarized by treatment Arm, as appropriate. 
Safety Analyses 
The safety evaluations will focus on AEs and laboratory assessments. All patients included in the AT 
analysis set will be evaluated by treatment Arm in the safety analysis. Special attention will be paid to 
dermatologic toxicities, hypomagnesemia, hypocalcemia, hypokalemia, and IRRs. 
Sample Size 
Considerations 
As of Amendment 5: Effective 20Dec2018, accrual to this trial has been halted; the total planned number of 
patients will not be enrolled. Two (2) patients consented prior to the trial discontinuation date and subsequently 
determined to be eligible have been entered to the study. The pre-Amendment 5 sample size considerations 
detailed below are no longer valid. 
Based on the results of Phase 1 and Phase 2 studies, 37% to 40% of patients receiving Sym004 9/6 
mg/kg weekly treatment are expected to have tumor shrinkage at Week 8. With no knowledge of the 
anti-cancer effect of futuximab and modotuximab, up to 18 patients per Arm may be enrolled and 
treated to differentiate the rates of 35% versus 10% using a Simon’s 2-stage Minimax design, with a 
5% significance level and 80% power for each of the futuximab and modotuximab Arms.  In Stage 1, 
11 patients will be enrolled in each Arm and treated. If no more than 1 patient has tumor shrinkage in 
an Arm, further enrollment will be stopped in that Arm. Otherwise, an additional 7 patients will be 
enrolled in Stage 2.  
A contemporary reference Sym004 Arm will be included in the study to ensure the interpretability of 
tumor shrinkage data for futuximab and modotuximab. If either of the futuximab or modotuximab 
Arms continues in Stage 2 or beyond, the Sym004 Arm enrollment will continue. 


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Interim Analysis 
As of Amendment 5: Due to the Sponsor’s decision to discontinue the trial (effective 20Dec2018), only clinical 
safety-related analyses will be conducted. The planned interim analyses as described below will not be performed. 
Tumor shrinkage will be evaluated at the end of Stage 1 and Stage 2.  No other interim analysis is 
planned. 
TRIAL REPORTING 
Final Clinical Trial 
Report (CTR) 
As of Amendment 5: Due to the Sponsor’s decision to discontinue the trial for administrative reasons (effective 
20Dec2018), the primary, secondary, and exploratory objectives as previously described are no longer applicable. 
Only clinical safety-related evaluations will be conducted. An abbreviated CTR will be prepared upon completion 
of the trial rather than the full integrated report described below. 
Final integrated clinical/statistical trial report will be prepared upon reaching the predefined data cut-
off for primary analysis (all patients complete their first on-study tumor assessment). 


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2 
SCIENTIFIC BACKGROUND AND RATIONALE 
2.1 Background 
2.1.1 Metastatic Colorectal Carcinoma 
In 2012, the worldwide incidence of colorectal carcinoma (CRC) was estimated to be over 1.36 
million (1). 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% (2). 
2.1.2 Current Treatment of Metastatic Colorectal Carcinoma 
Over the last 20 years, therapy for metastatic CRC (mCRC) has evolved rapidly with the 
approval of multiple new therapeutic agents as well as the development of combination regimens 
that have resulted in improved survival for patients with this malignancy. Novel 
chemotherapeutics approved during this period include irinotecan, oxaliplatin, and the 
fluoropyrimidine, capecitabine (2-8). More recently two additional orally administered agents, 
the tyrosine kinase inhibitor (TKI) regorafenib (9, 10) and the combination of trifluridine and 
tipiracil (TAS-102) (11) have been approved for third- and fourth-line therapy of mCRC. 
Targeted therapies that have been introduced include: (a) immune checkpoint blockers 
(pembrolizumab, nivolumab) in a population of CRC patients with a high level of microsatellite 
instability (MSI-H) due to defects in DNA mismatch repair (mismatch repair-deficient [dMMR]) 
(12-14); (b) inhibitors of angiogenesis (bevacizumab, ziv-aflibercept, and ramucirumab), (6-8, 
10, 15) and (c) anti-epidermal growth factor (EGFR) monoclonal antibodies (mAbs) (cetuximab 
and panitumumab) (2-8, 16-20).  
2.1.2.1 Therapy with anti-EGFR Monoclonal Antibodies 
Metastatic CRC (mCRC) is treated with a variety of regimens of combination chemotherapy and 
targeted agents, including mAbs targeting the epidermal growth factor receptor (EGFR). The 
approved anti-EGFR antibodies, cetuximab and panitumumab, have been shown to be active in 
first-, second-, and third-line therapy of CRC (2-8, 16-20). Cetuximab and panitumumab have 
been shown to have single agent activity (6-9), and to increase the effectiveness of regimens 
including both 5-fluorouracil (5-FU), folinic acid, and irinotecan (e.g., FOLFIRI) as well as 5-
FU, folinic acid, and oxaliplatin (FOLFOX) in the first- and second-line treatment of mCRC (2-
8, 16-20). 
2.1.2.2 Resistance to Anti-EGFR Antibodies 
Despite the clearly documented activity of anti-EGFR antibodies, only approximately 10% of 
naïve patients respond to these agents while many mCRC patients are refractory prior to 
beginning therapy (innate resistance), and patients who initially respond ultimately progress 
while on therapy (acquired resistance). Subsequent studies have documented that a variety of 
factors impact prognosis or are responsible for primary and acquired resistance, and have 
documented the evolution of changes in patients treated with anti-EGFR mAbs (21-24).   
RAS Mutations 


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Analysis of tumor genomic data first documented that efficacy was only demonstrable in patients 
whose CRC expressed the wild-type (WT) Kirsten Rat Sarcoma (KRAS) viral oncogene homolog 
genotype, but subsequent studies and analyses extended these findings of resistance to therapy to 
patients with evidence of specific mutations in either KRAS, exon 2, 3 and 4, or neuroblastoma 
rat sarcoma (NRAS) viral oncogene homolog, exon 2, 3 and 4 (25, 26). Patients with documented 
RAS mutations not only do not respond to treatment (25-28) with anti-EGFR antibodies but 
administration of these mAbs appears to have a deleterious effect in this population (6). The 
KRAS/NRAS mutations occur in approximately 50% of treatment-naïve CRC patients (29).  
BRAF mutation 
BRAF mutations occur in approximately 8% to12% of patients with CRC, are found primarily in 
right-sided colonic tumors, and have been well-established as a negative prognostic factor (3, 25-
28, 30-34). A specific mutation of the BRAF gene at amino-acid position 600 (BRAF V600E) has 
been documented to be associated with poor prognosis in patients with CRC, including patients 
receiving treatment with anti-EGFR mAbs. In addition to the well-documented prognostic effects 
of the BRAF V600E mutation, increasing evidence has accumulated supporting that the presence 
of this mutation in patients with RAS WT CRC, detected in tumor tissue or blood as assessed by 
circulating tumor deoxyribonucleic acid DNA (ctDNA), is also associated with lack of response 
to anti-EGFR mAbs (35-43). 
EGFR-ECD Mutations 
Mutations in EGFR-extracellular domain (ECD) are a recently discovered mechanism of 
acquired resistance in a subset of patients with mCRC who have responded to and progressed 
after treatment with the monoclonal anti-EGFR antibodies cetuximab and panitumumab.  
Specific mutations in the ECD of EGFR result in reduced mAb binding to the receptor and loss 
of response to these agents in clinical studies (25, 26). The first EGFR-ECD mutation noted that 
resulted in decreased binding was identified in patients who developed resistance to cetuximab 
but retained binding to panitumumab (44). Since this observation, several additional mutations 
resulting in decreased binding of either or both cetuximab and panitumumab have been identified 
and have been shown to be associated with acquired resistance in patients with mCRC who had 
received these therapies (26, 45-47). 
Other Factors 
A variety of other factors have been identified that are associated with innate and/or required 
resistance to therapy with anti-EGFR mAbs in patients with mCRC (48, 38-42). These include 
but are not limited to: (a) mutations in other elements of downstream EGFR signal transduction 
(e.g., ERBB2, PIK3CA, MEK1, FGFR1, PDGFRA); (b) gene amplification of MET and ERBB2; 
and (c) lower expression of EGFR ligands, including amphiregulin (AREG) and epiregulin 
(EREG) (25, 26, 41, 42). 
2.1.3 Target Patient Population 
2.1.3.1 Current Recommendation for Treatment of mCRC with anti-EGFR mAbs 
Approved mAbs directed against the EGFR, cetuximab and panitumumab, provide significant 
survival benefit to patients with WT KRAS (exon 2, 3, and 4) and NRAS (exon 2, 3, and 4) 
mCRC, and are now standard components of treatment regimens for these patients, either alone 


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or in combination with chemotherapy (2-8). Unfortunately, the clinical efficacy of anti-EGFR 
mAbs is limited by innate as well as the emergence of acquired resistance that eventually 
develops in all initially responding tumors due to a variety of mechanisms. 
2.1.3.2 Prior Results with Sym004: Genomic Selection of a Responsive Patient Subset 
Phase 1 results (Sym004-01) documented that Sym004 was well tolerated at doses up to 12 
mg/kg weekly, and provided initial evidence of anti-tumor activity in expansion cohorts 
exploring different doses and schedules in patients with mCRC previously treated with anti-
EGFR mAbs (49). The adverse event (AE) profile was similar to the approved anti-EGFR 
antibodies, although increased frequency and severity of two mechanism-based toxicities 
(dermatologic toxicity and hypomagnesemia) were observed at the highest doses evaluated. 
A recently completed Phase 2b randomized, controlled study (Sym004-05) compared two dose 
levels of Sym004 (12 mg/kg weekly and a 9 mg/kg loading dose followed by weekly doses of 6 
mg/kg) (9/6 mg/kg) versus Investigator’s Choice (IC) of 5-FU, capecitabine, or best supportive 
care (BSC) (50). Patients entered in this trial had to: have prior documentation that their tumors 
were KRAS WT (exon 2); be refractory to or intolerant of standard chemotherapy regimens 
including fluoropyrimidines, irinotecan and oxaliplatin; and have initially responded to (with a 
complete response [CR], partial response [PR], or stable disease [SD] > 16 weeks) and 
progressed on therapy with an anti-EGFR mAb within 6 months of protocol entry. Prior therapy 
with anti-angiogenic agents was allowed, but patients who had received prior therapy with 
regorafenib were excluded.   
Blood samples were obtained at baseline for analysis of biomarkers in ctDNA (by 
Guardant360® analysis, Guardant Health). The parameters evaluated were based on preclinical 
models and published clinical data on changes known to impact the response to anti-EGFR 
mAbs in mCRC patients. These assessments were utilized to evaluate the effects of known 
genomic parameters on potential clinical benefit from Sym004 treatment. Although the trial did 
not meet its primary endpoint of improved overall survival (OS) for the Sym-004 Arm versus IC, 
genomic analyses defined a highly responsive subset of mCRC patients appropriate for further 
study in subsequent trials. This population excludes patients with high levels of mutations 
associated with resistance, or acquisition of mutations that are also predicted to impact Sym004 
binding. This subpopulation is identified by:  
 absence of mutation allele frequency (MAF) of > 20% for KRAS (exon 2, 3 and 4) and 
NRAS (exon 2, 3 and 4);  
 absence of a specific mutation of the BRAF gene at amino acid position 600 (BRAF 
V600E); and  
 absence of specific EGFR-ECD mutations (EGFR V441D, V441G, S464L, G465E, 
G465R, or S492R)   
Evaluation of patients with available genomic data who were without the specified mutations (a 
group termed as having triple-negative mCRC [TNmCRC]) showed an improved median 
survival when treated with 12 mg/kg (10.6 months) and 9/6 mg/kg (12.8 months) of Sym004, 
compared to patients in the IC Arm (7.3 months) (50). The results of these exploratory analyses 
support further evaluation of the Sym004 9/6 mg/kg dosing regimen (Sym004-12) as well as an 
evaluation of the individual antibodies constituting Sym004 (Sym004-13). 


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In Sym004-13, a randomized trial in third-fourth line therapy of TNmCRC, Sym004 will be 
compared to either futuximab or modotuximab, the antibodies that are combined to constitute 
Sym004. The study is designed to provide evidence of the individual contributions of futuximab 
and modotuximab to the antitumor activity observed with Sym004. 
2.2 Overview of the Product: Sym004 
2.2.1 Description of Sym004 
The Investigational Medicinal Products (IMPs) tested in this trial are Sym004, futuximab, and 
modotuximab, the individual antibodies constituting Sym004. 
Sym004 is a 1:1 mixture of the two recombinant, human-mouse chimeric, immunoglobulin G1 
(IgG1) antibodies (futuximab and modotuximab), which bind specifically to non-overlapping 
epitopes located in the ECD of EGFR. Each antibody is manufactured individually as a drug 
substance, and the Sym004 drug product is prepared as a 1:1 ratio mixture of the two.  
Sym004, futuximab, and modotuximab are each clear to opalescent, colorless to slightly yellow, 
solutions to be administered via intravenous (IV) infusion through an indwelling catheter. 
2.2.2 Mechanism of Action of Sym004 and the Individual Antibodies 
The simultaneous binding to EGFR of both antibodies contained in Sym004 induces a distinct 
mechanism of action. Sym004 induces highly efficient internalization of EGFR on cancer cells, 
followed by degradation of the internalized receptor-antibody complexes that leads to down-
regulation of EGFR and subsequent inhibition of cancer cell growth (51). There is considerable 
preclinical in vitro and in vivo evidence suggesting that Sym004 is superior to the marketed anti-
EGFR antibodies, cetuximab and panitumumab, in a wide range of cancer models (51, 52).  
Sym004 has also demonstrated activity in cancer cells with acquired resistance to cetuximab (53, 
54). As described, in the completed Phase 2b study of two dose levels of Sym004 versus IC, 
there was evidence of survival prolongation in a genomically-defined population who had 
previously responded to and then progressed during or within 6 months of completion of prior 
anti-EGFR mAb therapy (50). 
The binding region of futuximab on the EGFR is similar to that of cetuximab and panitumumab 
and the mode of action of futuximab includes inhibition of cancer cell growth and survival by 
blocking ligand-binding, receptor activation and phosphorylation, and downstream receptor 
signaling. In contrast, futuximab binds a conformational epitope that is less accessible on the 
EGFR compared to the epitopes of cetuximab and panitumumab, and hence requires higher 
concentrations for maximum activity. Modotuximab only weakly blocks ligand binding and has 
limited effects on receptor activation and tumor cell growth. The primary mode of action of 
modotuximab is to stabilize a conformation of EGFR to which futuximab binds with much 
higher affinity than to the native conformation, thus inducing the simultaneous strong binding of 
both antibodies in Sym004 to EGFR. 
2.3 Summary of Nonclinical Studies  
A series of in vitro and in vivo studies were performed to support clinical trials (51-54). The 
ability of futuximab, modotuximab, and Sym004 to inhibit proliferation and motility of cancer 
cells was investigated in vitro and in vivo in a range of human cancer cell lines and patient-
derived xenografts, and compared to cetuximab and/or panitumumab (51-53). The effect of 


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Sym004 on cells with acquired resistance to cetuximab was also investigated (53), including 
studies of EGFR-ECD mutated cell lines and xenograft models. Mechanistic studies of Sym004 
action performed in a panel of human cancer cell lines included assessment of inhibition of 
ligand binding, EGFR activation, and downstream signaling, as well as effects on EGFR 
internalization and degradation (51). Futuximab-, modotuximab-, and Sym004-mediated 
secondary effector functions, such as antibody-dependent cellular cytotoxicity (ADCC) and 
complement-dependent cytotoxicity (CDC), were investigated in human cancer cell lines (52).   
Collectively, all these studies showed that while futuximab and modotuximab demonstrate some 
tumor growth inhibitory activity as single agents, Sym004 was clearly superior at inhibiting 
EGFR activity and tumor growth. Likewise, Sym004 was as good or better than the reference 
monoclonal antibodies, cetuximab and panitumumab, at inhibiting tumor growth in vitro and in 
vivo (51, 52). 
Toxicology studies in cynomolgus monkeys showed a profile for Sym004 consistent with other 
anti-EGFR antibodies, including documentation of dermatologic and gastrointestinal toxicities 
(55). Administering futuximab and modotuximab as separate antibodies at 7 mg/kg resulted in 
less toxicity than administering 7 mg/kg Sym004 (3.5 mg/kg of each antibody). 
Nonclinical pharmacokinetic (PK) studies indicate that the efficient down-modulation of EGFR 
observed after administration of futuximab and modotuximab in combination as Sym004 has an 
impact on the PK parameters (55). A dose of 7 mg/kg of Sym004 administered to cynomolgus 
monkeys was cleared rapidly with a serum elimination half-life (T½) of 1-3 days, and on repeated 
weekly dosing no accumulation was observed. In contrast, the T½ after administration of 7 mg/kg 
of either futuximab or modotuximab was longer and evidence of drug accumulation was noted 
on repeated weekly dosing. These findings suggest that the Sym004 antibody combination 
results in more rapid elimination due to enhanced target-mediated drug disposition. Conversely 
for futuximab and modotuximab, the target-mediated drug disposition was less pronounced, 
which could be explained by a less potent binding and internalization of EGFR when the 
antibodies are dosed separately. As a consequence, the individual antibodies, when administered 
as single agents, may accumulate resulting in higher serum levels compared to a similar dose of 
the individual antibodies administered as Sym004. 
2.4 Clinical Experience 
Several clinical trials have been completed with Sym004, and others are being planned. This is 
the first clinical study in which the individual antibodies, futuximab and modotuximab, are being 
administered to patients as single agents. These two antibodies have been administered as a 
combination in all human studies of Sym004 thus far. In this study, the individual antibodies will 
each be administered at the same dose (4.5 mg/kg loading dose followed by 3 mg/kg weekly) as 
contained in the planned dose of Sym004 (9 mg/kg loading dose followed by 6 mg/kg). Since 
weekly dosing of up to 12 mg/kg of Sym004 has been studied without evidence of dose limiting 
toxicities in over 100 patients, dose escalation of the individual antibodies is not warranted. 
2.4.1 Safety 
As of January 2018, approximately 380 patients with solid tumors have been exposed to Sym004 
in completed and ongoing Symphogen-sponsored trials, and 30 patients have been exposed to 
Sym004 in an investigator-initiated trial in patients with recurrent glioblastoma (Sym004-08). In 


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Phase 1 and Phase 2 studies in a variety of indications, patients have been exposed to weekly 
doses of up to 12 mg/kg, and in every second week doses of up to 18 mg/kg.  
The most common adverse reactions (i.e., AEs considered treatment-related by 
the investigator) in completed Symphogen-sponsored studies with a frequency of ≥ 10% 
are shown below, along with the percentage of those reactions that were ≥ Grade 3 in severity 
shown in parentheses (Table 1):   
Table 1: Sym004 Adverse Events ≥ 10% 
percentage of reactions ≥ Grade 3 shown in parentheses 
Skin-related reactions of:  
acneiform rash   
 
  
pruritus   
 
 
 
 
rash  
 
 
 
 
  
dry skin  
 
 
 
  
paronychia   
 
 
  
skin fissures   
 
 
  
xerosis   
 
 
 
 
erythema  
 
 
 
 
 
Infusion-related reactions   
 
 
Electrolyte imbalances including:  
hypomagnesemia* 
 
 
hypocalcemia  
 
 
  
hypokalemia  
 
 
 
 
Gastrointestinal symptoms including: 
diarrhea  
 
 
 
  
decreased appetite  
 
 
nausea   
 
 
 
  
stomatitis  
 
 
 
  
mucosal inflammation  
 
constipation   
 
 
  
abdominal pain   
 
  
vomiting  
 
 
 
  
 
Asthenia  
 
 
 
 
 
  
Fatigue   
 
 
 
 
  
Pyrexia   
 
 
 
 
  
Anemia   
 
 
 
 
  
Edema peripheral  
 
 
 
 
 
57.6% (24.1%) 
34.3% (1.6%) 
31.6% (14.1%) 
26.2% (2.4%) 
20.5% (1.1%) 
20.0% (3.0%) 
16.8% (1.9%) 
15.4% (3.5%) 
 
17.8% (1.6%) 
 
 
65.7% (23.8%) 
13.2% (2.4%) 
10.0% (1.9%) 
 
 
25.4% (2.2%) 
20.8% (1.1%) 
17.8% (0.5%) 
12.7% (0.8%) 
12.7% (0%) 
11.6% (0.3%) 
11.4% (2.2%) 
10.8% (0.8%) 
 
27.0% (5.7%) 
13.5% (3.5%) 
12.4% (0.5%) 
16.5% (4.6%) 
13.0% (0.8%) 
    *Includes blood magnesium decreased 
In the Sym004-05 study, the AE profile was consistent with other anti-EGFR mAbs, although the 
frequency and severity of both dermatologic AEs and hypomagnesemia were higher. This trial 
only included patients who had benefited from prior therapy with cetuximab or panitumumab 
and they hence also had a higher incidence of dermatologic toxicity, consistent with prior 
published observations (50). The frequency of gastrointestinal AEs appeared to be lower than has 
been reported for cetuximab or panitumumab. The frequency of many AEs was higher in patients 
receiving the 9/6 regimen compared to patients on the IC Arm. Such AEs include:  


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 Related treatment-emergent AEs (TEAEs) (95.2 vs. 59%) 
 Serious TEAEs (27.4 vs. 15.4%) 
 Serious-related TEAEs (7.1 vs. 2.6%) 
 ≥ Grade 3 TEAEs (63.1 vs. 32.1%)  
 Related TEAEs ≥ Grade 3 (48.8 vs. 11.5%)  
 TEAEs leading to dose reduction (20.2 vs. 10.3%)  
In contrast, the frequency of TEAEs leading to study treatment discontinuation (6.0 vs. 7.7%) 
and related TEAEs leading to study treatment discontinuation (2.4 vs. 3.8%) was not different in 
patients treated with Sym004 9/6 and IC, respectively. 
These adverse reactions were anticipated and appear to be consistent with the safety profile of 
other EGFR antagonists such as cetuximab (55) and panitumumab (57). Ongoing monitoring of 
patients and mitigation strategies to minimize the risk of and to treat these adverse reactions are 
in place to safeguard patients participating in ongoing and planned studies. 
In conclusion, based on the significant unmet need in patients with progressive disease (PD) 
refractory to other treatment regimens, and the current safety profile, the overall benefit/risk 
profile of Sym004 appears to be favorable. 
Additional data on the safety and tolerability of Sym004, including data on serious adverse 
events (SAE), are provided in detail in the IB. 
2.4.2 Pharmacokinetics 
PK analyses have been performed on patients participating in the Phase 1 trial Sym004 in 
patients with solid tumors (Sym004-01), in the Phase 2 trial in patients with squamous cell 
carcinoma of the head and neck (Sym004-02), and in the Phase 2b trial in patients with mCRC 
(Sym004-05) (50). In the Phase 1 trial, serum levels of Sym004 increased in a dose-dependent 
manner during the dose-escalation phase which evaluated weekly Sym004 dose levels ranging 
from 0.4 to 12 mg/kg. Doses of < 3 mg/kg were rapidly cleared from the circulation. A dose-
dependent, nonlinear increase in 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 two antibodies constituting 
Sym004 displayed similar serum elimination profiles (55).  
Data from the trials also documented that the two antibodies constituting Sym004 were generally 
present in serum in close to a 1:1 ratio at each visit. The calculated T½ increased from the first to 
the fourth infusion of Sym004, with comparable increases in maximum concentration (Cmax) and 
the calculated area under the concentration-time curve (AUC). The observed increase in 
exposure was considered to be consistent with saturation of the elimination mechanism 
proceeding via the antibody target (the EGFR) after repeated dosing of Sym004. 
In Sym004-05, the serum concentration of Sym004 at predose (trough) and end of infusion (EOI) 
(peak) were assessed Week 3, 5 and 7 and at the end of treatment visit (EOT). The trough serum 
concentration of Sym004 for the 9/6 mg/kg did not change with time between Week 3 and Week 
7, indicating that steady state was obtained after the first few dose administrations. For 12 mg/kg 
as well as 9/6 mg/kg, the trough and peak values in Weeks 5 and 7 were generally comparable to 
those of comparable dose regimens in Sym004-01. 
More complete PK analyses data are included in the Investigator’s Brochure (IB).  


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2.4.3 Pharmacodynamic Effects 
Tumor and skin biopsies were obtained before the first and planned fifth infusions of Sym004 in 
the Sym004-01 trial in patients with mCRC resistant to anti-EGFR antibody therapy.  Decreases 
in membranous EGFR levels and in the proliferation marker, Ki67, were observed in both tumor 
and skin biopsies (49). 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 cell 
proliferation. 
2.4.4 Antitumor Effects 
As a part of the Phase 1 dose-escalation trial (Sym004-01), antitumor activity was documented in 
patients with mCRC resistant to anti-EGFR antibody therapy (49). Five of the 39 documented 
refractory patients (13%) with adequate imaging studies achieved a PR. These responses were 
confirmed by independent radiologic review. A PR or disease stabilization was documented in 
67% of patients with available assessments.  
From the Phase 2b trial (Sym004-05), an exploratory analysis revealed that the responders to 
Sym004 had tumors with WT KRAS, NRAS, and BRAF genotype, as well as having no evidence 
of MET amplification.  The antitumor results of this trial are described in Section 2.1.3.2. 
2.5 Trial Rationale  
Patients with mCRC resistant to standard combination regimens including fluoropyrimidines, 
irinotecan, oxaliplatin, anti-angiogenic agents, and anti-EGFR mAbs have relatively few 
therapeutic options. Survival decreases with each line of therapy in patients with this life-
threatening malignancy. Currently, in the third- and fourth-line therapy settings the best OS 
results are in the range of 7-8 months. A subset of patients with MSI-H/dMMR mCRC may 
benefit from therapy with an antibody to programmed cell death protein-1(PD-1) (13, 14). The 
incremental benefit and OS observed with the two newer orally administered agents, regorafenib 
and TAS-102 compared to placebo and BSC in large Phase 3 studies (9) were 1.4 and 6.4 months 
and 1.8 months and 7.4 months, respectively (11). Given the limited options and relatively minor 
improvements in OS in the trials of these recently approved agents in treatment-refractory 
mCRC patients, additional therapeutic options are of great interest.     
There is considerable preclinical in vitro and in vivo evidence that suggests Sym004 to be 
superior to existing anti-EGFR antibodies (cetuximab and panitumumab) in a wide range of 
cancer types (51-54). Preliminary evidence of the antitumor activity of Sym004 in patients with 
mCRC refractory to standard chemotherapy, and who had received previous therapy with anti-
EGFR mAbs, has been documented in Phase 2 expansion cohorts evaluating a variety of doses 
and schedules (49). Although the overall trial (Sym004-05) did not meet the primary efficacy 
endpoint of a 3-month improvement in OS with either Sym004 Arm (12 and 9/6 mg/kg) when 
compared to the IC Arm, subsequent hypothesis-generating sub-analyses supporting the 
secondary objective of identifying biomarkers predictive of clinical benefit in patients treated 
with Sym004 yielded a discrete genetic signature that confers significant benefit in terms of OS. 
Positive signals of clinical benefit in patients with treatment-resistant/refractory TNmCRC (no 
RAS MAF ≥ 20%, no BRAF V600E and no EGFR-ECD mutations) were observed in the 
Sym004-05 study. The subpopulation analysis showed that patients with TNmCRC had an OS 


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benefit of 5.5 months when compared to the IC Arm, with a hazard ratio of 0.59. These results 
will require confirmation in a planned Phase 3 randomized controlled trial. 
Although preclinical data have clearly documented superiority of Sym004 compared to anti-
EGFR reference antibodies, cetuximab and panitumumab, and the two antibodies, futuximab and 
modotuximab in the Sym004 mixture, there is no direct clinical evidence that these preclinical 
data will translate into clinical superiority in patients with advanced, treatment-refractory mCRC. 
The predictive value of preclinical in vitro and in vivo studies in determining clinical efficacy is 
relatively limited (58-60). One of the many reasons for the failure of preclinical models to 
accurately predict clinical efficacy in patients is the heterogeneity of individual malignancies, 
including mCRC (26), as well as their evolution over time (61-66). For this reason, this Phase 2, 
randomized, controlled trial is being undertaken to evaluate the safety, PK profiles, and 
preliminary antitumor activity (as measured by tumor shrinkage) of Sym004 and its individual 
component mAbs, futuximab and modotuximab. 
2.6 Dose Rationale 
Based on the results from the Sym004-01 and Sym004-05 trials, a Sym004 dosing regimen of 9 
mg/kg loading, followed by 6 mg/kg/week has been chosen for this trial. This dosing regimen 
was administered to 20 patients in Sym004-01 and to 84 patients in Sym004-05 and resulted in a 
tolerable safety profile, with dermatologic toxicities and hypomagnesemia as the most frequent ≥ 
Grade 3 AEs. In Sym004-01 the median duration of treatment for patients on this regimen was 
9.0 weeks (min 2.1 and max 50.9).  Median progression-free survival (PFS) was 2.3 months, 
median time to progression was 3.1 months, and median OS was 9.6 months. In Sym004-05, the 
median duration of treatment for patients receiving the 9/6 regimen was 11.9 weeks (min 1 and 
max 77). Median PFS was 2.7 months and median OS was 10.3 months in the intent-to-treat 
(ITT) population from this larger Phase 2b randomized, active controlled trial. 
Futuximab and modotuximab dosing regimens of 4.5 mg/kg loading, followed by 3 mg/kg/week 
have been chosen for this trial to reflect the dose levels of the individual antibodies in the 
Sym004 mixture. The safety profile of futuximab and modotuximab is expected to be tolerable 
based on data obtained with Sym004. 
2.7 Summary of Overall Benefit and Risk 
As previously discussed, preclinical data in addition to preliminary clinical data in patients with 
mCRC and acquired resistance to anti-EGFR mAbs have shown activity for Sym004 in this 
advanced stage cancer population. Response rates of 10% and tumor shrinkage (of ≥ 10%) in 
approximately 30% of patients at doses of 9 mg/kg/week (n=13) and 12 mg/kg/week (n=29) 
were observed. Preclinical data have also shown some activity of the individual antibodies and 
although they appear to be less potent as single agents than the mixture in Sym004, this may not 
be predictive for clinical activity. One or both antibodies administered alone may demonstrate a 
clinical activity similar to that of Sym004. 
In previous clinical trials, Sym004 demonstrated an acceptable safety profile. The safety profile 
is similar to that of other anti-EGFR antibodies, although the percentage of patients with Grade 3 
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Based on the results from the Sym004-01 and Sym004-05 trials, a Sym004 dosing regimen of 9 
mg/kg loading dose, followed by 6 mg/kg/week was found to be acceptable and data from both 
of these trials provided preliminary evidence of activity (Section 2.6).  
Prophylactic and reactive treatment guidelines for dermatologic management are included in this 
current study to reduce the incidence of severe rash (Appendix 7). Based on data derived from a 
randomized controlled trial using this approach, e.g., skin toxicity evaluation protocol with 
panitumumab (STEPP) trial (67), it is anticipated, that the incidence of Grade 3 rash will be 
reduced by these measures.  
Given the setting of unmet need for alternative treatments for mCRC refractory to standard 
therapies, including anti-EGFR antibodies, and what is currently known about the safety profile 
for Sym004, the benefit-risk relationship has been carefully considered in the planning of this 
trial. Based on the preclinical and clinical data available to date, the conduct of the trial is 
considered justifiable when using the dose and dosage regimens of Sym004, futuximab, and 
modotuximab as specified in this clinical trial protocol. The trial will be discontinued in the 
event of any new findings that indicate a relevant deterioration of the benefit-risk relationship 
that would render continuation of the trial unjustifiable. 
FOR ADDITIONAL INFORMATION, PLEASE REFER TO THE IB 
 
 
 


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3 
TRIAL OBJECTIVES AND DESIGN 
3.1 Objectives 
As of Amendment 5: Due to the Sponsor’s decision to discontinue the trial for administrative reasons (effective 
20Dec2018), the primary, secondary, and exploratory objectives as detailed below are no longer applicable. Only 
clinical safety-related evaluations will be conducted. 
3.1.1 Primary Objective  
To evaluate the relative contribution of futuximab and modotuximab to the antitumor activity* of 
Sym004 following 8 weeks of treatment in genomically-selected** patients with chemotherapy 
refractory metastatic colorectal carcinoma (mCRC) and acquired resistance to anti-EGFR mAb 
therapy. 
*As assessed by changes in tumor measurements; evaluated according to Response Evaluation Criteria in Solid 
Tumors (RECIST v1.1) (Appendix 5). 
**Genomic analysis by Guardant360 to be performed at prescreening for assessment of RAS (KRAS/NRAS), BRAF 
V600E, and EGFR-ECD mutation status.  
3.1.2 Secondary Objective  
To evaluate the safety profile of a weekly dosing regimen of Sym004 versus single agent 
futuximab or single agent modotuximab 
3.1.3 Exploratory Objective  
To evaluate potential predictive and/or prognostic biomarkers of response to treatment 
(peripheral blood, skin biopsies, and tumor biopsies to be collected).  Tumor biopsies will be 
used to establish primary tumor and non-tumor cell lines, and patient-derived xenograft models. 
3.2 Trial Design Summary  
As of Amendment 5: This amendment to the clinical trial protocol is based on the Sponsor’s decision to discontinue 
the trial for administrative reasons, effective 20Dec2018; the intent to discontinue the trial was communicated to all 
active sites on this date.  As a result, the original trial design as described below is no longer applicable, future 
accrual has been halted, and a reduction in the scope of non-safety-related assessments being conducted under this 
protocol has been implemented. 
Patients consented as of the trial discontinuation date, and determined to meet study eligibility criteria, may be 
treated with IMP and may continue therapy until the occurrence of one of the following: unacceptable toxicity or 
other conditions preventing further administration, documented PD, or the patient’s decision to withdraw. 
 
Treated patients will be followed and assessed for only clinical safety-related concerns.  
 
Of the Specialty Assessments initially planned: ADA and samples for exploratory PK and PD assessments 
(in peripheral blood, skin biopsies, and tumor biopsies) will not be collected; genomic samples for 
eligibility assessment were obtained at prescreening and analyzed, however post-dosing genomic samples 
will not be collected.  
 
The frequency of disease status evaluations will be per either institutional guidelines or Investigator 
discretion until confirmation of PD. 
The visit schedule for safety assessments will apply as specified elsewhere in this clinical trial protocol. Once IMP 
has been discontinued, an EOT visit will be performed within 7 to 10 days from the decision to withdraw treatment, 
and a 1M FUP visit will be performed 30 days (+7 days) following the last dose.   


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The pre-Amendment 5 trial design was as follows: 
Patient Population  
This is a Phase 2, open-label, three-Arm trial with randomization in the ratio of 1:1:1 to either 
Sym004 (Arm A), futuximab drug product (Arm B), or modotuximab drug product (Arm C) in 
genomically-selected patients with chemotherapy refractory mCRC and acquired resistance to 
anti-EGFR mAb therapy. The study is designed to evaluate the relative antitumor activity of each 
agent following 8 weeks of treatment, as assessed by imaging studies and tumor measurements 
performed at the end of Cycle 2 (EOC2). Following the EOC2 assessment, ongoing patients from 
Arm A will continue to receive Sym004; ongoing patients from Arm B and Arm C will be 
crossed-over from futuximab or modotuximab to receive Sym0004.   
Approximately 54 evaluable male and female patients, 18 per Arm, with mCRC and measurable 
disease according to RECIST criteria will participate in this trial. Following consent and prior to 
randomization, centralized genomic analysis of RAS (KRAS/NRAS), BRAF V600, and EGFR-
ECD mutations in ctDNA from peripheral blood samples obtained from each potential patient 
will be conducted. Triple-negative (TN) mutation status as defined in trial eligibility criteria will 
be required for initial eligibility. 
Patients with TNmCRC will continue in the screening process. Site Investigators will evaluate 
patients for eligibility and submit relevant information. Designated Eligibility Reviewers and the 
Sponsor’s Medical Monitor(s) (or designee) will review patient eligibility information provided, 
confirm eligibility, and authorize patients for randomization. Once authorization is obtained, 
patients will be randomized to Arm A, Arm B, or Arm C. 
 
Dosing Schedule 
Cycle 1 dosing will occur ≤ 3 days (72 hours) after randomization. Beginning with the first dose, 
all patients will be premedicated with standard therapies prior to each dose to reduce the risk of 
infusion-related reactions (IRRs), and must be premedicated with standard therapies throughout 
at minimum Cycles 1 and 2 to reduce the risk of anti-EGFR-related dermatologic adverse events 
(AEs).   
Dosing will be as follows: 
 Patients randomized to Arm A will receive Sym004 by the intravenous (IV) route, at a 
loading dose of 9 mg/kg on Cycle 1 Day 1 (C1D1) followed by weekly doses of 6 mg/kg 
beginning on C1D8 (total of 4 doses per 28-day cycle).  
 Patients randomized to Arm B or Arm C will receive futuximab or modotuximab, 
respectively, by the IV route, at a loading dose of 4.5 mg/kg on C1D1 followed by 
weekly doses of 3 mg/kg beginning on C1D8 (total of 4 doses per 28-day cycle).   
Patients in both Arms will be treated and followed on an outpatient basis throughout the trial, 
unless hospitalization is required for other reasons, or to ensure patient safety. 
Treatment Duration   


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Patients will continue dosing cycles of 28 (± 2) days, provided specified retreatment criteria are 
met, until documented disease progression or the occurrence of unacceptable toxicity or another 
criterion necessitating discontinuation from the treatment. Antitumor activity will be assessed at 
the end of every 2 cycles (every 8 weeks [Q8W]).   
At the EOC2 tumor assessment: 
 Patients assigned to Arm A (Sym004) with a documented objective response (OR) or SD 
will continue to receive Sym004; patients with documented PD at the EOC2 will be 
discontinued from the study;  
 Patients assigned to Arm B (futuximab) or Arm C (modotuximab) with a documented OR 
or SD will be crossed-over to receive Sym004; patients with documented PD at the EOC2 
(or prior to the EOC2) will be offered the opportunity to crossover to receive Sym004 or 
will be discontinued from the study. Dosing of Sym004 may continue until further PD is 
observed.    
Criteria for Evaluability 
To be considered evaluable for antitumor activity assessment, patients must have completed 2 
cycles of dosing inclusive of EOC2 disease imaging studies (i.e., computed tomography 
[CT]/magnetic resonance imaging [MRI]), and must have received any amount of their assigned 
investigational medicinal product (IMP) during that period, or have PD documented by imaging 
studies prior to the EOC2. Nonevaluable patients and patients discontinuing from study prior to 
the EOC2 due to either documented PD or for reasons other than documented PD will not be 
replaced (every effort will be made to obtain imaging studies at the time of discontinuation). 
Safety Monitoring  
Clinical and laboratory safety data will be reviewed on an ongoing basis throughout the trial. A 
Study Safety Committee will be established and will be comprised of participating 
Investigator(s) and the Sponsor’s Medical Representative(s). If indicated, Study Safety 
Committee teleconferences will be held at intervals to discuss ongoing patient status and any 
emerging safety concerns. 
The overall trial schema is shown in Figure 1. 
 


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Figure 1: Trial Design 
 
Abbreviations (in alphabetical order): 9/6 mg per kg, 9 mg loading dose followed by weekly doses of 6 mg/kg ; C, cycle; ctDNA, 
circulating tumor DNA; EOC2, end of cycle 2; kg, kilogram; mg, milligram; OR, objective response; PD, progressive disease; SD, stable 
disease; TNmCRC, triple negative metastatic colorectal carcinoma 
Study Assessments 
For safety, patients will be monitored throughout the treatment and 1-month follow-up (1M 
FUP) period for changes in: clinical status, physical examination findings (including weekly 
assessments for dermatologic AEs); laboratory data (including weekly assessments for 
hypomagnesemia, hypocalcemia, and hypokalemia); and electrocardiogram (ECG) findings. 
Patients will be evaluated for evidence of acute as well as cumulative or delayed toxicities. 
Patients will also be evaluated for evidence of the development of antidrug antibodies (ADA) to 
IMP, and PK sampling will be performed to enable population PK modeling and to evaluate 
potential PK differences between Sym004, futuximab, and modotuximab as observed in 
nonclinical studies.  
For evaluation of the antitumor effects of Sym004, futuximab, and modotuximab, patients will 
undergo imaging studies and disease response assessments approximately every 8 weeks (Q8W), 
at the end of even-numbered cycles. Confirmed PD, as defined by RECIST v1.1, following 
initial treatment (Arm A) or after crossover treatment with Sym004 for patients in Arm B or Arm 
C will necessitate withdrawal of the patient from study so that alternative management of their 
malignancy may be considered. Antitumor effects observed in patients on all three Arms at the 
end of Week 8 (EOC2) will be assessed to evaluate potential differences between Sym004 and 
futuximab and modotuximab. Subsequent imaging studies will be performed as a part of standard 
practice for patient management.  
Exploratory biomarker studies will be conducted in blood samples obtained prior to and at 
intervals following dosing, including at the time of documented progression or study 
discontinuation for other reasons, in skin biopsies obtained prior to first dose and following 
Cycle 1 and Cycle 2 dosing, and in tumor biopsies obtained prior to first dose and following 
Cycle 2 dosing.    
The overall trial plan is introduced in Table 2. 
 


