An Open-label, Multicenter, Phase 1a/2a Trial Investigating the Safety, Tolerability and Antitumor Activity of Multiple Doses of Sym013, a mAb Mixture Targeting EGFR, HER2 and HER3, in Patients With Advanced Epithelial Malignancies
Phase: PHASE1
Conditions: Oncology
Sponsor: Symphogen A/S

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Trial ID: Sym013-01 
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CLINICAL TRIAL PROTOCOL 
 
Trial Title: 
An Open-label, Multicenter, Phase 1a/2a Trial Investigating the 
Safety, Tolerability and Antitumor Activity of Multiple Doses of 
Sym013 (Pan-HER), a Monoclonal Antibody Mixture Targeting 
EGFR, HER2 and HER3, in Patients with Advanced Epithelial 
Malignancies 
 
Short Title: 
Sym013 (Pan-HER) in Patients with Advanced Epithelial 
Malignancies 
 
Sponsor: 
Symphogen A/S 
Pederstrupvej 93 
DK-2750 Ballerup 
Denmark 
 
Sponsor’s Medical 
Expert: 
Ivan D. Horak, MD, FACP 
Chief Scientific and Medical Officer 
 
Coordinating 
Investigator: 
Jordan Berlin, MD 
Ingram Professor of Cancer Research 
Co-Director, GI Oncology / Director, Phase 1 Research 
Vanderbilt University Medical Center 
 
Trial ID: 
Sym013-01 
 
 
Trial Phase: 
Phase 1a/2a 
 
EudraCT number: 
Pending 
 
IND Number: 
116334 
 
Protocol Version/Date: 
7.0 / 14-Jun-2018 (Amendment 6) 
 
Previous Protocol 
Versions/Dates: 
 
6.0 / 23-Jan-2018 (Amendment 5) 
5.0 / 04-May-2017 (Amendment 4) 
4.0 / 26-Apr-2017 (Amendment 3) 
3.0 / 14-Nov-2016 (Amendment 2) 
2.0 / 03-Oct-2016 (Amendment 1) 
1.0 / 13-Jun-2016 

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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This confidential document is the property of Symphogen A/S. No unpublished information 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 of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
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 
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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Sponsor Signature Page 
I hereby approve this clinical trial protocol as suitable and appropriate for use. 
 
See attached electronic signature and date 
Ulla Holm Hansen 
Senior Clinical Trial Manager 
Symphogen A/S 
 
See attached electronic signature and date 
Ivan D. Horak, MD, FACP 
Chief Scientific and Medical Officer 
Symphogen A/S 
 
See attached electronic signature and date 
Cliff Ding, PhD 
Executive Director, Biostatistics and Data Management 
Symphogen A/S 
 
See attached electronic signature and date 
Angela Hu, PhD 
Director of Global Regulatory Affairs   
Symphogen A/S 
 

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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 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) 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 
1. 
SYNOPSIS ............................................................................................................................ 10 
2. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................... 17 
3. 
BACKGROUND AND TRIAL RATIONALE .................................................................... 21 
3.1 
Disease and Treatment ....................................................................................................... 21 
3.1.1 
Solid Tumor Malignancies .............................................................................................. 21 
3.1.2 
Epithelial Malignancies and the Role of the HER Family of Receptors ......................... 21 
3.1.3 
Current Treatment of Epithelial Malignancies with HER Family Inhibitors .................. 22 
3.2 
Investigational Medicinal Product ..................................................................................... 24 
3.2.1 
Sym013 (Pan-HER) ......................................................................................................... 24 
3.2.2 
Mechanism of Action ...................................................................................................... 25 
3.2.3 
Summary of Non-clinical Findings ................................................................................. 25 
3.2.4 
Summary of Clinical Findings ......................................................................................... 27 
3.2.4.1 
Protocol Sym013-01 ................................................................................................... 27 
3.2.4.2 
Other Anticipated Clinical Findings ........................................................................... 29 
3.3 
Trial Rationale .................................................................................................................... 30 
3.4 
Dose Rationale ................................................................................................................... 30 
3.5 
Overall Benefits/Risk ......................................................................................................... 30 
4. 
TRIAL OBJECTIVES .......................................................................................................... 32 
4.1 
Objectives of Part 1, Dose-Escalation ................................................................................ 32 
4.1.1 
Primary Objective (Part 1) ............................................................................................... 32 
4.1.2 
Secondary Objectives (Part 1) ......................................................................................... 32 
4.2 
Objectives of Part 2, Dose-Expansion ............................................................................... 32 
4.2.1 
Primary Objective (Part 2) ............................................................................................... 32 
4.2.2 
Secondary Objectives (Part 2) ......................................................................................... 32 
5. 
TRIAL DESIGN ................................................................................................................... 34 
5.1 
Overall Design and Plan..................................................................................................... 34 
5.2 
Discussion of Trial Design ................................................................................................. 37 
5.2.1 
Rationale for Trial Design ............................................................................................... 37 
5.2.2 
Rationale for Trial Population ......................................................................................... 38 
5.3 
Schedule of Events ............................................................................................................. 38 
5.3.1 
Screening ......................................................................................................................... 40 
5.3.2 
Screening Failures ........................................................................................................... 41 
5.3.3 
Treatment ......................................................................................................................... 41 
5.3.4 
End of Treatment and Follow-up Visit ............................................................................ 42 
5.3.5 
Schedule of Assessments ................................................................................................. 42 
5.4 
Recruitment Period............................................................................................................. 47 
5.5 
Number of Patients ............................................................................................................. 47 
5.6 
End of Trial ........................................................................................................................ 47 
6. 
PATIENT SELECTION AND WITHDRAWAL ................................................................ 48 
6.1 
Inclusion Criteria ................................................................................................................ 48 
6.2 
Exclusion Criteria............................................................................................................... 49 
6.3 
Withdrawal from Treatment and Trial ............................................................................... 52 
6.3.1 
Withdrawal from Treatment ............................................................................................ 52 
6.3.2 
Withdrawal from Trial ..................................................................................................... 53 