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Table 2: Overall Trial Plan 
Prescreening           Must have progressed from prior therapy 
Genomic Analysis 
(prescreening) 
 
Written informed consent  
(within 28 days prior to 1st dose; may be extended to allow for receipt of genomic analysis results, 
or collection of sample for genomic analysis may be performed under a separate ICF)  
 
Centralized ctDNA analysis by Guardant360 
Screening  
Patients with confirmed TNmCRC only 
Disease Status and 
Safety Evaluation 
(screening) 
 
Disease status evaluation  
(imaging studies may be used to document tumor status at screening if performed within 14 days 
prior to 1st dose) 
 
Safety evaluation 
(within 14 days prior to 1st dose unless otherwise stipulated) 
Randomization 
Patients confirmed/authorized as fully eligible 
Treatment 
Assignment 
 
Randomization to Sym004 versus futuximab versus modotuximab 
(within 14-day screening window; C1D1 dosing to occur ≤ 3 days (72 hours) after 
randomization)  
Treatment Period 
Treatment  
 
C1D1 initial dose of IMP  
 
28-day cycles until confirmed PD, unacceptable toxicity, or another discontinuation criterion is 
met   
 
Tumor assessment at EOC2 with continuation of Sym004, or crossover to Sym004, as indicated 
 
EOT visit within approximately 7 to 10 days following treatment discontinuation, or before 
initiation of a new treatment, whichever occurs first 
 
1M FUP visit 30 days (+7 days) following last dose*   
*Completion of the 1M FUP visit will be considered the end of study for the patient unless additional 
safety follow-up is required    
Follow-up Period 
Post-Treatment 
Follow-up  
 
Safety FUP if an IMP-related AE has not resolved by the 1M FUP  
(2 months [4 months if necessary] following last administration of IMP) 
Abbreviations (in alphabetical order): 1M FUP, 1-month follow-up; C1D1, Cycle 1 Day1; ctDNA, circulating tumor DNA; EOT, end of 
treatment; FUP, follow-up; ICF, informed consent form; PD, progressive disease; Q2M, every 2 months; Q2W, every 2 weeks 
 


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4 
PATIENT SELECTION 
4.1 Number of Patients 
As of Amendment 5: As of the trial discontinuation date (20Dec2018), a single center in the United States had 
consented and screened patients. Two (2) of 5 patients screened were determined to be eligible for participation and 
both were enrolled in the study. The total number of sites planned will not be participating; the total number of 
patients planned will not be enrolled.  
4.1.1 Investigational Sites 
This is a multicenter, multinational trial.  
 Number of Sites: Approximately 20 sites may participate based on anticipated accrual 
 Number of Countries: Approximately 4-6 countries in North America and Europe 
4.1.2 Planned Sample Size  
Up to approximately 54 evaluable patients (18 evaluable patients per Arm)  
Note:  To be considered evaluable for antitumor activity assessment, patients must have completed 2 cycles of 
dosing inclusive of EOC2 disease imaging studies and must have received at least 6 of 8 doses of their 
assigned IMP during that period or have PD documented by imaging studies prior to the EOC2. Non-
evaluable patients and patients discontinuing from study prior to the EOC2 due to either documented PD or 
for reasons other than documented PD, will not be replaced. 
4.2 Criteria for Inclusion 
As of Amendment 5: Effective 20Dec2018, accrual to this trial has been halted; however, patients consented prior 
to the effective date will be required to meet the following inclusion criteria: 
(Patients must meet all of the following criteria) 
1. Male or female patients, ≥ 18 years of age at the time of obtaining informed consent 
2. Patients with histologically- or cytologically-confirmed mCRC  
3. Patients with MSI-H/dMMR tumors must have received prior therapy with 
pembrolizumab, nivolumab, or other PD-1/PD-L1 pathway blocker, and must have 
progressed on that therapy. 
4. Patients meeting the protocol definition of TNmCRC assessed by screening blood test 
(ctDNA): 
a. Without RAS (KRAS and NRAS) MAF ≥ 20% for mutations in the following 
codons: 
 Exon 2: codon 12, 13  
 Exon 3: codon 59, 61  
 Exon 4: codon 117, 146 
b. Without BRAF V600E mutation at any MAF  


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c. Without EGFR-ECD V441D, V441G, S464L, G465E, G465R, S492R mutations 
at any MAF 
Note:  Centralized genomic analysis to be performed; peripheral blood to be collected for assessment of 
ctDNA by Guardant360.    
5. Patients with mCRC currently not amenable to surgical intervention due to either medical 
contraindications or non-resectability of the tumor 
6. Patients with measurable disease according to RECIST v1.1 (Appendix 5), and 
willingness to undergo a total of 2 biopsies of a primary or metastatic tumor site(s) 
considered safely accessible for biopsy   
7. Patients must have received at least 2 prior regimens of standard chemotherapy for 
mCRC and must have been refractory to or failed (includes intolerance to) those 
regimens   
Prior standard chemotherapy may not have included TAS-102 or regorafenib, but must 
have included all of the following agents (where approved in the country): 
a. Fluoropyrimidines, irinotecan, and oxaliplatin 
b. An anti-vascular endothelial growth factor (VEGF) pathway inhibitor approved 
for treatment of mCRC 
c. At least one anti-EGFR mAb approved for treatment of mCRC 
Note:  Patients who withdrew from standard therapy(ies) due to unacceptable toxicity warranting 
discontinuation of treatment and precluding retreatment with the same agent prior to progression of 
disease will be eligible to enter the study. 
Patients who received adjuvant chemotherapy and had documented recurrence (by imaging studies) 
during or within 6 calendar months of completion of the adjuvant chemotherapy are permitted to 
count the adjuvant therapy as one regimen of chemotherapy. 
8. Patients with “acquired” resistance to commercially available anti-EGFR mAbs approved 
for the treatment of mCRC. Patients must have: 
a. Received treatment with an anti-EGFR for >16 weeks 
b. PD documented by imaging or clinical findings < 6 calendar months after 
cessation of previous anti-EGFR mAb treatment 
c. No more than 6 calendar months from last dose of previous anti-EGFR mAb 
treatment to date of consent for this trial (regardless of the line of therapy in 
which it was used) 
9. Patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 
of 0 or 1 (or equivalent Karnofsky PS; Appendix 1) 
10. Patients, male and female, who are either not of childbearing potential or who agree to 
use a highly effective method of contraception during the study beginning within 2 weeks 
prior to the first dose and continuing until 3 months after the last dose of IMP.   
Note: 
Women are considered of childbearing potential unless they have undergone hysterectomy and/or 
bilateral tubal ligation or oophorectomy, or have been postmenopausal for at least one year.  
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confirmed with a serum follicle-stimulating hormone (FSH) level within laboratory reference 
range for postmenopausal women.  
A highly effective method of contraception is defined as non-hormonal contraception equivalent to 
a double-barrier method (includes a single-barrier method in combination with a spermicide) or 
intrauterine device (Section 11.1).  
Women of childbearing potential (WOCBP) must have a negative pregnancy test within ≤ 2 
working days prior to administration of the first dose of IMP. 
11. Must have the ability to understand and give written informed consent for participation in 
this trial, including all evaluations and procedures as specified by this protocol 
Note: 
Informed consent must be obtained prior to patient screening, and before any evaluations or 
procedures specifically related to this study are performed. 
4.3 Criteria for Exclusion 
As of Amendment 5: Effective 20Dec2018, accrual to this trial has been halted; however, patients consented prior 
to the effective date will be required to meet the following exclusion criteria: 
4.3.1 Patients to be Excluded  
(Patients must not meet any of the following criteria) 
1. Women who are pregnant or lactating or intending to become pregnant before, during, or 
within 3 months after the last dose of IMP. WOCBP, and fertile men with WOCBP-
partner(s) not using and not willing to use a highly effective method of contraception.  
Note:  
WOCBP includes any female who has experienced menarche and who has not undergone surgical 
sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or is not 
postmenopausal.  Post-menopause is defined as: 1) amenorrhea for > 12 months with no other 
cause, or 2) irregular menstrual periods, on hormone replacement therapy (HRT), with a 
documented FSH level > 35 mIU/mL.  
WOCBP and fertile men will be informed as to the potential risk of procreation while participating 
in this trial.  A pregnancy test will be performed, and the results reviewed, on each premenopausal 
WOCBP prior to first IMP administration. A negative pregnancy test performed within < 2 
working days prior to first IMP administration must be documented on the patient’s case report 
form (CRF) (Section 11.1). 
2. Patients with a prior history any of the following mutations in their tumor at the time of 
any previous assessment: 
a. RAS (KRAS and NRAS) mutations in the following codons: 
 Exon 2: codon 12, 13  
 Exon 3: codon 59, 61  
 Exon 4: codon 117, 146 
b. BRAF V600E mutation  
c. EGFR-ECD V441D, V441G, S464L, G465E, G465R, S492R mutations  
3. Patients with known, untreated central nervous system (CNS) or leptomeningeal 
metastases, or spinal cord compression; patients with any of these not controlled by prior 


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surgery or radiotherapy, or patients with 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 ≥ 4 weeks apart with the most recent performed within 4 
weeks prior to first IMP administration.   
Patients with newly identified CNS disease during study treatment will be considered to have PD 
and will be discontinued from treatment. 
4. Patients with an 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 (e.g., breast, cervix, endometrium) provided CR was 
achieved at least 5 years prior to study and no additional therapy is ongoing or 
required during study period) 
c. Controlled, superficial carcinoma of the bladder  
d. T1a carcinoma of the prostate comprising < 5% of resected tissue and prostate 
specific antigen (PSA) within normal limits (WNL) since resection 
5. Patients with any of the following hematologic abnormalities at baseline*:   
a. Hemoglobin < 9.0 g/dL 
b. Absolute neutrophil count (ANC) < 1,500 per mm3 
c. Platelet count < 100,000 per mm3 
Note: 
Patients may have received a blood/blood product transfusion prior to study, if clinically 
warranted.   
*Throughout this protocol “baseline” is defined as the last available observation prior to the first 
administration of IMP on C1D1. 
6. Patients with any of the following serum chemistry abnormalities at baseline: 
a. Total bilirubin > 2.0 × the upper limit of normal (ULN) for the institution  
b. Alkaline phosphatase (ALP) > 2.5 × the ULN for the institution (> 5 × ULN if 
due to hepatic involvement by tumor) 
c. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × the 
ULN for the institution (> 5 × ULN if due to hepatic involvement by tumor)  
d. Creatinine clearance (CrCl) < 30 mL/min as calculated by the Cockroft-Gault 
formula 
e.  Magnesium < 1.2 mg/dL 
7. Patients with: 


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a. Active thrombosis, or a history of deep vein thrombosis (DVT) or pulmonary 
embolism (PE), within 4 weeks prior to first administration of IMP, unless 
adequately treated and considered by the Investigator to be stable 
b. Active uncontrolled bleeding or a known bleeding diathesis  
8. Patients with a known clinically significant cardiovascular disease or condition, 
including: 
a. Need for antiarrhythmic medical therapy for a ventricular arrhythmia or other 
uncontrolled arrhythmia (patients with controlled atrial fibrillation (heart rate < 
90) for > 30 days prior to study entry are eligible) 
b. Severe conduction disturbance (e.g., 3rd degree heart block) 
c. HR-corrected QT interval (QTc interval) ≥ 480 msec (as calculated by Bazet’s 
formula) 
d. Uncontrolled hypertension (per the Investigator’s discretion) 
e. Congestive heart failure currently requiring therapy 
f. Class III or IV cardiovascular disease according to the New York Heart 
Association Functional Classification (Appendix 2) 
g. History of acute coronary syndromes (including myocardial infarction and unstable 
angina), coronary angioplasty, or stenting within 6 months prior to first 
administration of IMP 
9. Patients with non-healing wounds on any part of the body 
10. Patients with a significant gastrointestinal abnormality, including: 
a. Diarrhea > Grade 1* at the time of randomization 
b. Requirement for IV alimentation 
*AE grading based on Common Terminology Criteria for Adverse Events (Version 5) (CTCAE v5) 
Note:  
Patients with recent Grade 2 diarrhea secondary to administration of oral contrast are allowed, 
provided symptoms have resolved prior to first study drug administration. 
11. Patients with skin rash > Grade 1 from prior anti-EGFR therapy at the time of 
randomization 
12. Patients with any unresolved > Grade 1 toxicity associated with any prior antineoplastic 
therapy with the exception of persistent Grade 2 alopecia, decreased hemoglobin, 
peripheral neuropathy, and/or end-organ failure being adequately managed by hormone 
replacement therapy 
13. Patients with a known or suspected hypersensitivity to any of the excipients of 
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14. Patients with any other serious/active/uncontrolled infection, any infection requiring 
parenteral antibiotics, or unexplained fever > 38ºC within 2 weeks prior to first study 
administration of IMP 
15. Patients with inadequate recovery from any prior surgical procedure, or patients having 
undergone any major surgical procedure within 4 weeks prior to first administration of 
IMP 
Note:  
Patients having undergone recent placement of a central venous access device or port will be 
considered eligible for enrollment.  
16. Patients with any other serious, life-threatening, or unstable preexisting medical condition 
(aside from the underlying malignancy), including significant organ system dysfunction, 
or CS laboratory abnormality(ies), which, in the opinion of the Investigator, would either 
compromise the patient’s safety or interfere with obtaining informed consent, compliance 
with study procedures, or evaluation of the safety of IMP  
17. Patients with a psychiatric disorder or altered mental status that would preclude 
understanding of the informed consent process and/or completion of the necessary study-
related evaluations   
18. Patients with the inability or with foreseeable incapacity, in the opinion of the 
Investigator, to comply with the protocol requirements 
4.3.2 Drugs and Other Treatments to be Excluded  
(Patients must not be receiving any of the following) 
1. Prior treatment with TAS-102 or regorafenib  
2. Any antineoplastic agent for the primary malignancy (standard or investigational) without 
delayed toxicity within 4 weeks prior to first administration of IMP and during study, 
with the exception of:  
a. Nitrosoureas and mitomycin C within 6 weeks prior to first administration of IMP 
and during study 
Note:  Patients may have received and failed prior therapy with immune modulators (e.g., PD-1, PD-L1 
inhibitors) and be considered eligible for this trial. 
3. Any other investigational treatments within 4 weeks prior to and during study; includes 
participation in any medical device or other therapeutic intervention clinical trials    
4. Radiotherapy:  
a. For lesions to be used as target lesions, within 4 weeks prior to first 
administration of IMP unless disease progression has been documented in the 
lesion post-radiotherapy, and during study 
b. For non-target lesions, within 1 week prior to first administration of IMP 
Note:  Palliative (limited-field) radiotherapy for management of pain associated with bone metastases 
present at baseline is permitted during study. Patients with suspected new bone lesions requiring 
pain management should be treated and evaluated for potential disease progression. 


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5. Immunosuppressive or systemic hormonal therapy (> 10 mg daily prednisone equivalent) 
within 2 weeks prior to first administration of IMP and during study. The following 
therapies are allowed: 
a. Hormonal therapy for appetite stimulation (e.g., Megace) 
b. Nasal, ophthalmic, inhaled, and topical glucocorticoid preparations 
c. Hormone replacement therapy at standard doses for end-organ failure 
d. Stable hormonal therapy for ovarian suppression for non-malignant conditions, 
hormonal contraceptive therapy, or post-menopausal HRT* 
e. Steroid therapy for contrast reaction prophylaxis 
f. Low-dose maintenance steroid therapy for other conditions (e.g., asthma 
exacerbation) 
g. Intra-articular steroid injections 
h. Higher dose steroid therapy for treatment of an acute intercurrent illness in 
patients with SD or an ongoing OR. In such situations, IMP treatment should be 
interrupted for the duration of immunosuppressive therapy. 
*Prior or concomitant therapies are permitted; however, patients must have been on a stable dose for 
at least 6 months prior to study start, and if continuing must remain on the stable dose while receiving 
study treatment (i.e., such treatment will not be considered as systemic hormonal therapy for the 
purpose of study eligibility). 
Questions regarding eligibility criteria must be addressed and resolved by the Investigator in 
consultation with the Sponsor’s Medical Monitor(s) prior to randomization. 


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5 
INVESTIGATIONAL MEDICINAL PRODUCT AND COMPARATORS 
5.1 Investigational Medicinal Products 
The Investigational Medicinal Products (IMPs) are Sym004, futuximab drug product, and 
modotuximab drug product.   
Sym004 is a 1:1 mixture of two chimeric mAbs, futuximab and modotuximab, which bind 
specifically to 2 non-overlapping epitopes of the EGFR. 
In advance of study start, the Sponsor (or designee) will provide labeled supplies of IMPs to the 
site pharmacy.  Instructions for handling, administration, and disposal will be provided in the 
IMP Manual and are summarized below. 
5.1.1 Formulations  
Sym004, futuximab, and modotuximab are each clear to opalescent, colorless to slightly yellow, 
liquid formulations for IV infusion. Vialed supplies will be provided by the Sponsor with the 
following volume, concentration, and total content:  
 Sym004 
o Nominal fill volume of 20 mL  
o At a concentration of 25 mg/mL for a total vial content of 500 mg 
 Futuximab  
o Nominal fill volume of 10 mL  
o At a concentration of 25 mg/mL for a total vial content of 250 mg 
 Modotuximab  
o Nominal fill volume of 10 mL  
o At a concentration of 25 mg/mL for a total vial content of 250 mg 
5.1.2 Formulation Excipients 
Formulation excipients of Sym004, futuximab, and modotuximab include: 
 L-Histadine 
 L-Histadine monohydrochloride monohydrate 
 Trehalose dihydrate 
 Tween (polysorbate) 20  
5.2 Storage and Handling of IMPs 
Unused vials of IMPs must be stored refrigerated between 2° C to 8° C (36 to 46º F) in an 
access-controlled secure location.  IMPs may not be frozen. There is no evidence that ultraviolet 
(UV) light exposure affects the IMPs, but as a precaution vials should be stored protected from 
light in the carton until use. 


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The site will be required to maintain a temperature log documenting IMP storage conditions. The 
temperature must be logged and evaluated at minimum on all working days. 
Any deviations from the recommended storage conditions should be immediately reported to the 
Sponsor (or designee) and the use of IMP interrupted until authorization for its continued use has 
been given.   
All handling, storage and preparation of IMPs should take place at the site pharmacy. IMPs may 
be accessed only by the Investigator, a member of the Investigator’s staff specifically authorized 
by the Investigator, or a pharmacist, as appropriate. The site must ensure that IMPs are accessible 
to authorized personnel only.  
5.3 Stability of IMPs  
Long-term stability of IMPs is being assessed on an ongoing basis and expiry will be updated as 
data accrue. The stability of the IMPs will be monitored for at least the duration of the clinical 
trial.   
When diluted for use, the IMPs have been found to be stable at room temperature and should be 
administered within an 8-hour time window (Section 5.8) (see the IB and the IMP Manual for 
additional information). 
5.4 Labeling of IMPs 
Vials of IMPs will be open-label; label text will be in local language and in accordance with 
applicable local regulatory requirements. Each vial will be uniquely numbered for allocation, 
dispensing, and traceability purposes.    
5.5 Packaging of IMPs 
IMPs will be packed in cartons containing multiple vials. The vial number range in each carton 
will be detailed on the carton label.   
5.6 Administration of IMPs 
IMPs will be administered by IV infusion. An appropriate dose based on the patient’s body 
weight is to be diluted with commercially available 0.9% Sodium Chloride Injection, USP or 
local equivalent.   
During this trial, IMPs are to be administered once weekly (Q1W) ± 2 days. Four (4) weeks (28 
days) equals one dosing cycle as follows:   
 Sym004 (9/6 mg/kg) 
o 9 mg/kg loading dose on C1D1 administered in a total volume of 500 mL over 1 
hour (+ 10 min) 
o 6 mg/kg weekly maintenance doses beginning on C1D8 administered in a total 
volume of 250 mL over 30 minutes (+ 10 min) 
 Futuximab (4.5/3 mg/kg) 


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o 4.5 mg/kg loading dose on C1D1 administered in a total volume of 500 mL over 1 
hour (+ 10 min) 
o 3 mg/kg weekly maintenance doses beginning on C1D8 administered in a total 
volume of 250 mL over 30 minutes (+ 10 min) 
 Modotuximab (4.5/3 mg/kg) 
o 4.5 mg/kg loading dose on C1D1 administered in a total volume of 500 mL over 1 
hour (+ 10 min) 
o 3 mg/kg weekly maintenance doses beginning on C1D8 administered in a total 
volume of 250 mL over 30 minutes (+ 10 min) 
5.7 Dose Calculation 
The dose to be administered will be multiplied by the patient’s weight in kilograms to arrive at 
the total dose to be delivered. In situations where this calculation results in a value with an 
unwieldy number of decimal places, it is permissible to round the value to the nearest “tenth”.  
As a convention, values > 5 should be “rounded” to the next higher number.   
Dose adjustments should be made in the event of noted weight change (± 10%; less at the site’s 
discretion or if required by institutional procedures) as measured at the beginning of each dosing 
cycle (CxD1). Adjustments may be made in the event of lesser incremental changes in weight 
and/or more frequently at the site’s discretion. 
Dosing information will be recorded on the appropriate Accountability Form in use. This 
inventory will be maintained throughout the duration of the trial and will be periodically 
reviewed by a representative of the Sponsor.   
5.8 Dose Preparation  
All handling and preparation of IMPs should take place at the pharmacy of each trial site. The 
Investigator is responsible for informing the pharmacy of the dose to be administered based on 
the patient’s body weight as measured at the beginning of each dosing cycle.  
IMP should be administered by the study staff as soon as possible following preparation, within 
8 hours, and considering:  
 The total volume of IMP to be delivered will be withdrawn from the IMP vial(s) and 
added to a prefilled IV bag containing 0.9 % Sodium Chloride Injection, USP or local 
equivalent (following removal of an appropriate volume of saline, such that the final 
volume to be infused equals 500 mL for C1D1 loading dose infusions and 250 mL for 
subsequent infusions)     
 The IV bag containing the diluted IMP solution to be administered should be gently 
inverted to ensure that the material is well mixed.   
 Infusion sets must contain an in-line filter (0.22 micron pore size)   


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5.9 Accountability  
The Investigator acknowledges that IMP supplies are investigational and, as such, must be used 
strictly in accordance with the protocol and only under the supervision of the PI. IMPs will not 
be sent to the site until all required regulatory documents, including IRB or EC approval, are 
received by the Sponsor or its designee. 
The Investigator and site staff are responsible for maintaining an accurate inventory and 
accounting of IMPs. Receipt, use, and destruction of IMPs will be recorded on the appropriate 
Accountability Form in use.   
5.9.1 Disposition of Used IMPs  
Once IMPs are prepared for delivery and administered, the health care professional will maintain 
an inventory of all open/used vials.  Such residual supplies may be destroyed in an appropriate 
manner according to institutional policy.   
Note: 
The Sponsor authorizes no other use of IMP intended for use in this trial. The Investigator (or 
designee) will be responsible for the appropriate handling and disposition of residual IMP in partially used 
vials.   
 
5.9.2 Unused IMPs  
Unused study materials MUST be returned to the Sponsor (or designee) upon expiry or at the 
conclusion of the site’s participation in the trial, unless otherwise authorized in writing. 
5.9.3 Destruction of IMPs 
No unused IMPs may be destroyed or discarded at the site without the written authorization of 
the Sponsor (or designee). The destruction of IMP materials must be carefully documented per 
instructions outlined in the IMP Manual. Disposition records must be available for review by a 
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6 
EXPERIMENTAL PLAN 
6.1 Design Elements 
This is a randomized, open-label, parallel group trial. Investigators, other members of the site 
trial team, Sponsor personnel and patients will be aware of the identity of the trial treatments. 
6.2 Projected Recruitment Period and Duration of this Trial 
6.2.1 Recruitment Period 
As of Amendment 5: Effective 20Dec2018, accrual to this trial has been halted. Previous recruitment projections 
were as follows: 
It is anticipated that enrollment to this study will be completed in approximately 6 months.  
 Anticipated date of randomization of first patient: Q3 2018 
 Anticipated date of randomization of last patient: Q4 2018 
6.2.2 Trial Duration   
As of Amendment 5: Due to the Sponsor’s decision to discontinue the trial (effective 20Dec2018), the primary, 
secondary, and exploratory objectives as previously described are no longer applicable. Planned efficacy analyses, 
as well as planned specialty analyses (including ADA as well as exploratory PK and PD analyses) will not be 
performed.  Only clinical safety-related analyses will be conducted; data cut-off will occur and safety analyses will 
be performed at the end of trial. 
Data Cut-off for Primary Analysis: When the required number of evaluable patients (18 patients 
per Arm) have been treated for a minimum of 2 cycles, have received any amount of their 
assigned IMP during that period, and have either undergone EOC2 imaging studies or have had 
PD documented by imaging studies prior to the EOC2, the trial objectives will be considered to 
have been met. That date will be the data cut-off date for the primary analysis.  
Patients still in treatment will be given the opportunity to continue receiving Sym004.   
Data Collection beyond Primary Analysis: While the Sponsor still needs to collect certain safety-
related data to meet its regulatory obligations (AEs, serious adverse events [SAEs], IMP dosing, 
reason for discontinuation, etc.), the Sponsor may elect to reduce non-safety-related protocol-
stipulated assessments, and/or transition patients to an extension/rollover protocol. 
End of Trial: The end of trial will be reached at the latest 1 month (30 +7 days) after the last 
patient has been discontinued from study drug.   
6.2.3 Trial Closure   
As of Amendment 5: Effective 20Dec2018, accrual to this trial has been halted; the total planned number of 
patients will not be enrolled. Once the 2 patients entered to the trial have discontinued treatment and all required 
safety follow-up has been completed, the trial will be closed.  The pre-Amendment 5 trial closure plan detailed 
below will not be followed. 


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The Sponsor (or designee) will be in communication with the sites when the target total 
enrollment for the trial has been attained. Once recruitment is completed, accrual will be closed, 
and sites will be so notified in writing.   
6.3 Patient Prescreening, Screening and Randomization  
6.3.1 Prescreening for Mutation Status 
After obtaining written informed consent, genomic analysis including evaluation of RAS, BRAF 
V600, and EGFR-ECD mutations will be performed on blood samples obtained from each 
potential patient. Results will guide initial eligibility to determine whether to continue a patient 
in the trial screening process. Triple-negative (TN) results as defined in the trial eligibility 
criteria will be required for initial eligibility.  
All patients giving informed consent for prescreening will receive a unique prescreening number. 
The trial site must maintain a prescreening log detailing the results for prescreened patients. This 
log will list the patient’s prescreening number, and whether the patient continues into full 
screening. 
Prescreening activities are generally to be performed within 28 days prior to the first day of 
dosing (C1D1), however, this period may be extended briefly to allow for receipt of genomic 
analysis results. Alternatively, collection of samples for genomic analysis may be performed 
under a separate informed consent form (ICF).   
6.3.2 Screening for Trial Eligibility 
Once a potential patient has been determined to have TNmCRC, screening assessments will be 
conducted. The Sponsor (or designee) will be made aware of potential patients for enrollment to 
track such study-related activities.   
Imaging studies may be used to document tumor status at screening if performed within 14 days 
prior to C1D1.  Safety screening activities are to be performed within 14 days prior to C1D1, 
unless otherwise specified. 
6.3.3 Submission of Patient Eligibility Information 
Once the patient is screened and identified by the Investigator as meeting the study eligibility 
criteria, data supporting eligibility must be entered in the study CRF for the Sponsor (or 
designee) to review. Information including: date written informed consent was obtained, 
demographics, diagnoses of primary malignancy and metastases, prior CRC treatments with 
systemic drug therapies including those specified in the protocol inclusion criteria will be 
required.  
6.3.4 Eligibility Confirmation 
The designated Eligibility Reviewers will review patient eligibility information provided and 
confirm eligibility.  Upon confirmation, the site may proceed to request the randomized study 
treatment assignment for the patient.   


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6.3.5 Randomization 
As of Amendment 5: As of the trial discontinuation date (20Dec2018), 5 patients had provided written consent for 
trial participation; following screening, 2 were determined to be eligible. The first patient was deemed eligible prior 
to the trial discontinuation date and was randomized to Arm B (futuximab). The second patient was deemed eligible 
after the trial discontinuation date and although randomized to Arm B (futuximab), per Sponsor decision was 
enrolled to Arm A to receive Sym004. The pre-Amendment 5 randomization plan detailed below will not be 
followed. 
Eligible patients will be randomized in the ratio of 1:1:1 to Arm A (Sym004), Arm B 
(futuximab), or Arm C (modotuximab).  
Randomization is to be carried out within the 14-day screening window with C1D1 dosing to 
occur on the day of randomization or within 3 days (72 hours) after randomization. 
6.3.6 Patient Identification Code Assignment 
Each patient who signed informed consent will be assigned a unique identification code. 
Identification codes will be assigned in sequential order, and will be concatenated to indicate 
relevant study information, including at minimum the participating trial site and the patient’s 
order of randomization to the trial. 
6.3.7 Screen Failures 
A patient found not eligible for the trial after giving informed consent will be considered a screen 
failure. Patients will be followed for the occurrence of SAEs/AEs during the screening process 
until such time that it is determined that they will not be participating in this trial. 
Re-screening of a patient is allowed using the specified criteria and timing, if felt to be justified 
by the Investigator. 
6.4 Requirements for Patient Observation 
All patients will be treated and followed on an outpatient basis and will be evaluated and 
discharged from the clinic on days of scheduled study visits*, unless hospitalization is required 
for other reasons or to ensure patient safety.   
IMP must be administered under the close supervision of a physician or other qualified study 
personnel experienced in administration of IV agents, and in an environment where full 
resuscitation facilities are immediately available. Qualified site medical personnel will carefully 
monitor IV infusions to assess safety and tolerability. Such personnel must be available to 
evaluate and treat any AEs, as well as to evaluate whether continued participation of the patient 
in the study is warranted or advisable. 
 Patients will be carefully observed for a minimum of 2 hours following completion of the 
first administration of IMP (C1D1) for evidence of any treatment-related AE(s), and a 
minimum of 1 hour following completion of subsequent infusions (C1D8 and thereafter).   
 At the end of each infusion, the IV line must remain in place during the observation 
period to allow for administration of IV drugs, if necessary.   
*Clinical and laboratory assessments will occur at the frequencies indicated (Section 7). In the event of an AE, 
assessment frequencies may be increased, as clinically indicated.  


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6.5 Drug Treatment Regimen  
6.5.1 Study Start Day  
All patients will receive the initial dose of their assigned IMP on Day 1 of Cycle 1 (C1D1).   
On the day of the first scheduled administration of IMP, and prior to dosing, 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. 
6.5.2 Patient Availability  
The site should calculate study assessment days as well as sample collection dates and times in 
advance of scheduling a patient’s first day of IMP administration, so as to plan accordingly to 
avoid assessment or collection requirements during non-routine clinic times such as weekends, 
holidays, etc.   
Given the schedule of IMP administration and study assessments outlined herein, patients must 
be available each cycle on Days 1, 8, 15, and 22 (± 2 days). In addition, for PK sampling*, 
patients must be available during C1 on D2 and on D4 (± 1 day), and during C2 on D23 and on 
D25 (± 1 day).   
All patients must be available at the end of cycles to determine whether continuation to the next 
cycle is feasible based on tolerability, and at the end of even-numbered cycles* for imaging 
studies to evaluate disease status. These activities may be scheduled on Day 1 of the subsequent 
cycle, prior to dosing, provided assessment results are received and reviewed in advance of 
patient treatment. 
*As of Amendment 5: PK sampling has been omitted; the frequency of disease status evaluations will be per either 
institutional guidelines or Investigator discretion until confirmation of PD.  
6.5.3 IMP Assignments  
Based on randomization assignment, patients will receive one of the following IMPs: 
 Arm A: Sym004 
 Arm B: futuximab 
 Arm C: modotuximab 
6.5.4 Administration Details 
As of Amendment 5: Two (2) patients screened and determined to be eligible have been treated with IMP. The first 
patient deemed eligible prior to the trial discontinuation date (20Dec2018) was randomized to Arm B (futuximab) 
and crossed over to Arm A (Sym004) at the EOC1 per Sponsor decision; the second patient deemed eligible after the 
trial discontinuation date was randomized to Arm B (futuximab), however per Sponsor decision was enrolled to Arm 
A to receive Sym004.  
With this amendment, the doses of IMP to be delivered remain unchanged; however, the pre-Amendment 5 
crossover dose plan as detailed below is no longer in effect.  
6.5.4.1 Dose  
Doses of IMP to be administered are as follows: 


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 Arm A  
o Loading dose: 9 mg/kg on C1D1   
o Maintenance doses: 6 mg/kg weekly (± 2 days), beginning on C1D8 
 Arm B and Arm C  
o Loading dose: 4.5 mg/kg on C1D1   
o Maintenance doses: 3 mg/kg weekly (± 2 days), beginning on C1D8 
Changes in Dose to be Administered: Patients will continue to be treated with IMP at that same 
dose unless dose reduction is necessary due to the occurrence of an AE(s) warranting such 
action. Once the dose of any IMP is reduced, there will be no dose reescalation. There will be no 
intrapatient dose-escalation.  
Dose adjustments should be made in the event of noted weight change (± 10%; less at the site’s 
discretion or if required by institutional procedures) as measured at the beginning of each dosing 
cycle (CxD1). Adjustments may be made in the event of lesser incremental changes in weight 
and/or more frequently at the site's discretion.    
Crossover Dose of Sym004: At the EOC2, ongoing patients from Arm B and Arm C will be 
crossed-over from futuximab or modotuximab to Sym004; crossover may occur prior to the 
EOC2 in the event of early radiographic documentation of PD. 
Upon crossover, Sym004 will be administered at the dose level that contains the corresponding 
dose level of the individual antibody futuximab or modotuximab as was previously being 
administered (prior to crossover). Therefore, patients receiving futuximab or modotuximab at the 
dose of 3 mg/kg or the reduced dose of 1.5 mg/kg will crossover to receive Sym004 at the dose 
of 6 or 3 mg/kg, respectively.  
Sym004 treatment may be initiated at least one week after the latest dose of futuximab or 
modotuximab, unless AEs prevent this according to the protocol retreatment criteria (Section 
6.7). Dosing of Sym004 may continue until further PD is observed. 
6.5.4.2 Route of Administration 
IMP will be administered by the IV route, via an indwelling venous access catheter, utilizing a 
controlled infusion device. Infusion sets must contain an in-line filter (0.22 micron pore size). 
The catheter may be placed into a peripheral vein (if accessible); administration via central 
venous catheter or port (if in place) is allowed. 
In those instances when IMP administration is associated with PK sampling, and administration 
is via peripheral IV catheter, infusions will be delivered into the arm contralateral to that from 
which blood samples for PK analysis are being obtained. 
6.5.4.3 Diluent  
Commercially available sterile 0.9% Sodium Chloride Injection, USP or local equivalent to be 
utilized for IV infusion as the diluent.   


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6.5.4.4 Volume of Infusion 
Volumes of infusions are as follows:  
 Arm A 
o 9 mg/kg dose will be delivered in a total volume of 500 mL 
o 6 mg/kg (or lower) will be delivered in a total volume of 250 mL 
 Arm B and Arm C 
o 4.5 mg/kg dose will be delivered in a total volume of 500 mL 
o 3 mg/kg (or lower) will be delivered in a total volume of 250 mL 
6.5.4.5 Duration of Infusion 
Durations of infusions are as follows: 
 Arm A 
o The initial infusion (9 mg/kg in 500 mL) is to be administered over 1 hour (+ 10 
min). The maximum infusion rate of 500 mL/hour should not be exceeded 
throughout the administration. 
o Subsequent infusions (≤ 6 mg/kg in 250 mL) to be administered over 30 minutes 
(+10 min), with a maximum infusion rate of 500 mL/hour 
 Arm B and Arm C 
o The initial infusion (4.5 mg/kg in 500 mL) is to be administered over 1 hour (+ 10 
min). The maximum infusion rate of 500 mL/hour should not be exceeded 
throughout the administration. 
o Subsequent infusions (≤ 3 mg/kg in 250 mL) to be administered over 30 minutes 
(+10 min), with a maximum infusion rate of 500 mL/hour 
Administration should be at a constant rate using a programmable volumetric infusion pump to 
ensure accuracy of delivery. Start and stop times of each infusion, and any interruptions in 
infusion will be recorded on the patient’s CRF. 
Note: 
In the event of an IRR, instructions for prolongation of the current and subsequent infusions are provided 
(Section 8.2.1).  
6.5.4.6 Schedule  
The schedule of dosing is as follows: 
 Q1W on Day 1, 8, 15, and 22 of each cycle (± 2 days) (4 weeks [28 days] equals 1 dosing 
cycle).   
A weekly dosing schedule is to be maintained, unless delay is required to allow for amelioration 
of toxicities (or in the event of scheduling difficulties associated with weekends, holidays, etc.).   