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6.4 
Replacement of Patients ..................................................................................................... 53 
6.4.1 
Part 1, Dose-Escalation Cohorts ...................................................................................... 53 
6.4.2 
Part 2, Dose-Expansion ................................................................................................... 54 
7. 
TREATMENT ...................................................................................................................... 55 
7.1 
Investigational Medical Product/Sym013/Pan-HER ......................................................... 55 
7.1.1 
Packaging and Labeling of Pan-HER .............................................................................. 55 
7.1.2 
Handling, Storage and Preparation of Pan-HER ............................................................. 55 
7.1.3 
Administration of Pan-HER ............................................................................................ 56 
7.1.3.1 
Treatment Schedule .................................................................................................... 56 
7.1.3.2 
Part 1, Dose-Escalation ............................................................................................... 56 
7.1.3.3 
Part 2, Dose-Expansion Cohorts ................................................................................. 59 
7.1.3.4 
Duration of Infusion for Administration of Pan-HER ................................................ 60 
7.1.3.5 
Patient Monitoring During and After Infusion of Pan-HER ...................................... 61 
7.1.3.6 
Infusion-Related Reactions to Pan-HER .................................................................... 62 
7.1.3.7 
Handling of Infusion-Related Reactions to Pan-HER ................................................ 62 
7.1.4 
Dose Adjustment and Delays of Pan-HER ...................................................................... 64 
7.1.4.1 
Dose-Adjustment for Body Weight ............................................................................ 64 
7.1.4.2 
Dose-Delays for Pan-HER-Related or Disease-Related Toxicities ............................ 64 
7.1.4.3 
Dose-Reduction for Pan-HER-Related Toxicities ...................................................... 65 
7.2 
Other Drugs to be Used in the Trial ................................................................................... 66 
7.2.1 
Pre-Medication for Pan-HER Infusion-Related Reactions .............................................. 66 
7.2.2 
Treatment of Toxicities (Other Than IRRs) .................................................................... 67 
7.2.2.1 
Mandatory Prophylactic Treatment ............................................................................ 67 
7.2.2.2 
Therapeutic Treatment ................................................................................................ 68 
7.3 
Blinding .............................................................................................................................. 69 
7.4 
Drug Accountability and Compliance Check .................................................................... 70 
7.5 
Concomitant Medication/Therapy ..................................................................................... 70 
7.5.1 
Allowed Medication/Therapy and Procedures During the Trial ..................................... 70 
7.5.2 
Prohibited Medication/Therapy and Procedures During the Trial .................................. 70 
7.6 
Medical Care of Patients after End of Trial Participation .................................................. 71 
8. 
TRIAL ASSESSMENTS ...................................................................................................... 72 
8.1 
Baseline Characteristics / Eligibility Assessments ............................................................ 72 
8.1.1 
Signing of Informed Consent ........................................................................................... 72 
8.1.2 
Demographics .................................................................................................................. 72 
8.1.3 
Medical History ............................................................................................................... 72 
8.1.4 
Tumor Characteristics and Extent of Disease .................................................................. 72 
8.1.5 
Prior Cancer Treatments .................................................................................................. 72 
8.2 
Safety Assessments ............................................................................................................ 73 
8.2.1 
Medication/Procedure Survey ......................................................................................... 73 
8.2.2 
Adverse Events Survey .................................................................................................... 73 
8.2.3 
Dose-Limiting Toxicities Evaluation (Part 1 Only) ........................................................ 73 
8.2.4 
Vital Signs and Body Measurements ............................................................................... 73 
8.2.5 
ECOG Performance Status .............................................................................................. 74 
8.2.6 
Physical Examination ...................................................................................................... 74 
8.2.7 
Electrocardiogram (ECG) ................................................................................................ 74 
8.2.8 
Echocardiogram (ECHO) or Multi-Gated Acquisition (MUGA) Scan ........................... 75 

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8.2.9 
Laboratory Assessments and Pregnancy Test .................................................................. 75 
8.2.9.1 
Hematology Panel....................................................................................................... 76 
8.2.9.2 
Biochemistry Panel ..................................................................................................... 76 
8.2.9.3 
Coagulation Panel ....................................................................................................... 77 
8.2.9.4 
Urinalysis .................................................................................................................... 77 
8.2.9.5 
Pregnancy Test ........................................................................................................... 78 
8.2.10 Complement Panel (Part 2 only) (Central Laboratory) ................................................... 78 
8.3 
Disease Assessments .......................................................................................................... 78 
8.3.1 
Disease Status Evaluation by CT or MRI ........................................................................ 78 
8.3.2 
Tumor Marker Evaluation (as per standard practice of a trial site) ................................. 79 
8.3.3 
Archival Tumor Tissue for EGFR, HER2 Assessment (Part 1 only) .............................. 80 
8.4 
Pharmacokinetic Assessments (Central Laboratory) ......................................................... 80 
8.5 
Anti-Drug Antibody Testing (Central Laboratory) ............................................................ 81 
8.6 
Skin Biopsy (Central Laboratory) ...................................................................................... 82 
8.7 
Tumor Biopsy (Central Laboratory) .................................................................................. 82 
8.8 
Biomarker Blood Sample (Central Laboratory) ................................................................. 83 
8.9 
Handling of Biological Samples ........................................................................................ 84 
8.10 Follow-up Assessments ...................................................................................................... 84 
8.11 Appropriateness of Measurements ..................................................................................... 85 
9. 
ADVERSE EVENTS ............................................................................................................ 86 
9.1 
Definitions of Adverse Events ........................................................................................... 86 
9.1.1 
Adverse Event .................................................................................................................. 86 
9.1.2 
Events Not to be Considered as Adverse Events ............................................................. 86 
9.1.3 
Adverse Events of Medical Interest ................................................................................. 87 
9.1.4 
Serious Adverse Events ................................................................................................... 87 
9.1.5 
Events that Do Not Meet the Definition of Serious Adverse Events .............................. 87 
9.2 
Adverse Event Recording and Reporting Instructions ....................................................... 88 
9.2.1 
Adverse Event Recording Period ..................................................................................... 88 
9.2.2 
Diagnosis ......................................................................................................................... 88 
9.2.3 
Intensity ........................................................................................................................... 88 
9.2.4 
Relationship to Investigational Medicinal Product/Pan-HER ......................................... 89 
9.2.5 
Outcome ........................................................................................................................... 90 
9.2.6 
Follow-up of Adverse Events .......................................................................................... 91 
9.3 
Serious Adverse Event Recording and Reporting .............................................................. 91 
9.3.1 
Timeframes for Reporting to the Sponsor ....................................................................... 91 
9.4 
Safety Reporting to Health Authorities, Institutional Review Boards/Ethics Committees, 
and Investigators ........................................................................................................................... 92 
9.5 
Dose-Limiting Toxicities (Part 1 Only) ............................................................................. 92 
9.5.1 
Definition of Dose-Limiting Toxicities ........................................................................... 92 
9.5.2 
Observation Period for Dose-Limiting Toxicities ........................................................... 93 
9.5.3 
Reporting of Dose-Limiting Toxicities ........................................................................... 93 
9.6 
Reporting of Infusion-Related Reactions ........................................................................... 93 
9.7 
Pregnancy ........................................................................................................................... 94 
10. STATISTICS ........................................................................................................................ 95 
10.1 Sample Size Considerations ............................................................................................... 95 
10.2 Analysis Population ........................................................................................................... 95 

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10.3 Primary Endpoint and Analysis ......................................................................................... 96 
10.3.1 Part 1, Dose-Escalation .................................................................................................... 96 
10.3.2 Part 2, Dose-Expansion ................................................................................................... 96 
10.4 Secondary and Exploratory Endpoint and Analysis........................................................... 96 
10.4.1 Efficacy Endpoints and Analyses .................................................................................... 97 
10.4.2 Other Efficacy Assessments ............................................................................................ 97 
10.4.3 Safety Endpoints and Analyses ....................................................................................... 98 
10.4.3.1 
Adverse Events ........................................................................................................... 98 
10.4.3.2 
Clinical Laboratory Values ......................................................................................... 99 
10.4.3.3 
Other Safety Assessments .......................................................................................... 99 
10.4.4 Pharmacokinetic Endpoints and Analyses ....................................................................... 99 
10.4.5 Additional Endpoints and Analyses............................................................................... 101 
10.5 Interim Analysis ............................................................................................................... 101 
10.6 Deviations from the Statistical Plan ................................................................................. 102 
10.7 Modelling of Pharmacokinetics and Pharmacodynamics ................................................ 102 
11. ETHICS .............................................................................................................................. 103 
11.1 Institutional Review Board/Ethics Committee................................................................. 103 
11.2 Patient Information and Informed Consent ...................................................................... 103 
12. SAFETY SURVEILLANCE SET-UP ................................................................................ 104 
12.1 Safety Review .................................................................................................................. 104 
12.2 Other Safety Surveillance Activities ................................................................................ 104 
13. MONITORING AND QUALITY ASSURANCE ............................................................. 106 
13.1 Compliance with Good Clinical Practice ......................................................................... 106 
13.2 Source Documents ........................................................................................................... 106 
13.3 Monitoring ....................................................................................................................... 106 
14. HANDLING AND PROCESSING OF DATA .................................................................. 108 
14.1 Data Handling .................................................................................................................. 108 
14.2 Recording of Data ............................................................................................................ 108 
14.3 Data Review During this Study........................................................................................ 108 
14.4 Data Protection ................................................................................................................. 108 
14.5 Data Transactions and Access .......................................................................................... 109 
14.6 Case Report Form ............................................................................................................ 109 
14.7 Data Processing ................................................................................................................ 109 
14.8 Retention of Trial Documents at Site ............................................................................... 110 
14.9 Compliance with the General Data Protection Regulation .............................................. 110 
15. REGISTRATION AND COMMUNICATION OF RESULTS ......................................... 111 
15.1 Use of Information ........................................................................................................... 111 
15.2 Registration and Publication ............................................................................................ 111 
16. INSURANCE AND LIABILITY ....................................................................................... 112 
17. CHANGES TO THE FINAL CLINICAL TRIAL PROTOCOL ....................................... 113 
18. PREMATURE TERMINATION OF THE TRIAL OR A TRIAL SITE ........................... 114 
18.1 Premature Termination of the Trial.................................................................................. 114 
18.2 Premature Termination of a Trial Site ............................................................................. 114 
19. REFERENCE LIST ............................................................................................................ 115 
20. APPENDICES .................................................................................................................... 118 
Appendix 1:  Summary of Response Evaluation Criteria in Solid Tumors (RECIST v1.1) ...... 118 

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21. SUMMARY OF CHANGES .............................................................................................. 124 
21.1 Protocol Amendment 1 dated 03-Oct-2016 ..................................................................... 124 
21.2 Protocol Amendment 2 dated 14-Nov-2016 .................................................................... 125 
21.3 Protocol Amendment 3 dated 26-Apr-2017 ..................................................................... 128 
21.4 Protocol Amendment 4 dated 04-May-2017 .................................................................... 134 
21.5 Protocol Amendment 5 dated 23-Jan-2018 ...................................................................... 135 
21.6 Protocol Amendment 6 dated 14-Jun-2018...................................................................... 141 
 