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6.5.4.7 Premedication for Infusion-Related Reactions 
There is an inherent risk for IRRs with the administration of mAbs, therefore premedication for 
prophylaxis of IRRs will be mandatory prior to each dose of IMP. All patients will be 
premedicated with standard therapies that include a glucocorticoid and an H1 antagonist. Where 
indicated, consideration may be given to include an H2 antagonist and/or acetaminophen. 
Recommended premedication doses are provided (Section 8.1.1.2, Appendix 6). 
Should a patient experience an IRR while in the study, guidelines for premedication following an 
IRR are provided (Section 8.1.1.3). Guidelines for the grading and management of IRRs of all 
severities are also provided (Section 8.2.1, Appendix 6). 
6.5.4.8 Premedication for Dermatologic AEs 
To minimize the risk of dermatologic AEs known to be associated with Sym004, all patients 
receiving IMP will receive, at minimum during Cycle 1 and 2, minocycline or doxycycline, and 
will apply topical therapy to the face and chest with a low potency steroid cream, and 
moisturizing creams/ointments to the hands and body. Use of fragrance-free soaps will be 
encouraged throughout the treatment period. Guidelines for prophylaxis of dermatologic AEs are 
provided (see Section 8.1.2 and Appendix 7). Guidelines for grading and management of 
dermatologic AEs and dose reductions to be implemented in the event of such reactions are also 
provided (Appendix 7). 
6.5.4.9 Premedication for Other AEs 
In the event of other study-drug associated AEs, patients may be premedicated with standard 
therapies at the Investigator’s discretion to reduce the potential for such reactions in the future. 
The Sponsor may implement additional mandatory premedication for all patients should a pattern 
emerge of mild-to-moderate IMP-related AEs (e.g., mucositis, diarrhea) that are amenable to 
prophylaxis with standard agents. 
6.6 Cycle 1 
Cycle 1 of IMP will be administered and completed, if tolerated. Any delays in dosing or dose 
reductions, and the reason for such action must be documented. If an AE is the cause, it must be 
detailed on the Adverse Events page of the patient’s CRF.   
6.7 Continued Treatment  
Upon completion of Cycle 1, in the absence of unacceptable toxicity, documented PD, or another 
criterion for treatment discontinuation (Section 9.1) patients may continue to receive additional 
cycles of IMP unless delay is required to allow for amelioration of AEs. Continued 
administration is at the discretion of the Investigator, provided retreatment guidelines are met.   
6.7.1 Retreatment Guidelines 
Prior to starting any new cycle, a patient must meet the following criteria: 
 ANC ≥ 1,000 per mm3 
 Platelets ≥ 75,000 per mm3 


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 Any ongoing IMP-related AE should NOT meet study discontinuation criteria  
 Any ongoing IMP-related AE should have either ameliorated to ≤ Grade 1 severity, 
returned to baseline status, or resolved, with the exceptions of: 
o Grade 2 alopecia,  
o Grade 2 clinical events that are being adequately controlled with BSC (e.g., 
nausea, vomiting, diarrhea, fatigue, rash), and  
o Asymptomatic laboratory abnormalities that are considered clinically 
insignificant, clinically uncomplicated, and/or that are resolving spontaneously or 
with conventional medical interventions (Grade 2 hypomagnesemia not included 
as an exception; Appendix 8) 
Should the above criteria not be met, dosing must be delayed until further evaluation is 
completed and it is determined that the patient is eligible for continued treatment (for 
information on dose delays, see Section 8.2.2). If a delay is required to allow for amelioration of 
ongoing AEs, additional cycles should be initiated within approximately 2 weeks after the 
completion of the previous cycle, if feasible. 
6.7.2 Cycle 2 
Administration will be at the same dose (unless dose reduction is necessary) and infusion 
duration established for the patient during the previous cycle, and on the same weekly schedule 
provided retreatment guidelines are met.  
6.7.3 Treatment after Cycle 2 
As of Amendment 5: Due to the Sponsor’s decision to discontinue the trial (effective 20Dec2018), the frequency of 
disease status evaluations will be per either institutional guidelines or Investigator discretion.  Enrolled patients (2 
total) have been either crossed over to receive or are receiving Sym004, and may continue to receive Sym004 until 
confirmation of PD. The pre-Amendment 5 plan for continued treatment after Cycle 2 as detailed below will not be 
followed. 
Disease assessment and tumor measurements will be conducted at the EOC2.  Instructions for 
continued dosing are as follows: 
 Patients assigned to Arm A (Sym004) with a documented OR or SD will continue to 
receive Sym004; patients with documented PD at the EOC2 will be discontinued from 
study.   
 Patients assigned to Arm B (futuximab) or Arm C (modotuximab) with a documented OR 
or SD will be crossed-over to receive Sym004; patients with documented PD at the EOC2 
(or prior to the EOC2) will be offered the opportunity to crossover to receive Sym004 or 
will be discontinued from study.  
Upon crossover, Sym004 will be administered at the dose level that contains the corresponding 
dose level of the individual antibody futuximab or modotuximab as was previously being 
administered (prior to crossover) (Table 3). Dosing will be at the same infusion duration 
established for the patient during the previous cycle, and on the same weekly schedule. Sym004 


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treatment may be initiated at least one week after the latest dose of futuximab or modotuximab, 
unless AEs prevent this according to the protocol retreatment criteria. Dosing of Sym004 may 
continue until further PD is observed. 
Table 3: Crossover Dose of Sym004 
Previous Futuximab or Modotuximab Dose 
Crossover Dose of Sym004 
3 mg/kg 
6 mg/kg 
1.5 mg/kg 
3.0 mg/kg 
Abbreviations (in alphabetical order):  kg, kilogram; mg, milligram 
 
6.8 Duration of Study Follow-Up 
Once a criterion for treatment discontinuation is met (Section 9.1), every effort will be made to 
conduct follow-up assessments as detailed below.   
For patients continuing to another therapy, the expectation is that Investigators will show due 
diligence in obtaining adequate follow-up for this study, as indicated. In the event of ongoing 
AEs, Investigators will do their best to continue patient follow-up, based on both patient 
availability and Investigator ability to determine the etiology of noted AEs within the context of 
initiation of any new therapy (i.e., whether the finding is due to IMP or due to the other therapy).   
 EOT evaluations will be conducted within approximately 7 to 10 days following the 
decision to discontinue the patient from treatment with IMP, or before initiation of a new 
treatment, whichever occurs first.   
 1M FUP evaluations will be conducted approximately 30 days (+7 days) following the 
last dose of IMP.  
Note: 
The 1M FUP evaluation should be conducted ≥ 30 days following the last dose of IMP as all 
patients are to be followed for a minimum of 30 days to monitor for the occurrence of suspected 
AEs that are both serious and unexpected.      
 Long-Term FUP for Safety: If an observed toxicity thought to be related to IMP has not 
resolved by the 1M FUP evaluation, an additional follow-up AE assessment will be 
conducted approximately 2 months (may be repeated at 4 months if needed) following 
the last dose of IMP, if feasible, to confirm that the event has either resolved, returned to 
baseline status, or been adequately explained and assessed by the Investigator as chronic 
and/or stable, and that no long-term deleterious effects have become evident*      
*Investigator discretion may be used with respect to the method of contact for this AE assessment.  Clinical 
events may be followed by telephone, e-mail, or in writing; an in-person visit will not be required. 
6.9 Concurrent Treatments and Supportive Care 
Therapy for other ongoing medical conditions, as well as palliative and supportive care for the 
underlying malignancy will be provided prior to and during this trial, as clinically indicated, and 
in accordance with the standard practices of the institution, except as stipulated by study 
eligibility criteria (Section 4.3.2). 


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Other therapies allowed during the conduct of this trial include: 
1. Prophylaxis for IRRs, Dermatologic AEs, and Other IMP-Related AEs: Premedications 
for IRRs are mandatory throughout the study. Premedications for dermatologic AEs are 
mandatory during Cycles 1 and 2, and as indicated thereafter based on the occurrence of 
related AEs.  Premedication for other patient-specific IMP-related reactions may be 
implemented as indicated at the Investigator’s discretion.   
 
2. Treatment of AEs or Concurrent Diseases: Instructions for management of 
hypomagnesemia are provided (Appendix 8). Clinical judgment should be used in the 
treatment of any other treatment-related AEs or concurrent diseases/conditions that 
require management during the study and follow-up period.   
 
3. Blood Products and Growth Factors: Blood products and hematopoietic growth factor use 
is allowed, as clinically indicated.   
 
4. Radiotherapy: Radiotherapy for pain control against non-target lesions, provided it does 
not substantially influence bone marrow function is allowed.   
5. Bisphosphonates and denosumab: Bisphosphonates and denosumab for bone metastases 
and other skeletal conditions are allowed, provided the patient is on a stable dose for at 
least 2 months prior to study start and remains on the stable dose while receiving study 
treatment. 
6. Immunosuppressive or systemic hormonal therapy not exceeding 10 mg daily prednisone 
equivalent is allowed, see Section 4.3.2 for additional details. 
Information on all concomitant therapies administered, as well as other interventions or 
procedures occurring during the trial period, must be recorded on the appropriate page of the 
patient’s CRF. 


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7 
STUDY ASSESSMENTS   
As of Amendment 5: Due to the Sponsor’s decision to discontinue the trial (effective 20Dec2018), the original trial 
design is no longer applicable. Only clinical safety-related evaluations will be conducted. The visit schedule for the 
treatment period will apply as specified below, with indicated exceptions. Once IMP has been discontinued, an EOT 
visit will be performed within 7 to 10 days from the decision to withdraw treatment, and a 1M FUP visit will be 
performed 30 days (+7 days) following the last dose.  
The pre-Amendment 5 study assessment schedule was as follows: 
All patients will be evaluated by clinical, laboratory, and other diagnostic assessments 
throughout the study.  All efforts should be made to perform assessments as close as possible to 
the scheduled timepoints. The projection of visit days within each cycle should be made from 
Day 1 of the respective cycle.   
Visit windows are provided below. Study assessments are to be performed as follows: 
 Genomic analysis by Guardant360 (required for eligibility at prescreening) is to be 
performed within 28 days prior to first administration of IMP; this window may be 
extended to allow for receipt of analysis result (Section 7.3.1) 
 Screening disease imaging studies may be used to document tumor status if performed 
within 14 days prior to first administration of IMP. 
 Screening safety evaluations are to be performed within 14 days prior to first 
administration of IMP, unless otherwise specified (for exceptions see Section 7.1.1, 
Section 7.2.7.6, Section 7.3).   
 The day of first administration of IMP will be considered Day 1 of study.   
 On-study evaluations (including laboratory assessments; beginning at C1D1) are to be 
performed on or about the indicated visit day (i.e., ± 2 working days). A slightly longer 
allowance for routine assessments is permissible in the event of scheduling difficulties 
associated with weekends, holidays, etc.   
 End of Cycle assessments may be conducted at any time during the week prior to Day 1 
of the next cycle, including on Day 1 of the next cycle, provided results are available 
prior to dosing. 
 EOT* evaluations are to be performed within approximately 7 to 10 days following the 
decision to discontinue treatment, or before initiation of a new treatment, whichever 
occurs first.   
 1M FUP* evaluations are to be performed approximately 30 days (+7 days) following the 
last dose of IMP (i.e., as all patients are to be followed for a minimum of 30 days after 
IMP discontinuation to monitor for the occurrence of AEs). 
*When a patient discontinues treatment with IMP, for any reason, every effort will be made to collect 
routine EOT evaluations as well as subsequent 1M FUP evaluations, per protocol, until all protocol-
specified assessments have been conducted.   


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If during the study, significant changes in clinical or laboratory findings are noted, additional 
monitoring or on-study assessments may be undertaken by the Investigator, or requested by the 
Sponsor (or designee), to determine both the relevance of the finding(s) and the duration of the 
event(s).  
Refer to Appendix 9 and Appendix 10 for the maximum total blood collection volumes and the 
schedule of assessments, respectively. 
7.1 Consent and Medical History 
7.1.1 Signing of Informed Consent 
(Within 28 days prior to 1st dose; may be extended to allow for receipt of genomic analysis 
results, or collection of sample for genomic analysis may be performed under a separate 
ICF; see Section 7.3.1) 
 Prior to Screening 
Note:  
All patients must sign an IRB/EC-approved ICF prior to submitting to any protocol-related procedure, 
unless such testing was performed previously as part of the routine clinical management of the patient.  
A copy of the fully executed ICF will be given to the patient. 
7.1.2 Assessment of Eligibility  
(Eligibility assessment to be reviewed by Third-Party Investigator Reviewers and the 
Sponsor’s Medical Monitor(s) (or designee) prior to randomization of each patient) 
 Prescreening/Screening 
7.1.3 Demography  
(To include date of birth, sex, race, and ethnicity as allowed in country of study) 
 Screening 
7.1.4 Past Medical History  
(To include prior and ongoing medical illnesses and conditions, prior surgical procedures 
[not related to the primary diagnosis]) 
 Screening 
 C1D1 (prior to dosing)  
7.1.5 History of mCRC  
(To include diagnoses of primary malignancy and metastases, prior CRC treatments with 
surgical procedures, radiation therapies, systemic drug therapies including those specified in 
the protocol inclusion criteria) 
 Screening 
7.2 Safety Assessments  
(To be performed within 14 days prior to first dose of IMP unless otherwise specified) 


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7.2.1 Medication and Procedure Surveys  
(To include all medications taken other than IMP and all procedures performed during trial.  
For medications: Include name, indication for use, route of administration, start and stop 
dates or if ongoing at 1M FUP Visit. For procedures: Include date and reason for 
procedure.  Corresponding illness or condition must appear on the Medical History or 
Adverse Event pages of the CRF, as appropriate) 
 Prior Medication/Procedure Surveys 
o Screening (to assess eligibility) 
o For 14 days prior to first dose  
 Concomitant Medication/Procedure Surveys  
o Throughout the study 
o For 30 days following last dose 
7.2.2 Adverse Event Reporting  
 Starting from signing of informed consent*  
 Throughout the study 
 For 30 days following last dose  
 Long-Term FUP for Safety 
o For AEs ongoing at the 1M FUP 
 For 2 to 4 months following last dose, if events related to IMP persist**#   
 As clinically indicated 
*To detail any symptoms that may be present prior to first dose.  Patients who sign informed consent and are 
subsequently deemed to be screen failures will be followed for the occurrence of SAEs/AEs until it is determined 
that they will not be participating in the trial. 
**To confirm that events have resolved, returned to baseline status, or been adequately explained   
#Investigator discretion may be used with respect to the method of contact for this AE assessment. Clinical 
events may be followed by telephone, e-mail, or in writing; an in-person visit will not be required. 
7.2.3 Performance Status Evaluation 
(To be assessed by ECOG score; Appendix 1) 
 Screening 
 Cycle 1 
o Day 1 (within ≤ 7 working days prior to dosing)* 
 Each cycle thereafter 
o Day 1 (prior to dosing) 
 EOT  
 1M FUP 
 As clinically indicated 


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*Need not be assessed prior to the first dose of Cycle 1 if ≤ 7 days since screening 
7.2.4 Vital Signs  
(Vital signs to include temperature, pulse, respiratory rate, and blood pressure) 
 Screening 
 Cycle 1 
o 
Day 1 
 
Start of infusion (SOI) 
 
End of infusion (EOI) (± 5 min)   
o 
Day 8, 15, and 22 (prior to dosing)  
 Each cycle thereafter 
o 
Day 1, 8, 15, and 22 (prior to dosing) 
 EOT  
 1M FUP 
 As clinically indicated 
7.2.5 
Physical Examination  
(To include measurement of height and weight at screening, and weight** during  physical 
examinations thereafter; assessment of the skin is to be performed during each physical 
examination) 
 Screening 
 Cycle 1 
o 
Day 1 (within ≤ 7 working days prior to dosing)* 
 Each cycle thereafter 
o 
Day 1 (prior to dosing) 
 EOT  
 1M FUP 
 As clinically indicated 
* Need not be assessed prior to the first dose of Cycle 1 if ≤ 7 days since screening 
** Dose adjustments may be made in the event of noted weight change (± 10% [less at the site’s discretion or if 
required by institutional procedures]) as measured at the beginning of each dosing cycle. Adjustments may be 
made in the event of lesser incremental changes in weight and more frequently at the site's discretion.   
7.2.6 Dermatologic Examination 
(Timepoints shown are in addition to skin assessments performed as part of scheduled physical 
examinations; intention is to achieve weekly assessment during the treatment period) 
 Screening 
 Cycle 1 
o Day 8, 15, and 22 (prior to dosing) 
 Each cycle thereafter 


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o Day 8, 15, and 22 (prior to dosing) 
 As clinically indicated 
7.2.7 Laboratory Assessments and Pregnancy Test (Local Laboratory) 
All routine laboratory analyses will be performed at a laboratory facility local to the trial site.  
Sponsor (or designee) must be provided with 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 obtained at scheduled visits and analyzed (Table 4, Appendix 10). 
Results must be available and assessed prior to dosing, when sampling is scheduled on days of 
dosing. 
 
Table 4: Schedule of Safety Blood and Urine Analyses 
Sample Analysis 
Screen 
Cycle 1 
Cycles Thereafter 
EOT 
1M 
FUP 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
Hematology Panel 
X 
X1 
 
X 
 
X 
 
 
 
X 
X 
Biochemistry Panel 
X 
X1 
 
X 
 
X 
 
 
 
X 
X 
Serum Mg, Ca, K* 
 
 
X 
 
X 
 
X 
X 
X 
 
 
Coagulation Panel 
X 
X1 
 
 
 
C2/3 
only 
 
 
 
X 
X 
Urinalysis 
X 
X1 
 
 
 
C2/3 
only 
 
 
 
X 
X 
Pregnancy Test 
X 
X 
 
 
 
 
 
 
 
X 
 
Abbreviations (in alphabetical order): Ca, calcium; D, day; EOT, end of treatment; K, potassium; Mg, magnesium;1M FUP, 1-month 
follow-up 
*In addition to magnesium, calcium, and potassium monitoring included with standard biochemistry panel 
1Does not need to be performed prior to C1D1, if performed during screening ≤7 days from C1D1 
In the event of laboratory abnormalities of concern, the evaluation frequency should be increased to include additional 
evaluations between the scheduled assessments, as clinically indicated 
 
7.2.7.1 Hematology Panel  
(To include complete blood count [CBC] with red blood cell [RBC] count, hemoglobin, 
hematocrit, white blood cell [WBC] count with differential, ANC, and platelet count) 
 Screening 
 Cycle 1 
o Day 1 (within ≤ 7 working days prior to dosing)* 
o Day 15 (prior to dosing) 
 Each cycle thereafter 
o Day 1 (prior to dosing) 
 EOT  
 1M FUP 
 As clinically indicated**   


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*Need not be performed prior to the first dose of Cycle 1 if ≤ 7 days since screening 
**In the event of hematologic toxicity, the evaluation frequency should be increased to include additional 
evaluations between the scheduled assessments, as clinically indicated. 
7.2.7.2 Biochemistry Panel  
(Fasting not required; to include sodium, potassium, chloride, bicarbonate or carbon 
dioxide, blood urea nitrogen, creatinine, glucose, bilirubin [total and direct], AST, ALT, 
ALP, calcium, magnesium, phosphorus, albumin, total protein, uric acid, amylase, lipase, 
and creatine kinase)  
 Screening 
 Cycle 1 
o Day 1 (within ≤ 7 working days prior to dosing)* 
o Day 15 (prior to dosing) 
 Each cycle thereafter 
o Day 1 (prior to dosing) 
 EOT  
 1M FUP 
 As clinically indicated**   
*Need not be performed prior to the first dose of Cycle 1 if ≤ 7 days since screening 
**In the event of significant serum chemistry abnormalities, the evaluation frequency should be increased to 
include additional evaluations between the scheduled assessments, as clinically indicated.  CS electrolyte 
abnormalities should be corrected prior to dosing. 
7.2.7.3 Serum Magnesium, Calcium, and Potassium 
(Timepoints shown are in addition to testing performed as part of scheduled biochemistry 
panels; intention is to achieve weekly magnesium, calcium, and potassium testing during the 
treatment period) 
 Screening 
 Cycle 1 
o Day 8 and 22 (prior to dosing) 
 Each cycle thereafter 
o Day 8, 15, and 22 (prior to dosing) 
 As clinically indicated*   
* An ECG should be performed in the event of ≥ Grade 3 hypomagnesemia and if otherwise clinically indicated. 
7.2.7.4 Coagulation Panel 
(To include partial thromboplastin time [PTT] or activated PTT [aPTT], prothrombin time 
[PT], international normalized ratio [INR]) 
 Screening 
 Cycle 1 


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o Day 1 (within ≤ 7 working days prior to dosing)* 
 Cycle 2 and 3  
o Day 1 (prior to dosing) 
 EOT  
 1M FUP  
 As clinically indicated   
*Need not be performed prior to the first dose of Cycle 1 if ≤ 7 days since screening 
7.2.7.5 Urinalysis   
(Multipanel chemical test strips are acceptable and should include assessment of specific 
gravity, pH, protein, glucose, ketones, leukocytes, nitrite, bilirubin, urobilinogen, and blood.  
Microscopic examination of sediment, if clinically indicated, to include assessment of cells 
[WBC and RBC] per high power field and casts) 
 Screening 
 Cycle 1 
o Day 1 (within ≤ 7 working days prior to dosing)* 
 Cycle 2 and 3  
o Day 1 (prior to dosing) 
 EOT  
 1M FUP  
 As clinically indicated   
*Need not be performed prior to the first dose of Cycle 1 if ≤ 7 days since screening 
7.2.7.6 Pregnancy Testing 
(Beta-human chorionic gonadotropin [β-hCG] in WOCBP; serum at screening, serum or 
urine thereafter; negative test must be confirmed within 2 working days prior to first dose of 
IMP) 
 Screening  
 Cycle 1 
o Day 1 (within ≤ 2 working days prior to dosing) 
 EOT 
 As clinically indicated (frequency may be increased based on local requirements) 
7.2.8 Electrocardiogram (ECG)  
(To include standard 12-lead ECG with measurement of PR interval, QRS duration, QT 
interval, and QTc interval [msec], as well as heart rate) 
(To be evaluated locally; ECGs should be performed using the same calibrated instrument at 
each study center, and should be conducted after the patient has been supine (or semi-
recumbent) for > 10 minutes.)  


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(Patients with a QTc ≥ 500 msec should not be treated; dosing should be delayed.)  
 Screening 
 Cycle 1  
o Day 1 (within ≤ 7 working days prior to dosing)* 
 Cycle 2 and 3 
o Day 1 (prior to dosing) 
 EOT 
 As clinically indicated** 
*Need not be performed prior to the first dose of Cycle 1 if ≤ 7 days since screening  
**In the event of significant electrolyte abnormalities, the evaluation frequency should be increased to include 
additional evaluations between the scheduled assessments, as clinically indicated.  An ECG should be 
performed in the event of ≥ Grade 3 hypomagnesemia. 
When evaluating QTc interval, baseline should be considered the ECG immediate preceding dosing on the day 
of assessment.   
7.3 Specialty Assessments  
As of Amendment 5: Due to the Sponsor’s decision to discontinue the trial (effective 20Dec2018), only clinical 
safety-related evaluations will be conducted.  Of the Specialty Assessments detailed below, ADA and samples for 
exploratory PK and PD assessments (in peripheral blood, skin biopsies, and tumor biopsies) will not be collected.  
Genomic samples for eligibility assessment were obtained at prescreening and analyzed; however post-dosing 
genomic samples will not be collected. 
Note:  Samples for ADA and samples for exploratory PK and PD assessments, if collected prior to implementation 
of this amendment, will not be analyzed and will be destroyed. 
The pre-Amendment 5 specialty assessments were as follows: 
Laboratory analyses detailed below will be performed at centralized Specialty Laboratory 
facilities.  A detailed laboratory manual specifying sample collection, handling, storage, and 
shipment will be provided to the trial sites; retention time for specimens will be specified therein. 
Blood samples, skin biopsies, and tumor biopsies will be taken according to the schedule shown 
(Table 5; Appendix 10). 
Every effort will be made to collect samples at the timepoints specified.  All analyses will be 
related to and used only with the data collected in the present trial or other Sym004-related trials, 
and the identity of the patient will remain confidential. The analyses will not have any medical 
consequences for the patient or their relatives. 
 
 
 


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Table 5: Timepoints for Specialty Assessments (Arm A, Arm B, and Arm C) 
Sample Time 
Cycle 1 
Cycle 2 
C Thereafter 
EOT 
1M 
FUP 
D1 
D4 
+24h 
D8 
D15 
D22 
D1 
D22 
D25 
+24h 
D1 
D15 
ADA (peripheral blood) 
Prior to SOI 
X 
 
 
X 
 
X 
 
 
Odd # C 
 
 
 
Visit Day 
 
 
 
 
 
 
 
 
 
 
X 
X 
PK (peripheral blood) 
Prior to SOI 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
 
 
EOI (+ 10m) 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
 
 
6h > EOI (+ 1h) 
X 
 
 
 
 
 
X 
 
 
 
 
 
24h > EOI (+ 8h) 
D2 
 
 
 
 
 
D23 
 
 
 
 
 
Visit Day 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
Genomic Analysis (peripheral blood)  
Visit Day 
prescreen* 
 
 
 
 
 
 
X** 
 
 
X*** 
 
Pharmacodynamic Analyses (after confirmation of eligibility)  
Peripheral blood 
screening/ 
pre-C1D1 
 
 
 
 
 
 
X**,^ 
 
 
X*** 
 
Skin biopsy 
screening/ 
pre-C1D1 
 
 
 
 
EOC1^ 
 
X**,^ 
 
 
 
 
Tumor biopsy  
screening/ 
pre-C1D1 
 
 
 
 
 
 
X**,^ 
 
 
 
 
Abbreviations (in alphabetical order): ADA, anti-drug antibody; C, cycle(s); D, day; EOI, end of infusion; EOT, end of treatment; h, hour; m, 
minutes; 1M FUP, 1-month follow-up; SOI, start of infusion 
*required at prescreening for eligibility 
**preferred day of sampling; coincides with “prior to crossover” for patients in Arm B and Arm C 
***EOT with Sym004; need not be repeated if patient is discontinuing at the EOC2 
^ End of Cycle assessment may be conducted at any time during the week prior to Day 1 of the next cycle, including on Day 1 of the next 
cycle prior to dosing 
As of Amendment 5:  All specialty assessments have been omitted (effective 20Dec2018) with the exception of prescreening 
genomic sampling for eligibility assessment (*). 
7.3.1 Immunogenicity Assessment (Specialty Laboratory)   
As of Amendment 5: Immunogenicity assessments have been omitted.  Immunogenicity assessments were initially 
planned as follows: 
(To assess for formation of ADA; serum to be isolated)   
(All samples must be taken prior to the IMP infusion of that visit. If a collected serum sample is 
inadequate or insufficient for ADA analysis, analysis may be done using serum from a PK 
sample from the same timepoint, if available) 
 Cycle 1 
o Day 1 (prior to dosing) 
o Day 15 (prior to dosing) 
 Cycle 2 
o Day 1 (prior to dosing) 
 Odd numbered cycles thereafter 


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o Day 1 (prior to dosing) 
 EOT  
 1M FUP 
Note: 
Whole blood (~ 5 mL) to be collected in serum acquisition tubes at each of the indicated timepoints.   
7.3.2 Exploratory Pharmacokinetic Assessment (Specialty Laboratory)  
As of Amendment 5: Exploratory PK assessments have been omitted.  Exploratory PK assessments were initially 
planned as follows: 
(To support determination of the AUCinf, AUC0-168h, t½, CL, CLss, Vd, Ctrough (SOI) and Cmax 
(EOI) concentrations for Sym004, futuximab and modotuximab for exploratory purposes. Data 
will also enable population PK modeling for further PK characterization; serum to be isolated) 
(No additional samples will be collected without formal amendment to this protocol. If a 
collected serum sample is inadequate or insufficient for PK analysis, the analysis may be done 
using serum from an ADA sample from the same timepoint, if available) 
(If no infusion is planned on a sampling day, the “SOI” sample should be taken during the 
visit. The exact time point of PK sampling should be noted in the CRF. In case no dosing is 
planned for C2D22, the samples for the PK profile at EOI and 6 hours after EOI, D23, and 
D25 should be skipped.) 
(In case of crossover from futuximab or modotuximab to Sym004 before EOC2, sampling 
should continue according to the schedule outlined.) 
 Cycle 1 
o Day 1  
 
SOI 
 
EOI 
 
6 hours after EOI 
o Day 2 (24 hours after EOI) 
o Day 4 (± 24 hours) 
o Day 8 (prior to dosing and at the EOI) 
o Day 15 (prior to dosing and at the EOI) 
o Day 22 (prior to dosing and at the EOI) 
 Cycle 2 
o Day 1 (prior to dosing and at the EOI) 
o Day 22 
 
SOI 
 
EOI 
 
6 hours after EOI 
o Day 23 (24 hours after EOI) 
o Day 25 (± 24 hours) 
o Day 29 (EOC2 or equivalent to C3D1 SOI for patients continuing on Sym004) 
 Cycles thereafter (patients continuing on or crossing over to Sym004) 


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o Day 1 (prior to dosing and at the EOI) 
o Day 15 (prior to dosing and at the EOI) 
 EOT 
 1M FUP  
Note: 
Whole blood (~ 5 mL) to be collected in serum acquisition tubes at each of the indicated timepoints.    
7.3.3 Genomic Analysis in Peripheral Blood (Specialty Laboratory)  
As of Amendment 5:  Genomic assessments have been omitted with the exception of prescreening genomic 
sampling for eligibility assessment (*).  Genomic assessments were initially planned as follows: 
(To be performed at prescreening for eligibility determination; within 28 days prior to first 
dose of IMP; may be extended to allow for receipt of genomic analysis results. Peripheral 
blood to be collected) 
 Prescreening (for eligibility)*  
 EOC2 
o Day 25 (± 24 hours) (coincides with PK sampling and pharmacodynamic 
sampling for all patients and “prior to crossover” for patients in Arm B and Arm 
C) 
 EOT with Sym004 (need not be repeated if patient is discontinuing at the EOC2) 
 At the time of radiographically confirmed PD if different from the above 
Note: 
Whole blood (~ 2 × 10 mL) to be collected at each timepoint (plus additional ~ 2 × 10 mL at 
prescreening to be stored for assay validation purposes); for assessment of ctDNA by Guardant360; 
where blood sample is to be drawn on the day of biopsy (skin; tumor if performed), blood collection to 
occur prior to performing biopsy procedure(s)   
7.3.4 Pharmacodynamic Analyses (Specialty Laboratory) 
As of Amendment 5:  Pharmacodynamic assessments (including collection of peripheral blood, skin biopsies, and 
tumor biopsies) have been omitted.   Pharmacodynamic assessments were initially planned as follows: 
(To be performed after eligibility has been confirmed) 
The purpose of pharmacodynamic assessments is to develop an approach for the identification 
and validation of biomarkers that may predict which patients are likely to respond to Sym004, 
and that may change with the possible development of acquired resistance. 
Analysis may include biomarkers that are unknown or have not been included in the scientific 
hypotheses of this trial, but that, during the collection of data from this trial, may emerge as 
indicators related to Sym004 safety, efficacy, or mechanism of action.  
All analyses will be related to and used only in connection with the data collected in the present 
trial and the development of Sym004.  The identity of the patient will remain confidential. The 
analyses will not have any medical consequences for the patient or their relatives. 
Residuals from samples collected will be stored for up to 15 years after completion of the trial, 
where after all samples will be destroyed. 


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7.3.4.1 Peripheral Blood 
(Samples will be assessed for serum proteins and other potential biomarkers)  
 Screening (after confirmation of eligibility)* 
 EOC2** 
o Day 25 (± 24 hours) (preferred day of sampling; coincides with PK sampling 
and genomic analysis for all patients and “prior to crossover” for patients in 
Arm B and Arm C) 
 EOT with Sym004 (need not be repeated if patient is discontinuing at the EOC2) 
 At the time of radiographically confirmed PD if different from the above 
*Screening sampling may be conducted at any time prior to C1D1, including on C1D1 prior to dosing. 
**End of Cycle sampling may be conducted at any time during the week prior to Day 1 of the next cycle, including 
on Day 1 of the next cycle, prior to dosing. 
Note: Whole blood (~ 1 × 20 mL) to be collected at each timepoint; where blood sample is to be drawn on the 
day of biopsy (skin; tumor if performed), blood collection to occur prior to performing biopsy 
procedure(s). 
7.3.4.2 Skin Biopsies 
(Biopsy specimens to be obtained using standard techniques and formalin-fixed, paraffin-
embedded according to standard laboratory techniques. Skin biopsies are requested from a 
rash-free area) 
(Samples will be assessed for various parameters, which may include but are not limited to 
EGFR expression and downstream signaling, markers(s) of proliferation, genomic alterations, 
etc.) 
 
Screening (after confirmation of eligibility)* 
 
EOC1** 
 
EOC2** 
o Day 25 (± 24 hours) (preferred day of sampling; coincides with PK sampling and 
genomic analysis for all patients and “prior to crossover” for patients in Arm B 
and Arm C) 
*Screening sampling may be conducted at any time prior to C1D1, including on C1D1 prior to dosing. 
**End of Cycle sampling may be conducted at any time during the week prior to Day 1 of the next cycle, including 
on Day 1 of the next cycle, prior to dosing. 
 
Note: Procedure to be performed after collecting blood sample for pharmacodynamic analyses.  
7.3.4.3 Tumor Biopsies  
(Samples will be assessed for various parameters, which may include but are not limited to 
EGFR expression and downstream signaling, markers(s) of proliferation, genomic alterations, 
etc.) Tissue obtained will be cultured in vitro in order to derive primary tumor and non-tumor 
cell lines. Selected tumor tissue will also be used for engraftment in immuno-compromised 
mice. Once the tumor is established, it will be expanded by engrafting in multiple mouse 


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recipients, followed by cryopreservation to be used for subsequent biomarker, genotyping, and 
preclinical drug evaluation studies by the Sponsor.   
 Screening (after confirmation of eligibility)* 
 EOC2** 
o Day 25 (± 24 hours) (preferred day of sampling; coincides with PK sampling 
and genomic analysis for all patients and “prior to crossover” for patients in 
Arm B and Arm C) 
*Screening sampling may be conducted at any time prior to C1D1, including on C1D1 prior to dosing. 
**End of Cycle sampling may be conducted at any time during the week prior to Day 1 of the next cycle, including 
on Day 1 of the next cycle, prior to dosing. 
Note: Tumor tissue for fresh/frozen cells to be collected at each timepoint; procedure to be performed after 
collecting blood samples for genomic and pharmacodynamic analyses.  
 
Tumor biopsies to include core samples (if feasible, 3 at screening, 2 at EOC2) of a locally 
recurrent or metastatic lesion; to be performed with minimal morbidity to the patient by a 
percutaneous core needle biopsy 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 handled as 
directed. A detailed laboratory manual specifying sample collection, handling, storage, and 
shipment will be provided to the trial sites.  
7.4 Disease Assessments 
7.4.1 Diagnostic Imaging for Tumor Measurements (Local Assessment) 
(Imaging studies may be used to document tumor status at screening if performed within 14 
days prior to first dose of IMP) 
To include diagnostic imaging by CT or MRI of the chest, abdomen and pelvis, and other sites 
as indicated based on suspected tumor location and clinical judgment to assess the status of 
the underlying malignancy. Use of contrast is preferred but is at the discretion of the 
Investigator, as medically indicated.  
The same method(s) of disease evaluation and the same technique should be used throughout 
the study. Additional imaging (such as bone scan) must be performed when other areas of 
disease are suspected.   
For all imaging timepoints, 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 lesions; non-
target lesions including size, location, and type; any new lesions noted during trial, including 
size, location, and type (nodal/non-nodal). 
 Screening 
 As of Amendment 5: frequency per either institutional guidelines or Investigator 
discretion until confirmation of PD 
Patients receiving Sym004 with confirmed PD will be discontinued from further treatment so 
that alternative management of their malignancy may be considered. Patients receiving 


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futuximab or modotuximab with confirmed PD will be offered the opportunity to crossover to 
receive Sym004 or will be discontinued from further treatment so that alternative management 
of their malignancy may be considered. 
Once PD is documented and treatment is discontinued and/or another therapeutic intervention 
is initiated, no further disease assessments will be required.   
Imaging data (imaging studies and derived assessments) will be stored according to usual 
practice by the sites and will be available upon request for potential review by the Sponsor 
or an independent radiology reviewer.  
7.4.2 Response Assessment (Local Assessment) 
(To be assessed by the Investigator or qualified designee as per RECIST v1.1; to be noted at 
each evaluation point as CR, PR, SD, PD, or Not Evaluable [NE] for patient management 
purposes and to make decisions on continued study treatment)  
 As of Amendment 5: frequency per either institutional guidelines or Investigator 
discretion until confirmation of PD 
Standard response criteria will be applied (RECIST v1.1, Appendix 5).   
 


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8 
MANAGEMENT OF TOXICITY 
Comprehensive assessments of any toxicity experienced by the patient will be performed 
throughout the course of this study. The Principal Investigator, Sub-Investigator, or designated 
health professional must be available throughout the course of the study to evaluate and treat any 
AE(s), as well as to evaluate whether continued participation in the trial is warranted or 
advisable.  
If, at any point during the study, significant changes occur in either the patient’s clinical status or 
laboratory assessments, such changes will be followed until the abnormality either resolves, 
returns to baseline status, or is adequately explained. 
Anticipated toxicities that may be experienced with IMPs are detailed in this protocol (Section 
2.5, Section 11), as well as in the IB. Patients will be evaluated throughout the course of the trial 
for evidence of acute as well as delayed and/or cumulative toxicities.   
If a significant toxicity thought to be related to IMP is experienced at any point during the 
patient’s participation in the study, the Investigator will determine appropriate management, 
including determining whether that toxicity is such that a change in premedication or a dose 
modification option such as infusion prolongation, temporary dose delay or dose reduction is 
warranted. Toxicities where management requires discontinuation from study treatment are 
detailed in Section 9.1.   
8.1 Premedication  
8.1.1 Premedication for Infusion-Related Reactions 
8.1.1.1 Infusion-Related Reactions 
There is an inherent risk for IRRs with the administration of mAbs. An IRR is defined as an AE 
occurring during the IMP infusion and up to 24 hours after the EOI, which is assessed by the 
Investigator to be related to the infusion. Signs and symptoms of IRRs may include but are not 
limited to:   
 facial flushing and swelling 
 rash including urticaria  
 headache 
 fever  
 chills, rigors 
 diaphoresis 
 tachycardia  
 hypotension 
 nausea 
 dry mouth  
 chest/back/abdominal pain/discomfort 
 chest and throat tightness  
 shortness of breath 
 cough, wheeze, stridor  
 hypoxia 
 bronchospasm 


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 laryngeal edema  
 angioedema  
 shock  
The risk of an IRR is highest for the first administration of a mAb and diminishes with 
subsequent infusions. 
If an IRR occurs, it should be classified according to the CTCAE v5. Guidelines for grading and 
management of IRRs of all severities are provided (Appendix 6). In each case, the Investigator 
should use best clinical judgment in managing such reactions. All ≥ Grade 3 IRRs must be 
reported promptly to the Sponsor (or designee).  
8.1.1.2 Premedication for Infusion-Related Reactions   
Premedication for prophylaxis of IRRs will be mandatory prior to each dose of IMP.    
The following agents are required; recommended doses are provided:    
 Glucocorticoid therapy: equivalent to 80-100 mg IV methylprednisolone, approximately 
0.5 to 2 hours prior to the start of Sym004 infusion 
 Antihistamine (H1 antagonist): equivalent to 25-50 mg IV diphenhydramine, 
approximately 0.5 hours prior to the start of Sym004 infusion 
The following agents are optional, and may be added to the premedication regimen at any time 
during the study at the Investigator’s discretion; recommended doses are provided: 
 Antihistamine (H2 antagonist): equivalent to 50 mg IV ranitidine or 30 mg IV famotidine 
or equivalent, approximately 0.5 hours prior to the start of Sym004 infusion 
 Acetaminophen: 1000 mg IV (where available, or PO), or equivalent, approximately 0.5 
hours prior to the start of Sym04 infusion 
Note:  Doses may be adjusted based on institutional practices. Administration of oral dexamethasone, 10 mg po, (or 
equivalent) 12 and 6 hours prior to administration of Sym004 is permissible in patients experiencing IRRs or 
if an increased incidence or severity of IRRs is observed. 
8.1.1.3 Premedication for Infusion-Related Reactions (Following an IRR) 
For IRRs while in the study, the following premedication instructions are provided (for infusion 
prolongation instructions following an IRR, see Section 8.2.1.1): 
 For Grade 1, Grade 2, or Grade 3 reactions, consider additional premedication or 
adjustment to premedications for subsequent infusions.   
 For Grade 4 reactions, not applicable as no further treatment with IMP is allowed. 
8.1.2 Premedication for Dermatologic Toxicity 
To minimize the risk of dermatologic toxicity, all patients will receive at minimum during Cycle 
1 and 2 minocycline or doxycycline, and will apply topical therapy to the face and chest with a 
low potency steroid cream, and moisturizing creams/ointments to the hands and body. Use of 


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fragrance-free soaps will be encouraged throughout the treatment period. Guidelines for grading 
and management of dermatologic AEs of all severities are provided (Appendix 7). 
8.1.3 Premedication for other IMP-Related Toxicities 
Following the first dose, should a patient experience symptoms suggestive of other mild-to-
moderate IMP-related reactions (e.g., nausea, vomiting, diarrhea, etc.), the patient may be 
premedicated with standard therapies to reduce the potential for such reactions in the future.   
8.1.4 Institution of Mandatory Premedications 
Based on ongoing review of patient safety data, the Sponsor may implement additional 
mandatory premedication for all patients treated in this study should a pattern emerge of other 
mild-to-moderate IMP-related reactions (e.g., IRRs and/or any other trends in IMP-related 
toxicities) that are amenable to prophylaxis with standard agents. Such action will occur 
following discussions between the Investigator(s) and the Sponsor's Medical Representative(s). 
Any medications administered for either prophylaxis or therapy of signs/symptoms related to 
IMP will be documented on the appropriate page of the CRF.   
8.2 Dose Modification Options 
8.2.1 Prolongation of Infusion Duration 
The option to prolong IMP infusion is most applicable during or following an IRR.   
8.2.1.1 Instructions for Infusion Prolongation  
For IRRs, the following infusion prolongation instructions are provided (for premedication 
instructions, see Section 8.1.1.   
 For Grade 1 reactions, the infusion may be slowed to 50% of the prior rate such that the 
remaining dose to be delivered is administered 2× longer than the amount of time that 
was initially scheduled.     
 For Grade 2 reactions, the infusion should be interrupted for a minimum of 30 minutes, 
and at least until there is either amelioration to ≤ Grade 1 severity or return to baseline 
status.  Supportive care should be provided. The infusion should then be restarted at 50% 
of the prior rate, as described above.  Subsequent infusions should be administered at the 
prolonged rate. 
 For Grade 3 reactions, the infusion will be STOPPED and supportive care will be 
provided. The patient will be either discontinued from treatment, or must receive 
subsequent treatments at a reduced dose and at a prolonged infusion rate (slowed to 50% 
of the prior rate or longer). 
 For Grade 4 reactions, the infusion will be STOPPED and supportive care will be 
provided. The patient will be permanently discontinued from treatment. 
In all cases, the Investigator should use best clinical judgment in managing such reactions.   