LIST OF FIGURES 
Figure 1  Overall Trial Design ...................................................................................................... 37 
 
LIST OF TABLES 
Table 1   Overall Trial Plan ........................................................................................................... 39 
Table 2   Schedule of Assessments: Q1W Dosing ........................................................................ 43 
Table 3   Schedule of Assessments: Q2W Dosing ........................................................................ 45 
Table 4   Description of Investigational Medicinal Product/Sym013/Pan-HER .......................... 55 
Table 5   Infusion Rate for First Infusion of Pan-HER ................................................................. 60 
Table 6   Infusion Rate for Second Infusion of Pan-HER ............................................................ 60 
Table 7   Infusion Rate for Third and Subsequent Infusions of Pan-HER ................................... 61 
Table 8   Infusion-Related Reactions Management Guidelines .................................................... 63 
Table 9   Pan-HER Dose-Reduction Schedule ............................................................................. 66 
Table 10   Schedule of Safety Blood and Urine Samples ............................................................. 75 
Table 11   Schedule of Pharmacokinetic (PK) Assessments: Q1W Dosing ................................. 80 
Table 12   Schedule of Pharmacokinetic (PK) Assessments: Q2W Dosing ................................. 81 
Table 13   Pharmacokinetic (PK) Endpoints, Definitions, and Derivations ............................... 100 
Table 14   Response Criteria for Evaluation of Target Lesions .................................................. 121 
Table 15   Response Criteria for Evaluation of Non-Target Lesions ......................................... 121 
Table 16   Overall Response Status for Patients with Baseline Measurable Disease ................. 122 
Table 17   Best Overall Response when Confirmation of CR and PR Required ........................ 123 
Table 18   Protocol Amendment 1 .............................................................................................. 124 
Table 19   Protocol Amendment 2 .............................................................................................. 126 
Table 20   Protocol Amendment 3 .............................................................................................. 129 
Table 21   Protocol Amendment 4 .............................................................................................. 134 
Table 22   Protocol Amendment 5 .............................................................................................. 135 
Table 23   Protocol Amendment 6 .............................................................................................. 142 
 

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1. 
SYNOPSIS 
Item 
Summary 
Trial Title 
An Open-label, Multicenter, Phase 1a/2a Trial Investigating the Safety, Tolerability and Antitumor 
Activity of Multiple Doses of Sym013 (Pan-HER), a Monoclonal Antibody Mixture Targeting EGFR, 
HER2 and HER3, in Patients with Advanced Epithelial Malignancies 
Trial ID 
Sym013-01 
Investigational 
Medicinal 
Product 
The investigational medicinal product (IMP) tested in this trial is Sym013, referenced as Pan-HER. 
Pan-HER is a recombinant antibody mixture containing 6 humanized immunoglobulin G1 (IgG1) 
monoclonal antibodies (mAbs), which bind specifically to non-overlapping epitopes on the epidermal 
growth factor receptor (EGFR), and the human epidermal growth factor receptors (HER) HER2 and 
HER3.  
Overall Trial 
Design  
This is an open-label, multicenter trial composed of 2 parts in which Pan-HER will be evaluated when 
administered by the intravenous (IV) route to patients with advanced epithelial malignancies without 
available therapeutic options.  
• 
Part 1 is a Phase 1a dose-escalation evaluating weekly (Q1W ) and every second week (Q2W) 
schedules of administration in separate dose-escalation cohorts to determine the recommended 
phase 2 dose (RP2D) and regimen of Pan-HER.  
• 
Part 2 is a Phase 2a dose-expansion at the RP2D and regimen. Four (4) dose-expansion cohorts 
will be evaluated in this part of the trial and will be selected based upon findings from Part 1, 
additional preclinical data, and additional clinical data available at that time from other agents 
inhibiting these targets. Patients will be entered, depending upon either a defined molecular 
profile or profiles, or their underlying malignancy, to 1 of 4 corresponding expansion cohorts: 
Cohort A (HER2+ solid tumor malignancy Basket Cohort), Cohort B (pancreatic carcinoma), 
Cohort C (to be determined [TBD]), or Cohort D (TBD). 
The RP2D and regimen ultimately identified for use in Part 2 may be comprised of a fixed dose and 
schedule, a combination of doses to be administered on either a Q1W or Q2W schedule, or a combination 
dose and regimen. The RP2D and regimen will be selected based on tolerability demonstrated with Q1W 
and Q2W dosing during Part 1, as well as available pharmacokinetic (PK) and target engagement results, 
as applicable. Doses lower than the maximum tolerated dose(s) (MTD(s)) but between doses investigated 
in Part 1 may be selected if data indicate them to be optimal. 
 
As of Amendment 6  
At the time of Amendment 3 to this protocol, a total of 6 patients had been entered to Part 1; 1 patient 
each at Dose Levels 1 and 2 (1 mg/kg and 2 mg/kg, respectively), and 4 patients at Dose Level 3 (4 
mg/kg) had been treated weekly (Q1W; 4 doses equaling 1 cycle).  Due to the occurrence of Grade 1-2 
oral mucositis, rash, and diarrhea at the 4 mg/kg Q1W dose, Q1W dosing was halted, and the dosing 
interval was changed to every second week (Q2W; 2 doses equaling 1 cycle).  Dose Levels 4 and 5 (6 
mg/kg and 9 mg/kg, respectively) were evaluated on the Q2W schedule. Due to the occurrence of Grade 
3 infusion-related reaction (IRR) and oral mucositis at the 9 mg/kg Q2W dose, a mandatory prophylaxis 
regimen was implemented. 
Per Amendment 5, all patients must receive intensive prophylaxis, as defined herein, on a mandatory 
basis to reduce the risk of IRRs and oropharyngeal mucositis, and must receive Pan-HER infusions over 
a fixed (at minimum) 4-hour (+10 min) period unless further prolongation is required for an individual 
patient due to the occurrence of an IRR. The dose of 9 mg/kg Q2W was further evaluated with these 
modifications in place, and found to be tolerated; dose-escalation under these conditions continues. 
With Amendment 6, Q1W dosing is reintroduced under the prophylaxis and infusion duration conditions 
outlined in Amendment 5. Since Dose Level 3 (4 mg/kg) was previously evaluated on the Q1W schedule, 
reevaluation of Q1W dosing will resume at the next higher Dose Level 4 (6 mg/kg); however, lower 
doses may be explored if indicated based on tolerability. 
 

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Part 1/Dose-escalation 
The starting dose of Pan-HER will be 1 mg/kg Q1W.  The following dose levels of Pan-HER are planned 
to be evaluated: 
Q1W 
• 
Dose Level 1:        1 mg/kg Q1W  
• 
Dose Level 2:        2 mg/kg Q1W 
• 
Dose Level 3:        4 mg/kg Q1W 
• 
*Dose Level 4P:    6 mg/kg Q1W + P (lower doses with prophylaxis may be explored, if 
indicated) 
• 
*Dose Level 5P:    9 mg/kg Q1W + P  
• 
*Dose Level 6P:    12 mg/kg Q1W + P  
• 
*Dose Level 7P:    15 mg/kg Q1W + P 
• 
*Dose Level 8P:    18 mg/kg Q1W + P (highest potential dose allowed per protocol) 
Q2W 
• 
Dose Level 4:        6 mg/kg Q2W 
• 
Dose Level 5:        9 mg/kg Q2W 
• 
*Dose Level 5P:    9 mg/kg Q2W + P 
• 
*Dose Level 6P:    12 mg/kg Q2W + P 
• 
*Dose Level 7P:    15 mg/kg Q2W + P 
• 
*Dose Level 8P:    18 mg/kg Q2W + P (highest potential dose allowed per protocol) 
*Mandatory intensive IRR and oropharyngeal mucositis prophylaxis; 4-hour infusion (designated “P”) 
Initially, one patient will be treated at each dose level until the occurrence of a toxicity* during Cycle 1 
that activates the stopping rule of the single-patient cohort titration design. The cohort will expand to 3 
patients and the design will switch to a classical 3+3 dose-escalation design. 
*Grade 2 toxicity, assessed by the Investigator as possibly, probably, or related to Pan-HER with the 
exception of Grade 2 alopecia, nausea, anemia, lymphopenia, and/or eosinophilia. Toxicity grading will 
be according to the Common Terminology Criteria for Adverse Events (Version 4.03) (CTCAE v4.03). 
If such a toxicity has not occurred in the first 3 cohorts (i.e., 1 mg/kg, 2 mg/kg, and 4 mg/kg, Q1W), the 
next cohort to open will be a 3-patient cohort and the design will switch to the 3+3 design. 
Further dose-escalation will follow a standard 3+3 design with a target toxicity level of < 33% as 
determined by dose-limiting toxicities (DLTs).  
Note:  The transition from single patient cohorts to 3+3 dose-escalation design occurred beginning with Dose Level 3 
(4 mg/kg; Q1W). All Dose Levels evaluated thereafter are to be comprised of a minimum of 3 patients. 
 
Staggered Dosing: Enrollment will be staggered between the first and second patient in each new dose 
level tested. The first patient must have completed and tolerated the first 2 doses with Q1W dosing, or 
the first dose with Q2W dosing, including follow-up until Day 15 of Cycle 1 (C1/D15) in order to allow 
for review of clinical and laboratory assessments. Thereafter, patients within a cohort may be added 
concurrently. 
 
Escalation Rules: Escalation from a current dose level to the next will only proceed following 
evaluation of tolerability of the current dose level. Thus, dosing of the first patient at any new dose level 
will commence only after all patients to be treated at the current dose level have completed Cycle 1, and 
the current dose level has been found to be tolerable. The dose-escalation decision points are listed 
below: 
• 
If no DLTs are encountered in any of the first 3 patients completing Cycle 1 within a dose level, 
dose-escalation may continue to the next level. 

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• 
If 1 of 3 patients within a dose level experiences a DLT, 3 more patients will be enrolled at the same 
dose level (to a total of 6 patients). If no DLTs are encountered in the 3 additional patients, dose-
escalation may continue to the next level when all patients have completed and tolerated Cycle 1. 
• 
If ≥ 2 patients within a dose level (of up to 6 patients) experience a DLT, then that dose will be 
considered to have exceeded the MTD and the dose level just below this maximum administered 
dose (MAD) will be considered to be the potential MTD. 
• 
Once the potential MTD has been declared, the MTD dose level will be completed to a total of 6 
patients, if not already accomplished. In order to confirm the MTD, ≤1 of 6 patients within the dose 
level may have experienced a DLT. 
• 
An MTD may or may not be found within the dose levels tested. Dose-escalation may be stopped 
due to toxicity observations other than DLTs and/or results from PK and/or target engagement 
analyses. 
During Part 1, intermediate dose level(s) between 2 planned dose levels may be evaluated to further 
characterize safety and tolerability of Pan-HER, if indicated based on toxicity observations and/or results 
from PK and/or target engagement analyses.    
 