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All infusion interruptions and subsequent prolongations, including modified infusion times, as 
well as the toxicity that necessitated them, will be clearly documented on the appropriate page of 
the patient’s CRF. 
Note: 
Any assessments to be performed or samples to be collected (e.g., vital signs, PK) at the end of or 
following the EOI will still be performed or collected beginning at the delayed EOI timepoint 
Guidelines for the grading and management of IRRs of all severities are provided (Appendix 6). 
8.2.1.2 Treatment Following Infusion Prolongation 
To enhance patient safety following an infusion prolongation, subsequent infusions will be 
administered at the prolonged rate. 
8.2.2 Dose Delay 
All delays of IMP must be documented on the appropriate page of the patient’s CRF.  
8.2.2.1 Delay Between Dosing 
AEs that warrant dose modification may be managed by delay in dosing, provided they do not 
meet the criteria for study discontinuation (Section 9.1).   
In such cases, the period between any 2 scheduled doses may be extended as indicated to allow 
for amelioration of the toxicity. Such delays will be considered an extension within the current 
cycle. 
8.2.2.2 Retreatment Following Dose Delay 
For AEs that are managed by dose delay, dosing may be restarted at the same dose, as clinically 
indicated.  However, administration of IMP may only be restarted upon amelioration to ≤ Grade 
1, return to baseline status, or resolution of the observed toxicity, and provided all other 
retreatment criteria are met (see Section 6.7.1). 
8.2.3 Dose Reduction  
All reductions of IMP dose must be documented on the appropriate page of the patient’s CRF.  
Dose reduction may occur either during treatment cycles, or between cycles, as clinically 
indicated.   
In the event of Grade 3 treatment-related AEs that are self-limiting or manageable by supportive 
care or other therapy, the patient may continue in the study if there is evidence of OR, SD, or 
other clinical benefit, but must do so at a reduced dose of IMP. Patients may not be retreated 
until retreatment criteria are met (see Section 6.7.1). 
8.2.3.1 Dose Reduction Schedule 
If toxicity is to be managed by dose reduction, the IMP dose will be decreased as follows 
(Table 6, Table 7):   


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Table 6: Dose-Reduction of Sym004 
Sym004 Dose 
First Reduction 
Second Reduction 
6 mg/kg 
4.5 mg/kg 
3 mg/kg 
Abbreviations (in alphabetical order):  kg, kilogram; mg, milligram 
Note:  Dose Reductions for 9 mg/kg loading dose NA; the number of dose reductions allowed is limited to 2 (Appendix 7)   
Table 7: Dose-Reduction of Futuximab and Modotuximab 
Futuximab or Modotuximab  
Dose 
First Reduction 
Second Reduction 
3 mg/kg 
1.5 mg/kg 
Not applicable 
Abbreviations (in alphabetical order):  kg, kilogram; mg, milligram;  
Note:  Dose Reductions for 4.5 mg/kg loading dose NA; the number of dose reductions allowed is limited to 1   
8.2.4 Reescalation/Rechallenge Following Dose Reduction 
Once a patient has undergone a dose reduction, the patient will continue to be treated at the 
reduced dose throughout the remainder of their time on study treatment. There is no provision in 
this study for either reescalation to the previous dose or challenge with a higher dose of IMP.  
 


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9 
DISCONTINUING PATIENTS FROM STUDY TREATMENT 
Every reasonable effort will be made to keep patients in the study; however, if a patient is 
discontinued from study treatment, every effort will be made by the Investigator to complete and 
report the reasons for treatment discontinuation as thoroughly as possible. This includes EOT 
observations, as required by the protocol at the time of treatment discontinuation, or before 
initiation of a new treatment, whichever comes first, as well as 1M FUP evaluations (Section 7). 
The reason for treatment discontinuation must be clearly documented on the appropriate page of 
the CRF. A CRF must be completed for any patient who receives any amount of IMP.  
9.1 Criteria for Treatment Discontinuation 
Patients will be discontinued from further treatment with IMP in the event of any of the 
following:  
1. Progressive Disease: Confirmed radiographically (and evaluated according to RECIST 
v1.1)  
Note: Patients receiving futuximab or modotuximab with documented PD at the EOC2 (or prior to the 
EOC2) will be offered the opportunity to crossover to receive Sym004 or will be discontinued from study. 
2. Clinical Progression: Treatment failure not meeting the criteria for PD, but considered by 
the Investigator to require treatment discontinuation (i.e., global deterioration 
characterized by worsening PS, weight loss, and/or worsening clinical symptoms). Every 
effort will be made to obtain imaging studies at the time of clinical progression. 
3. Adverse Event including: 
 Hepatotoxicity characterized by:  
o AST and/or ALT elevation > 3 × ULN (or > 3 × baseline if elevated at study 
entry due to hepatic involvement by tumor), with  
o total bilirubin ≥ 2 × ULN without initial findings of cholestasis (i.e., serum 
ALP < 2 × ULN), and  
o No explanation for the above findings such as viral hepatic injury, preexisting 
or acute liver disease, or another drug or condition capable of causing the 
observed injury 
Adapted from:  Hy’s Law. Drug–induced liver injury: premarketing clinical evaluation. Guidance 
for Industry. U.S. Department of HHS, FDA, CDER, CBER, 2009 
 Any of the following AEs: 
o Need for more than 2 dose reductions (Arm A), or more than 1 dose reduction 
(Arm B or Arm C)  
o Grade 4 IRR 
o Grade 4 EGFR-associated dermatologic AE 
o Torsade de pointes arrhythmia or other life-threatening arrhythmias 
 Any other AE or SAE considered by the Investigator to require treatment 
discontinuation 


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Note: 
AEs resulting in a patient’s permanent discontinuation from study treatment, regardless of 
seriousness or relationship to IMP, MUST be reported promptly to the Sponsor (or designee). 
In the event of Grade 3 treatment-related AEs that are self-limiting or manageable by supportive 
care or other therapy, the patient may continue in study if there is evidence of response, disease 
stabilization, or other clinical benefit, but must do so at a reduced dose of IMP (see Section 8.2.3). 
Patients may not be retreated until retreatment criteria are met (see Section 6.7.1).   
4. Physician Decision: Includes any reason which in the opinion of the Investigator would 
justify treatment discontinuation (e.g., use/requirement for a non-permitted concomitant 
medication; requirement for a significant surgical procedure; intercurrent illness which 
would prevent completion of study-related evaluations)  
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's Medical 
Monitor(s).  A brief interruption in therapy may be considered.  
5. Withdrawal by Patient: Withdrawal of consent and election to discontinue treatment 
(patients may leave the study at any time for any reason if they wish to do so, without 
consequence) 
6. Protocol Deviation: Significant deviation from the protocol or eligibility criteria; such 
patients will be considered for discontinuation only following discussion with the 
Medical Monitor(s) 
7. Noncompliance with study procedures 
8. Pregnancy 
9. Lost to Follow-up 
10. Death 
11. Study Terminated by the Sponsor 
9.2 Replacements 
After randomization to the study, no patients will be replaced. Patients NE for antitumor activity 
assessment, as defined (Section 3.2), or patients discontinuing from study prior to the EOC2 due 
to either documented PD or for reasons other than documented PD, will not be replaced. 
9.3 Criteria for Premature Discontinuation of the Trial 
This trial may be prematurely discontinued in the event of, but not limited to, any of the 
following: 
 New information leading to an unfavorable benefit-risk profile of the IMP, e.g., due to: 
o Evidence of lack of efficacy of the IMP 
o Occurrence of significant previously unanticipated AEs 
o Clinically significant increase in the frequency or severity of anticipated AEs 
o Other clinically important safety findings 
Note:  Evidence of lack of efficacy may arise from this trial or from other trials; unfavorable safety findings 
may arise from clinical or non-clinical examinations, e.g., toxicology. 


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 Sponsor’s decision that continuation of the trial is unjustifiable for medical or ethical reasons 
 Poor enrollment making completion of the trial within an acceptable time frame unlikely 
 Discontinuation of development of the Sponsor’s IMP 
 Upon request of Health Authorities 
 
Health Authorities and IRBs/ECs will be informed about the discontinuation of the trial in 
accordance with applicable regulations. 
 
 


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10 ADVERSE EVENTS 
(Instructions for reporting AEs/SAEs apply to any IMP being evaluated in this trial)  
10.1 Definitions of Adverse Events 
10.1.1 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. 
Causality for an AE will be assessed as related or not-related to IMP. Any AE, regardless of 
causality, that also meets the seriousness criteria, will be reported as an SAE. 
10.1.2 Events Not to be Considered as Adverse Events 
A preexisting 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. 
PD will not be captured as an AE as this will be recorded as part of the patient’s efficacy 
evaluation. PD should be reported as an AE if the nature of the PD is different than expected 
(i.e., signs/symptoms are not typical of PD).   
Note: PD may be reported as an AE in the case of patient death, with death being the outcome of the event. 
An abnormal laboratory value or an abnormal physiological test finding (e.g., ECG) need not be 
reported as an AE unless one of the following applies: 
 The Investigator considers the abnormality clinically significant 
 The event meets the definition of an SAE 
 The event requires an intervention 
 The event results in an action taken with IMP (e.g., dose-delay and/or discontinuation) 
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, 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. 
10.1.3 Adverse Events of Medical Interest 
Not applicable 
10.1.4 Serious Adverse Events  
An SAE is an AE that meets one or more of the following regulatory outcome criteria:      


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 Results in death    
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 is unknown (e.g., in case of unexplained or sudden death)   
 Is life-threatening    
The term “life-threatening” 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   
A disability is defined as any substantial disruption of a person’s ability to conduct 
normal life functions.   
 Is a congenital anomaly/birth defect 
 Is medically important 
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 this definition.  
10.1.5 Events That Do Not Meet the Definition of Serious Adverse Events 
PD will not be captured as an SAE unless the nature of the PD is different than expected (i.e., 
signs/symptoms that are not typical of PD).   
Note:  PD may be reported as an SAE in the case of patient death, with death being the outcome of the 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 of the 
surgery/hospitalization was considered serious.  
Hospitalization for observation or convenience prior to or following IMP administration 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 begins or finalizes the infusion at a time of day requiring a 
convenience overnight stay in the hospital.  
Procedures to support the treatment regimen that require hospitalization 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. 
 
10.2 Adverse Event Recording and Reporting  
All AEs will be recorded from signing of informed consent for participation in the trial.  The 
recording period ends 30 days after receiving the final dose of IMP (at the time of the 1M FUP 
Visit), unless extended FUP is indicated, per the clinical trial protocol.   


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Note:  Patients who sign informed consent and are subsequently deemed to be screen failures will be followed for 
the occurrence of SAEs/AEs until it is determined that they will not be participating in the trial. 
10.2.1 Information to be Provided for Each AE 
The Investigator must record all directly observed AEs and all AEs spontaneously reported by 
the patient. Information regarding the occurrence of AEs should be elicited through open-ended 
questioning of the patient, review of physical examination findings, and review of laboratory 
results or other safety information, e.g., ECGs.  
All AEs that occur in patients during the AE recording period must be recorded/entered to the 
AE section of the CRF, whether or not the event is assessed as related to IMP. If the AE is 
serious, the SAE report forms must also be completed and submitted. Information to be provided 
for each AE term reported includes: 
 Diagnosis 
A diagnosis should be recorded, if possible. If no diagnosis is available, signs and 
symptoms should be recorded instead. For fatal AEs, death is an outcome of the AE. The 
cause of death (rather than the term “death”) should be recorded.   
 Severity 
The Investigator will use the CTCAE version 5* 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 (Appendix 3): 
o Grade 1: Mild 
o Grade 2: Moderate 
o Grade 3: Severe 
o Grade 4: Life-threatening or disabling 
o 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 Grade 4 does not need to be reported as 
an SAE, unless it meets one of the SAE criteria.  
*See <https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50> 
 Relationship to IMP/Causality 
The Investigator will attempt to assess causal relationship of the event to the IMP.  
Relatedness must be assessed and recorded within the initial report (CRF and SAE report 
form).   
The causal relationship is an assessment of whether the event is related to the use of the 
IMP. It is not an evaluation of whether the event could hypothetically occur in the 
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The causal relationship of an AE to the IMP will be rated using a 2-point causality scale 
(Appendix 4): 
o Not-related  
o Related    
 Outcome 
The outcome of the AE must be assessed by the Investigator utilizing one of the 
following options: 
o Recovered/resolved  
o Recovered/resolved with sequelae  
o Recovering/resolving 
o Not recovered/not resolved 
o Fatal  
o Unknown  
Instructions for reporting changes in an ongoing AE during a patient's participation in the trial 
will be provided. 
10.2.2 Required Follow-up for AEs 
Appropriate consultation and follow-up evaluations should be carried out until the event either 
resolves, returns to baseline status, or has been adequately explained and assessed by the 
Investigator as chronic and/or stable, and that no long-term deleterious effects have become 
evident.   
This follow-up may extend beyond the 1M FUP Visit, to up to 4 months after the EOT if 
indicated, if the event has not resolved or been adequately explained.   
Note:  Patients who sign informed consent and are subsequently deemed to be screen failures will be followed for 
the occurrence of SAEs/AEs until it is determined that they will not be participating in the trial. 
10.3 Serious Adverse Event Recording and Reporting 
10.3.1 Timeframes for Reporting to the Sponsor 
All SAEs occurring at any time from signing of informed consent for participation in the trial 
and until 30 days after receiving the final dose of IMP (at the time of the 1M FUP Visit) must be 
recorded on the SAE Report Form and recorded as an SAE in the CRF. 
Note:  Patients who sign informed consent and are subsequently deemed to be screen failures will be followed for 
the occurrence of SAEs/AEs until it is determined that they will not be participating in the trial. 
In case of an SAE, the Investigator must, within 24 hours of awareness of the event, report the 
SAE to the Sponsor (or designee) by telefax or e-mail transmission. Fax number(s) and e-mail 
address(es) will be stated on the SAE Report Form and the SAE Report Form Completion 
Instructions.  SAE follow-up information must also be reported to the Sponsor (or designee) 
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SAEs, still ongoing after the 1M FUP Visit, should be followed on a regular basis according to 
the Investigator’s clinical judgment, until the event resolves 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 and finds it to 
be related to the IMP (possibly-, probably-, or related to the IMP) or trial conduct, it must be 
recorded and reported to the Sponsor (or designee) as an SAE.  
The Investigator should be aware of local reporting regulations to the IRB/EC.  The Sponsor (or 
designee) will either supply the Investigator with the reports, which should be forwarded to the 
IRB/EC, or report directly to the IRB/EC depending on local regulations.    
10.3.2 Safety Reporting to Health Authorities, IRBs/ECs, and Investigators  
Reportability of an SAE as a “Suspected Unexpected Serious Adverse Reaction” (SUSAR) will 
be determined solely by the Sponsor, based on seriousness, causality, and expectedness criteria.   
In addition to SUSARs, the Sponsor or designee is responsible for reporting all relevant safety 
information regarding SUSARs, or other safety developments, to appropriate Health Authorities 
and central IRBs/ECs, as well as participating Investigators. Reporting of SUSARs to local 
IRBs/ECs will be handled either by the Sponsor or designee, or the Investigator depending on 
local regulations.  
The timeline for notification of SUSARs is within 7 calendar days for fatal/life-threatening 
events and within 15 calendar days for all other SUSARs.   
10.4 Pregnancy 
If any trial patient becomes pregnant during the trial, the patient must be discontinued from IMP 
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 to follow-up on exposure to the fetus/infant. 
Pregnancies reported in female partners of male trial patients must also be included in the safety 
database; therefore, a female partner of a male patient on the trial who becomes pregnant will be 
approached for consent to have the pregnancy followed until term and reported upon to the 
Sponsor (or designee). 
All pregnancies must be followed up every third month and 1-month post-delivery to determine 
outcome and status of mother and child. Pregnancy complications and elective terminations for 
medical reasons must be reported as AEs or SAEs as appropriate.  Elective terminations for non-
medical reasons should be reported as follow-up, but not as a separate AE/SAE unless 
complications meet AE/SAE criteria. Spontaneous abortion must be reported as an SAE. 
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-, probably-, or 
related to the IMP, must be promptly reported to the Sponsor (or designee). 
All pregnancy information including follow-up information must be reported on a designated 
pregnancy form provided by the Sponsor (or designee). 


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11 PRECAUTIONS WHEN DOSING  
11.1 Precautions Regarding Procreation 
Studies have not been performed to determine whether Sym004, futuximab, or modotuximab 
affect reproductive function in males or can cause fetal harm. For this reason, men with partners 
of childbearing potential must use a highly effective method of contraception while receiving 
IMP.  “A highly effective method of contraception” is defined as non-hormonal 
contraception equivalent to a double-barrier method (includes a single-barrier method in 
combination with a spermicide) or intrauterine device. 
There have been no studies in pregnant females; therefore, it is not known whether Sym004, 
futuximab, or modotuximab can cause fetal harm when administered to a pregnant woman, or 
whether they can affect reproductive capacity. For this reason, WOCBP should only be 
administered IMP when highly effective contraceptive measures have been taken and when 
pregnancy tests are negative.   
WOCBP includes any female who has experienced menarche and who has not undergone 
surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or is not 
postmenopausal.  Post-menopause is defined as: 
 Amenorrhea for ≥ 12 months with no other cause 
 Irregular menstrual periods, on HRT, with documented FSH level > 35 mIU/mL 
Note:  
Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, transdermal 
patches, or implanted or injectable products), or mechanical products such as an intrauterine device or 
barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence, or 
where their partner is sterile (e.g., vasectomy), should be considered of childbearing potential. 
 
Women and men of childbearing potential will be informed as to the unknown risk to procreation 
while participating in this trial and will be advised that they must use highly effective 
contraception within 2 weeks prior to the first dose and continuing until 3 months after final 
administration of IMP. A pregnancy test will be performed on each premenopausal female of 
childbearing potential within ≤ 2 working days prior to first IMP administration, and again at the 
end of the final treatment cycle.   
11.2 Infusion-Related Reactions 
Premedication to reduce the risk of IRRs associated with IMP administration is required. 
Instructions for premedication (Section 8.1.1, Appendix 6) and guidelines for treatment and 
management of IRRs are provided. Facilities and personnel to treat such reactions, if they occur, 
should be available.  
11.3 Dermatologic AEs 
The incidence and severity of dermatologic AEs observed in studies of Sym004 are discussed 
(Section 2.4.1). Premedication to reduce the risk of dermatologic AEs associated with IMP 
administration is required during Cycle 1 and 2.  
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Recommendations for management of Grade 1 through 3 dermatologic AEs, and for dose delays 
and reductions in the event of Grade 3 dermatologic AEs are provided (Appendix 7). Patients 
must be withdrawn from IMP treatment in the event of a Grade 4 dermatologic AE.  
11.4 Hypomagnesemia, Hypocalcemia, and Hypokalemia 
Patients receiving IMP will be monitored weekly for evidence of hypomagnesemia, 
hypocalcemia, and hypokalemia.  Hypomagnesemia should be treated according to the criteria 
outlined (Appendix 8). 
11.5 Additional Precautions 
There are no known contraindications to the administration of Sym004, futuximab, or 
modotuximab, however the following additional precautions are provided:   
 Lactating women and children: Use in lactating women or in children has not been 
evaluated. These patients will be excluded from study entry.   
 Drug interactions: No formal drug interaction studies have been performed, therefore no 
specific guidance can be provided about use of concomitant medications.   
 Overdose: There is no experience with clinical overdose. If severe reactions occur in 
patients, IMP should be discontinued and all appropriate supportive medical care should 
be instituted to ameliorate these potential adverse effects. 
 
 


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12 SAFETY SURVEILLANCE DURING STUDY 
12.1 Safety Review 
Clinical and laboratory safety data will be reviewed on an ongoing basis throughout the study to 
make decisions regarding the advisability of continuing accrual. To facilitate this:   
 The following will be promptly reported to the Sponsor (or designee): 
o SAEs within 24 hours of Investigator awareness 
o AEs resulting in permanent discontinuation from study, regardless of seriousness 
or relationship to IMP 
o IRRs (≥ Grade 3) 
 AEs will be recorded in the CRF in a timely manner following a patient completing (or 
being discontinued from) a dosing cycle. Each event will be assessed as to grade and 
causality. 
 Dose delays and dose reductions will be recorded in the CRF in a timely manner  
 The Investigator will make critical laboratory safety data available in a timely manner.    
 Patients will be carefully evaluated for evidence of all AEs, including potential 
cumulative and/or delayed toxicities, throughout the duration of their time in the study.  
 The Investigational Site’s staff and the Sponsor’s Medical Monitor(s) will maintain 
contact in the form of email, newsletters, and teleconferences as needed regarding 
ongoing patient status and any emerging safety concerns 
Availability of these data also will enable the Sponsor (or designee) to act promptly in response 
to safety signals and ensure that governing Health Authorities, as well as Investigators who may 
be participating at other sites or in other clinical trials of the IMP, are informed of events 
occurring during the trial.  
12.2 Other Safety Surveillance Activities 
At least one Medical Monitor will be 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: 
 Review of the site’s assessment of eligibility 
 Consultation with Investigator(s) regarding evaluation of patients to be enrolled to the 
study, treatment delays, restarts, and/or discontinuations   
 Ongoing safety monitoring of all patients being treated in the study 
 Evaluation of 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 
 Evaluating abnormal laboratory values and other relevant safety data, e.g., ECGs 


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 Providing medical support to the Sponsor in answering questions related to the study 
protocol 
 Updating the Safety Team on trial status  
A Drug Safety physician will be 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 medical coding of SAEs 
 Discuss with the Sponsor’s Chief Medical Officer any cases which may present a concern 
regarding a signal or safety issue. 
12.3 Study Safety Committee 
Clinical and laboratory safety data will be reviewed on an ongoing basis throughout the trial. A 
Study Safety Committee will be established and will be comprised of participating 
Investigator(s) and the Sponsor’s Medical Representative(s). If indicated, Study Safety 
Committee teleconferences will be held to discuss ongoing patient status and any emerging 
safety concerns; frequency of teleconferences may fluctuate based on accrual and study activity, 
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13 REGULATORY AND ETHICAL CONSIDERATIONS 
13.1 Conditions of Testing 
In sponsoring this study, it is the intention of the Sponsor to obtain patient safety data for 
submission to governing Health Authorities. In agreeing to conduct this investigation, the 
investigative facility agrees to follow all requirements stipulated in this protocol as well as 
regulations described in the United States (U.S.) Code of Federal Regulations (CFR) and/or by 
governing Health Authorities concerning: 
 Responsibilities of Investigators (in the U.S. Title 21 CFR Part 312) 
 Informed Consent of Human Subjects (in the U.S. Title 21 CFR Part 50) 
 Institutional Review Boards (in the U.S. Title 21 CFR Part 56) 
In addition, the Investigator agrees to perform the study in accordance with the principles of the 
Declaration of Helsinki and ICH E6(R2) GCP. 
13.2 Institutional Review 
The Investigator will submit this protocol, any protocol modifications, and the patient ICF to be 
utilized in this study to the appropriate IRB/EC for review and approval.  This committee must 
operate in accordance with ICH E6(R2) GCP, the U.S. Title 21 CFR Part 56, and/or governing 
Health Authorities, as appropriate. A letter confirming approval of the protocol and the ICF must 
be forwarded to the Sponsor (or designee) prior to initiation of this study. The Investigator will 
not start the study, nor will IMP be shipped to the investigational site, before providing the 
Sponsor (or designee) with evidence of this approval.  
The Investigator is responsible for assuring continuing review and approval of the clinical study.  
The Investigator must also promptly report all changes in the research activity and all 
unanticipated problems involving risk to the patients or others to the IRB/EC.  The Investigator 
will not make any changes in the protocol without IRB/EC approval, except where necessary to 
eliminate apparent immediate hazards to the patients. The Investigator will provide progress 
reports to the IRB/EC as required by the IRB/EC. If the study remains in progress for more than 
the IRB/EC-specified approval period, the Investigator must obtain renewal and re-approval 
from the IRB/EC where appropriate. Documentation of renewal must be submitted to the 
Sponsor (or designee).  The Investigator will provide notice to the IRB/EC of completion of 
participation in the study.  
13.3 Informed Consent 
The Investigator agrees to protect the rights, safety, and welfare of the patients entered into the 
study, including obtaining written informed consent prior to performing any study-related 
procedures, and informing each patient that the IMP is being used for investigational purposes.   
Prior to study start, the Sponsor will provide a sample ICF for modification, as appropriate, by 
each Investigator. The sample ICF must include all elements required by ICH E6(R2) GCP and 
must adhere to the IRB/EC requirements and ethical principles that have their origin in the 
Declaration of Helsinki.   


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The Investigator's revision to the Sponsor's sample ICF, along with any other written study 
information to be provided to the patient, must be reviewed and approved by the IRB/EC. A 
copy of the IRB/EC-approved ICF to be utilized during the study must be submitted to the 
Sponsor (or designee) prior to study initiation. 
Prior to each patient's entry to the study, the Investigator or his/her staff will explain the nature 
of the study, its purpose and associated procedures, its expected duration, and the potential risks 
associated with participation. All questions about the trial will be answered to the satisfaction of 
the patient or the patient’s legal representative. The patient will be informed of the right to 
withdraw from the study at any time without consequence, and without having to provide a 
reason for this decision. Following the discussion, the patient will be asked if they are willing to 
personally sign and date the ICF. Only if the patient voluntarily agrees to sign the ICF and has 
done so, may he/she enter the study.   
It is the responsibility of the Investigator to obtain written informed consent from each patient, 
thereby attesting that consent was given freely in accordance with ICH E6(R2) GCP, the U.S. 
Title 21 CFR Part 50, or governing Health Authorities, as appropriate. An Investigator listed on 
the Form FDA 1572 will then co-sign the ICF. A copy of the signed and dated ICF will be 
provided to the patient. The original executed version must remain in the Investigator's file, per 
local requirements, and must be available for verification by a representative of the Sponsor (or 
designee). 
13.4 Conditions for Modifying or Terminating the Study 
13.4.1 Modification of the Study Protocol 
The study is to be conducted as described in this protocol.  Departures from either the protocol 
eligibility criteria or the experimental plan, as outlined herein, will not be allowed. No protocol 
waivers will be granted.   
If modifications in the experimental design, dosages, assessments, patient selection, etc. of the 
protocol are indicated or required, such changes will only be instituted following consultation 
between the Sponsor (or designee) and Investigator and will be accomplished through formal 
amendment(s) to this protocol and approval by the appropriate regulatory authority (as indicated) 
and review committees, except where necessary to immediately eliminate apparent hazards to 
patients.   
A modification to the protocol will not be made without the express written approval of the 
Sponsor (or designee).  Any amendment prepared by the Sponsor (or designee) will be 
implemented according to the Sponsor’s (or designee’s) standard operating procedures (SOPs) 
and will be reported to the appropriate regulatory authority, the appropriate IRB/EC, and made a 
formal component of the protocol document. 
Protocol changes to eliminate an apparent hazard to a trial patient may be implemented by the 
Investigator immediately. The Investigator must then, without delay, inform the local IRB/EC, 
and the Sponsor (or designee) will immediately notify local governing Health Authorities.  


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13.4.2 Modification of the Informed Consent Form 
If modifications to the experimental design, dosages, assessments, patient selection, etc. of the 
protocol are indicated or required, and if such modifications substantially alter the study design 
or increase the potential risk to patients, the Sponsor (or designee) will prepare a revision to the 
existing sample ICF for modification, as appropriate, by each Investigator.  Any revision to the 
sample ICF prepared by the Sponsor (or designee) will be implemented according to the 
Sponsor’s (or designee’s) SOPs. Such a revision will be reviewed and approved by the 
appropriate regulatory authority (as indicated) and IRB/EC. 
In addition, all current patients, as well as subsequent study candidates, will be informed of the 
study design modification or increase in potential risk, and written informed consent for the 
modification/risk will be obtained as outlined (Section 13.3). 
13.4.3 Conditions for Termination of the Study or a Study Site 
The Sponsor reserves the right to terminate the study, or terminate a clinical trial site's 
participation in the study, at any time. Should the Sponsor, the Sponsor’s designee, and/or the 
Investigator(s) discover conditions that indicate the study or a study site should be discontinued, 
an appropriate procedure for termination will be instituted. Reasons for termination may include, 
but are not limited to, the following: 
 Termination of the Study 
o Safety concerns; incidence and/or severity of AEs in the study that indicate a 
potential health hazard or unexpected, serious, or unacceptable risk caused by the 
study treatment 
o Discovery of lack of efficacy 
o Unsatisfactory enrollment across the entirety of the trial 
o Drug supply or manufacturing issues 
o The Sponsor’s decision to modify or discontinue development of the IMP 
o A request to discontinue the study by a regulatory authority or Health Authority 
 Termination of a Study Site 
o Investigator non-compliance with the protocol, ICH E6(R2) GCP, or regulatory 
requirements 
o Unsatisfactory enrollment at the site with respect to quantity or quality 
o Incomplete data collection; inaccurate or knowingly false data submission 
If terminating the study, the Sponsor and Investigator(s) will ensure that adequate consideration 
is given to the protection of patients' interests. Further, the governing Health Authority and 
IRB/EC will be notified in writing and the reason for termination will be stated. 


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13.5 Trial Registration 
The trial will be registered in one or more public trial registries (e.g., ClinicalTrials.gov). The 
trial results will be posted in the same clinical trial registries as the initial registration in 
accordance with the latest International Committee of Medical Journal Editors (ICMJE) 
recommendations (URL: www.icmje.org). 
13.6 Insurance and Liability 
The Sponsor will obtain 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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14 INVESTIGATOR RESPONSIBILITIES 
14.1 Medical Supervision 
An Investigator conducting a clinical study with an investigational agent is required to comply 
with regulations described in U.S. Title 21 CFR Parts 50, 56, and 312 and/or by governing 
Health Authorities, as well as ICH E6(R2) GCP. 
Medical supervision for the conduct of this protocol is the responsibility of the Principal 
Investigator. The Principal Investigator must name all Sub-Investigators and may delegate 
certain day-to-day activities to such Sub-Investigators, but retains overall responsibility for 
ensuring that the study is conducted properly and in accordance with the design and intent 
herein. A document outlining the specifics of the delegation will be maintained at the 
investigational site, in the study files, and will be updated as appropriate.   
The Principal Investigator is responsible for ensuring that drugs and devices are available for 
treating possible medical emergencies. The Principal Investigator is required to ensure 
compliance with respect to the IMP schedule, visit schedule, and procedures required by the 
protocol. The Principal Investigator is responsible for ensuring that the study is conducted 
according to sound medical practices. 
14.2 Confidentiality 
All goods, materials, information (oral or written) and unpublished documentation provided to 
the Investigator (or any company acting on their behalf), inclusive of this protocol, the patient 
CRFs, and the IB, are the exclusive property of the Sponsor. Documents and information 
provided to the Investigator by the Sponsor may not be given or disclosed by the Investigator or 
by any person within his/her authority either in part or in totality to any unauthorized person 
without the prior written formal consent of the Sponsor. 
The submission of this protocol and other necessary documentation to the IRB/EC is expressly 
permitted; the IRB/EC members have the same obligation of confidentiality. 
The Investigator shall consider as confidential, and shall take all necessary measures to ensure 
that there is no breach of confidentiality, all information accumulated, acquired or deduced 
during the trial, other than that information to be disclosed to a third party mandated by 
applicable law. 
Note: 
Any language relating to these issues appearing in the clinical trial agreement will supersede that which is 
outlined in this section. 
14.3 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 relating to the development of the IMP, and 
therefore, may disclose it as required to Investigators, government-licensing authorities, Health 
Authorities of other governments, investors, and commercial partners as indicated. 


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14.4 Publications 
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.  Publication 
of a summary of the results of the study is permissible according to the Sponsor and is not 
inconsistent with the preceding affirmation regarding confidentiality. Scientific dissemination of 
the results of this study is encouraged. Any formal publication of data collected from the study 
will be considered a joint publication by the Investigator and the appropriate personnel of the 
Sponsor or their designees. Authorship will be determined by agreement with the Coordinating 
Investigator and Study Steering Committee.   
The Sponsor retains the right to designate one of the authors or someone else involved to be 
named as the Coordinating Investigator. The Coordinating Investigator and the Sponsor will 
decide on the publication strategy. The Coordinating Investigator will have the right to publish 
and present the results and methods as first or last author of multicenter publications. Co-
authorship will be decided by the Sponsor and the Coordinating Investigator and will be limited 
to 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 communication and cannot 
extend the embargo. 
Note:   Any language relating to these issues appearing in the Clinical Trial Agreement will supersede that which 
is outlined in this section. 
14.5 Patient Screening Log 
A record listing all patients entered into the study, as well as those considered for entry into the 
study and subsequently excluded, must be maintained by the Investigator.  Patients excluded 
from the study will have the reason for exclusion recorded on the Patient Screening Log (or 
similar document).  
14.6 Drug Dispensing Inventory 
Study site personnel will maintain adequate records of the receipt, dispensing, and disposition of 
all IMP that the Sponsor ships to the site. Records will be maintained either on a form to be 
provided by the Sponsor or another similar document authorized for use by the Sponsor, and 
should include appropriate dates, quantities received, quantities dispensed, lot number (or kit 
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The Investigator agrees to administer IMP only to patients under his/her personal supervision. 
The Investigator will not supply IMP to any person not authorized to receive it. 
14.7 Handling and Disposal of IMP 
IMP should be stored in a secure location, under the indicated conditions (Section 5.2).  
Information regarding the number of vials utilized for each patient, as well as the dose of IMP 
administered to the patient, will be recorded on the appropriate drug inventory form. 
Periodically throughout and at the conclusion of the study, vials of IMP will be inventoried by a 
representative of the Sponsor (or designee). At the completion of the study, all unused study 
materials MUST be returned to the Sponsor (or designee), unless otherwise authorized in 
writing.  
Information regarding the storage, handling, inventory, and disposition of IMP will be provided 
by the Sponsor (or designee).   
14.8 Recording of Data 
Clinical trial data for this study will be captured in a CRF. The Investigator agrees to provide all 
information requested in the CRF in an accurate manner according to instructions provided. All 
data must be carefully entered to permit meaningful interpretation. Corrections to entered data 
will be identified and tracked. Data must be entered into CRFs in a timely fashion. 
A CRF is required to be submitted for every patient who receives any amount of IMP.  This 
includes submission of retrievable data on patients who withdraw before completion of the study. 
Prior to submission, CRFs must be reviewed for completeness and accuracy, and signed and 
dated where indicated, by either the Principal Investigator or a physician Sub-Investigator whose 
name is listed on the Form FDA 1572 for this study. 
All collected data will be entered into a validated database. 
14.9 Source Document Requirements 
The Investigator will maintain adequate and accurate records for each patient treated with IMP.   
Source documents including but not limited to hospital, clinic or office charts, laboratory reports, 
radiology and pathology reports, pharmacy records, study worksheets, anonymized photographs 
aimed at documenting study-associated clinical findings, and signed ICFs, must completely 
reflect the nature and extent of the patient’s medical care, must be included in the Investigator’s 
files along with patient study records, and must be available for source document verification 
against entries in the CRF.    
Each trial site will permit authorized representatives of the Sponsor and relevant Health 
Authorities direct access to (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. 
The Sponsor (or designee) will check CRF entries against source documents according to the 
guidelines of ICH E6(R2) GCP. Data not requiring a separate written record, i.e., data which 
may be recorded directly in the CRF, will be determined before trial start. 
The ICF will include a statement by which patients allow the Sponsor (or designee), as well as 
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(e.g., patient medical files, appointment books, original laboratory records, etc.). The Sponsor (or 
designee), bound by confidentiality and privacy regulations, will not disclose patient identities or 
personal medical information. 
14.10 Laboratory Reports 
Prior to initiation of this study, the Investigator must supply the Sponsor (or designee) with the 
normal laboratory values for the laboratories to be utilized; specifically, the normal laboratory 
values for analytes required to be measured, per protocol, are to be supplied.   
Laboratory safety evaluations must be performed at the intervals specified.  If unexplained 
laboratory abnormalities occur, corroborative tests will be performed until the laboratory 
abnormality has resolved, returned to baseline status, and/or adequate explanation of the 
abnormality has been provided. 
Copies of any additional records pertinent to the study (e.g., laboratory data, radiological reports, 
patient chart summaries, autopsy reports) must be made available to the Sponsor (or designee) or 
governing Health Authorities, if requested, with due precaution taken to ensure patient 
confidentiality. 
14.11 Record Retention 
Regulatory authorities require that the Investigator retain copies of all files pertaining to the 
study according to local requirements. In addition, the Investigator is responsible for archiving 
all relevant source documents so that trial data may be compared against source data after 
completion of the trial, e.g., in case of inspection from authorities. Study records must be stored 
in a safe and secure location permitting timely retrieval, if necessary. The Investigator must 
obtain written permission from the Sponsor prior to disposing of any records. 
If the Investigator relocates, retires, or withdraws for any reason from the study, trial records 
may be transferred to an acceptable designee, such as another Investigator within the institution. 
The Sponsor (or designee), as well as the responsible IRB/EC, must be notified of the identity of 
the individual assuming responsibility for maintaining the study records and the location of their 
storage.   
14.12 Monitoring of the Study 
The Sponsor has responsibility to governing Health Authorities to take all reasonable steps to 
ensure the proper conduct of the study with respect to trial ethics, protocol adherence, and data 
integrity and validity. 
This study will be closely monitored by representatives of the Sponsor (and/or designee) 
throughout its duration. Monitoring will be in the form of periodic personal visits with the 
Investigator and his/her staff as well as any appropriate communications by telephone, telefax, 
mail, or e-mail transmission. The purpose of these contacts is to review study progress, 
Investigator and patient adherence to protocol requirements, and any emergent problems 
associated with the conduct of the study. The following usually will be assessed during 
monitoring visits at the site: 
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 Signed ICFs 
 Patient accrual and follow-up 
 IMP inventory records 
 Investigator and patient compliance to the study protocol 
 Concomitant therapy usage 
 AE documentation  
 Data is accurate, complete, and verifiable when compared to source documents 
The Investigator and study staff are expected to cooperate with monitors during such visits and 
provide them with all relevant study documents. The Investigator must give the Sponsor (and/or 
designee) direct access to all relevant source documents to confirm consistency with the CRF 
entries. It is important that the Investigator and relevant personnel are available during 
monitoring visits and possible audits and that sufficient time is devoted to the process. 
In addition, the study may be evaluated by Sponsor auditors (and/or designees) and government 
inspectors who must be allowed access to CRFs, source documents, and other study files. 
Sponsor reports will be kept confidential. The Investigator should promptly notify the Sponsor of 
any audits scheduled by any regulatory authorities, and promptly forward copies of audit reports. 
As applicable, in accordance with the Health Insurance Portability and Accountability Act 
(HIPAA) and associated privacy regulations, patient authorization to use personally identifiable 
health information may be required from each patient before research activities. This 
authorization document must clearly specify what parties will have access to a patient’s personal 
health information, for what purpose, and for how long. 
14.13 Patient Confidentiality 
Every effort will be made to maintain the anonymity and confidentiality of patients during this 
clinical study. Each participating site will maintain appropriate medical and research records for 
this trial, in compliance with ICH E6(R2) GCP, regulatory, and institutional requirements for the 
protection of confidentiality of patients.   
Coded patient identifiers will be utilized always (including in any publications) when referring to 
a patient. However, because of the experimental nature of this treatment, the Investigator agrees 
to allow representatives of the Sponsor (and/or designee), as well as authorized representatives of 
the governing Health Authority, to inspect the facilities used in this study and to inspect, for 
purposes of verification, the hospital or clinic records of all patients enrolled into this study. A 
statement to this effect should be included in the ICF. 
14.14  Financing and Insurance 
The study will be supported by the Sponsor. Specifics of the financing and insurance coverage 
will be addressed in the clinical study agreement between the Sponsor and the Investigator or 
Institution. 


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15 HANDLING AND PROCESSING OF DATA 
15.1 Data Handling 
Study data collection, processing, transfer, and reporting, as well as handling of study personnel 
information, will be done in compliance with ICH E6(R2) GCP and all applicable data protection 
regulations, including Regulation (EU) 2016/679 of the European Parliament and of the Council 
of 27 April 2016 on the protection of natural persons with regard to the processing of personal 
data and on the free movement of such data (General Data Protection Regulation). 
15.2 Data Review During this Study 
Data obtained from the study will be reviewed in a timely manner throughout by the Sponsor (or 
designee) and Sponsor's Medical Representative(s) to assess safety and the progress of the 
project. 
15.3 Data Processing 
A Data Management Plan (DMP) will be prepared for this trial. The Sponsor (or designee) will 
be responsible for data processing in accordance with applicable Data Management SOPs and 
the trial DMP. 
Once recorded within the CRF, study data will be checked to identify inconsistencies and other 
data errors, and also will undergo an additional study-specific data review process, as stated 
above in Section 15.2.  Data issues will be queried and query resolutions will be documented. 
Entry and processing of data other than those directly recorded on CRFs by trial sites (e.g., 
imports of laboratory results) will follow vendor(s) SOPs. Transfer of such data from vendor(s) 
to Sponsor (or designee) will be handled according to vendor(s) data transfer SOPs and the 
Sponsor data transfer requirements with full compliance to applicable regulations. 
Database Lock will occur upon reaching the predefined data cut-off and completion of Sponsor’s 
(or designee’s) quality control procedures and quality assurance procedures. 
Portable Document Format (PDF) files of the CRFs will be provided to the Investigator at the 
end of the trial. 
15.4 Clinical Trial Report 
As of Amendment 5: Due to the Sponsor’s decision to discontinue the trial for administrative reasons (effective 
20Dec2018), the primary, secondary, and exploratory objectives as previously described are no longer applicable. 
Only clinical safety-related evaluations will be conducted. An abbreviated CTR will be prepared upon completion of 
the trial rather than the full integrated report described below. 
A final integrated clinical/statistical trial report will be prepared upon reaching the predefined 
data cut-off for primary analysis (i.e., all patients complete their first on-study tumor 
assessment). 
15.5 Compliance with the General Data Protection Regulation 
The applicable data protection legislation requires that parties enter into a written contract if one 
party (data processor) processes personal data on behalf of the other party (data controller). This 


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written contract must regulate the subject-matter and duration of the processing, the nature and 
purpose of the processing, the types of personal data and categories of data subjects, as well as 
the obligations and rights of the data controller. Accordingly, the parties must enter into a data 
processing agreement. To the extent the processing of personal data involves transfers of 
personal data to third countries (e.g., jurisdictions outside of the European Economic Area 
[EEA]), the parties will enter into the European Commission's standard contractual clauses 
between the data controller, the data processor, and all sub-processors, if any. The European 
Commission's standard contractual clauses ensure an adequate level of protection in relation to 
transfers of personal data to third countries. 
 


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16 STATISTICAL ANALYSIS  
16.1 Statistical Analysis Plan 
A Statistical Analysis Plan (SAP) that includes a more technical and detailed description 
(including templates for Tables, Listings, and Figures) of the planned statistical summaries 
analyses will be prepared and finalized prior to database lock. 
Further data-driven and exploratory analyses may be defined and performed and presented in the 
CTR as appropriate.   
16.2 Sample Size Considerations 
As of Amendment 5: Effective 20Dec2018, accrual to this trial has been halted; the total planned number of 
patients will not be enrolled. Two (2) patients consented prior to the trial discontinuation date and subsequently 
determined to be eligible have been entered to the study. The pre-Amendment 5 sample size considerations detailed 
below are no longer valid. 
Based on Phase 1 and Phase 2 study results, 37-40% of patients receiving Sym004 9/6 mg/kg 
weekly treatment are expected to have tumor shrinkage at Week 8 (EOC2). With no knowledge 
of the anti-cancer effect of futuximab and modotuximab, up to 18 patients per Arm may be 
enrolled and treated to differentiate the rates of 35% versus 10% using a Simon’s 2-stage 
Minimax design, with a 5% significance level and 80% power, for each of the futuximab and 
modotuximab Arms. In Stage 1, 11 patients will be enrolled in each Arm and treated. If no more 
than 1 patient has tumor shrinkage in an Arm, further enrollment will be stopped in that Arm. 
Otherwise, an additional 7 patients will be enrolled in Stage 2.  
A contemporary reference Sym004 Arm will be included in the study to ensure the 
interpretability of tumor shrinkage data for the Futuximab Arm and Modotuximab Arm. 
If either of the Futuximab or Modotuximab Arms continues in Stage 2 or beyond, the Sym004 
Arm enrollment will continue. 
16.3 Analysis Sets 
The efficacy and safety analysis sets are defined as follows:  
 As-Treated (AT) Analysis Set: This analysis set includes all patients who took part of any 
dose of study treatment, will be used as basis for the evaluation of antitumor effects and 
safety analyses. All analyses using this population will be based on the treatment actually 
received.  
 PK Analysis Set*: All patients in the AT analysis set who receive any amount of their 
assigned dose of the IMPs, Sym004, futuximab or modotuximab, have a measurable 
concentration of at least one of the IMPs for at least one timepoint after the first dose, 
with no significant protocol deviations that may impact the data. 
*As of Amendment 5: PK analysis will not be performed, therefore the PK analysis set is no longer 
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16.4 Trial Endpoints 
As of Amendment 5: Due to the Sponsor’s decision to discontinue the trial (effective 20Dec2018), only clinical 
safety-related analyses will be conducted.  The pre-Amendment 5 efficacy and exploratory endpoints as detailed 
below are no longer valid and will not be analyzed.  
16.4.1 Primary Efficacy Endpoint (omitted as of Amendment 5) 
Percentage change from baseline in the sum of the diameter of tumors designated as target 
lesions, as documented at the EOC2 tumor assessment. 
16.4.2 Exploratory Endpoints and Analyses (omitted as of Amendment 5) 
16.4.2.1 Pharmacokinetic Endpoints  
The PK profile of the IMPs will be derived based on the concentration time curves after the first 
and the 8th infusion on Cycle 2, Day 22. For patients dosed with Sym004, the serum 
concentration of futuximab and modotuximab will be measured in separate bioanalytical assays. 
The Sym004 serum concentration is defined as the sum of futuximab and modotuximab serum 
concentrations measured in a sample. The bioanalytical assays used for Sym004 assessment will 
also be applied for measurement of serum concentrations of futuximab and modotuximab in the 
patients dosed with futuximab drug product and modotuximab drug product, respectively. 
For all three IMPs, the Cmax, CEOI, Ctrough and Tmax will be derived from observed data while 
AUCinf, AUC0-168h, CL, CLss, Vd, and T½ will be estimated using non-compartmental methods 
and actual time points. For selected infusions during repeated dosing, CEOI and/or Ctrough 
(equivalent to the concentration at EOI and SOI, respectively) will be assessed. 
Individual curves of serum concentration of the IMPs versus time after the first and 8th infusion 
will be presented on log- and linear scale for all patients in the PK population. Furthermore, peak 
and trough serum concentrations for the period from first dose to EOC2 and EOT, before and 
after cross-over to Sym004 will be presented on a linear scale individual plots as appropriate. In 
addition, mean concentration time curves will be presented on linear scale using nominal time 
point by cohort and trial part. All PK endpoints will be listed and summarized by trial part and 
cohort (Table 8). 
 
Table 8: PK Endpoint, Definitions, and Derivations 
Symbol 
Definition and Derivation 
AUCinf 
Area under the concentration-time curve from start of infusion to infinity for the first dose 
AUC0-168h 
Area under the Concentration-Time Curve from Start of Infusion up to 168 hours 
CL 
Clearance after the first dose 
CLss 
Clearance in steady state at the nominal 8th infusion 
CEOI 
Concentration at the end of infusion 
Cmax 
Maximum concentration 
Ctrough 
Observed trough concentration (i.e., concentration of IMP measured pre-infusion) 
T½  
Terminal elimination half-life 
Vd 
Volume of Distribution During the Terminal Phase after the First Dose 
 


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16.4.2.2 Modeling of Pharmacokinetic and Pharmacodynamic Data  
All data collected in this trial may be used for modeling of PK, tumor size, safety, and biomarker 
assessments. Preliminary data generated during the trial may be used for exploratory modelling. 
The final data, i.e., after database lock, will be used for the final model and potentially for cross-
trial modelling. These modelling activities will be reported separately from the current trial. 
16.5 Statistical Analysis  
As of Amendment 5: Due to the Sponsor’s decision to discontinue the trial (effective 20Dec2018), only data from 
clinical safety-related evaluations will be summarized. Since only 2 patients are being treated in the study, the 
available baseline and safety data for these two patients will be presented as either patient profiles or patient listings. 
The pre-Amendment 5 full statistical analysis as detailed below will not be performed. 
16.5.1 General Specifications  
Statistical analyses will be carried out using Statistical Analysis System (SAS®) Version 9.4 or 
higher. 
The data cut-off for primary analysis date will be determined once all patients in the AT analysis 
set complete their first on-study tumor assessment.  
In general, continuous variables will be summarized using descriptive statistics by reporting the 
number of observations, mean, standard deviation, median, minimum, and maximum; 
Categorical/discrete variables will be summarized using frequency distributions showing the 
number and percentage of patients within each category; unless otherwise specified.   
Baseline is defined as the last available observation prior to the first administration of study drug 
on C1D1.  If a baseline value is missing, no change from baseline will be calculated.   
Unless indicated otherwise, summary statistics will be presented using observed data only.  
Missing data will not be imputed unless otherwise specified.  
Data from all study sites will be pooled in the summaries if more than one site is involved in the 
study. Study sites will be identified in the data listings. 
16.5.2 Patient Disposition and Baseline Characteristics  
16.5.2.1 Patient Disposition 
Number of patients in each analysis set, reasons for exclusion, withdrawals of patients from 
study drug and reason, as well as withdrawal from study follow-up, will be summarized using 
frequency distributions. Randomization and/or stratification errors, if any, will be summarized. 
 
16.5.2.2 Baseline and Disease Characteristics 
Patient demographics, baseline and disease characteristics such as age, sex, race, duration of 
metastatic disease, prior anti-cancer therapies, measurable/non-measurable disease, left or right 
colon, and ECOG PS, will be presented using descriptive statistics or frequency distributions, as 
appropriate. 
 


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16.5.3 Exposure 
Exposure to study drug and the administration profile will be summarized descriptively for each 
treatment Arm with respect to duration of exposure, number of treatment cycles, cumulative 
dose, relative dose intensity, and dose modifications. 
16.6 Primary Analysis 
As of Amendment 5: Due to the Sponsor’s decision to discontinue the trial (effective 20Dec2018), only clinical 
safety-related analyses will be conducted. The planned efficacy analyses as detailed below will not be performed. 
16.6.1 Efficacy Analysis  
Percentage change from baseline in the sum of the diameters of tumors designated as target 
lesions, as tumor volume documented at the EOC2 tumor assessment will be calculated and 
plotted by treatment Arm using Waterfall plots. Percent of patients with on-study tumor 
shrinkage will be presented along with the associated 95% CIs. Magnitude of tumor shrinkage 
will also be summarized by treatment Arm, as appropriate. 
16.7 Secondary Analysis 
16.7.1 Safety Analysis  
The safety evaluations will focus on AEs and laboratory assessments. All patients included in the 
AT analysis set will be evaluated by treatment Arm in the safety analysis. 
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology and the severity of the toxicities will be graded according to the CTCAE 
v5, where applicable. Concomitant medications will be coded according to the World Health 
Organization (WHO) Medication Dictionary for Concomitant Medication. 
All AEs will be summarized (incidence) and listed by the System Organ Class (SOC), preferred 
term, toxicity/severity grade, and causal relationship to study medication.  In addition, separate 
summaries of SAEs and Grade 3 and 4 AEs will be presented. 
Special attention will be paid to dermatologic toxicities, hypomagnesemia, hypocalcemia, 
hypokalemia, and IRRs. 
Hematological and chemistry laboratory parameters will be graded according to the CTCAE v5 
criteria, where applicable. Absolute values and changes from baseline will be summarized by 
cycle.  The on-study worst severity grade will also be summarized.  In addition, time to event 
(certain severity of selected laboratory tests), and time to resolution will also be summarized as 
appropriate. 
Further safety analysis details will be provided in the SAP. 
16.8 Exploratory Analysis 
As of Amendment 5: Due to the Sponsor’s decision to discontinue the trial (effective 20Dec2018), only clinical 
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16.8.1 Exploratory Biomarker and Pharmacodynamic Analyses 
Biomarker and pharmacodynamic assessments, to include collection of peripheral blood, skin 
biopsies, and tumor biopsies, will be conducted in all patients and will evaluate potential 
predictive and/or prognostic biomarkers of response to treatment, including but not limited to: 
mutations; gene amplification and altered protein expression of members of the human EGFR 
family and other receptor tyrosine kinases; and downstream signaling mediators. 
Biomarker analyses will be performed according to standard methodologies. Analyses will be 
described in the SAP. 
16.9 Deviations from the Preplanned Statistical Analyses 
Any deviation(s) from preplanned statistical analyses defined prior to randomization of the first 
patient will be described in a protocol amendment and/or in the SAP and/or in the final CTR, as 
appropriate. 
16.10 Interim Analysis  
As of Amendment 5: Due to the Sponsor’s decision to discontinue the trial (effective 20Dec2018), only clinical 
safety-related analyses will be conducted. The planned interim analyses as detailed below will not be performed. 
Per study design, tumor shrinkage will be evaluated at the end of Stage 1 and Stage 2. No other 
interim analysis is planned. 


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17 REFERENCES 
1. 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. Available from: http://globocan.iarc.fr, accessed 
on 29/Feb/2016. 
2. Brenner H, Kloor M, and Pox CP. Colorectal cancer. Lancet 2014; 383:1490-1502. 
3. Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the 
management of patients with metastatic colorectal cancer. Annals of Oncology 2016; 
27:1386-1422. 
4. Davies JM and Goldberg RM. Treatment of metastatic colorectal cancer. Seminars Oncol 
2011; 38(4):552-560. 
5. Wolpin BM and Mayer RJ. Systemic treatment of colorectal cancer. Gastroenterol 2008; 
134(5):1296-1310. 
6. Kirstein MM, Lange A, Prenzler A, et al. Targeted therapies in metastatic colorectal 
cancer: a systematic review and assessment of currently available data. The Oncologist 
2014; 19:1156-1168. 
7. National Comprehensive Cancer Network. Clinical practice guidelines in oncology: 
Colon cancer. NCCN.org. Version 2.2017.  
8. National Comprehensive Cancer Network. Clinical practice guidelines in oncology: 
Rectal cancer. NCCN.org. Version 3.2017. 
9. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously 
treated metastatic colorectal cancer (CORRECT): an international, multicentre, 
randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381:303-312.  
10. Yan Y and Grothey A. Molecular profiling in the treatment of colorectal cancer: focus on 
regorafenib. OncoTargets and Therapy 2015; 8:2949-2957. 
11. Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory 
metastatic colorectal cancer. N Engl J Med 2015; 372(20):1909-1919.  
12. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair 
deficiency. N Eng J Med 2015; 372(26):2509-2520. 
13. Overman, MJ, McDermott R, Leach J, et al.  Nivolumab in patients with metastatic DNA 
mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 
142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017; 18:1182-1191.  
14. Lin AY and Lin E. Programmed death 1 blockage, an Achilles heel for MMR-deficient 
tumors? J Hematol Oncol 2015; 8:124. 
15. Verdaguer H, Tabernero J, and Macarulla T. Ramucirumab in metastatic colorectal 
cancer: evidence to data and place in therapy. Ther Adv Med Oncol 2016; 8(3):230-242. 


Symphogen 
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Trial ID: Sym004-13 
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Page 109 of 169 
 
 
16. Azizi E, Kittai A, and Kozuch P. Antiepidermal growth factor receptor monoclonal 
antibodies: applications in colorectal cancer. Chemother Res Pract 2012; 
doi:10.1155/2012/198197. 
17. Segelov E, Chan D, Shapiro J, et al. The role of biological therapy in metastatic 
colorectal cancer after first-line treatment: a meta-analysis of randomised trials. Brit J 
Cancer 2014; 111:1122-1131. 
18. Chung KY and Saltz LB. Antibody-based therapies for colorectal cancer. The Oncologist 
2005; 10:701-709. 
19. Cerea G, Ricotta R, Schiavetto I, et al.  Cetuximab for treatment of metastatic colorectal 
cancer. Ann Oncol 2006; 17(Supplement 7):vii66-vii67. 
20. Grothey A. Defining the role of panitumumab in colorectal cancer. Comm Oncol 2006; 
3(10)(Supplement 4):10-16. 
21. Chung KY, Shia J, Kemeny NE, et al. Cetuximab shows activity in colorectal cancer 
patients with tumors that do not express the epidermal growth factor receptor by 
immunohistochemistry. J Clin Oncol 2005; 23(9):1803-1810. 
22. Heinemann V, Stintzing S, Kirchner T, et al.  Clinical relevance of EGFR- and KRAS-
status in colorectal cancer patients treated with monoclonal antibodies directed against 
the EGFR. Cancer Treatment Reviews 2008; 35:262-271. 
23. Liu J, Zhou Q, Xu J, et al. Detection of EGFR expression in patients with colorectal 
cancer and the therapeutic effect of cetuximab. JBUON 2016; 21(1):95-100. 
24. Hutchinson RA, Adams RA, McArt DG, et al. Epidermal growth factor receptor 
immunohistochemistry: new opportunities in metastatic colorectal cancer. J Transl Med 
2015; 13:217 doi: 10.1186/s12967-015-0531-z. 
25. Van Emburgh BO, Sartore-Bianchi A, Di Nicolantonio, F, et al.  Acquired resistance to 
EGFR-targeted therapies in colorectal cancer. Molecular Oncology 2014; 8:1084-1094. 
26. Dienstmann R, Vermeulen L, Guinney J, et al. Consensus molecular subtypes and the 
evolution of precision medicine in colorectal cancer. Nat Rev Cancer 2017; 17:79-92.  
27. Kulendran M, Stebbing JF, Marks CG, et al. Predictive and prognostic factors in 
colorectal cancer: a personalized approach. Cancers 2011; 3:1622-1638. 
28. De Divitiis C, Nasti, G, Montano M, et al. Prognostic and predictive response factors in 
colorectal cancer patients: between hope and reality. World J Gastroenterol 2014; 
20(41):15049-15059. 
29. Sorich MJ, Wiese MD, Rowland A, et al. Extended RAS mutations and anti-EGFR 
monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of 
randomized, controlled trials. Annals of Oncology 2015; 26:13-21. 
doi:10.1093/annonc/mdu378. 


Symphogen 
Clinical Trial Protocol 
Trial ID: Sym004-13 
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Confidential 
 
Page 110 of 169 
 
 
30. Van Cutsem E, Köhne C-H, Láng I, et al. Cetuximab plus irinotecan, fluorouracil, and 
leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of 
overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 2011; 
29(15):2011-2019. 
31. Evaluation of the Genomic Applications in Practice and Prevention (EGAPP) Working 
Group.  Recommendations from the EGAPP Working Group: can testing of tumor tissue 
for mutations in EGFR pathway downstream effector genes in patients with metastatic 
colorectal cancer improve health outcomes by guiding decisions regarding anti-EGFR 
therapy? Genet Med 2013; 15(7):517-527. 
32. Sepulveda AR, Hamilton SR, Allegra CJ, et al. Molecular biomarkers for the evaluation 
of colorectal cancer: guideline from the American Society for Clinical Pathology, College 
of American Pathologists, Association for Molecular Pathology, and the American 
Society of Clinical Oncology. J Clin Oncol 2017; 35(13):1453-1486. 
33. Rowland A, Dias MM, Wiese MD, et al. Meta-analysis of BRAF mutation as a predictive 
biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type 
metastatic colorectal cancer. Brit J Cancer 2015; 112:1888-1894. 
34. Yuan Z-X, Wang X-Y, Qin Q-Y, et al. The prognostic role of BRAF mutation in 
metastatic colorectal cancer receiving anti-EGFR monoclonal antibodies: a meta-
analysis. PLoS ONE 2013; 8(6): e65995. doi:10.1371/journal.pone.0065995. 
35. Pietrantonio F, Petrelli F, Coinu A, et al. Predictive role of BRAF mutations in patients 
with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. 
Eur J Cancer 2015; 51(5):587-594. 
36. Di Nicolantonio F, Martini, M, Molinari, F, et al. Wild-type BRAF is required for 
response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 
2008; 26(35):5705-5712. 
37. De Roock W, Claes B, Bernasconi D, et al.  Effects of KRAS, BRAF, NRAS, and PIK3CA 
mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory 
metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 2010; 
11:753–762. 
38. Peeters M, Oliner KS, Parker A, et al.  Massively parallel tumor multigene sequencing to 
evaluate response to panitumumab in a randomized phase III study of metastatic 
colorectal cancer. Clin Cancer Res 2013; 19(7):1902-1912. 
39. Yang Z-Y, Wu X-Y, Huang Y-F, et al. Promising biomarkers for predicting the outcomes 
of patients with KRAS wild-type metastatic colorectal cancer treated with anti-epidermal 
growth factor receptor monoclonal antibodies: a systematic review with meta-analysis. 
Int J. Cancer 2013; 133:1914-1925.  
40. Therkildsen C, Bergmann TK, Henrichsen-Schnack T, et al.  The predictive value of 
KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic 


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colorectal cancer: A systematic review and meta-analysis. Acta Oncologica 2014; 
53(7):852-864. 
41. Liu J, Hu J, Cheng L, et al. Biomarkers predicting resistance to epidermal growth factor 
receptor-targeted therapy in metastatic colorectal cancer with wild-type KRAS. 
OncoTargets and Therapy 2016; 9:557-565. 
42. Zhao B, Wang L, Qui H, et al. Mechanisms of resistance to anti-EGFR therapy in 
colorectal cancer. Oncotarget 2017; 8(3):3980-4000. 
43. van Brummelen EMJ, de Boer A, Beijnen JH and Schellens JHM.  BRAF mutations as 
predictive biomarker for response to anti-EGFR monoclonal antibodies. The Oncologist 
2017; 22:864-872. 
44. Montagut C, Dalmases A, Bellosillo B, et al. Identification of a mutation in the 
extracellular domain of the epidermal growth factor receptor conferring cetuximab 
resistance in colorectal cancer. Nat Med 2012; 18(2):221-223.  
45. Esposito C, Rachiglio AM, La Porta ML, et al. The S492R EGFR ectodomain mutation is 
never detected in KRAS wild-type colorectal carcinoma before exposure to EGFR 
monoclonal antibodies. Cancer Biology & Therapy 2013; 14(12):1143-1146. 
46. Braig F, März M, Schieferdecker A, et al. Epidermal growth factor receptor mutation 
mediates cross-resistance to panitumumab and cetuximab in gastrointestinal cancer. 
Oncotarget 2015; 6(14):12035-12047. 
47. Van Emburgh BO, Arena S, Siravegna G, et al. Acquired RAS or EGFR mutations and 
duration of response to EGFR blockade in colorectal cancer. Nat Commun 2016; 7:13665 
doi: 10.1038/ncomms13665. 
48. Misale S, Di Nicolantonio F, Sartore-Bianchi A, et al. Resistance to anti-EGFR therapy 
in colorectal cancer: from heterogeneity to convergent evolution. Cancer Discovery 2014; 
4(11):1269-1280. 
49. 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):598-609. 
50. Tabernero J, Ciardiello F, Montagut C, et al.  Efficacy and safety of Sym004 in refractory 
metastatic colorectal cancer with acquired resistance to anti-EGFR therapy: results of a 
randomized phase II study (RP2S). Eur Soc Med Oncol 2017; Abst 3115.   
51. 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. 
52. Koefoed K, Steinaa L, Søderberg JN, et al. Rational identification of an optimal antibody 
mixture for targeting the epidermal growth factor receptor. mAbs 2011; 3(6):584-595. 


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53. 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. 
54. Sánchez-Martín FJ, Bellosillo B, Gelabert-Baldrich M, et al. The first-in-class anti-EGFR 
antibody mixture Sym004 overcomes cetuximab resistance mediated by EGFR 
extracellular domain mutations in colorectal cancer. Clin Cancer Res 2016; 22(13):3260-
3267. 
55. Skartved NJØ, 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. 
56. Erbitux® (cetuximab) injection, for intravenous infusion. ImClone LLC US Package 
Insert Rev October 2016. Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125084s265lbl.pdf 
57. Vectibix® (panitumumab) Injection for intravenous infusion. Amgen Inc. US Package 
Insert Rev June 2017. Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125147s207lbl.pdf 
58. Herter-Sprie GS, Kung AL, and Wong KK. New cast for a new era: preclinical cancer 
drug development revisited. J Clin Invest 2013; 123(9):3639-3645. 
59. Kamb A. What’s wrong with our cancer models? Nature Reviews Drug Discovery 2005; 
4:161-165. 
60. Pompili L, Porru M, Caruso C, et al.  Patient-derived xenografts: a relevant preclinical 
model for drug development. J Exp and Clin Cancer Res 2016; 35:189 DOI 
10.1186/s13046-016-0462-4. 
61. Diaz LA, Jr., Williams RT, Wu J, et al. The molecular evolution of acquired resistance to 
targeted EGFR blockade in colorectal cancers. Nature 2012; 486:537-540. 
62. Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS mutations and acquired 
resistance to anti-EGFR therapy in colorectal cancer. Nature 2012; 486:532-536. 
63. Hasovits C, Pavlakis N, Howell V, et al.  Resistance to EGFR targeted antibodies-
expansion of clones present from the start of treatment. The more things change, the more 
they stay the same (Plus ca change, plus ca ne change pas!). Transl Gastrointest Cancer 
2013; 2(1):44-46. 
64. Leto SM and Trusolino L. Primary and acquired resistance to EGFR-targeted therapies in 
colorectal cancer: impact on future treatment strategies. J Mol Med 2014; 92:709-722. 
65. Arena S, Bellosillo B, Siravegna G, et al. Emergence of multiple EGFR extracellular 
mutations during cetuximab treatment in colorectal cancer. Clin Cancer Res 2015; 21(9): 
2157–2166. 
66. Morelli MP, Overman MJ, Dasari A, et al.  Characterizing the patterns of clonal selection 
in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR 
treatment. Annals of Oncology 2015; 26(4): 731-736.  


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67. Lacouture ME, Mitchell EP, Piperdi B, et al. Skin toxicity evaluation protocol with 
panitumumab (STEPP), a Phase II, open-label, randomized trial evaluating the impact of 
a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with 
metastatic colorectal cancer. J Clin Oncol 2010; 28:1351-1357. 
 
 
 


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18 APPENDICES 
Appendix 1 
Performance Status Evaluation 
Table 9: Measures of Performance Status 
 
Percent 
 
KARNOFSKY  
Performance Status Description1 
 
 
 
Level 
 
Eastern Cooperative Oncology Group 
(ECOG)  
Performance Status Description2 
 
 
100 
 
Normal; no complaints, no evidence of 
disease 
 
 
0 
 
 
 
Normal activity 
 
90 
 
Able to carry on normal activity; minor signs 
or symptoms of disease 
 
 
80 
 
Normal activity with effort; some signs or 
symptoms of disease 
 
 
1 
 
 
 
Symptoms but ambulatory 
 
70 
 
Cares for self; unable to carry on normal 
activity or do active work 
 
 
60 
 
Requires occasional assistance but is able to 
care for most needs 
 
 
2 
 
 
 
In bed < 50% of time 
 
50 
 
Requires considerable assistance and 
frequent medical care 
 
 
40 
 
Disabled; requires special care and assistance 
 
 
3 
 
 
 
In bed > 50 % of time 
 
30 
 
Severely disabled; hospitalization is 
indicated although death is not imminent 
 
 
20 
 
Very sick; hospitalization is necessary 
 
 
 
4 
 
 
 
100 % bedridden 
 
10 
 
Moribund; fatal processes progressing 
rapidly 
 
 
0 
 
Death 
 
 
 
5 
 
Death 
 
1Karnofsky DA, Abelman WH, Craver LF, Burchenal JH. The use of nitrogen mustards in the palliative treatment of carcinoma.  Cancer. 
1948;1:634-656. 
2Oken M, Creech RH, Tormey DC, Horton J, Davis TE, McFadden E, Carbone PP. Toxicity and response criteria of the eastern cooperative 
oncology group.  Am J Clin Oncol. (CCT) 1982; 5:649-655.  


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Appendix 2 
New York Heart Association Functional Criteria 
 
Table 10: New York Heart Association Functional Criteria 
 
Class I 
 
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
 
 
Class II 
 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
 
 
Class III 
 
Marked limitation of physical activity. Comfortable at rest, but less than ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain. 
 
 
Class IV 
 
 
Unable to carry on any physical activity without discomfort. Symptoms of cardiac 
insufficiency or anginal syndrome may be present even at rest. If any physical activity is 
undertaken discomfort increases. 
 
 
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great 
Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256 
 


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Appendix 3 
Clinical Adverse Events: Grading Scale 
 
Table 11: Clinical Adverse Event Grading 
Severity 
CTCAE*Grade 
Definition 
Mild 
1 
Awareness of symptom, but easily tolerated.  Event is usually transient 
requiring no special treatment; does not interfere with usual status or 
activities 
 
Moderate 
2 
Event may be ameliorated by simple therapeutic measures; may 
interfere with usual activities 
 
Severe 
3 
Event results in temporary disability or incapacity; inability to perform 
usual activities; requires intervention 
 
Life-threatening 
4 
Event requires immediate intervention; need for emergency treatment; 
patient is at risk of death at the time of the event 
 
Fatal 
5 
Event resulting in the subsequent death of the patient 
 
 
Note: 
In those cases where further definition of an event is provided by the CTCAE (v5), please refer to that document for 
grading and severity information. 
* <https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50> 


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Appendix 4 
Clinical Adverse Events: Determining Relationship to IMP 
 
Table 12: Clinical Adverse Event Attribution 
NOT-RELATED 
This category applies to those AEs which, after careful medical consideration, are clearly felt to be due to 
extraneous causes (disease, environment, etc.) that are not-related to the administration of IMP. 
RELATED (must have first 3) 
This category applies to those AEs, which, after careful medical consideration, are felt to be related to the 
administration of the IMP. The relationship of an AE to the IMP can be considered related if: 
 
It follows a reasonable temporal sequence from administration of the drug or drug levels have been 
established in body fluids or tissues. 
 
It could not be reasonably explained by the known characteristics of the patient’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the patient. 
 
It disappears or decreases upon cessation of drug or reduction on dose (if applicable) and appears upon 
rechallenge.* 
 
It follows a known response pattern to the suspected drug. 
 
Adapted from:  Karch FE and Lasagna L. Adverse drug reactions: a critical review. JAMA. 1975 Dec 22; 234 (12):1236-1241.  
 
*There are exceptions when an AE does not disappear upon discontinuation of the drug, yet drug-relatedness clearly exists, e.g., 
1) tardive dyskinesia, 2) fixed drug eruptions. 
 
 


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Appendix 5 
Response Evaluation Criteria in Solid Tumors (RECIST v1.1) 
 
Table 13: Summary of RECIST v1.1 Guidelines 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks. In addition to a baseline scan, 
confirmatory scans should also be obtained > 4 weeks following initial documentation of objective response (OR). 
 
Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest 
diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes 
are used in the RECIST v1.1 criteria. 
 
A. DEFINITIONS 
 
Evaluable for Toxicity: All patients will be evaluable for toxicity from the time of their first treatment with IMP.   
Evaluable for Objective Response: Only those patients who have measurable disease present at baseline, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These patients 
will have their response classified according to the definitions stated below.   
 
Note:        Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable. 
 
Evaluable Non-Target Disease Response:  Patients who have lesions present at baseline that are evaluable but do not meet 
the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for non-target disease. The response assessment is based on the presence, absence, or unequivocal 
progression of the lesions.  
 
B. DISEASE PARAMETERS 
 
Measurable Disease: Measurable lesions are defined as those that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥ 20 mm by chest x-ray, as ≥10 mm with CT scan, or as ≥10 mm with calipers by clinical 
examination. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Note:  
Tumor lesions that are situated in a previously irradiated area might or might not be considered measurable.   
If the investigator thinks it appropriate to include them, the conditions under which such lesions should be considered must be 
defined in the protocol. 
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 at follow-
up, only the short axis will be measured and followed. 
Non-Measurable Disease: All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI) are considered as non-measurable. 
 
Note:  
Cystic 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. 
 
Target Lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all 
involved organs, should be identified as target lesions and recorded and measured at baseline. Target lesions should be 
selected based on their size (lesions with the longest diameter), be representative of all involved organs, but in addition should 
be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion 


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does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease. 
 
Non-Target Lesions: All other lesions (or sites of disease) including any measurable lesions over and above the 5 target 
lesions should be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are 
not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow-
up. 
 
C. METHODS FOR EVALUATION OF MEASURABLE DISEASE 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All baseline evaluations should be 
performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
Note: 
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 is preferred to evaluation by clinical examination unless the lesion(s) 
being followed cannot be imaged but are assessable by clinical examination. 
 
Clinical Lesions: Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and 
palpable lymph nodes) and  10 mm diameter as assessed using calipers (e.g., skin nodules). In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest X-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by 
aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI: This guideline defines measurability of lesions on CT scan based on the assumption that CT 
slice thickness is 5 mm or less. If 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).   
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, there are many 
image acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, and measurement.  
Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of 
the scanning sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, 
the modality used at follow-up should be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence. It is beyond the scope of the RECIST v1.1 guidelines to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with breath-hold 
scanning techniques, if possible. 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of optimal 
diagnostic CT quality for use with RECIST v1.1 measurements. However, if the site can document that the CT performed as 
part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the 
PET-CT can be used for RECIST v1.1 measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET portion of the CT introduces additional data which may bias 
an Investigator if it is not routinely or serially performed.   
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement.  
Ultrasound examinations cannot be reproduced in their entirety for independent review later, and, because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will be taken from one assessment to the next.  
If new lesions are identified by ultrasound during the study, confirmation by CT or MRI is advised. If there is concern about 
radiation exposure using CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not advised.  However, such 
techniques may be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in 
trials where recurrence following complete response (CR) or surgical resection is an endpoint. 
 


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Tumor Markers: Tumor markers alone cannot be used to assess response. If markers are initially above the upper normal 
limit, they must normalize for a patient to be considered in complete clinical response. Specific guidelines for both CA-125 
response (in recurrent ovarian cancer) and prostate specific antigen (PSA) response (in recurrent prostate cancer) have been 
published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with objective tumor 
assessment for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) and complete responses 
(CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known residual benign tumors can 
remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the 
measurable tumor has met criteria for response or stable disease is mandatory to differentiate between response or stable 
disease (an effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate the use of 
FDG-PET scanning to complement CT scanning in assessment of progression (particularly possible 'new' disease). New 
lesions based on FDG-PET imaging can be identified according to the following algorithm:  
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new lesion. 
No FDG-PET at baseline and a positive FDG-PET at follow-up:   
 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.   
 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT 
scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be 
the date of the initial abnormal FDG-PET scan).   
 
If the positive FDG-PET at follow-up corresponds to a preexisting site of disease on CT that is not progressing 
based on the anatomic images, this is not PD. 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual 
radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this circumstance 
should be prospectively described in the protocol and supported by disease-specific medical literature for the 
indication. However, it must be acknowledged that both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/sensitivity. 
 
Note: 
A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surrounding 
tissue on the attenuation corrected image. 
D. RESPONSE CRITERIA 
 
1. 
Evaluation of Target Lesions 
 
 Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes (whether target or non-
target) must have reduction in short axis to < 10 mm. 
 
 Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the 
baseline sum diameters. 
 
 Progressive Disease (PD): At least a 20% increase in the sum of the 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 progressions. 
 
 Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study. 
 
2.  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). 


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Note:  
 If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the 
normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-
target lesions.  Unequivocal progression should not normally trump target lesion status. It must be representative of 
overall disease status change, not a single lesion increase.     
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating physician should 
prevail in such circumstances, and the progression status should be confirmed later by the review panel (or Principal 
Investigator). 
 
3.  
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence 
(taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's 
best response assignment will depend on the achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥ 4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
 
≥ 4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/Not evaluated 
No 
PR 
SD 
Non-CR/Non-PD/Not evaluated 
No 
SD 
Documented at least once  
≥ 4 wks. from baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST v1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. 
 
Note:   Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration.”  Every effort 
should be made to document the objective progression even after discontinuation of treatment. 
 
Abbreviations (in alphabetical order):  CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/Non-PD* 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*   Non-CR/non-PD is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as an 
endpoint for assessment of efficacy in some trials, so to assign this category when no lesions can be measured is not 
advised. 
 
Abbreviations (in alphabetical order):  CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease 
 
 
 


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E. DURATION OF RESPONSE 
 
Duration of Overall Response: The duration of overall response is measured from the time measurement criteria are met for 
CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that 
progressive disease is objectively documented. 
 
 
Duration of Stable Disease: Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements.  
 
F. PROGRESSION FREE SURVIVAL 
 
Progression Free Survival (PFS) is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
 
Adapted from: Eisenhauer EA, Therasse P, Bogaerts J, et. al.  New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur. J. Cancer. 2009; 45:229-247. 
 
 
<http://www.eortc.be/recist/documents/RECISTGuidelines.pdf >  
 
 


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Appendix 6 
Management of Infusion-Related Reactions 
 
A. Prophylaxis for Infusion-Related Reactions 
Premedication for prophylaxis of IRRs will be mandatory prior to each dose of IMP.  All patients must be 
premedicated with standard therapies that include a glucocorticoid and an H1 antagonist.  Where 
indicated, consideration may be given to include an H2 antagonist and/or acetaminophen.   
Required and optional agents, as well as recommended doses, are provided (Table 14). 
Table 14: Premedications for Infusion-Related Reactions 
Drug Class 
Recommended Dose 
When to Administer prior 
to infusion 
Required Agents 
 
 
Glucocorticoid  
equivalent to 80-100 mg IV methylprednisolone 
approximately 0.5 to 2 hours 
Antihistamine (H1 antagonist) 
equivalent to 25-50 mg IV diphenhydramine 
approximately 0.5 hours 
Optional Agents 
 
 
Antihistamine (H2 antagonist) 
equivalent to 50 mg IV ranitidine  
or 30 mg IV famotidine, or equivalent 
approximately 0.5 hours 
Acetaminophen 
1000 mg IV (where available, or PO), or equivalent 
approximately 0.5 hours 
Abbreviations (in alphabetical order):  IV, intravenous; mg, milligram  
Note:  Doses may be adjusted based on institutional practices.  Administration of oral dexamethasone, 10 mg po, (or equivalent) 12 and 6 hours 
prior to administration of Sym004 is permissible in patients experiencing IRRs or if an increased incidence or severity of IRRs are 
observed.   
For IRRs while in the study, the following premedication instructions are provided: 
 
For Grade 1, Grade 2, or Grade 3 reactions, consider additional premedication or adjustment to 
premedications for subsequent infusions.    
 