RP2D: The RP2D may include a dose or a combination of doses (e.g., initial loading dose followed by a 
lower maintenance dose) equal to or lower than the MTD for the Q1W and/or Q2W dosing regimens.  A 
dose or doses between tolerated doses investigated in Part 1 may also be selected if data indicate this to 
be optimal. Further, the RP2D and regimen ultimately identified for use in Part 2 of this trial may be a 
dose or a combination of to be administered on a Q1W schedule, a Q2W schedule, or a combination 
thereof. The selection will be based on tolerability demonstrated with Q1W and Q2W dosing, as well as 
available PK and target engagement results, as applicable. 
 
Part 2/Dose-expansion  
Once the RP2D and regimen have been established during dose-escalation, enrollment into the 4 separate 
dose-expansion cohorts will commence (Cohort A, Cohort B, Cohort C, or Cohort D). All patients 
enrolled will be treated with Pan-HER at the established RP2D and regimen. 
Trial Sites  
Part 1/Dose-escalation: Approximately 3 investigational trial sites, hereafter called “trial sites” 
Part 2/Dose-expansion: Approximately 25 trial sites 
Planned Trial 
Period 
Part 1 of the trial is expected to begin Q4 2016.  
Patients will be sequentially enrolled to dose-escalation cohorts on either a Q1W or a Q2W schedule 
until establishment of a RP2D and regimen, expectedly Q1 2019.   
Enrollment to the expansion cohorts in Part 2 of the trial will commence upon approval of a protocol 
amendment defining the expansion cohorts to be further explored. Enrollment to Part 2 is expected to be 
from Q1 2019 to Q3 2020. 
Primary and 
Secondary 
Objectives 
Primary objective of Part 1/Dose-escalation: To assess the safety and tolerability of Pan-HER when 
administered either Q1W or Q2W by IV infusion to separate dose-escalation cohorts of patients with 
advanced epithelial malignancies without available therapeutic options.   
Secondary objectives of Part 1/Dose-escalation:  
1. 
To determine a RP2D and regimen of Pan-HER 
2. 
To evaluate the PK profile of Pan-HER 
3. 
To evaluate the immunogenicity of Pan-HER 
4. 
To evaluate target engagement in skin biopsy tissue (EGFR and HER3) and tumor biopsy tissue 
(EGFR, HER2 and HER3), if available  
5. 
To evaluate other potential pharmacodynamic biomarkers of Pan-HER action, and estimate, if 
feasible, the magnitude of biological activity in peripheral blood and in skin biopsy (and tumor 
biopsy, if available) tissue 
6. 
To make a preliminary evaluation of the antitumor effect of Pan-HER 

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Primary objective of Part 2/Dose-expansion: To evaluate the antitumor effect of Pan-HER when 
administered at the RP2D and regimen to patients with advanced epithelial malignancies without 
available therapeutic options. Four (4) dose-expansion cohorts will be evaluated. 
Secondary objectives of Part 2/Dose-expansion:  
1. 
To further evaluate the safety and tolerability of Pan-HER 
2. 
To further evaluate the PK profile of Pan-HER 
3. 
To further evaluate the immunogenicity of Pan-HER 
4. 
To further evaluate target engagement in skin biopsy tissue (EGFR and HER3) and tumor biopsy 
tissue (EGFR, HER2 and HER3) (tumor biopsy required) 
5. 
To further evaluate other potential pharmacodynamic biomarkers of Pan-HER action, and estimate, 
if feasible, the magnitude of biological activity in peripheral blood and in skin and tumor biopsy 
tissue (tumor biopsy required) 
Primary 
Endpoints 
Primary endpoint of Part 1/Dose-escalation: The occurrence of DLTs during Cycle 1 for each of the 
Pan-HER dosing regimens.  
Primary endpoint of Part 2/Dose-expansion: Documented objective response (OR), defined as 
documented partial response (PR) or complete response (CR) assessed by Response Evaluation Criteria 
in Solid Tumors (Version 1.1) (RECIST v1.1) at any time during trial participation, with radiologic 
evaluation to be performed locally. 
Trial Periods 
Screening period: After providing informed consent, the eligibility of patients will be established 
according to the protocol-defined inclusion and exclusion criteria. 
Treatment period: Patients in the trial will receive either Q1W or Q2W IV infusions of Pan-HER, 
depending upon cohort assignment, until occurrence of any of the following: unacceptable toxicity or 
other conditions preventing further treatment, disease progression, termination of the trial, or patient’s 
decision to withdraw. 
End of treatment/follow-up: Once Pan-HER has been discontinued, an End of Treatment (EOT) visit 
will be performed within 10 days following the decision to withdraw treatment. A follow-up visit will be 
performed 30 (+7) days after the last dose of Pan-HER. This 1-Month Follow-up (1M FUP) visit 
constitutes the end of trial participation for the patient. 
Part 2 ONLY, continued follow-up for response and/or overall survival: After the 1M FUP Visit, the 
Investigator will make every effort to obtain follow-up information on response assessment and/or 
overall survival (OS) every 2 months. Response assessment follow-up is required in the event of an 
ongoing stable disease (SD) or OR (defined as PR or CR), as per RECIST v1.1 at the 1M FUP Visit, 
until progressive disease (PD) or another therapeutic intervention is initiated. Survival follow-up is 
required until death, withdrawal of consent, or termination of the trial. This continued follow-up does not 
require an in-person visit at the trial site, but may be obtained by collection of data/documentation. 
Number of 
Patients 
In total, approximately 134 patients will be included in this trial. 
It is estimated that approximately 34 patients will be enrolled to receive increasing doses of Pan-HER 
during Part 1. The exact number of patients will depend upon the observed tolerability of Pan-HER and 
the potential for adding additional patients to a cohort to ensure a sufficient number of evaluable patients 
per cohort. 
It is planned to enroll and treat approximately 100 patients during Part 2. 
Main Inclusion 
and Exclusion 
Criteria 
Main inclusion criteria all patients, Part 1 and Part 2: 
• 
Male or female, at least 18 years of age at the time of informed consent 
• 
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 
• 
Life expectancy >3 months assessed during Screening 
• 
Documented (histologically- or cytologically-proven) epithelial malignancy that is locally advanced 
or metastatic, having received all therapy known to confer clinical benefit  
Additional inclusion criteria applicable to Part 2 ONLY: 
• 
Epithelial malignancy (HER2+ solid tumor malignancies, pancreatic carcinoma, and 2 other tumor 