For Grade 4 reactions, not applicable as no further treatment with IMP is allowed 
 
 


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B. Grading of Infusion-Related Reactions 
The CTCAE v5* definition of IRRs (General Disorders and Administration Site Conditions) is shown 
below. Symptoms occurring during or following infusion of investigational therapy may also be defined 
according to AE categories such as allergic reaction, anaphylaxis, or cytokine release syndrome. In the 
setting of symptoms occurring during or following infusion of investigational therapy, investigators are 
encouraged to use the AE term “Infusion-Related Reaction” and any additional terms (including those not 
listed here) that best describe the event. Those described should be graded as follows (Table 15): 
Table 15: Grading of Infusion-Related Reactions 
Adverse 
Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Infusion-
related 
reaction 
Mild transient 
reaction; infusion 
interruption not 
indicated; 
intervention not 
indicated 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤ 24 hours 
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 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Definition: A disorder characterized by adverse reaction to the infusion of pharmacological or biological substances. 
Allergic 
reaction 
Transient flushing 
or rash, drug fever 
<38 degrees C 
(<100.4 degrees F); 
intervention not 
indicated 
Intervention or infusion 
interruption indicated; 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics); 
prophylactic medications 
indicated for ≤ 24 hours 
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 
(e.g., renal impairment, 
pulmonary infiltrates) 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Definition: A disorder characterized by an adverse local or general response from exposure to an allergen. 
Anaphylaxis 
- 
- 
Symptomatic bronchospasm, 
with or without urticaria; 
parenteral intervention 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-like substances 
from mast cells, causing a hypersensitivity immune response. Clinically, it presents with breathing difficulty, dizziness, hypotension, cyanosis 
and loss of consciousness and may lead to death. 
Cytokine 
release 
syndrome 
Mild reaction; 
infusion interruption 
not indicated; 
intervention not 
indicated 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤ 24 hours 
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 
(e.g., renal impairment, 
pulmonary infiltrates) 
Life-threatening 
consequences; 
pressor or 
ventilatory support 
indicated 
Death 
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and shortness of breath; it is caused by the release of 
cytokines from the cells. 
*See <https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50> 
 


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C. Guidelines for Management of Infusion-Related Reactions 
Consistent with usual medical practice, selected parenteral medications may be utilized for Grade > 2 
allergic/hypersensitivity reactions.  The Sponsor should be contacted immediately if questions arise 
concerning the grade of the reaction.  The following are recommended management guidelines for IRRs 
associated with IMP administration.  In all cases the Investigator should use best clinical judgment in 
managing such reactions (Table 16). 
Table 16: Management of Infusion-Related Reactions 
Grade 1 
 Consider slowing the infusion to 50% of the prior rate 
 Monitor the patient for worsening condition 
 If the infusion is extended, administer subsequent infusions at the prolonged rate 
 Consider additional premedication or adjustment to premedications for subsequent infusions 
Grade 2 
 
 
Interrupt the infusion for a minimum of 30 minutes 
 
Administer additional pharmacologic therapy (e.g., diphenhydramine, acetaminophen) and appropriate 
supportive care (e.g., oxygen), as medically indicated  
 
Resume the infusion at 50% of the prior rate once the infusion-related reaction has resolved or 
decreased to ≤ Grade 1 
 
Monitor the patient for worsening condition 
 
Administer subsequent infusions at the prolonged rate 
 
Consider additional premedication or adjustment to premedications for subsequent infusions 
≥ Grade 3 
 
 
Stop the infusion  
 
Administer additional pharmacologic therapy (diphenhydramine, dexamethasone) and appropriate 
supportive care (e.g., oxygen), as medically indicated  
 
Administer epinephrine or bronchodilators as medically indicated 
 
Hospital admission for observation may be indicated 
 
Do not resume infusion after a ≥ Grade 3 reaction 
 
Patients who have a Grade 3 infusion-related reaction will be either discontinued from treatment, or must 
receive subsequent treatments at a reduced dose and a prolonged infusion rate (slowed to 50% of the prior 
rate or longer) 
 
Consider additional premedication or adjustment to premedications for subsequent infusions 
 
Patients who have a > Grade 3 infusion-related reaction will be discontinued from treatment 
 
In the Event of Infusion Prolongation 
Any assessments to be performed or samples to be collected (e.g., vital signs, PK) at the end of or following EOI 
will still be performed or collected beginning at the delayed EOI timepoint.   
All infusion interruptions and subsequent prolongations, including modified infusion times, as well as the toxicity 
that necessitated them, will be clearly documented on the appropriate page of the patient’s CRF. 
 


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Appendix 7 
Management of Dermatologic Adverse Events  
 
A. Prophylaxis for IMP-Related Dermatologic AEs 
Patients receiving Sym004, futuximab, or modotuximab are to receive mandatory prophylactic treatments 
for acneiform rash during Cycle 1 and 2 as described (Table 17). 
Table 17: Mandatory Premedications for Dermatologic AEs 
Treatment 
Dose 
Start 
Stop 
Alternatives 
Systemic Therapy 
 
 
 
 
minocycline or doxycycline 
1 × 100 mg/day 
2 × 100 mg/day 
C1D1 
EOC2b 
In case of intolerance 
 first generation cephalosporin 
 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 
C1D1 
EOC2 
 
moisturizer (creams or 
ointments) 
3 × daily to the hands, and 
after hand washingc;  
2 × daily on the rest of the 
body 
C1D1 
Continue 
 
Abbreviations (in alphabetical order):  C1D1, Cycle 1 Day 1; EOC2, end of Cycle 2; mg, milligram 
a. 
If infection is suspected (yellow crusts, purulent discharge, painful skin / nares), obtain culture and change to oral antibiotic based on 
sensitivities. 
b. 
May be continued beyond EOC2 at the Investigator’s discretion or in the event of CTCAE Grade 2 rash. 
c. 
Use fragrance free soap. 
 
 


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B. Grading and Management of IMP-Related Dermatologic AEs 
The incidence and severity of dermatologic AEs observed in studies of Sym004 are discussed (Section 
2.4.1).  Recommendations for management of Grade 1 to Grade 3 dermatologic AEs are provided below 
(Table 18-Table 23). 
If a patient experiences any Grade 4 dermatologic AE, the patient must be withdrawn from IMP 
treatment.  It is strongly recommended that a dermatologist is consulted in the event of Grade 3 or Grade 
4 dermatologic AE. 
 
Table 18: Management of Rash – Sym004, Futuximab, or Modotuximab 
CTCAE Grade 
Action with IMP 
Treatment- Rash 
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% or desonide 0.05% or 
fluocinolone 0.01%; 2×daily 
Topical: Rest-of-body 
moisturizers; 2×daily 
Systemic1:   
minocycline 100 mg/day or doxycycline 200 
mg/day; for at least 4 weeks   
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 
following guidelines for 
dose-delay and dose-
reduction as outlined in 
Table 24 and Table 25   
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:  
o Day 1: 2-1-1-2  
o Day 2: 1-1-1-2  
o Day 3: 1-1-1-1  
o Day 4: 1-1-1  
o Day 5 1-0-1  
o Day 6: 1 
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-assess.   
Refer to Table 24 and 
Table 25 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, Common Terminology Criteria for 
Adverse Events v5 
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 sensitivity 
 
 


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Table 19: Management of Xerosis – Sym004, Futuximab, or Modotuximab 
CTCAE Grade 
Action with IMP  
Treatment-Xerosis 
1 
<10% BSA and no associated 
erythema or pruritus 
Continue at the same 
dose 
Topical:  Face 
moisturizing cream or ointment1; 2×daily 
and 
Topical:  Body 
ammonium lactate 6-12% cream; 2×daily 
2 
10-30% BSA associated with 
erythema or pruritus; limited 
instrumental ADL 
 
Continue at the same 
dose 
 
If locally debilitating 
for the patient, consider 
following guidelines for 
dose-delay and dose-
reduction as outlined in 
Table 24 and Table 25   
Topical:  Face 
moisturizing cream or ointment1; 2×daily 
and 
Topical:  Body 
ammonium lactate 12% cream or salicylic acid 3-6% 
cream or urea 10-20% cream; 2×daily 
3 
>30% BSA associated with 
pruritus; limited self-care ADL 
Delay dose of Sym004, 
continue skin treatment 
and re-assess.  
Refer to Table 24 and 
Table 25 for further 
guidelines on dose-
reduction 
Topical:  Face 
moisturizing cream or ointment1; 2×daily 
and 
Topical:  Body 
ammonium lactate 12% cream or salicylic acid 3-6% 
cream or urea 10-20% cream; 2×daily 
and 
Topical: Eczematous areas  
topical steroid (e.g., triamcinolone acetonide 0.025% 
or desonide 0.05% or alclometasone 0.05% or 
fluticasone propionate 0.05%); 2×daily 
Abbreviations (in alphabetical order):  ADL, activities of daily living; BSA, body surface area; CTCAE, Common Terminology Criteria for 
Adverse Events v5 
1. 
If prescription is not available, recommendation by pharmacist/dermatologist is acceptable 
 
 


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Table 20: Management of Paronychia – Sym004, Futuximab, or Modotuximab 
CTCAE Grade 
Action with IMP 
Treatment-Paronychia 
1 
Nail fold edema or erythema; 
disruption of the cuticle 
Continue at the same 
dose 
Topical:  
antibiotics (e.g., clindamycin 1% or erythromycin 
1%) 
and 
vinegar soaks (i.e., soaking fingers or toes in a 1:1 
solution of white vinegar in water for 15 min daily 
 
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 
following guidelines for 
dose-delay and dose-
reduction as outlined in 
Table 24 and Table 25   
Same as for Grade 1 
and 
Topical:  
silver nitrate application weekly (needs consultation 
with dermatologist or surgeon) 
and 
Systemic: 
bacterial culture, oral antibiotic if infection 
confirmed 
3 
Surgical intervention or IV 
antibiotics indicated; limiting 
self-care ADL 
 
Delay dose of Sym004, 
continue skin treatment 
and re-assess.  
Refer to Table 24 and 
Table 25 for further 
guidelines on dose-
reduction 
Same as for Grade 1 
and 
Topical: 
silver nitrate application weekly (needs consultation 
with dermatologist or surgeon) 
and 
consider nail avulsion (needs consultation with 
dermatologist or surgeon) 
and 
Systemic: 
bacterial culture, oral antibiotic if infection 
confirmed 
Abbreviations (in alphabetical order):  ADL, activities of daily living; IV, intravenous; CTCAE, Common Terminology Criteria for Adverse 
Events v5 
 
 


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Table 21: Management of Pruritus – Sym004, Futuximab, or Modotuximab 
CTCAE Grade 
Action with IMP 
Treatment-Pruritus 
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 
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 
following guidelines for 
dose-delay and dose-
reduction as outlined in 
Table 24 and Table 25   
Same as for Grade 1 
and 
Systemic: 
oral antihistamines (diphenhydramine 25-50 mg; 
hydroxyzine 25 mg; fexofenadine 60 mg; 3×daily  
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-assess.  
Refer to Table 24 and 
Table 25 for further 
guidelines on dose-
reduction 
Same as for Grade 2 
 
Abbreviations (in alphabetical order):  ADL, activities of daily living; CTCAE, Common Terminology Criteria for Adverse Events v5 
 
 


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Table 22: Management of Photosensitivity – Sym004, Futuximab, or Modotuximab 
CTCAE Grade 
Action with IMP 
Treatment-Photosensitivity 
1 
Painless erythema and erythema 
covering <10% BSA 
Continue at the same 
dose 
Topical:  
broad spectrum sunscreen with an SPF of at least 15; 
reapplied every 2 hours or more frequently if 
swimming or perspiring 
and 
Systemic: 
bacterial culture, oral antibiotic if infection 
confirmed 
2 
Tender erythema covering 10-
30% BSA 
 
Continue at the same 
dose 
 
If locally debilitating 
for the patient, consider 
following guidelines for 
dose-delay and dose-
reduction as outlined in 
Table 24 and Table 25 
Same as for Grade 1 
and 
Topical:  
corticosteroids (e.g., triamcinolone acetonide 
0.025% or desonide 0.05% or alclometasone 0.05% 
cream or  fluticasone propionate 0.05%); 2×daily 
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-assess.  
Refer to Table 24 and 
Table 25 for further 
guidelines on dose-
reduction 
Same as Grade 2 
 
Abbreviations (in alphabetical order):  BSA, body surface area; CTCAE, Common Terminology Criteria for Adverse Events v5; NSAID, 
nonsteroidal anti-inflammatory drug; SPF, sun protection factor 
 
Table 23: Management of Fissures – Sym004, Futuximab, or Modotuximab 
Treatment Step 
Action with IMP 
Treatment-Fissures 
1 
Initiated at first occurrence 
No action 
Topical:  
 thick moisturizers of zinc oxide (13-40%) cream 
 liquid glues of cyanoacrylate to seal cracks 
2 
If no improvement after 2 weeks 
from initiation of Step 1 
No action 
Topical:  
 thick moisturizers of zinc oxide (13-40%) cream 
under occlusion at night 
 salicylic acid 6% cream or ammonium 
lactate/lactic acid 12% 
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 
 
Prophylaxis for 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 above should be followed. 


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If fissures occur which are unresponsive to intensive therapeutic treatment as specified above, Sym004, 
futuximab, or modotuximab dosing should be delayed. The need for dose-reduction and/or continued 
dose-delays should be discussed with the Sponsor or designee, if adequate improvement is not seen after 
the initial dose-delay. 
 
C. Dose Reduction Guidelines for IMP-Related Dermatologic AEs 
Dose delay and/or intrapatient dose-reduction(s) will be required upon occurrence of Grade 3 anti-EGFR-
associated dermatologic AE, and should be implemented according to the following tables (Table 24, 
Table 25): 
Table 24: Dose Reduction for Grade 3 Dermatologic AEs - Sym004 
Dermatologic AE 
Grade 3 
Immediate 
Action 
Outcome Improvement 
Sym004 
First occurrence 
Delay dose 
 
Grade ≤1 
Continue at same dose  
Grade 2 
Reduce to 4.5 mg/kg 
No improvement 
Discontinue 
Second occurrence 
Delay dose 
 
Grade ≤1 
Continue at same dose 
Grade 2 
At dose of 6.0 mg/kg:  Reduce to 4.5 mg/kg 
At dose of 4.5 mg/kg:  Reduce to 3.0 mg 
No improvement 
Discontinue 
Third occurrence 
Delay dose 
 
Grade ≤1 
Continue at same dose 
Grade 2 
At dose of 6.0 mg/kg:  Reduce to 4.5 mg/kg 
At dose of 4.5 mg/kg:  Reduce to 3.0 mg/kg 
At dose of 3.0 mg/kg:  Discontinue 
No improvement 
Discontinue 
Fourth occurrence 
Discontinue 
Any 
Discontinue 
Abbreviations (in alphabetical order):  kg, kilogram; mg, milligram 
Note: Dose reductions for 9 mg/kg loading NA. For dose delays, re-assess after < 2 weeks. Longer delays are allowed if no recovery to < Grade 2 
after 2 weeks 
 
Table 25: Dose Reduction for Grade 3 Dermatologic AEs - Futuximab or Modotuximab 
Dermatologic AE 
Grade 3 
Immediate 
Action 
Outcome Improvement 
Futuximab or Modotuximab 
First occurrence 
Delay dose 
 
Grade ≤1 
Continue at same dose  
Grade 2 
Reduce to 1.5 mg/kg 
No improvement 
Discontinue 
Second occurrence 
Delay dose 
 
Grade ≤1 
Continue at same dose 
Grade 2 
At dose of 3.0 mg/kg:  Reduce to 1.5 mg/kg 
At dose of 1.5 mg/kg:  Discontinue 
No improvement 
Discontinue 
Abbreviations (in alphabetical order):  kg, kilogram; mg, milligram 
Note:  Dose reductions for 9 mg/kg loading NA.  For dose delays, re-assess after < 2 weeks.  Longer delays are allowed if no recovery to < Grade 
2 after 2 weeks 
 
In each case, the next treatment should be delayed, and the patient’s condition should be re-assessed after 
1-2 weeks. Treatment should be delayed further if the AE remains at Grade 3 after 2 weeks. 
In the case of a Grade 2 dermatologic AE which is locally debilitating for the patient, the guidelines 
outlined above may be followed at the Investigator’s discretion.   
Patients must be withdrawn from IMP treatment in the event of a Grade 4 dermatologic AE. 


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Appendix 8 
Management of Hypomagnesemia 
 
A. Grading of Hypomagnesemia and QTc Prolongation 
 
Table 26: CTCAE Grading of Hypomagnesemia and QTc Prolongation 
Event 
1 
2 
3 
4 
5 
Hypomagnesemia 
<LLN-1.2 mg/dL 
<LLN-0.5 mmol/L 
<1.2-0.9 mg/dL 
<0.5-0.4 mmol/L 
<0.9-0.7 mg/dL 
<0.4-0.3 mmol/L 
<0.7mg/dL 
<0.3 mmol/L 
life-threatening consequences 
Death 
ECG QT-corrected 
interval prolonged 
 
 
QTc 450-480 ms 
QTc 481-500 ms 
QTc ≥ 501ms on 
at least 2 separate 
ECGs 
QTc ≥ 501 or ≥ 60 ms change from 
baseline and Torsade de pointes or 
polymorphic ventricular 
tachycardia or signs/symptoms of 
serious arrhythmia  
-- 
Abbreviations (in alphabetical order):  CTCAE, Common Terminology Criteria for Adverse Events v5; dL, deciliter; ECG, electrocardiogram; L, 
liter; LLN, lower limit of normal; mg, milligram; mmol, millimole; ms, millisecond; QTc, QT-corrected interval  
 
 
 
B. Management of Hypomagnesemia 
Patients receiving IMP will be monitored weekly for evidence of hypomagnesemia, which should be 
managed as follows (Table 27):  
 
Table 27: Management of Hypomagnesemia and QTc Prolongation 
Grade 
Action 
Grade 1-2 
No replacement therapy required, weekly monitoring to continue, but may be administered at 
treating physician’s discretion, weekly monitoring to continue 
Grade 2 or higher 
Use of concomitant QTc-prolonging drugs* should be discontinued unless urgently needed for 
medical care and no alternative therapy is available   
Grade 3-4 
Administer MgSO4 (6 to 10g IV) at minimum 2 times per week until ≤ Grade 1 
Perform predosing ECG (required) to monitor for QTc prolongation** 
 In the event of Grade 3 QTc prolongation potentially due to hypomagnesemia, Sym004 
administration should be delayed while magnesium repletion is undertaken   
 Sym004 may be restarted with continued intensive magnesium therapy at the same dose or at a 
reduced dose once hypomagnesemia returns to ≤ Grade 1 severity, and once the QTc returns to 
WNL or baseline status 
 In the event of Torsade de pointes (TdP) or other life-threatening arrhythmias discontinue Sym004 
Grade 4 
For Grade 4 hypomagnesemia that is refractory to IV magnesium-replacement therapy, dosing with 
IMP should be delayed or reduced.   
Abbreviations (in alphabetical order):  g, gram; IV, intravenous  
 
  * Listings of QTc prolonging drugs may be found at:   <https://crediblemeds.org/index.php?cID=222> 
** ECG is required before IMP administration to monitor QT prolongation that may result in severe arrhythmias such as TdP. 
 


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Appendix 9 
Maximum Total Blood Collection Volumes 
 
Table 28: Maximum Total Blood Collection Volumes 
Study  
Assessments 
Vol/ 
sample 
Screen 
C1 
C2 
C# 
EOT 
 
1M FUP 
Total 
Volume 
# 
Vol 
mL 
# 
Vol 
mL 
# 
Vol 
mL 
# 
Vol 
mL 
# 
Vol 
mL 
# 
Vol 
mL 
*Genomic Analysis 
20+20^ 
1 
40 
0 
 
1 
20 
0 
 
1 
20 
0 
 
80 
Hematology Panel 
5 
1 
5 
2 
10 
1 
5 
1 
5 
1 
5 
1 
5 
35 
Biochemistry Panel 
10 
1 
10 
2 
20 
1 
10 
1 
10 
1 
10 
1 
10 
70 
Serum Mg, Ca, K 
5 
0 
 
2 
10 
3 
15 
3 
15 
0 
 
0 
 
40 
Coagulation Panel 
5 
1 
5 
1 
5 
1 
5 
1 
5# 
1 
5 
1 
5 
30 
Pregnancy Test 
5 
1 
5 
1 
5 
0 
 
0 
 
1 
5 
0 
 
15 
**ADA Testing 
5 
1 
5 
2 
10 
1 
5 
1 
5## 
1 
5 
1 
5 
35 
**PK Studies 
5 
0 
11 
55 
7 
35 
4 
20 
1 
5 
1 
5 
120 
**Pharmacodynamic 
Testing 
20 
1 
20 
0 
 
1 
20 
0 
 
1 
20 
0 
 
60 
Total Volume 
90 
 
115 
 
115 
 
60 
 
75 
 
30 
485 
Abbreviations (in alphabetical order): #, number of samples; 1M FUP, 1-month follow-up; ADA, anti-drug antibody; C, cycle(s); Ca, calcium; 
EOT, end of treatment; K, potassium; Mg, magnesium; mL, milliliter; PK, pharmacokinetic; Vol, volume 
 
*As of Amendment 5:  Omitted with the exception of prescreening genomic sampling for eligibility assessment 
**As of Amendment 5:  Omitted 
 
^Whole blood (~ 2 × 10 mL) to be collected at each timepoint (plus additional ~ 2 × 10 mL at prescreening to be stored for assay validation 
purposes); for assessment of ctDNA by Guardant360 
 
#C3 only 
##Odd number cycles only 
 
If sites can perform hematology, serum chemistry, and coagulation studies with smaller volumes of blood per sample, they are encouraged to do 
so. Required PK, ADA, and PD/biomarker volumes are fixed and should not be reduced.   
To estimate a patient’s total blood collection volume during study participation, maximum estimates are used.  During a patient’s study 
participation, the maximum amounts of venous blood that will be collected are listed above. Study duration is based on 12 weeks estimated 
average patient participation, i.e., an average of Cycle 1 (4 weeks) plus Cycle 2 and 3 (8 weeks).   
When an indwelling catheter (or equivalent venous access) is utilized, a blood flush discard of up to 3 mL is to be done before drawing the first 
blood tube collected on the scheduled day/time for routine laboratory tests and PK samples. Blood flush discard volumes ARE NOT included 
in volume calculations in table above and should be considered when summarizing actual blood collection volumes. 
 


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Appendix 10 Schedule of Study Activities 
Table 29: Schedule of Study Activities 
STUDY ASSESSMENTS 
 
Screen 
CYCLE 1 
CYCLE 2 
SUBSEQUENT CYCLES 
EOT 
<10d after 
decision to 
discontinue 
1M FUP* 
30 d (+7) 
after last 
dose 
Extended 
Follow 
Up*        
for 
ongoing 
AE 
As 
Clinically 
Indicated 
D1 
D8 
±2 
D15 
±2 
D22 
±2 
D1 
±2 
D8 
±2 
D15 
±2 
D22 
±2 
End of 
Cycle 2 
(final 
week or 
prior to 
C3D1 
dosing) 
D1 
±2 
D8 
±2 
D1
5 
±2 
D22 
±2 
End of Even 
Number 
Cycles 
(final week 
or prior to 
CxD1 
dosing) 
CONSENT AND MEDICAL HISTORY 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Past Medical History 
X 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History of mCRC 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAFETY ASSESSMENTS (screening within 14 days prior to first dose of IMP unless otherwise specified) 
Medication/Procedure Survey 
from 14 days prior to 1st dose through 30 days after last dose 
 
 
AE Reporting 1 
from signing of informed consent through 30 days after last dose; through 2-month (or 4-month) follow-up with continuing IMP-related (S)AEs 
X 
ECOG PS Evaluation 
X 
Xa 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
X 
Vital Signs  
X 
SOI 
EOI 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
Physical Exam/include weight, skin 2 
X 
Xa 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
X 
Dermatologic Exam 3 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
 
X 
Hematology 4/Biochemistry Panel 5 
X 
Xa 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
X 
Serum Mg, Ca, K 6 
 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
 
X 
Coagulation Panel 7/Urinalysis 8 
X 
Xa 
 
 
 
X 
 
 
 
 
C3 
only 
 
 
 
 
X 
X 
 
X 
Pregnancy Test 9  (w/in 2d of 1st dose) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
ECG (12-lead) 10 
X 
X 
 
 
 
X 
 
 
 
 
C3 
only 
 
 
 
 
X 
 
 
X 
SPECIALTY ASSESSMENTS (on study assessments) 
**Blood for ADA Assessment 11  
(see Specialty Assessments Table) 
 
X 
 
X 
 
X 
 
 
 
 
Odd 
# Cs 
 
 
 
 
X 
X 
 
 
**Blood for PK Assessment 12  
(see Specialty Assessments Table) 
 
SOI 
EOI  
6h 24h 
D4 
SOI 
EOI 
SOI 
EOI 
SOI 
EOI 
SOI 
EOI 
 
 
SOI 
EOI  
6h 24h 
D25 
 
SOI 
EOI 
 
SOI 
EOI 
 
 
X 
X 
 
 
SPECIALTY ASSESSMENTS (screening within 14 days prior to first dose of IMP) 
*Blood for Genomic Analysis 13 
Prescreen 
 
 
 
 
 
 
 
 
D25 ±1d 
 
 
 
 
 
Xc 
 
 
Upon PD if 
different 
**Blood for Pharmacodynamics14 
Screening/             
prior to C1D1 
 
 
 
 
 
 
 
D25 ±1d 
 
 
 
 
 
Xc 
 
 
Upon PD if 
different 
**Skin Bx for Pharmacodynamics14 
Screening/             
prior to C1D1 
 
 
 
EOC1 
 
 
 
D25 ±1d 
 
 
 
 
 
 
 
 
 
**Tumor Bx for Pharmacodynamics14 
Screening/             
prior to C1D1 
 
 
 
 
 
 
 
D25 ±1d 
 
 
 
 
 
 
 
 
 


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Table 29: Schedule of Study Activities 
STUDY ASSESSMENTS 
 
Screen 
CYCLE 1 
CYCLE 2 
SUBSEQUENT CYCLES 
EOT 
<10d after 
decision to 
discontinue 
1M FUP* 
30 d (+7) 
after last 
dose 
Extended 
Follow 
Up*        
for 
ongoing 
AE 
As 
Clinically 
Indicated 
D1 
D8 
±2 
D15 
±2 
D22 
±2 
D1 
±2 
D8 
±2 
D15 
±2 
D22 
±2 
End of 
Cycle 2 
(final 
week or 
prior to 
C3D1 
dosing) 
D1 
±2 
D8 
±2 
D1
5 
±2 
D22 
±2 
End of Even 
Number 
Cycles 
(final week 
or prior to 
CxD1 
dosing) 
DISEASE ASSESSMENTS (screening within 14 days prior to first dose of IMP) 
***Imaging for Tumor Measurements 15 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
xb 
 
 
 
***Response Assessment 16 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
xb 
 
 
 
TRIAL TREATMENT 
IMP Infusion/Post Inf. Monitoring 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
 
Abbreviations (in alphabetical order): 1M FUP, 1-month follow-up; ADA, anti-drug antibody; AE, adverse event; Bx, biopsy; C, cycle; Ca, calcium; d/D, day; ECG, electrocardiogram; EOT, end of treatment; EOC1, End of Cycle 1; EOI, end of infusion; 
K, potassium; Mg, magnesium; PK, pharmacokinetic; PS, performance status; SOI, start of infusion 
 
* As of Amendment 5:  Omitted with the exception of prescreening genomic sampling for eligibility assessment 
**As of Amendment 5:  Omitted 
***As of Amendment 5: Frequency per either institutional guidelines or Investigator discretion until confirmation of PD 
 
a Need not be assessed prior to Cycle 1 if ≤ 7 days since screening  
b Conduct only if > 6 weeks since the previous assessment or if discontinuing study for reasons other than documented PD prior to EOC2 
c Need not be repeated if patient is discontinuing at the EOC2 
 
1. 
AE Assessments: To be assessed from signing of ICF until 30 days following last IMP dose; continue to assess for 2-months (and if necessary 4 months) following last IMP dose 
if related AEs persist to confirm that events have resolved, returned to baseline status, or been adequately explained. Investigator discretion may be used with respect to the 
method of contact for AE assessment. Clinical events may be followed by telephone, e-mail, or in writing; an in-person visit will not be required.  
2. 
Physical Examination: To include measurement of height and weight at screening, and weight during physical examinations thereafter; assessment of the skin is to be performed 
during each physical examination. 
3. 
Dermatologic Examination: In addition to skin assessment performed as part of the PE during visits when PE is required (to achieve weekly dermatological assessment) 
4. 
Hematology Panel: To include CBC with differential, ANC, and platelet count. Evaluation frequency should be increased in the event of hematologic toxicity. 
5. 
Biochemistry Panel (nonfasting): To include Na, K, Cl, bicarbonate or carbon dioxide, BUN or equivalent, creatinine, glucose, bilirubin [total and direct], AST, ALT, ALP, Ca, 
Mg, phosphorous, albumin, total protein, uric acid, amylase, lipase, and CK. Evaluation frequency should be increased in the event of significant serum chemistry abnormalities. 
Clinically significant electrolyte abnormalities should be corrected prior to dosing. 
6. 
Serum Magnesium, Calcium, and Potassium: To include magnesium, calcium, and potassium assessments in addition to testing performed as part of the biochemistry panel 
during visits when biochemistry panel is required (to achieve weekly magnesium, calcium, and potassium assessment) 
7. 
Coagulation Panel: To include PTT (or aPTT), PT/INR 
8. 
Urinalysis: Multi-panel chemical test strip analysis acceptable and should include assessment of specific gravity, pH, protein, glucose, ketones, leukocyte esterase, nitrite, 
bilirubin, urobilinogen, and blood. Perform microscopic examination of sediment, if clinically indicated (may include assessment of cells [WBC and RBC per high power field] 
and casts).   
9. 
Pregnancy Testing: Serum at Screening, serum or urine thereafter. Frequency may be increased as indicated, based on local requirements. 
10. ECG (12-Lead): In addition to scheduled EGCs, perform in the event of documented ≥ Grade 3 hypomagnesemia and if otherwise clinically indicated.  
11. ADA (Specialty Lab): See in-text table for timepoints. Whole blood (~5 mL/timepoint) to be collected for serum acquisition. If a collected sample is inadequate or insufficient, 
analysis may be done using a PK serum sample from the same timepoint, if available. A detailed laboratory manual will be provided.   


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12. PK Sampling (Specialty Lab): See in-text table for timepoints. Whole blood (~5 mL/timepoint) to be collected for serum acquisition. If a collected sample is inadequate or 
insufficient, analysis may be done using an ADA serum sample from the same timepoint, if available. A detailed laboratory will be provided. PK sampling times may be adjusted 
according to early trial results to optimize evaluation.    
13. Genomic Analysis (Specialty Lab): Peripheral blood at prescreening (~40 mL) to be collected as 4×10 mL; 2×10mL to be submitted for mutation analysis required for eligibility; 
remaining 2×10 mL to be stored for assay validation purposes. Thereafter, 2×10mL to be collected. Where blood sample is to be drawn on the day of biopsy (skin; tumor if 
performed), blood collection to occur prior to performing biopsy procedure(s). A detailed laboratory manual will be provided.    
EOC2 sample coincides with “prior to crossover” for patients in Arm B and Arm C.   
EOT sample need not be repeated in patients discontinuing at the EOC2.  
Final timepoint = EOT with Sym004. 
Additional sample to be obtained at the time of radiographic documentation of PD, if different from other required timepoints   
14. Pharmacodynamic Analysis (Specialty Lab): Peripheral blood collection, skin biopsies (from rash-free area), and tumor biopsies to be performed. Screening assessment may be 
conducted at any time after confirmation of eligibility and prior to C1D1. End of Cycle assessments may be conducted at any time during the week prior to Day 1 of the next 
cycle; EOC2 sample collection preferred on Day 25 (± 24 hours) to coincide with PK sampling and genomic analysis. Where blood sample is to be drawn on the day of biopsy 
(skin; tumor if performed), blood collection to occur prior to performing biopsy procedure(s). A detailed laboratory manual will be provided. Additional sample to be obtained at 
the time of radiographic documentation of PD, if different from other required timepoints.    
15. Imaging for Tumor Measurements: To include imaging by CT or MRI of the chest, abdomen and pelvis, and other sites as indicated based on tumor location and clinical 
judgment. Use of contrast is preferred but is at the discretion of the Investigator, as medically indicated. The same method(s) and technique should be used throughout study. 
Response Assessment: To be assessed by the Investigator or qualified designee per RECIST v1.1. Note as CR, PR, SD, PD, or NE at each evaluation point for patient 
management purposes and to make decisions on continued study treatment 
 
As of Amendment 5: The visit schedule for the treatment period will apply as specified above, with indicated exceptions. Once IMP has been discontinued, an EOT visit will be 
performed within 7 to 10 days from the decision to withdraw treatment, and a 1M FUP visit will be performed 30 days (+7 days) following the last dose. 


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19 SUMMARY OF CHANGES 
19.1 Protocol Amendment 1 dated 02-Jan-2018 
 Previously premedication to reduce the risk of IRRs was required prior to all doses in Cycle 1, and thereafter if a patient 
was without evidence of IRRs the Investigator could opt to withdraw premedication on a patient-by-patient basis. With 
this amendment, premedication to reduce the risk of IRRs is required prior to all doses of study drug; withdrawal of 
premedication is not permitted at any time. 
 Given the risk of hypocalcemia and hypokalemia, the monitoring plan has been amended to include more frequent serum 
calcium and potassium assessments in all patients. Calcium and potassium are now to be monitored weekly, at the same 
frequency as specified for magnesium monitoring. 
 Previously the protocol stated that non-evaluable or discontinued patients would be replaced. With this amendment it is 
now stipulated that non-evaluable patients and patients discontinuing from study prior to the EOC2 due to either 
documented PR or for reasons other than documented PD, will not be replaced. 
 Previously Exclusion Criterion 6f (in the synopsis only) suggested that patients with coagulation parameter abnormalities 
at baseline would not be eligible.  This incomplete text (meant to outline PT and PTT entry criteria) was holdover from 
an early draft and was included in version 1 in error; it has been removed. The Sponsor feels it is not necessary to set 
eligibility based on PT/PTT as data collected thus far on Sym004 administration do not suggest Sym004 adversely 
affects these parameters. 
 Although there are restrictions on prior and concomitant immunosuppressive or systemic hormonal therapy, the protocol 
previously allowed oral replacement glucocorticoid therapy for patients with preexisting adrenal insufficiency only. With 
this amendment this allowance has been broadened to allow hormone replacement therapy at standard doses for 
(unspecified) end-organ failure that can be adequately managed in this way. 
 Pre- and post-dosing (end of Cycles 1 and 2) skin biopsies have been added for exploratory pharmacodynamic 
evaluation. Samples will be assessed for EGFR expression and downstream signaling, marker(s) of proliferation, and 
other exploratory parameters. 
 Minor formatting adjustments and wording corrections have been made.     
 
Refer to Table 30 for the changes in Protocol Amendment 1.  
 
 
 


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Table 30: Protocol Amendment 1 
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ORIGINAL TEXT 
NEW TEXT 
1 Synopsis: Trial 
Objectives: 
Exploratory 
Objectives 
To evaluate potential predictive and/or prognostic biomarkers of response 
to treatment (peripheral blood to be collected) 
To evaluate potential predictive and/or prognostic biomarkers of response 
to treatment (peripheral blood and skin biopsies to be collected) 
1 Synopsis: Trial 
Design: Design 
Summary 
Non-evaluable patients and patients discontinuing from study prior to the 
EOC2 for reasons other than documented PD will be replaced (every 
effort will be made to obtain imaging studies at the time of 
discontinuation). 
Non-evaluable patients and patients discontinuing from study prior to the 
EOC2 for reasons other than documented PD will not be replaced (every 
effort will be made to obtain imaging studies at the time of 
discontinuation). 
1 Synopsis: Patient 
Selection: Key 
Eligibility Criteria 
Patients to be Excluded 
6. 
Patients with any of the following serum chemistry abnormalities at 
baseline: 
f. 
Patients with any of the following coagulation parameter 
abnormalities at baseline (unless on a stable dose of anticoagulant for 
a prior thrombotic event, as determined by the Investigator): 
 
12. Patients with any unresolved > Grade 1 toxicity associated with any 
prior antineoplastic therapy with the exception of persistent Grade 2 
alopecia, decreased hemoglobin, and/or peripheral neuropathy 
Patients to be Excluded 
6. 
Patients with any of the following serum chemistry abnormalities at 
baseline: 
Bullet point f. has been removed 
 
12. Patients with any unresolved > Grade 1 toxicity associated with any 
prior antineoplastic therapy with the exception of persistent Grade 2 
alopecia, decreased hemoglobin, peripheral neuropathy, and/or end-organ 
failure being adequately managed by hormone replacement therapy 
1 Synopsis: IMP 
Administration: 
Premedication 
Premedication for Infusion-Related Reactions (IRRs) 
Premedication for prophylaxis of IRRs will be mandatory prior to each 
dose of IMPs during Cycle 1. 
Premedication for Infusion-Related Reactions (IRRs) 
Premedication for prophylaxis of IRRs will be mandatory prior to each 
dose of IMP. 
1 Synopsis: Toxicity 
Management: 
Hypomagnesemia, 
Hypocalcemia, and 
Hypokalemia 
Synopsis: Toxicity Management: Hypomagnesemia 
 
Patients will be monitored weekly for hypomagnesemia. 
Added hypocalcemia and hypokalemia to section heading 
 
Patients will be monitored weekly for hypomagnesemia, hypocalcemia, 
and hypokalemia. 
1 Synopsis: Study 
Assessments: ADA, 
PK, Genomic, and 
Pharmacodynamic 
Assessments 
Synopsis: Study Assessments: ADA, PK, and Genomic Assessments 
Added pharmacodynamic to section heading 
 
Pharmacodynamic Analyses (Specialty Lab) 
Skin biopsies for potential predictive and/or prognostic biomarker 
assessment 
1 Synopsis: 
Discontinuation and 
Follow-Up: 
Replacements 
Patients will be replaced if they are not evaluable (NE) for antitumor 
activity assessment, as defined.   
After randomization to the study, no patients will be replaced. Patients not 
evaluable (NE) for antitumor activity assessment, as defined, or patients 
discontinuing from study prior to the EOC2 due to either documented PD 
or for reasons other than documented PD, will not be replaced.   


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Table 30: Protocol Amendment 1 
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ORIGINAL TEXT 
NEW TEXT 
1 Synopsis: Analysis 
Plan: Statistical 
Methods 
Safety Analyses 
Special attention will be paid to dermatologic toxicities, 
hypomagnesemia, and infusion reactions. 
 
Safety Analyses 
Special attention will be paid to dermatologic toxicities, 
hypomagnesemia, hypocalcemia, hypokalemia, and infusion reactions. 
3.1.3 Exploratory 
Objective 
To evaluate potential predictive and/or prognostic biomarkers of response 
to treatment (peripheral blood to be collected) 
To evaluate potential predictive and/or prognostic biomarkers of response 
to treatment (peripheral blood and skin biopsies to be collected) 
3.2 Trial Design 
Summary 
Dosing Schedule 
Beginning with the first dose, all patients will be premedicated with 
standard therapies for at minimum prior to each Cycle 1 dose to reduce 
the risk of infusion-related reactions (IRRs), and must be premedicated 
with standard therapies throughout at minimum Cycles 1 and 2 to reduce 
the risk of anti-EGFR-related dermatological adverse events (AEs). 
Thereafter, premedication of individuals for both potential toxicities is at 
the Investigator’s discretion and as needed.   
Dosing Schedule 
Beginning with the first dose, all patients will be premedicated with 
standard therapies prior to each dose to reduce the risk of infusion-related 
reactions (IRRs), and must be premedicated with standard therapies 
throughout at minimum Cycles 1 and 2 to reduce the risk of anti-EGFR-
related dermatological adverse events (AEs).   
 
  
Criteria for Evaluability 
Non-evaluable patients and patients discontinuing from study prior to the 
EOC2 for reasons other than documented PD will be replaced (every 
effort will be made to obtain imaging studies at the time of 
discontinuation). 
Criteria for Evaluability 
Non-evaluable patients and patients discontinuing from study prior to the 
EOC2 due to either documented PD or for reasons other than documented 
PD will not be replaced (every effort will be made to obtain imaging 
studies at the time of discontinuation). 
 
Not applicable 
Safety Monitoring  
A Study Safety Committee will be established and will be comprised of 
participating Investigator(s) and the Sponsor’s Medical Representative(s). 
Study Safety Committee Teleconferences will be held at intervals to 
discuss ongoing patient status and any emerging safety concerns; 
frequency of teleconferences may fluctuate based on accrual and study 
activity, as indicated. 
 


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Table 30: Protocol Amendment 1 
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Study Assessments 
For safety, patients will be monitored throughout the treatment and 1-
month follow-up (1M FUP) period for changes in: clinical status, physical 
exam findings (including weekly assessments for dermatologic AEs); 
laboratory data (including weekly assessments for hypomagnesemia); and 
electrocardiogram (ECG) findings… 
 
 
Exploratory biomarker studies will be conducted in blood samples 
obtained prior to and at intervals following dosing including at the time of 
documented progression or study discontinuation for other reasons.    
Study Assessments 
For safety, patients will be monitored throughout the treatment and 1-
month follow-up (1M FUP) period for changes in: clinical status, physical 
exam findings (including weekly assessments for dermatologic AEs); 
laboratory data (including weekly assessments for hypomagnesemia, 
hypocalcemia, and hypokalemia); and electrocardiogram (ECG) 
findings… 
 
Exploratory biomarker studies will be conducted in blood samples 
obtained prior to and at intervals following dosing including at the time of 
documented progression or study discontinuation for other reasons, and in 
skin biopsies obtained prior to and following Cycle 1 and Cycle 2 dosing.    
4.1.2 Planned Sample 
Size 
Note: …Non-evaluable patients and patients discontinuing from study 
prior to the EOC2 for reasons other than documented PD will be replaced. 
Note: …Non-evaluable patients and patients discontinuing from study 
prior to the EOC2 due to either documented PD or for reasons other than 
documented PD, will not be replaced. 
4.2 Criteria for 
Inclusion 
Note for inclusion criterion 10: 
A highly effective method of contraception is defined as non-hormonal 
contraception equivalent to a double-barrier method (e.g. double-barrier 
method or single-barrier method in combination with a spermicide or 
intrauterine device). 
 
Women of childbearing potential (WOCBP) must have a negative serum 
pregnancy test within ≤ 2 working days prior to administration of the first 
dose of IMP. 
Note for inclusion criterion 10: 
A highly effective method of contraception is defined as non-hormonal 
contraception equivalent to a double-barrier method (includes a single-
barrier method in combination with a spermicide or intrauterine device).  
 
 
Women of childbearing potential (WOCBP) must have a negative serum 
pregnancy test within ≤ 2 working days prior to administration of the first 
dose of IMP. 
4.3.1 Patients to be 
Excluded 
12. Patients with other unresolved > Grade 1 toxicity associated with any 
prior antineoplastic therapy with the exception of persistent Grade 2 
alopecia, decreased hemoglobin, and/or peripheral neuropathy 
12. Patients with any unresolved > Grade 1 toxicity associated with any 
prior antineoplastic therapy with the exception of persistent Grade 2 
alopecia, decreased hemoglobin, peripheral neuropathy, and/or end-organ 
failure being adequately managed by hormone replacement therapy 
4.3.2 Drugs and 
Other Treatments to 
be Excluded 
5. 
Immunosuppressive or systemic hormonal therapy…The following 
therapies are allowed: 
c. 
Oral replacement glucocorticoid therapy for adrenal 
insufficiency 
5. 
Immunosuppressive or systemic hormonal therapy…The following 
therapies are allowed: 
c. 
Hormone replacement therapy at standard doses for end-organ 
failure 


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Table 30: Protocol Amendment 1 
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NEW TEXT 
6.5.4.7 Premedication 
for Infusion-Related 
Reactions 
There is an inherent risk for IRRs with the administration of mAbs, 
therefore premedication for prophylaxis of IRRs will be mandatory prior 
to each dose of IMP during Cycle 1. If a patient is without evidence of 
IRRs after Cycle 1, the Investigator may choose, on a patient-by-patient 
basis, to withdraw premedication with subsequent dosing to determine 
whether such continued therapy is necessary in that patient.  
 
All patients will be premedicated with standard therapies that include a 
glucocorticoid and an H1 antagonist. Where indicated, consideration may 
be given to including an H2 antagonist and/or acetaminophen. 
Recommended premedication doses are provided. 
 
Should a patient experience an IRR while on study, including after Cycle 
1, guidelines for premedication following an IRR are provided. 
Guidelines for the grading and management of IRRs of all severities are 
also provided. 
There is an inherent risk for IRRs with the administration of mAbs, 
therefore premedication for prophylaxis of IRRs will be mandatory prior 
to each dose of IMP. All patients will be premedicated with standard 
therapies that include a glucocorticoid and an H1 antagonist. Where 
indicated, consideration may be given to including an H2 antagonist 
and/or acetaminophen. Recommended premedication doses are provided. 
 
Should a patient experience an IRR while on study, guidelines for 
premedication following an IRR are provided. Guidelines for the grading 
and management of IRRs of all severities are also provided. 
6.9 Concurrent 
Treatments and 
Supportive Care 
1. 
Prophylaxis for IRRs, Dermatologic AEs, and Other IMP-Related 
AEs (Sym004):  Premedications for IRRs and dermatologic AEs are 
mandatory during Cycle 1 and during Cycles 1 and 2, respectively, and as 
indicated thereafter based on the occurrence of related AEs…   
1. 
Prophylaxis for IRRs, Dermatologic AEs, and Other IMP-Related 
AEs (Sym004):  Premedications for IRRs are mandatory throughout the 
study. Premedications for dermatologic AEs are mandatory during Cycles 
1 and 2, and as indicated thereafter based on the occurrence of related 
AEs…   
7.2.7.3 Serum 
Magnesium, Calcium, 
and Potassium 
7.2.7.3 Serum Magnesium 
 
(Timepoints shown are in addition to testing performed as part of 
scheduled biochemistry panels; intention is to achieve weekly magnesium 
testing during the treatment period) 
Added calcium and potassium to section heading 
 
(Timepoints shown are in addition to testing performed as part of 
scheduled biochemistry panels; intention is to achieve weekly 
magnesium, calcium, and potassium testing during the treatment period) 
7.3 Specialty 
Assessments 
7.3 Immunogenicity and Pharmacokinetic Assessments (Specialty 
Laboratory) 
 
…Blood samples will be taken according to the schedule shown.  
Every effort will be made to collect ADA and PK samples at the 
timepoints specified…   
Section heading renamed to Specialty Assessments 
 
…Blood samples and skin biopsies will be taken according to the 
schedule shown.  
Every effort will be made to collect samples at the timepoints specified…   
7.3.2 Exploratory 
Pharmacokinetic 
Assessment 
(Specialty 
Laboratory) 
(…Data will also enable population PK modeling for further PK 
characterization) 
(…Data will also enable population PK modeling for further PK 
characterization; serum to be isolated) 
 
Removed “Disease/Tumor Assessments” text included in the Note at the 
end of the section. 
 


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7.3.3 Genomic 
Analysis in Peripheral 
Blood (Specialty 
Laboratory) 
• 
Cycle 2 
o 
Day 25 (± 24 hours) (coincides with PK sampling for all 
patients and “prior to crossover” for patients in Arm B and C) 
• 
Cycle 2 
o 
Day 25 (± 24 hours) (coincides with PK sampling and skin 
biopsy for all patients and “prior to crossover” for patients in Arm B 
and C) 
7.3.4 
Pharmacodynamic 
Analysis in Skin 
Biopsies (Specialty 
Laboratory) 
Not applicable as this is a new section 
(To be performed after eligibility has been confirmed. Biopsy specimens 
will be obtained using standard techniques and formalin-fixed, paraffin-
embedded according to standard laboratory techniques. Skin biopsies are 
requested from a rash-free area) 
(Samples will be assessed for EGFR expression and downstream 
signaling, markers(s) of proliferation, and other exploratory parameters) 
• 
Screening (after confirmation of eligibility)* 
• 
EOC1** 
• 
EOC2** 
o 
Day 25 (± 24 hours) (coincides with PK sampling and genomic 
analysis for all patients and “prior to crossover” for patients in Arm 
B and C) 
 
*Screening assessments may be conducted at any time prior to C1D1, 
including on C1D1 prior to dosing. 
***End of Cycle assessments may be conducted at any time during the 
week prior to Day 1 of the next cycle, including on Day 1 of the next 
cycle, prior to dosing. 
 
The purpose of pharmacodynamic 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. 
8.1.1.2 Premedication 
for IRRs (Beginning 
at Cycle 1) 
Premedication for prophylaxis of IRRs will be mandatory prior to each 
dose of Sym004 during Cycle 1.    
 
The following agents are required during Cycle 1; recommended doses 
are provided…    
 
If a patient is without evidence of IRRs after Cycle 1, the Investigator 
may opt to withdraw premedication on a patient-by-patient basis with 
subsequent dosing to determine whether such continued therapy is 
necessary in that patient. Where practical, it is recommended that 
withdrawal of premedication be done in a gradual fashion. 
Premedication for prophylaxis of IRRs will be mandatory prior to each 
dose of Sym004.    
 
The following agents are required; recommended doses are provided…    
 
 
This text has been removed 


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8.1.1.3 Premedication 
for IRRs (Following 
an IRR) 
• 
For Grade 1 or Grade 2 reactions, premedication prior to subsequent 
infusions should be considered. Thereafter, if a patient is without 
recurrence of an IRR, the Investigator may choose to withdraw 
premedication to determine whether such continued therapy is necessary 
for that patient. Where practical, it is recommended that withdrawal of 
premedication be done in a gradual fashion (e.g. by reduction in dose, 
frequency, or number of agents administered, at the Investigator’s 
discretion). For those patients who experience recurrent signs/symptoms 
suggestive of an IRR, premedication should be re-instituted for at 
minimum 2 additional doses before any future attempt to withdraw.  
• 
For Grade 3 reactions, premedication prior to subsequent infusions 
will be required (if the patient is to be retreated).   
• 
For Grade 1, Grade 2, or Grade 3 reactions, consider additional 
premedication or adjustment to premedications for subsequent infusions.   
9.2 Replacements 
Patients will be replaced if they are NE for antitumor activity assessment, 
as defined. 
After randomization to the study, no patients will be replaced. Patients NE 
for antitumor activity assessment, as defined, or patients discontinuing 
from study prior to the EOC2 due to either documented PD or for reasons 
other than documented PD, will not be replaced. 
11.1 Precautions 
Regarding 
Procreation 
“A highly effective method of contraception” is defined as non-hormonal 
contraception equivalent to a double-barrier method (e.g. double-barrier 
method can be single-barrier method in combination with a spermicide or 
intrauterine device). 
“A highly effective method of contraception” is defined as non-hormonal 
contraception equivalent to a double-barrier method (includes a single-
barrier method in combination with a spermicide or intrauterine device). 
11.2 Infusion-Related 
Reactions 
Premedication to reduce the risk of IRRs associated with IMP 
administration is required during Cycle 1 and following the occurrence of 
an IRR. 
Premedication to reduce the risk of IRRs associated with IMP 
administration is required. 
11.4 
Hypomagnesemia, 
Hypocalcemia, and 
Hypokalemia 
11.4 Hypomagnesemia 
 
Patients receiving IMP will be monitored weekly for evidence of 
hypomagnesemia.   
Added hypocalcemia and hypokalemia to section heading 
 
Patients receiving IMP will be monitored weekly for evidence of 
hypomagnesemia, hypocalcemia, and hypokalemia.   
14.4 Publications 
 
Authorship will be determined by agreement.   
Authorship will be determined by agreement with the Coordinating 
Investigator and Study Steering Committee.   
16.7.1 Safety 
Analysis 
Special attention will be paid to dermatologic toxicities, 
hypomagnesemia, and infusion reactions. 
Special attention will be paid to dermatologic toxicities, 
hypomagnesemia, hypocalcemia, hypokalemia, and infusion reactions. 
16.7.3 Exploratory 
Biomarker Analysis 
Biomarker assessments, to include collection of peripheral blood, will be 
conducted in all patients and will evaluate potential predictive and/or 
prognostic biomarkers of response to treatment… 
Biomarker assessments, to include collection of peripheral blood and skin 
biopsies, will be conducted in all patients and will evaluate potential 
predictive and/or prognostic biomarkers of response to treatment… 


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18 Appendices:  
Appendix 6: 
Management of 
Infusion-Related 
Reactions 
Premedication for prophylaxis of IRRs will be mandatory prior to each 
dose of IMP during Cycle 1.   
 
If a patient is without evidence of IRRs after Cycle 1, the Investigator 
may opt to withdraw premedication on a patient-by-patient basis with 
subsequent dosing in order to determine whether such continued therapy 
is necessary in that patient. Where practical, it is recommended that 
withdrawal of premedication be done in a gradual fashion. 
 
For IRRs while on study, the following premedication instructions are 
provided: 
• 
For Grade 1 or Grade 2 reactions, premedication prior to subsequent 
infusions should be considered. Thereafter, if a patient is without 
recurrence of an IRR, the Investigator may choose to withdraw 
premedication to determine whether such continued therapy is necessary 
for that patient. Where practical, it is recommended that withdrawal of 
premedication be done in a gradual fashion (e.g. by reduction in dose, 
frequency, or number of agents administered, at the Investigator’s 
discretion). For those patients who experience recurrent symptoms 
suggestive of an IRR, premedication should be re-instituted for at 
minimum 2 additional doses before any future attempt to withdraw.  
• 
For Grade 3 reactions, premedication prior to subsequent infusions 
will be required (if the patient is to be retreated).    
 
Premedication for prophylaxis of IRRs will be mandatory prior to each 
dose of IMP.   
 
For IRRs while on study, the following premedication instructions are 
provided: 
• 
For Grade 1, Grade 2, or Grade 3 reactions, consider additional 
premedication or adjustment to premedications for subsequent infusions.    
 
19.2 Protocol Amendment 2 dated 08-Mar-2018 
 Additional peripheral blood sampling has been added for assessment of serum proteins and other potential biomarkers; 
timepoints and instructions are provided. 
 Optional tumor biopsies have been added. Tumor biopsies, if consent is obtained, will be used to establish primary tumor 
and non-tumor cell lines, and patient-derived xenograft models. Timepoints and instructions are provided. 
 Previously it was stated that patients must have received at least 2 prior regimens of standard chemotherapy for mCRC 
and must have been refractory to or failed those regimens.  With this amendment it has been clarified that patients 
intolerant of previous regimens may also be included. 
 For study eligibility, patients must have “acquired” resistance to commercially available anti-EGFR mAbs approved for 
the treatment of mCRC.  Previously it was stated that prior therapy must have been received no more than 6 calendar 
months prior to randomization for this study.  With this amendment the window has been changed to no more than 6 


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calendar months prior to consent for this trial, and it has been included that this is regardless of the line of therapy in 
which prior anti-EGFR therapy was used. 
 Based on preclinical pharmacokinetic data, the required duration for post-dosing contraception has been changed to 3 
months. 
 Patients with a significant gastrointestinal abnormality, including diarrhea > Grade 1 at the time of randomization, are to 
be excluded.  With this amendment, it is noted that an exception would be made in the case of patients with recent Grade 
2 diarrhea secondary to administration of oral contrast.  Such patients will be allowed, provided symptoms have resolved 
prior to first study drug administration. 
 Coagulation studies, urinalysis, and ECG have been added as assessments to be conducted on Cycle 3 Day 1. 
 The number of investigational sites planned to participate in this trial has been decreased from 30 to 20, and the number 
of patients per arm has been corrected from 20 to 18. 
 Patients who received adjuvant chemotherapy and had documented recurrence (by imaging studies) during or within 6 
months of completion of the adjuvant chemotherapy are permitted to count the adjuvant therapy as one regimen of 
required prior chemotherapy.  With this amendment, it has been clarified that the imposed 6-month window refers to 6 
calendar months. 
 The inclusion criteria mutation requirements are reworded and restated as an exclusion criterion. 
 The IMPs, futuximab and modotuximab, are also referred to as drug products. 
 The frequency of pregnancy testing may be increased during the study, as clinically indicated, based on local 
requirements. 
 The outcome of AEs must be assessed by the Investigator; the option of “ongoing” has been added. 
 Clarified that initial SAEs and follow-up SAE information are to be submitted to the Sponsor (or designee) within 24 
hours of awareness.  
 Clarified that the bioanalytical assays used for Sym004 assessment will also be applied for measurement of serum 
concentrations of futuximab and modotuximab in the patients dosed with futuximab drug product and modotuximab drug 
product, respectively. 
 Newly included pharmacodynamic analyses are now mentioned as an exploratory endpoint. 
 Tables have been updated based on changes described. 
 Formatting adjustments, outline modifications, cross-reference links and link corrections, and other minor typographical 
corrections and slight wording changes are included. 
   
Refer to Table 31 for the changes in Protocol Amendment 2.  
 


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1 Synopsis: 
Investigational 
Medicinal Products 
The Investigational Medicinal Products (IMPs) in this trial are Sym004, 
futuximab, modotuximab.   
 
Supplies 
Sym004:  Single-use clear glass vials contain: 
• A nominal fill volume of 20 mL  
• At a concentration of 25 mg/mL for a total vial content of 500 mg 
Futuximab and modotuximab, each: Single-use clear glass vials contain: 
• A nominal fill volume of 10 mL  
• At a concentration 25 mg/mL for a total vial content of 250 mg 
The Investigational Medicinal Products (IMPs) in this trial are Sym004 (a 
mixture of futuximab and modotuximab), the drug product futuximab, and 
the drug product modotuximab.   
 
Supplies 
Sym004:  Single-use clear glass vials contain: 
• A nominal fill volume of 20 mL  
• At a concentration of 25 mg/mL for a total vial content of 500 mg 
Futuximab: Single-use clear glass vials contain: 
• A nominal fill volume of 10 mL  
• At a concentration of 25 mg/mL for a total vial content of 250 mg  
Modotuximab: Single-use clear glass vials contain: 
• A nominal fill volume of 10 mL  
• At a concentration of 25 mg/mL for a total vial content of 250 mg 
1 Synopsis: Trial 
Objectives: 
Secondary Objective 
 
3.1.2 Secondary 
Objective 
To evaluate the safety profile of a weekly dosing regimen of Sym004 
versus futuximab or modotuximab. 
To evaluate the safety profile of a weekly dosing regimen of Sym004 
versus single agent futuximab or single agent modotuximab. 
1 Synopsis: Trial 
Objectives: 
Exploratory 
Objective 
 
3.1.3 Exploratory 
Objective 
To evaluate potential predictive and/or prognostic biomarkers of response 
to treatment (peripheral blood and skin biopsies to be collected) 
To evaluate potential predictive and/or prognostic biomarkers of response 
to treatment (peripheral blood, skin biopsies, and tumor biopsies [tumor 
biopsies optional] to be collected). Tumor biopsies, if consent is obtained, 
will be used to establish primary tumor and non-tumor cell lines, and 
patient-derived xenograft models. 
1 Synopsis: Trial 
Design: Design 
Summary 
 
12.3 Study Safety 
Committee 
A Study Safety Committee comprised of the participating Investigators 
and the Sponsor’s Medical Monitor(s) will review clinical and laboratory 
safety data on an ongoing basis throughout the trial. 
Clinical and laboratory safety data will be reviewed on an ongoing basis 
throughout the trial. A Study Safety Committee will be established and 
will be comprised of participating Investigator(s) and the Sponsor’s 
Medical Representative(s).  If indicated, Study Safety Committee 
teleconferences will be held to discuss ongoing patient status and any 
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1 Synopsis: Patient 
Selection: 
Investigational Sites 
 
4.1.1 Investigational 
Sites 
Number of Sites: Approximately 30 sites may participate based on 
anticipated accrual 
 
Expected Countries: 5-10 countries in North America and Europe 
Number of Sites: Approximately 20 sites may participate based on 
anticipated accrual 
 
Number of Countries: Approximately 4-6 countries in North America and 
Europe   
1 Synopsis: Patient 
Selection: Key 
Eligibility Criteria 
Patients to be Included 
7. 
Patients must have received at least 2 prior regimens of standard 
chemotherapy for mCRC and must have been refractory to or failed those 
regimens. 
8. 
Patients with “acquired” resistance to commercially available anti-
EGFR mAbs approved for the treatment of mCRC must have: 
c. 
No more than 6 calendar months from last dose of previous anti-
EGFR mAb treatment to randomization for this trial 
Patients to be Excluded 
1. 
Women who are pregnant or lactating or intending to become 
pregnant before, during, or within 6 months after the last dose of IMP.     
2. 
Patients with a prior history of RAS (KRAS or NRAS), BRAF, or 
EGFR-ECD mutation in their tumor at the time of any previous 
assessment 
Patients to be Included 
7. 
Patients must have received at least 2 prior regimens of standard 
chemotherapy for mCRC and must have been refractory to or failed 
(includes intolerance to) those regimens.  
8. 
Patients with “acquired” resistance to commercially available anti-
EGFR mAbs approved for the treatment of mCRC must have: 
c. 
No more than 6 calendar months from last dose of previous anti-
EGFR mAb treatment to date of consent for this trial (regardless 
of the line of therapy in which it was used) 
Patients to be Excluded 
1. 
Women who are pregnant or lactating or intending to become 
pregnant before, during, or within 3 months after the last dose of IMP.     
2. 
Patients with a prior history of any of the following mutations in 
their tumor at the time of any previous assessment: 
a. 
RAS (KRAS and NRAS) mutations in the following codons: 
o 
Exon 2: codon 12, 13  
o 
Exon 3: codon 59, 61  
o 
Exon 4: codon 117, 146 
b. 
BRAF V600E mutation  
c. 
EGFR-ECD V441D, V441G, S464L, G465E, G465R, S492R 
mutations 
1 Synopsis: IMP 
Administration: 
Doses to be 
Administered 
 
6.5.4.1 Dose 
 
6.7.3 Treatment after 
Cycle 2 
Upon crossover, Sym004 will be administered at the dose level that 
contains the corresponding concentration of futuximab or modotuximab 
as was previously being administered. 
Upon crossover, Sym004 will be administered at the dose level that 
contains the corresponding dose level of the individual antibody 
futuximab or modotuximab as was previously being administered (prior to 
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1 Synopsis: Safety 
Monitoring: Safety 
Monitoring 
A Study Safety Committee will be established and will be comprised of 
the Investigators(s) and the Sponsor’s Medical Representative(s). Study 
Safety Committee teleconferences will be held at intervals to discuss 
ongoing patient status and any emerging safety concerns; the frequency of 
teleconferences may fluctuate based on accrual and study activity, as 
indicated. 
Clinical and laboratory safety data will be reviewed on an ongoing basis 
throughout the trial. A Study Safety Committee will be established and 
will be comprised of participating Investigators(s) and the Sponsor’s 
Medical Representative(s). If indicated, Study Safety Committee 
teleconferences will be held to discuss ongoing patient status and any 
emerging safety concerns. 
1 Synopsis: Safety 
Assessments: ADA, 
PK, Genomic, and 
Pharmacodynamic 
Assessments  
Pharmacodynamic Analyses (Specialty Lab) 
Skin biopsies for potential predictive and/or prognostic biomarker 
assessment 
Pharmacodynamic Analyses (Specialty Lab) 
Peripheral blood, skin biopsies, and tumor biopsies (tumor biopsies 
optional) for potential predictive and/or prognostic biomarker assessment 
2.3 Summary of 
Nonclinical Studies 
Futuximab-, modotuximab-, and Sym004-mediated secondary effector 
functions, such as antibody-dependent cellular cytotoxicity (ADCC) and 
complement-dependent cytotoxicity (CDC), were investigated using 51-
chromium release assays in human cancer cell lines. 
Futuximab-, modotuximab-, and Sym004-mediated secondary effector 
functions, such as antibody-dependent cellular cytotoxicity (ADCC) and 
complement-dependent cytotoxicity (CDC), were investigated in human 
cancer cell lines. 
2.4 Clinical 
Experience 
This is the first clinical study in which the individual antibodies, 
futuximab and modotuximab are being administered to patients as single 
agents. These two antibodies have been administered as a combination in 
all studies of Sym004. 
This is the first clinical study in which the individual antibodies, 
futuximab and modotuximab, are being administered to patients as single 
agents. These two antibodies have been administered as a combination in 
all human studies of Sym004 thus far. 
2.4.4 Antitumor 
Effects 
An exploratory analysis revealed that the responders to Sym004 were 
shown to have tumors with WT KRAS, NRAS, and BRAF genotype, as 
well as having no evidence of MET amplification.  The antitumor results 
of the completed Phase 2b trial, Sym004-05, are described in Section 
2.1.3.2. 
From the Phase 2b trial (Sym004-05), an exploratory analysis revealed 
that the responders to Sym004 had tumors with WT KRAS, NRAS, and 
BRAF genotype, as well as having no evidence of MET amplification.  
The antitumor results of this trial are described in Section 2.1.3.2. 
2.7 Summary of 
Overall Benefit and 
Risk 
One or both antibodies may demonstrate a clinical activity similar to that 
of Sym004 when administered alone. 
One or both antibodies administered alone may demonstrate a clinical 
activity similar to that of Sym004. 
3.2 Trial Design 
Summary 
Patient Population 
This is a Phase 2, open-label, 3-arm trial with randomization in the ratio 
of 1:1:1 to either Sym004 (Arm A), futuximab (Arm B), or modotuximab 
(Arm C)... 
Following consent and prior to randomization, centralized genomic 
analysis of RAS (KRAS/NRAS), BRAF V600, and EGFR-ECD mutation 
status as assessed in ctDNA will be conducted on peripheral blood 
samples obtained from each potential patient.  
Patient Population 
This is a Phase 2, open-label, three-arm trial with randomization in the 
ratio of 1:1:1 to either Sym004 (Arm A), futuximab drug product (Arm 
B), or modotuximab drug product (Arm C)... 
Following consent and prior to randomization, centralized genomic 
analysis of RAS (KRAS/NRAS), BRAF V600, and EGFR-ECD mutations 
in ctDNA from peripheral blood samples obtained from each potential 
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Safety Monitoring 
A Study Safety Committee will be established and will be comprised of 
the Investigators(s) and the Sponsor’s Medical Representative(s). Study 
Safety Committee teleconferences will be held at intervals to discuss 
ongoing patient status and any emerging safety concerns; the frequency of 
teleconferences may fluctuate based on accrual and study activity, as 
indicated. 
 
Study Assessments 
Exploratory biomarker studies will be conducted in blood samples 
obtained prior to and at intervals following dosing including at the time of 
documented progression or study discontinuation for other reasons, and in 
skin biopsies obtained prior to and following Cycle 1 and Cycle 2 dosing.    
 
 
Safety Monitoring 
Clinical and laboratory safety data will be reviewed on an ongoing basis 
throughout the trial. A Study Safety Committee will be established and 
will be comprised of participating Investigators(s) and the Sponsor’s 
Medical Representative(s). If indicated, Study Safety Committee 
teleconferences will be held to discuss ongoing patient status and any 
emerging safety concerns. 
 
Study Assessments 
Exploratory biomarker studies will be conducted in blood samples 
obtained prior to and at intervals following dosing including at the time of 
documented progression or study discontinuation for other reasons, in 
skin biopsies obtained prior to and following Cycle 1 and Cycle 2 dosing, 
and in tumor biopsies (tumor biopsies optional) obtained prior to and 
following Cycle 2 dosing.    
4.2 Criteria for 
Inclusion 
7. 
Patients must have received at least 2 prior regimens of standard 
chemotherapy for mCRC and must have been refractory to or failed those 
regimens.   
8. 
Patients with “acquired” resistance to commercially available anti-
EGFR mAbs approved for the treatment of mCRC. Patients must have: 
c. 
No more than 6 calendar months from last dose of previous anti-
EGFR mAb treatment to randomization for this trial 
10. Patients, male and female, who are either not of childbearing 
potential or who agree to use a highly effective method of contraception 
during the study beginning within 2 weeks prior to the first dose and 
continuing until 6 months after the last dose of IMP.   
7. 
Patients must have received at least 2 prior regimens of standard 
chemotherapy for mCRC and must have been refractory to or failed 
(includes intolerance to) those regimens.   
8. 
Patients with “acquired” resistance to commercially available anti-
EGFR mAbs approved for the treatment of mCRC. Patients must have: 
c. 
No more than 6 calendar months from last dose of previous 
anti-EGFR mAb treatment to date of consent for this trial (regardless 
of the line of therapy in which it was used) 
10. Patients, male and female, who are either not of childbearing 
potential or who agree to use a highly effective method of contraception 
during the study beginning within 2 weeks prior to the first dose and 
continuing until 3 months after the last dose of IMP.   
4.3.1 Patients to be 
Excluded 
1. 
Women who are pregnant or lactating or intending to become 
pregnant before, during, or within 6 months after the last dose of IMP. 
WOCBP, and fertile men with WOCBP-partner(s) not using and not 
willing to use a highly effective method of contraception. 
2. 
Patients with a prior history of RAS (KRAS or NRAS), BRAF, or 
EGFR-ECD mutation in their tumor at the time of any previous 
assessment 
1. 
Women who are pregnant or lactating or intending to become 
pregnant before, during, or within 3 months after the last dose of IMP. 
WOCBP, and fertile men with WOCBP-partner(s) not using and not 
willing to use a highly effective method of contraception. 
2. 
Patients with a prior history any of the following mutations in their 
tumor at the time of any previous assessment: 
a. 
RAS (KRAS and NRAS) mutations in the following codons: 
• Exon 2: codon 12, 13  


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• Exon 3: codon 59, 61  
• Exon 4: codon 117, 146 
b. 
BRAF V600E mutation  
c. 
EGFR-ECD V441D, V441G, S464L, G465E, G465R, S492R 
mutations 
10. Patients with a significant gastrointestinal abnormality… 
Note: Patients with recent Grade 2 diarrhea secondary to administration of oral 
contrast are allowed, provided symptoms have resolved prior to first study drug 
administration. 
5.1 Investigational 
Medicinal Products 
The Investigational Medicinal Products (IMPs) are Sym004, futuximab, 
and modotuximab.   
The Investigational Medicinal Products (IMPs) are Sym004, futuximab 
drug product, and modotuximab drug product.   
5.1.1 Formulations 
• Sym004 
o Nominal fill volume of 20 mL  
o At a concentration of 25 mg/mL for a total vial content of 500 mg 
• futuximab and modotuximab (each) 
o Nominal fill volume of 10 mL  
o At a concentration 25 mg/mL for a total vial content of 250 mg 
• Sym004 
o Nominal fill volume of 20 mL  
o At a concentration of 25 mg/mL for a total vial content of 500 mg 
• Futuximab  
o Nominal fill volume of 10 mL  
o At a concentration of 25 mg/mL for a total vial content of 250 mg 
• Modotuximab  
o Nominal fill volume of 10 mL  
o At a concentration of 25 mg/mL for a total vial content of 250 mg 
5.1.7 Administration 
of IMPs 
• futuximab and modotuximab (each) (4.5/3 mg/kg) 
o 4.5 mg/kg loading dose on C1D1 administered in a total volume of 
500 mL over 1 hour (+ 10 min) 
o 3 mg/kg weekly maintenance doses beginning on C1D8 administered 
in a total volume of 250 mL over 30 minutes (+ 10 min) 
• Futuximab (4.5/3 mg/kg) 
o 4.5 mg/kg loading dose on C1D1 administered in a total volume of 
500 mL over 1 hour (+ 10 min) 
o 3 mg/kg weekly maintenance doses beginning on C1D8 administered 
in a total volume of 250 mL over 30 minutes (+ 10 min) 
• Modotuximab (4.5/3 mg/kg) 
o 4.5 mg/kg loading dose on C1D1 administered in a total volume of 
500 mL over 1 hour (+ 10 min) 
o 3 mg/kg weekly maintenance doses beginning on C1D8 administered 
in a total volume of 250 mL over 30 minutes (+ 10 min) 
6.2.1 Recruitment 
Period 
It is anticipated that enrollment to this study will be completed in 
approximately 9 months.  
• Anticipated date of randomization of first patient: Q4 2020 
• Anticipated date of randomization of last patient: Q2 2021 
It is anticipated that enrollment to this study will be completed in 
approximately 6 months.  
• Anticipated date of randomization of first patient: Q3 2018 
• Anticipated date of randomization of last patient: Q4 2018 


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6.2.2 Trial Duration 
Data Cut-off for Primary Analysis: When the required number of 
evaluable patients (20 patients per arm) have been treated… 
Data Cut-off for Primary Analysis: When the required number of 
evaluable patients (18 patients per arm) have been treated… 
6.3.5 Randomization 
Randomization will be in blocks of 9 patients. 
Text removed 
6.9 Concurrent 
Treatments and 
Supportive Care 
1. Prophylaxis for IRRs, Dermatologic AEs, and Other IMP-Related AEs 
(Sym004): Premedications for IRRs are mandatory throughout the 
study… 
1. Prophylaxis for IRRs, Dermatologic AEs, and Other IMP-Related AEs: 
Premedications for IRRs are mandatory throughout the study… 
7.2.7.4 Coagulation 
Panel 
 
7.2.7.5 Urinalysis 
• Cycle 2 only 
o 
Day 1 (prior to dosing) 
• Cycle 2 and 3 
o 
Day 1 (prior to dosing) 
7.2.7.6 Pregnancy 
Testing 
As clinically indicated 
As clinically indicated (frequency may be increased based on local 
requirements) 
7.2.8 
Electrocardiogram 
• Cycle 2 
o 
Day 1 (prior to dosing) 
• Cycle 2 and 3 
o 
Day 1 (prior to dosing) 
7.3 Specialty 
Assessments 
Blood samples and skin biopsies will be taken according to the schedule 
shown. 
Blood samples, skin biopsies, and tumor biopsies (tumor biopsies 
optional) will be taken according to the schedule shown. 
7.3.3 Genomic 
Analysis in Peripheral 
Blood (Specialty 
Laboratory) 
• Prescreening (for eligibility) 
• Cycle 2 
o Day 25 (± 24 hours) (coincides with PK sampling and skin biopsy 
for all patients and “prior to crossover” for patients in Arm B and 
C) 
• EOT with Sym004 (need not be repeated if patient is discontinuing at 
the EOC2) 
• At the time of radiographically confirmed PD if different for the above 
 
Note: Whole blood (~ 2 × 10 mL) to be collected at each timepoint (plus additional 
~ 2 × 10 mL at prescreening to be stored for assay validation purposes); for 
assessment of ctDNA by Guardant360. 
• Prescreening (for eligibility) 
• EOC2 
o Day 25 (± 24 hours) (coincides with PK sampling and 
pharmacodynamic sampling for all patients and “prior to 
crossover” for patients in Arms B and C) 
• EOT with Sym004 (need not be repeated if patient is discontinuing at 
the EOC2) 
• At the time of radiographically confirmed PD if different for the above 
 
Note: Whole blood (~ 2 × 10 mL) to be collected at each timepoint (plus additional 
~ 2 × 10 mL at prescreening to be stored for assay validation purposes); for 
assessment of ctDNA by Guardant360; where blood sample is to be drawn on the 
day of biopsy (skin; tumor if performed), blood collection to occur prior to 
performing biopsy procedure(s). 
7.3.4 
Pharmacodynamic 
Analyses (Specialty 
Laboratory) 
Not applicable as this is a new section. 
7.3.4 
Pharmacodynamic Analyses (Specialty Laboratory)  
(To be performed after eligibility has been confirmed) 
The purpose of pharmacodynamic assessments is to develop an approach 
for the identification and validation of biomarkers that may predict which 


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patients are likely to respond to Sym004, and that may change with the 
possible development of acquired resistance… 
7.3.4.1 Peripheral 
Blood 
Not applicable as this is a new section. 
7.3.4.1 
Peripheral Blood 
(Samples will be assessed for serum proteins and other potential 
biomarkers)…  
7.3.4.2 Skin Biopsies 
7.3.4 Pharmacodynamic Analysis in Skin Biopsies (Specialty Laboratory) 
(To be performed after eligibility has been confirmed. Biopsy specimens 
will be obtained using standard techniques and formalin-fixed, paraffin-
embedded according to standard laboratory techniques. Skin biopsies are 
requested from a rash-free area) 
(Samples will be assessed for EGFR expression and downstream 
signaling, markers(s) of proliferation, and other exploratory parameters) 
 
• Screening (after confirmation of eligibility)* 
• EOC1** 
• EOC2** 
o Day 25 (± 24 hours) (coincides with PK sampling and genomic 
analysis for all patients and “prior to crossover” for patients in 
Arm B and C) 
 
*Screening assessments may be conducted at any time prior to C1D1, including on 
C1D1 prior to dosing. 
***End of Cycle assessments may be conducted at any time during the week prior 
to Day 1 of the next cycle, including on Day 1 of the next cycle, prior to dosing. 
 
The purpose of pharmacodynamic 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. 
7.3.4.2 
Skin Biopsies  
(Biopsy specimens to be obtained using standard techniques and 
formalin-fixed, paraffin-embedded according to standard laboratory 
techniques. Skin biopsies are requested from a rash-free area) 
(Samples will be assessed for various parameters, which may include but 
are not limited to EGFR expression and downstream signaling, 
markers(s) of proliferation, genomic alterations, etc.) 
 
• Screening (after confirmation of eligibility)* 
• EOC1** 
• EOC2** 
o Day 25 (± 24 hours) (preferred day of sampling; coincides with 
PK sampling and genomic analysis for all patients and “prior to 
crossover” for patients in Arms B and C) 
 
*Screening sampling may be conducted at any time prior to C1D1, including on 
C1D1 prior to dosing. 
**End of Cycle sampling may be conducted at any time during the week prior to 
Day 1 of the next cycle, including on Day 1 of the next cycle, prior to dosing. 
 
Note: Procedure to be performed after collecting blood sample for 
pharmacodynamic analyses. 
7.3.4.3 Tumor 
Biopsies (Optional) 
Not applicable as this is a new section. 
7.3.4.3 
Tumor Biopsies (Optional)  
(Samples will be assessed for various parameters, which may include but 
are not limited to EGFR expression and downstream signaling, 
markers(s) of proliferation, genomic alterations, etc.)… 
8.1.1.2 Premedication 
for IRRs 
8.1.1.2 
Premedication for IRRs (Beginning at Cycle 1) 
Premedication for prophylaxis of IRRs will be mandatory prior to each 
dose of Sym004.    
8.1.1.2 
Premedication for IRRs  
Premedication for prophylaxis of IRRs will be mandatory prior to each 
dose of IMP.    


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9.1 Criteria for 
Treatment 
Discontinuation 
1. Progressive Disease:… 
(patients receiving futuximab or modotuximab may opt to crossover and 
receive Sym004) 
 
2. Clinical Progression:… 
(patients receiving futuximab or modotuximab may opt to crossover and 
receive Sym004) 
1. Progressive Disease:… 
Note: Patients receiving futuximab or modotuximab with documented PD at the 
EOC2 (or prior to the EOC2) will be offered the opportunity to crossover to 
receive Sym004 or will be discontinued from study. 
 
2. Clinical Progression:… 
Removed italicized text 
10.1.2 Events Not to 
be Considered as 
Adverse Events 
PD may be reported as an AE/SAE in the case of patient death, with death 
being the outcome of the event, but only when the nature of the PD is 
different than expected. 
Note: PD may be reported as an AE in the case of patient death, with death being 
the outcome of the event. 
10.1.5 Events That 
Do Not Meet the 
Definition of Serious 
Adverse Events 
PD may be reported as an SAE in the case of patient death, with death 
being the outcome of the event, but only when the nature of the PD is 
different than expected. 
Note: PD may be reported as an SAE in the case of patient death, with death being 
the outcome of the event. 
10.2.1 Information to 
be Provided for Each 
AE 
• Outcome 
The outcome of the AE must be assessed by the Investigator utilizing one 
of the following options: 
o 
Recovered/resolved  
o 
Recovered/resolved with sequelae  
o 
Recovering/resolving 
o 
Not recovered/not resolved  
o 
Fatal  
o 
Unknown 
• Outcome 
The outcome of the AE must be assessed by the Investigator utilizing one 
of the following options: 
o 
Recovered/resolved  
o 
Recovered/resolved with sequelae  
o 
Recovering/resolving 
o 
Not recovered/not resolved 
o 
Ongoing  
o 
Fatal  
o 
Unknown 
10.3.1 Timeframes 
for Reporting to the 
Sponsor 
In case of an SAE, the Investigator must, within 24 hours of awareness of 
the event, report the SAE to the Sponsor (or designee) by telefax or e-mail 
transmission. Fax number(s) and e-mail address(es) will be stated on the 
SAE Report Form and the SAE Report Form Completion Instructions. 
 