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types to be specified in a protocol amendment), measurable according to RECIST v1.1 that has been 
confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) within 4 weeks 
prior to C1/D1 
• 
Willingness to undergo a pre-and post-dosing biopsy (total of 2 biopsies) from primary or metastatic 
tumor site(s) considered safe for biopsy 
Main exclusion criteria: 
• 
Any antineoplastic agent for the primary malignancy (standard or investigational) without delayed 
toxicity within 4 weeks or 5 plasma half-lives, whichever is shortest, prior to C1/D1except: 
a. 
Nitrosoureas and mitomycin C within 6 weeks prior to C1/D1 
• 
Part 2 ONLY: Radiotherapy against target lesions within 4 weeks prior to C1/D1, unless there is 
documented progression of the lesion following the radiotherapy 
• 
Immunosuppressive or systemic hormonal therapy within 2 weeks prior to C1/D1, with allowed 
exceptions 
• 
Use of hematopoietic growth factors within 2 weeks prior to C1/D1 
• 
Active second malignancy or history of another malignancy within the last 3 years, with allowed 
exceptions 
• 
Central nervous system (CNS) malignancies including:   
a. 
Primary malignancies of the CNS 
b. 
Known, untreated CNS or leptomeningeal metastases, or spinal cord compression; patients with 
any of these not controlled by prior surgery or radiotherapy, or symptoms suggesting CNS 
metastatic involvement for which treatment is required 
• 
Inadequate recovery from an acute toxicity associated with any prior antineoplastic therapy 
• 
Major surgical procedure within 4 weeks prior to C1/D1 or inadequate recovery from any prior 
surgical procedure 
• 
Non-healing wounds on any part of the body 
• 
Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within 4 weeks 
prior to C1/D1, unless adequately treated and stable 
• 
Active uncontrolled bleeding or a known bleeding diathesis 
• 
Significant gastrointestinal abnormalities 
• 
Significant cardiovascular disease or condition 
• 
Abnormal hematologic, renal or hepatic function as defined by the following criteria: 
a. 
Absolute neutrophil count (ANC) <1.5 ×109/L (1500/mm3) 
b. 
Hemoglobin ≤8 g/dL 
c. 
Platelet count <100 ×109/L (100,000/mm3)  
d. 
Serum creatinine >1.5 × upper limit of normal (ULN) for the institution 
e. 
Aspartate aminotransferase (AST) >3.5 × ULN for the institution or AST >5 × ULN for the 
institution in case of known liver metastases 
f. 
Alanine aminotransferase (ALT) >3.5 × ULN for the institution or ALT >5 × ULN for the 
institution in case of known liver metastases 
g. 
Total bilirubin >1.5 × ULN for the institution 
h. 
Prothrombin time (PT) as assessed by International Normalized Ratio (INR) >1.5 × ULN for 
the institution* 
i. 
Partial thromboplastin time (PTT) >1.5 × ULN for the institution* 
*Unless on a stable dose (per the Investigator’s discretion) of anticoagulant therapy for a prior 
thrombotic event 
• 
Any of the following within 2 weeks prior to C1/D1: 
a. 
Any serious or uncontrolled infection 
b. 
Any infection requiring parenteral antibiotics 
c. 
Unexplained fever >38.0 °C 

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Investigational 
Medicinal 
Product: 
Dose(s) and 
Treatment 
Schedule 
Pan-HER will be initiated on C1/D1 and, based on cohort assignment, will be administered either Q1W 
or Q2W to separate dose-escalation cohorts of patients by IV infusion in cycles of treatment: 
• 
Q1W: Dosing on Day 1, 8, 15, and 22 of each 28-day cycle (±2 days)  
• 
Q2W: Dosing on Day 1 and 15 of each 28-day cycle (±2 days) 
All patients will receive the allocated dose and schedule of Pan-HER until treatment withdrawal. There 
will be no intra-patient dose-escalation. Dose-delays of Pan-HER and/or intra-patient dose-reduction(s) 
may be required upon occurrence of specific toxicities. 
 
For Part 1 of the trial, Pan-HER will be administered following delivery of intensive prophylaxis, as 
defined herein, on a mandatory basis to reduce the risk of IRRs and oropharyngeal mucositis.    
 
For Part 2, IRR and oropharyngeal mucositis prophylaxis is mandatory during Cycle 1 and Cycle 2. If the 
patient is without evidence of IRRs or oropharyngeal mucositis after Cycle 2, the Investigator may 
choose to withdraw related medications with subsequent dosing. Gradual withdrawal of medications is 
recommended. 
 
The duration of infusion will be (effective with Amendment 5): 
• 
Minimum of 4 hours (+10 min) for all infusions. Titrated rate increases during infusions, and 
infusion duration reductions after C1/D1, will no longer be allowed.         
 