Timelines for reporting of SAEs and SAE follow-up information are 
shown (Table 8). 
In case of an SAE, the Investigator must, within 24 hours of awareness of 
the event, report the SAE to the Sponsor (or designee) by telefax or e-mail 
transmission. Fax number(s) and e-mail address(es) will be stated on the 
SAE Report Form and the SAE Report Form Completion Instructions.  
SAE follow-up information must also be reported to the Sponsor (or 
designee) within 24 hours of awareness. 
 
Removed Table 8: Timelines for Submission of SAEs and SAE Follow-up 
10.4 Pregnancy 
Elective terminations for non-medical reasons should not be reported as 
AEs. 
Elective terminations for non-medical reasons should be reported as 
follow-up, but not as a separate AE/SAE unless complications meet 
AE/SAE criteria. 


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11.1 Precautions 
Regarding 
Procreation 
Studies have not been performed to determine whether Sym004, 
futuximab, or modotuximab affect reproductive function in males. For 
this reason, men with partners with childbearing potential must use a 
highly effective method of contraception while receiving IMP. 
 
Women and men of childbearing potential… must use highly effective 
contraception within 2 weeks prior to the first dose and continuing until 6 
months after final administration of IMP. 
Studies have not been performed to determine whether Sym004, 
futuximab, or modotuximab affect reproductive function in males or can 
cause fetal harm. For this reason, men with partners of childbearing 
potential must use a highly effective method of contraception while 
receiving IMP. 
 
Women and men of childbearing potential… must use highly effective 
contraception within 2 weeks prior to the first dose and continuing until 3 
months after final administration of IMP. 
13.4.1. Modification 
of the Study Protocol 
If modifications in the experimental design… and approval by the 
appropriate review committees, except where necessary to immediately 
eliminate apparent hazards to patients.   
If modifications in the experimental design… and approval by the 
appropriate regulatory authority (as indicated) and review committees, 
except where necessary to immediately eliminate apparent hazards to 
patients.   
13.4.2 Modification 
of the Informed 
Consent Form 
If modifications to the experimental design, dosages, assessments, patient 
selection, etc. of the protocol are indicated or required, and if such 
modifications substantially alter the study design or increase the potential 
risk to patients, the Investigator will prepare a revision to the existing ICF.  
Such a revision will be reviewed and approved by the appropriate 
IRB/EC, and documentation of this approval will be forwarded to the 
Sponsor (or designee) for submission to the appropriate regulatory body. 
If modifications to the experimental design, dosages, assessments, patient 
selection, etc. of the protocol are indicated or required, and if such 
modifications substantially alter the study design or increase the potential 
risk to patients, the Sponsor (or designee) will prepare a revision to the 
existing sample ICF for modification, as appropriate, by each Investigator.  
Any revision to the sample ICF prepared by the Sponsor (or designee) 
will be implemented according to the Sponsor’s (or designee’s) SOPs. 
Such a revision will be reviewed and approved by the appropriate 
regulatory authority (as indicated) and IRB/EC. 
14.1 Medical 
Supervision 
An Investigator conducting a clinical study with an investigational agent 
is required to comply with regulations described in U.S. Title 21 CFR Part 
312 and ICH E6(R2) GCP. 
An Investigator conducting a clinical study with an investigational agent 
is required to comply with regulations described in U.S. Title 21 CFR 
Parts 50, 56, and 312 and/or by governing Health Authorities, as well as 
ICH E6(R2) GCP. 
14.11 Record 
Retention 
Regulatory authorities require that the Investigator retain copies of all 
files pertaining to the study (i.e. records of IMP disposition, signed ICFs, 
CRFs, all correspondence, dates of monitoring visits, and records which 
support them) for a period of 2 years following the date of marketing 
application approval of the drug, for the indication that is the subject of 
the study. If no application is filed, or the application is not approved for 
the indication under study, all files pertaining to the study are to be 
maintained for 2 years after the investigation is discontinued and 
governing Health Authorities have been so notified. 
Regulatory authorities require that the Investigator retain copies of all 
files pertaining to the study according to local requirements. 


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15.3 Data Processing 
Not applicable 
Once recorded within the electronic CRF, study data will pass through a 
set of pre-programmed data validation checks designed to identify 
inconsistencies and other data errors, and will undergo an additional 
study-specific data review process, as stated above in Section 15.2.  Data 
issues will be queried via the EDC system and query resolutions will be 
documented. 
16.4.2.1 
Pharmacokinetic 
(PK) Endpoints 
The PK profile of the study drugs will be derived based on the 
concentration time curves after the first and the 8th infusion on Cycle 2, 
Day 22. For patients dosed with Sym004, the serum concentration of 
futuximab and modotuximab will be measured in separate bioanalytical 
assays. The sum of futuximab and modotuximab is defined as the Sym004 
serum concentration. 
The PK profile of the IMPs will be derived based on the concentration 
time curves after the first and the 8th infusion on Cycle 2, Day 22. For 
patients dosed with Sym004, the serum concentration of futuximab and 
modotuximab will be measured in separate bioanalytical assays. The 
Sym004 serum concentration is defined as the sum of futuximab and 
modotuximab serum concentrations measured in a sample. The 
bioanalytical assays used for Sym004 assessment will also be applied for 
measurement of serum concentrations of futuximab and modotuximab in 
the patients dosed with futuximab drug product and modotuximab drug 
product, respectively. 
16.8 Exploratory 
Analysis 
16.8.1 Exploratory 
Biomarker and 
Pharmacodynamic 
Analyses 
16.7.2 
Exploratory Analysis 
16.7.3 
Exploratory Biomarker Analysis 
Biomarker assessments, to include collection of peripheral blood and skin 
biopsies, will be conducted in all patients... 
16.8  Exploratory Analysis 
16.8.1 
Exploratory Biomarker and Pharmacodynamic Analyses 
Biomarker and pharmacodynamic assessments, to include collection of 
peripheral blood, skin biopsies, and tumor biopsies (tumor biopsies 
optional), will be conducted in all patients… 
 
19.3 Protocol Amendment 3 dated 08-May-2018 
 Tumor biopsies have been made mandatory; patients must be willing to undergo a total of 2 biopsies of a primary or 
metastatic tumor site(s) considered safely accessible for biopsy.  
 AE grading will be based on the updated CTCAE v5 (previously CTCAE v4.03). 
 Additional details regarding the process of eligibility confirmation have been provided. 
 Details regarding the specific information to be collected regarding the patient’s colorectal carcinoma history and prior 
therapy are no longer listed; however, there is no intended change in the scope of information to be obtained and 
documented in the patient’s case report form. 


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 The body systems to be evaluated at the time of physical examination are no longer listed; however, there is no intended 
change in the scope or frequency of physical examinations to be conducted during this trial.  It is emphasized that the 
skin is to be assessed at each visit. 
 Analytes to be assessed in the event of abnormalities of creatine kinase are no longer listed; however, it is understood 
that best clinical judgment should be employed in evaluating patients with this or any other laboratory abnormality. 
 Coagulation panel assessment and urinalysis have been added on Cycle 3/Day 1. 
 ECGs may now be performed when patients are in a semi-recumbent (as well as a supine) position. 
 Guidelines pertaining to the General Data Protection Regulation have been added. 
 Tables have been updated based on changes described. 
 Formatting adjustments, outline modifications, cross-reference links and link corrections, and other minor typographical 
corrections and slight wording changes are included. 
   
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1 Synopsis: Trial 
Objectives: 
Exploratory 
Objective 
 
3.1.3 Exploratory 
Objective 
To evaluate potential predictive and/or prognostic biomarkers of response 
to treatment (peripheral blood, skin biopsies, and tumor biopsies [tumor 
biopsies optional] to be collected). Tumor biopsies, if consent is obtained, 
will be used to establish primary tumor and non-tumor cell lines, and 
patient-derived xenograft models. 
To evaluate potential predictive and/or prognostic biomarkers of response 
to treatment (peripheral blood, skin biopsies, and tumor biopsies to be 
collected). Tumor biopsies will be used to establish primary tumor and 
non-tumor cell lines, and patient-derived xenograft models. 
1 Synopsis: Trial 
Design: Design 
Summary 
Third-Party Investigator Reviewers and the Sponsor’s Medical Monitor(s) 
(or designee) will review patient eligibility information provided, confirm 
eligibility, and authorize patients for randomization.   
Designated Eligibility Reviewers and the Sponsor’s Medical Monitor(s) 
(or designee) will review patient eligibility information provided, confirm 
eligibility, and authorize patients for randomization.   
1 Synopsis: Patient 
Selection: Key 
Eligibility Criteria 
6. 
Patients with measurable disease according to RECIST v1.1 
6. 
Patients with measurable disease according to RECIST v1.1, and 
willingness to undergo a total of 2 biopsies of a primary or metastatic 
tumor site(s) considered safely accessible for biopsy 
1 Synopsis: Safety 
Assessments: ADA, 
PK, Genomic, and 
Pharmacodynamic 
Assessments  
Pharmacodynamic Analyses (Specialty Lab) 
Peripheral blood, skin biopsies, and tumor biopsies (tumor biopsies 
optional) for potential predictive and/or prognostic biomarker assessment 
Pharmacodynamic Analyses (Specialty Lab) 
Peripheral blood, skin biopsies, and tumor biopsies for potential 
predictive and/or prognostic biomarker assessment 


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3.2 Trial Design 
Summary 
Patient Population 
…Third-Party Investigator Reviewers and the Sponsor’s Medical 
Monitor(s) (or designee) will review patient eligibility information 
provided, confirm eligibility, and authorize patients for randomization. 
 
Study Assessments 
…Exploratory biomarker studies will be conducted in blood samples… in 
skin biopsies… and in tumor biopsies (tumor biopsies optional) obtained 
prior to and following Cycle 2 dosing.    
Patient Population 
…Designated Eligibility Reviewers and the Sponsor’s Medical Monitor(s) 
(or designee) will review patient eligibility information provided, confirm 
eligibility, and authorize patients for randomization. 
 
Study Assessments 
…Exploratory biomarker studies will be conducted in blood samples… in 
skin biopsies… and in tumor biopsies obtained prior to and following 
Cycle 2 dosing.    
4.2 Criteria for 
Inclusion 
6. 
Patients with measurable disease according to RECIST v1.1 
(Appendix 5) 
6. 
Patients with measurable disease according to RECIST v1.1 
(Appendix 5), and willingness to undergo a total of 2 biopsies of a 
primary or metastatic tumor site(s) considered safely accessible for biopsy 
5.7 Dose Calculation 
Not applicable 
Dose adjustments should be made in the event of noted weight change (± 
10%; less at the site’s discretion or if required by institutional procedures) 
as measured at the beginning of each dosing cycle (CxD1). Adjustments 
may be made in the event of lesser incremental changes in weight and/or 
more frequently at the site's discretion. 
6.3.3 Submission of 
Patient Eligibility 
Information 
Once the patient is screened and identified by the Investigator as meeting 
the study eligibility criteria, eligibility information must be submitted to 
the Sponsor (or designee) for review. The following information must be 
provided by the site:   
• 
Consent 
• 
Patient gender  
• 
Date of birth (or age), as allowed by local regulatory requirements 
• 
Date written informed consent was obtained 
• 
Confirmation of mCRC 
• 
Sites of measurable metastases  
• 
Confirmation of genomic analysis and patient TN mutation status 
• 
Confirmation of compliance with all inclusion/exclusion criteria 
• 
Brief description of prior therapy for the primary diagnosis, 
including dates of initiation and discontinuation as well as best response 
The following information may be requested of the site: 
• 
Patient weight (for dose calculation) 
• 
Date of screening 
• 
Current PS 
• 
Planned date of first dosing 
Once the patient is screened and identified by the Investigator as meeting 
the study eligibility criteria, data supporting eligibility must be entered in 
the study electronic CRF for the Sponsor (or designee) to review. 
Information including: date written informed consent was obtained, 
demographics, diagnoses of primary malignancy and metastases, prior 
CRC treatments with systemic drug therapies including those specified in 
the protocol inclusion criteria will be required. 


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6.3.4 Eligibility 
Confirmation 
6.3.4  Authorization for Randomization 
Third-Party Investigator Reviewers and the Sponsor’s Medical Monitor(s) 
(or designee) will review patient eligibility information provided, confirm 
eligibility, and authorize patients for randomization. Patients will be 
randomized in the order of confirmation of their eligibility and receipt of 
authorization.   
6.3.4  Eligibility Confirmation  
The designated Eligibility Reviewers will review patient eligibility 
information provided and confirm eligibility.  Upon confirmation, the site 
may proceed to request the randomized study treatment assignment for the 
patient.   
6.3.5 Randomization 
Authorized patients will be randomized in the ratio of 1:1:1 to Arm A 
(Sym004), Arm B (futuximab) or Arm C (modotuximab). 
Eligible patients will be randomized in the ratio of 1:1:1 to Arm A 
(Sym004), Arm B (futuximab), or Arm C (modotuximab). 
6.3.6 Patient 
Identification Code 
Assignment 
Each patient to be randomized will be assigned a unique identification 
code. Identification codes will be assigned in chronological order, and 
will be concatenated to indicate relevant study information, including at 
minimum the participating trial site and the patient’s order of 
randomization to the trial. 
Each patient who signed informed consent will be assigned a unique 
identification code. Identification codes will be assigned in sequential 
order, and will be concatenated to indicate relevant study information, 
including at minimum the participating trial site and the patient’s order of 
randomization to the trial. 
6.3.7 Screen Failures 
A list of patients failing screening, and the reason for ineligibility, will be 
maintained by the site on a Patient Screening Log or other similar 
document.   
Text removed 
7.1.5 History of 
mCRC 
7.1.5  History of the Primary Malignancy (mCRC)  
 (Details of the primary malignancy to include:   
- 
diagnosis and histological/ cytological classification  
- 
date of initial diagnosis 
- 
date metastatic disease was identified  
- 
current sites of metastases 
- 
prior surgical procedures for the malignancy and dates 
- 
prior radiation therapy for the malignancy and dates   
- 
prior embolic therapy/procedures for the malignancy and dates 
- 
prior antineoplastic therapy, dates of treatments, numbers of cycles, 
indication of treatment [e.g. neoadjuvant, adjuvant, therapeutic for 
metastatic disease], reason for stopping, and best response to each 
therapy  
- 
prior anti-EGFR mAb therapy, dates of treatments, numbers of 
cycles, reason for stopping, and best response to each therapy 
- 
date of most recent disease progression) 
• 
Screening 
7.1.5  History of mCRC  
(To include diagnoses of primary malignancy and metastases, prior CRC 
treatments with surgical procedures, radiation therapies, systemic drug 
therapies including those specified in the protocol inclusion criteria) 
• 
Screening 
7.2.5 Physical 
Examination 
(Complete at screening including height, weight, general appearance, 
skin, head, eyes, ears, nose, throat, neck/thyroid, chest [includes 
pulmonary assessment, breasts], cardiovascular [includes heart, 
(To include measurement of height and weight at screening, and weight** 
during  physical examinations thereafter; assessment of the skin is to be 


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peripheral pulses] abdomen, musculoskeletal system, lymph nodes, 
neurologic and mental status; directed thereafter, must include weight**) 
performed during each physical examination) 
7.2.7.2 Biochemistry 
Panel 
***In the event of creatine kinase abnormalities while on study, perform 
isoenzyme analysis (to include at minimum CK-MB); in the event of ECG 
abnormalities while on study, perform isoenzyme analysis (to include at 
minimum CK-MB), serial troponins, and measurement of brain 
natriuretic peptide (BNP) 
Text removed 
7.2.8 
Electrocardiogram 
(To be evaluated locally; ECGs should be performed using the same 
calibrated instrument at each study center, and should be conducted after 
the patient has been supine for > 10 minutes.)  
 
(Patients with a QTc ≥ 500 msec should not be treated; dosing should be 
delayed.)  
 
(If abnormalities suggest new evidence of myocardial ischemia, perform 
isoenzyme analysis [to include at minimum CK-MB], serial troponins, 
and measurement of BNP) 
(To be evaluated locally; ECGs should be performed using the same 
calibrated instrument at each study center, and should be conducted after 
the patient has been supine (or semi-recumbent) for > 10 minutes.) 
  
(Patients with a QTc ≥ 500 msec should not be treated; dosing should be 
delayed.) 
 
Text removed 
7.3 Specialty 
Assessments 
Blood samples, skin biopsies, and tumor biopsies (tumor biopsies 
optional) will be taken according to the schedule shown (Table 5; 
Appendix 10). 
Blood samples, skin biopsies, and tumor biopsies will be taken according 
to the schedule shown (Table 5; Appendix 10). 
9.1 Criteria for 
Treatment 
Discontinuation 
12. Site Terminated by the Sponsor 
Text removed 
15.1 Data Handling 
Study data collection, processing, transfer, and reporting as well as 
handling of study personnel information will be in compliance with ICH 
E6(R2) GCP and all applicable data protection regulations. 
Study data collection, processing, transfer, and reporting, as well as 
handling of study personnel information, will be done in compliance with 
ICH E6(R2) GCP and all applicable data protection regulations, including 
Regulation (EU) 2016/679 of the European Parliament and of the Council 
of 27 April 2016 on the protection of natural persons with regard to the 
processing of personal data and on the free movement of such data 
(General Data Protection Regulation). 
15.5 Compliance with 
the General Data 
Protection Regulation 
Not applicable 
The applicable data protection legislation requires that parties enter into a 
written contract if one party (data processor) processes personal data on 
behalf of the other party (data controller). This written contract must 
regulate the subject-matter and duration of the processing, the nature and 
purpose of the processing, the types of personal data and categories of 


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data subjects, as well as the obligations and rights of the data controller. 
Accordingly, the parties must enter into a data processing agreement. To 
the extent the processing of personal data involves transfers of personal 
data to third countries (e.g., jurisdictions outside of the European 
Economic Area), the parties will enter into the European Commission's 
standard contractual clauses between the data controller, the data 
processor, and all sub-processors, if any. The European Commission's 
standard contractual clauses ensure an adequate level of protection in 
relation to transfers of personal data to third countries. 
16.8.1 Exploratory 
Biomarker and 
Pharmacodynamic 
Analyses 
Biomarker and pharmacodynamic assessments, to include collection of 
peripheral blood, skin biopsies, and tumor biopsies (tumor biopsies 
optional), will be conducted in all patients and will evaluate potential 
predictive and/or prognostic biomarkers of response to treatment… 
Biomarker and pharmacodynamic assessments, to include collection of 
peripheral blood, skin biopsies, and tumor biopsies, will be conducted in 
all patients and will evaluate potential predictive and/or prognostic 
biomarkers of response to treatment… 
 
19.4 Protocol Amendment 4 dated 02-Aug-2018 
 Inclusion criterion 3 has been refined to indicate patients may have received other PD-1/PD-L1 pathway blockers to 
fulfill this prior treatment requirement. 
 Clarified that 0.9% Sodium Chloride Injection, USP or local equivalent will be utilized as diluent. 
 The End of Trial event has been more fully defined. 
 Clarified final sample size. 
 Formatting adjustments, minor typographical corrections, and slight wording changes are included. 
 The synopsis and tables have been updated based on changes described, where applicable. 
   
Refer to Table 33 for the changes in Protocol Amendment 4.  
 
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3.2 Trial Design 
Summary 
Exploratory biomarker studies will be conducted in blood samples 
obtained prior to and at intervals following dosing including at the time of 
documented progression or study discontinuation for other reasons, in 
skin biopsies obtained prior to and following Cycle 1 and Cycle 2 dosing, 
and in tumor biopsies obtained prior to and following Cycle 2 dosing.    
Exploratory biomarker studies will be conducted in blood samples 
obtained prior to and at intervals following dosing, including at the time 
of documented progression or study discontinuation for other reasons, in 
skin biopsies obtained prior to first dose and following Cycle 1 and Cycle 
2 dosing, and in tumor biopsies obtained prior to first dose and following 


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Cycle 2 dosing.    
4.2 Criteria for 
Inclusion 
3. 
Patients with MSI-H/dMMR tumors must have received prior 
therapy with pembrolizumab or nivolumab (where approved in the 
country) and must have progressed on that therapy. 
3. 
Patients with MSI-H/dMMR tumors must have received prior 
therapy with pembrolizumab, nivolumab, or other PD-1/PD-L1 pathway 
blocker, and must have progressed on that therapy. 
5.6 Administration of 
IMPs 
 
IMPs will be administered by IV infusion. An appropriate dose based on 
the patient’s body weight is to be diluted with commercially available 
0.9% sodium chloride (NaCl).   
IMPs will be administered by IV infusion. An appropriate dose based on 
the patient’s body weight is to be diluted with commercially available 
0.9% Sodium Chloride Injection, USP or local equivalent.   
5.8 Dose Preparation  
 
• 
The total volume of IMP to be delivered will be withdrawn from the 
IMP vial(s) and added to a prefilled IV bag containing 0.9 % NaCl 
(following removal of an appropriate volume of saline, such that the final 
volume to be infused equals 500 mL for C1D1 loading dose infusions and 
250 mL for subsequent infusions)     
• 
The total volume of IMP to be delivered will be withdrawn from the 
IMP vial(s) and added to a prefilled IV bag containing 0.9 % Sodium 
Chloride Injection, USP or local equivalent (following removal of an 
appropriate volume of saline, such that the final volume to be infused 
equals 500 mL for C1D1 loading dose infusions and 250 mL for 
subsequent infusions)     
6.2.2 Trial Duration   
 
Not applicable 
End of Trial: The end of trial will be reached at the latest 1 month (30 +7 
days) after the last patient has been discontinued from study drug.   
6.5.4.3 Diluent 
Commercially available sterile 0.9% NaCl for IV infusion is to be used as 
the diluent.   
Commercially available sterile 0.9% Sodium Chloride Injection, USP or 
local equivalent to be utilized for IV infusion as the diluent.   
16.2 Sample Size 
Considerations 
At the end of Stage 2, if greater than 20% rate is observed in either the 
futuximab or modotuximab Arms, an additional 10 patients may be added 
to obtain a more precise tumor shrinkage rate estimate and confidence 
interval (CI). 
Text has been removed 
 
 
19.5 Protocol Amendment 5 dated 18-Jan-2019 
 Effective 20Dec2018, Sponsor decided to discontinue the trial for administrative reasons, and future accrual has been 
halted.  As a result, the primary, secondary, and exploratory objectives are no longer applicable. Only clinical safety-
related evaluations will continue to be conducted. 
 ADA and samples for exploratory PK and PD assessments will not be collected. To date approximately 380 patients have 
been exposed to Sym004 (i.e., which includes the component antibodies futuximab and modotuximab); thus far 
immunogenicity or deleterious effects suggestive of development of ADA (serum sickness or related immune complex 
phenomena) have not been observed in the clinical setting. Therefore, in an effort to reduce overall blood collection from 
patients, it was considered acceptable to omit this assessment in this abbreviated study.  


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 Genomic samples for eligibility assessment will be obtained at prescreening and analyzed; however, post-dosing 
genomic samples for bioanalysis will not be collected. 
 The schedule for tumor assessments has been modified and will be per institutional guidelines or Investigator discretion 
until confirmation of PD. 
 A single center in the United States consented patients prior to the trial discontinuation date and will participate in the 
study going forward.  Two (2) of 5 patients consented were determined to meet all eligibility criteria and have been 
enrolled in the study. Since only Sym004 has been shown to have potential clinical benefit, the protocol rules for cross-
over and randomization were suspended; participating patients have been switched to or enrolled to receive Sym004. 
 The statistical section has been modified to detail the planned reduction in data collection to information needed for 
safety reporting only. 
 Reference to electronic data capture has been removed to allow the flexibility of using paper CRFs, if necessary. 
 Formatting adjustments and administrative wording changes are included. 
 The synopsis and tables have been updated based on changes described, where applicable. 
   
Refer to Table 34 for the changes in Protocol Amendment 5.  
 
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2.4.1 Safety 
 
As of January 2017, approximately 380 patients with solid tumors have 
been exposed to Sym004 in completed and ongoing Symphogen-
sponsored trials, and 23 patients have been exposed to Sym004 in an 
investigator-initiated trial in patients with recurrent glioblastoma 
(Sym004-08). 
As of January 2018, approximately 380 patients with solid tumors have 
been exposed to Sym004 in completed and ongoing Symphogen-
sponsored trials, and 30 patients have been exposed to Sym004 in an 
investigator-initiated trial in patients with recurrent glioblastoma 
(Sym004-08). 
3.1 Objectives 
 
Not applicable 
As of Amendment 5: Due to the Sponsor’s decision to discontinue the 
trial for administrative reasons (effective 20Dec2018), the primary, 
secondary, and exploratory objectives as detailed below are no longer 
applicable. Only clinical safety-related evaluations will be conducted. 
3.2 Trial Design 
Summary 
Not applicable 
As of Amendment 5: This amendment to the clinical trial protocol is 
based on the Sponsor’s decision to discontinue the trial for administrative 
reasons, effective 20Dec2018; the intent to discontinue the trial was 
communicated to all active sites on this date.  As a result, the original trial 
design as described below is no longer applicable, future accrual has been 
halted, and a reduction in the scope of non-safety-related assessments 
being conducted under this protocol has been implemented. 
Patients consented as of the trial discontinuation date, and determined to 


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meet study eligibility criteria, may be treated with IMP and may continue 
therapy until the occurrence of one of the following: unacceptable toxicity 
or other conditions preventing further administration, documented PD, or 
the patient’s decision to withdraw. 
• Treated patients will be followed and assessed for only clinical safety-
related concerns.  
• Of the Specialty Assessments initially planned: ADA and samples for 
exploratory PK and PD assessments (in peripheral blood, skin biopsies, 
and tumor biopsies) will not be collected; genomic samples for eligibility 
assessment were obtained at prescreening and analyzed, however post-
dosing genomic samples will not be collected.  
• The frequency of disease status evaluations will be per either 
institutional guidelines or Investigator discretion until confirmation of PD. 
The visit schedule for safety assessments will apply as specified 
elsewhere in this clinical trial protocol. Once IMP has been discontinued, 
an EOT visit will be performed within 7 to 10 days from the decision to 
withdraw treatment, and a 1M FUP visit will be performed 30 days (+7 
days) following the last dose.   
The pre-Amendment 5 trial design was as follows: 
4.1 Number of 
Patients 
 
Not applicable 
As of Amendment 5: As of the trial discontinuation date (20Dec2018), a 
single center in the United States had consented and screened patients. 
Two (2) of 5 patients screened were determined to be eligible for 
participation and both were enrolled in the study. The total number of 
sites planned will not be participating; the total number of patients 
planned will not be enrolled. 
4.2 Criteria for 
Inclusion 
 
Not applicable 
As of Amendment 5: Effective 20Dec2018, accrual to this trial has been 
halted; however, patients consented prior to the effective date will be 
required to meet the following inclusion criteria: 
4.3 Criteria for 
Exclusion 
 
Not applicable 
As of Amendment 5: Effective 20Dec2018, accrual to this trial has been 
halted; however, patients consented prior to the effective date will be 
required to meet the following exclusion criteria: 
6.2.1 Recruitment 
Period 
Not applicable 
As of Amendment 5: Effective 20Dec2018, accrual to this trial has been 
halted. Previous recruitment projections were as follows: 
6.2.2 Trial Duration   
 
Not applicable 
As of Amendment 5: Due to the Sponsor’s decision to discontinue the 
trial (effective 20Dec2018), the primary, secondary, and exploratory 


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objectives as previously described are no longer applicable. Planned 
efficacy analyses, as well as planned specialty analyses (including ADA 
as well as exploratory PK and PD analyses) will not be performed.  Only 
clinical safety-related analyses will be conducted; data cut-off will occur 
and safety analyses will be performed at the end of trial. 
6.2.3 Trial Closure   
 
Not applicable 
As of Amendment 5: Effective 20Dec2018, accrual to this trial has been 
halted; the total planned number of patients will not be enrolled. Once the 
2 patients entered to the trial have discontinued treatment and all required 
safety follow-up has been completed, the trial will be closed.  The pre-
Amendment 5 trial closure plan detailed below will not be followed. 
6.3.3 Submission of 
Patient Eligibility 
Information 
Once the patient is screened and identified by the Investigator as meeting 
the study eligibility criteria, data supporting eligibility must be entered in 
the study electronic CRF for the Sponsor (or designee) to review. 
Once the patient is screened and identified by the Investigator as meeting 
the study eligibility criteria, data supporting eligibility must be entered in 
the study CRF for the Sponsor (or designee) to review. 
6.3.5 Randomization 
 
Not applicable 
As of Amendment 5: As of the trial discontinuation date (20Dec2018), 5 
patients had provided written consent for trial participation; following 
screening, 2 were determined to be eligible. The first patient was deemed 
eligible prior to the trial discontinuation date and was randomized to Arm 
B (futuximab). The second patient was deemed eligible after the trial 
discontinuation date and although randomized to Arm B (futuximab), per 
Sponsor decision was enrolled to Arm A to receive Sym004. The pre-
Amendment 5 randomization plan detailed below will not be followed. 
6.5.2 Patient 
Availability 
Not applicable 
*As of Amendment 5: PK sampling has been omitted; the frequency of 
disease status evaluations will be per either institutional guidelines or 
Investigator discretion until confirmation of PD. 
6.5.4 Administration 
Details 
 
Not applicable 
As of Amendment 5: Two (2) patients screened and determined to be 
eligible have been treated with IMP. The first patient deemed eligible 
prior to the trial discontinuation date (20Dec2018) was randomized to 
Arm B (futuximab) and crossed over to Arm A (Sym004) at the EOC1 per 
Sponsor decision; the second patient deemed eligible after the trial 
discontinuation date was randomized to Arm B (futuximab), however per 
Sponsor decision was enrolled to Arm A to receive Sym004.  
With this amendment, the doses of IMP to be delivered remain 
unchanged; however, the pre-Amendment 5 crossover dose plan as 
detailed below is no longer in effect. 


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6.7.3 Treatment after 
Cycle 2 
 
Not applicable 
As of Amendment 5: Due to the Sponsor’s decision to discontinue the 
trial (effective 20Dec2018), the frequency of disease status evaluations 
will be per either institutional guidelines or Investigator discretion.  
Enrolled patients (2 total) have been either crossed over to receive or are 
receiving Sym004, and may continue to receive Sym004 until 
confirmation of PD. The pre-Amendment 5 plan for continued treatment 
after Cycle 2 as detailed below will not be followed. 
7 Study Assessments   
 
Not applicable 
As of Amendment 5: Due to the Sponsor’s decision to discontinue the 
trial (effective 20Dec2018), the original trial design is no longer 
applicable. Only clinical safety-related evaluations will be conducted. The 
visit schedule for the treatment period will apply as specified below, with 
indicated exceptions. Once IMP has been discontinued, an EOT visit will 
be performed within 7 to 10 days from the decision to withdraw 
treatment, and a 1M FUP visit will be performed 30 days (+7 days) 
following the last dose.  
The pre-Amendment 5 study assessment schedule was as follows: 
7.3 Specialty 
Assessments  
 
Not applicable 
As of Amendment 5: Due to the Sponsor’s decision to discontinue the 
trial (effective 20Dec2018), only clinical safety-related evaluations will 
be conducted.  Of the Specialty Assessments detailed below, ADA and 
samples for exploratory PK and PD assessments (in peripheral blood, skin 
biopsies, and tumor biopsies) will not be collected.  Genomic samples for 
eligibility assessment were obtained at prescreening and analyzed; 
however post-dosing genomic samples will not be collected. 
Note:  Samples for ADA and samples for exploratory PK and PD 
assessments, if collected prior to implementation of this amendment, will 
not be analyzed and will be destroyed. 
The pre-Amendment 5 specialty assessments were as follows: 
7.3.1 Immunogenicity 
Assessment 
(Specialty 
Laboratory)   
Not applicable 
As of Amendment 5: Immunogenicity assessments have been omitted.  
Immunogenicity assessments were initially planned as follows: 
7.3.2 Exploratory 
Pharmacokinetic 
Assessment 
(Specialty 
Laboratory)  
Not applicable 
As of Amendment 5: Exploratory PK assessments have been omitted.  
Exploratory PK assessments were initially planned as follows: 


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7.3.3 Genomic 
Analysis in Peripheral 
Blood (Specialty 
Laboratory)  
Not applicable 
As of Amendment 5:  Genomic assessments have been omitted with the 
exception of prescreening genomic sampling for eligibility assessment 
(*).  Genomic assessments were initially planned as follows: 
7.3.4 
Pharmacodynamic 
Analyses (Specialty 
Laboratory) 
Not applicable 
As of Amendment 5:  Pharmacodynamic assessments (including 
collection of peripheral blood, skin biopsies, and tumor biopsies) have 
been omitted.   Pharmacodynamic assessments were initially planned as 
follows: 
7.4.1 Diagnostic 
Imaging for Tumor 
Measurements (Local 
Assessment) 
 
• Screening 
• EOC2 and every even-numbered cycle thereafter (i.e., approximately 
every 8 weeks)* 
• EOT (if > 6 weeks since previous assessment) 
• As clinically indicated (in the event of suspected PD) 
*End of Cycle assessments may be conducted at any time during the week 
prior to Day 1 of the next cycle, including on Day 1 of the next cycle, 
prior to dosing. 
• Screening 
• As of Amendment 5: frequency per either institutional guidelines or 
Investigator discretion until confirmation of PD 
7.4.2 Response 
Assessment (Local 
Assessment) 
• EOC2 and every even-numbered cycle thereafter (i.e., approximately 
every 8 weeks)* 
• EOT (if > 6 weeks since previous assessment) 
• As clinically indicated (in the event of suspected PD) 
*End of Cycle assessments may be conducted at any time during the week 
prior to Day 1 of the next cycle, including on Day 1 of the next cycle, 
prior to dosing. 
• As of Amendment 5: frequency per either institutional guidelines or 
Investigator discretion until confirmation of PD 
14.8 Recording of 
Data 
 
Clinical trial data for this study will be captured in an electronic format. 
Electronic data capture (EDC) services will be provided by a vendor to be 
determined by the Sponsor. The Investigator agrees to provide all 
information requested in the CRF in an accurate manner according to 
instructions provided. CRFs are designed for computer processing and 
analysis. All data must be carefully entered to permit meaningful 
interpretation. Corrections to entered data will be identified and tracked 
by audit trails within the EDC system. Data must be entered into CRFs in 
a timely fashion. 
Clinical trial data for this study will be captured in a CRF. The 
Investigator agrees to provide all information requested in the CRF in an 
accurate manner according to instructions provided. All data must be 
carefully entered to permit meaningful interpretation. Corrections to 
entered data will be identified and tracked. Data must be entered into 
CRFs in a timely fashion. 
15.3 Data Processing 
 
Once recorded within the electronic CRF, study data will pass through a 
set of preprogrammed data validation checks designed to identify 
inconsistencies and other data errors, and also will undergo an additional 
study-specific data review process, as stated above in Section 15.2.  Data 
Once recorded within the CRF, study data will be checked to identify 
inconsistencies and other data errors, and also will undergo an additional 
study-specific data review process, as stated above in Section 15.2.  Data 
issues will be queried and query resolutions will be documented. 


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issues will be queried via the EDC system and query resolutions will be 
documented. 
Entry and processing of data other than those directly recorded on 
electronic CRFs by trial sites (e.g., imports of laboratory results) will 
follow vendor(s) SOPs. Transfer of such data from vendor(s) to Sponsor 
(or designee) will be handled according to vendor(s) data transfer SOPs 
and the Sponsor data transfer requirements with full compliance to 
applicable regulations. 
Database Lock will occur upon reaching the predefined data cut-off for 
primary analysis and completion of Sponsor’s (or designee’s) quality 
control procedures and quality assurance procedures. 
Portable Document Format (PDF) files of the electronic CRFs will be 
provided to the Investigator upon removal of access to the electronic 
CRFs. 
Entry and processing of data other than those directly recorded on CRFs 
by trial sites (e.g., imports of laboratory results) will follow vendor(s) 
SOPs. Transfer of such data from vendor(s) to Sponsor (or designee) will 
be handled according to vendor(s) data transfer SOPs and the Sponsor 
data transfer requirements with full compliance to applicable regulations. 
Database Lock will occur upon reaching the predefined data cut-off and 
completion of Sponsor’s (or designee’s) quality control procedures and 
quality assurance procedures. 
Portable Document Format (PDF) files of the CRFs will be provided to 
the Investigator at the end of the trial. 
15.4 Clinical Trial 
Report 
 
A final integrated clinical/statistical Clinical Trial Report (CTR) will be 
prepared upon reaching the predefined data cut-off for primary analysis 
(i.e., all patients complete their first on-study tumor assessment). 
As of Amendment 5: Due to the Sponsor’s decision to discontinue the 
trial for administrative reasons (effective 20Dec2018), the primary, 
secondary, and exploratory objectives as previously described are no 
longer applicable. Only clinical safety-related evaluations will be 
conducted. An abbreviated CTR will be prepared upon completion of the 
trial rather than the full integrated report described below. 
A final integrated clinical/statistical trial report will be prepared upon 
reaching the predefined data cut-off for primary analysis (i.e., all patients 
complete their first on-study tumor assessment). 
16.2 Sample Size 
Considerations 
 
Not applicable 
As of Amendment 5: Effective 20Dec2018, accrual to this trial has been 
halted; the total planned number of patients will not be enrolled. Two (2) 
patients consented prior to the trial discontinuation date and subsequently 
determined to be eligible have been entered to the study. The pre-
Amendment 5 sample size considerations detailed below are no longer 
valid. 
16.3 Analysis Sets 
 
• PK Analysis Set: All patients in the AT analysis set who receive any 
amount of their assigned dose of the IMPs, Sym004, futuximab or 
modotuximab, have a measurable concentration of at least one of the 
IMPs for at least one timepoint after the first dose, with no significant 
protocol deviations that may impact the data. 
• PK Analysis Set*:… 
*As of Amendment 5: PK analysis will not be performed, therefore the 
PK analysis set is no longer applicable. 


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16.4 Trial Endpoints 
 
Not applicable 
As of Amendment 5: Due to the Sponsor’s decision to discontinue the 
trial (effective 20Dec2018), only clinical safety-related analyses will be 
conducted.  The pre-Amendment 5 efficacy and exploratory endpoints as 
detailed below are no longer valid and will not be analyzed. 
16.4.1 Primary 
Efficacy Endpoint  
Not applicable 
“(omitted as of Amendment 5)” added to section heading 
16.4.2 Exploratory 
Endpoints and 
Analyses  
Not applicable 
“(omitted as of Amendment 5)” added to section heading 
16.5 Statistical 
Analysis  
 
Not applicable 
As of Amendment 5: Due to the Sponsor’s decision to discontinue the 
trial (effective 20Dec2018), only data from clinical safety-related 
evaluations will be summarized. Since only 2 patients are being treated in 
the study, the available baseline and safety data for these two patients will 
be presented as either patient profiles or patient listings. The pre-
Amendment 5 full statistical analysis as detailed below will not be 
performed. 
16.6 Primary 
Analysis 
 
Not applicable 
As of Amendment 5: Due to the Sponsor’s decision to discontinue the 
trial (effective 20Dec2018), only clinical safety-related analyses will be 
conducted. The planned efficacy analyses as detailed below will not be 
performed. 
16.8 Exploratory 
Analysis 
 
Not applicable 
As of Amendment 5: Due to the Sponsor’s decision to discontinue the 
trial (effective 20Dec2018), only clinical safety-related analyses will be 
conducted. The planned exploratory analyses as detailed below will not be 
performed. 
16.10 Interim 
Analysis  
 
Not applicable 
As of Amendment 5: Due to the Sponsor’s decision to discontinue the 
trial (effective 20Dec2018), only clinical safety-related analyses will be 
conducted. The planned interim analyses as detailed below will not be 
performed.