Patients will be carefully observed for a minimum of 2 hours following completion of the first infusion 
and a minimum of 1 hour following completion of subsequent infusions. Recommended guidelines for 
management of IRRs are provided.  
Dose-Limiting 
Toxicities 
(Part 1 only) 
The decision to dose-escalate will be based on monitoring of safety during Cycle 1. 
A minimum of 4 infusions with Q1W dosing, and 2 infusions with Q2W dosing must have been 
administered at the assigned dose for a patient to have completed the DLT-observation period. 
All applied DLT criteria are provided. 
Trial Assessments 
Safety Assessments: 
• 
Medication survey 
• 
(Serious) Adverse Event ([S]AE) survey 
• 
DLT evaluation during Cycle 1, applicable for Part 1 
• 
Vital signs and body measurements 
• 
ECOG PS 
• 
Physical examination 
• 
Electrocardiogram (ECG) 
• 
Transthoracic echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan 
• 
Safety blood samples 
• 
Urinalysis 
• 
Pregnancy test  
• 
Complement Panel, applicable for Part 2 
Disease Assessments: 
• 
Disease status evaluation by CT or MRI according to RECIST v1.1 
• 
Tumor marker evaluation, as indicated by tumor type, if applicable 
• 
Archival tumor tissue, for local assessment of EGFR and HER2 status, applicable for Part 1 (only if 
tissue is available) 
Additional Assessments: 
• 
PK sampling with extended PK-profiling after the first and fourth infusion of Pan-HER (C1/D1 and 

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C1/D22, respectively) for Q1W dosing, and after the first and third infusion of Pan-HER (C1/D1 
and C2/D1, respectively) for Q2W dosing 
• 
Anti-drug antibody (ADA) testing 
• 
Skin biopsy for biomarker analysis  
• 
Tumor biopsy for biomarker analysis: Optional for Part 1, Mandatory for Part 2 
• 
Peripheral blood sample for biomarker analysis  
Safety 
Surveillance  
A safety monitoring committee (SMC) will be established. This committee will include Investigator(s), 
Medical Monitor(s), and Sponsor’s medical representatives.  
The SMC will review clinical and laboratory safety data regularly throughout the trial and make 
decisions regarding the advisability of continuing accrual to a particular dose cohort, and/or escalating 
the dose and allowing accrual to a higher dose cohort.  In order to do so, the Investigator must ensure to 
report safety data to the Sponsor or designee in a timely manner.  
Regular safety teleconferences will be held between the trial site(s) and the Sponsor and/or designee. 
Such safety teleconferences may fluctuate in frequency based on accrual and trial activity, as indicated. 
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 trial. 
Statistical 
Methods and 
Sample Size 
Considerations 
The primary endpoint of Part 1 of the trial is the occurrence of DLTs during Cycle 1 for each of the Pan-
HER dosing regimens. The number of enrolled patients will depend on the extent of observed DLTs 
independently in each cohort. Based on the dose-escalation design, it is planned to enroll approximately 
34 patients during the first part of the trial. 
All DLT events will be listed by dose cohort and patient. A summary table of DLTs across dose cohorts 
by System Organ Class (SOC) and preferred term will be presented, if applicable. The summaries will 
include number of DLTs and number and percentages of patients experiencing a DLT. 
The MTD is defined as the highest dose with a maximum of 1 out of 6 patients experiencing a DLT. The 
MTD may or may not be found within the dose levels tested. Based on an overall evaluation of the dose-
escalation part of the trial, the RP2D to be used in Part 2 will be selected. 
In Part 2 of the trial, the primary endpoint is documented OR, defined as documented PR or CR assessed 
by RECIST v1.1 at any time during trial participation, with radiologic evaluation to be performed locally. 
It is planned to enroll and treat approximately 100 patients during Part 2. The planned number of patients 
to be enrolled may be adjusted when the 4 expansion cohorts (i.e., based on defined molecular profile(s) 
and tumor types) have been selected. The protocol amendment defining the expansion cohorts will 
contain a detailed sample size calculation covering the four expansion cohorts, including the expected 
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2. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
1M FUP 
 1-Month Follow-up 
ADA  
 Anti-Drug Antibody 
ADC  
 Antibody Drug Conjugate 
ADCC  
 Antibody-Dependent Cellular Cytotoxicity  
AE 
 
 Adverse Event 
ALP 
 
 Alkaline Phosphatase 
ALT 
 
 Alanine Aminotransferase 
ANC  
 Absolute Neutrophil Count 
AST   
 Aspartate Aminotransferase 
BUN  
 Blood Urea Nitrogen 
C#/D#  
 Cycle # / Day # 
CDC  
 Complement-Dependent Cytotoxicity 
CI 
 
 Confidence Interval 
CNS  
 Central Nervous System 
CR 
 
 Complete Response 
CRC  
 Colorectal Cancer 
CRF 
 
 Case Report Form 
CT 
 
 Computed Tomography 
CTCAE v4.03  Common Terminology Criteria for Adverse Events (Version 4.03) 
CTR 
 
 Clinical Trial Report 
DLT 
 
 Dose-Limiting Toxicity 
DMP  
 Data Management Plan 
DSUR  
 Development Safety Update Report 
EC 
 
 Ethics Committee 
ECG  
 Electrocardiogram 
ECHO  
 Echocardiogram 
ECOG  
 Eastern Cooperative Oncology Group 
EDC  
 Electronic Data Capture 
EEA 
 
 European Economic Area 
EGFR  
 Epidermal Growth Factor Receptor 
EOI 
 
 End of Infusion 

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EOT 
 
 End of Treatment 
EU 
 
 European Union 
18F-FDG  
 Fluorine-18 Radiolabeled Fluorodeoxyglucose 
FAS 
 
 Full Analysis Set 
FDG  
 Fluorodeoxyglucose 
GCP  
 Good Clinical Practice 
GnRH  
 Gonadotropin-Releasing Hormone 
G2T 
 
 Grade 2 Toxicity 
HA 
 
 Health Authority 
hCG 
 
 Human Chorionic Gonadotropin 
HER  
 Human Epidermal Growth Factor Receptor 
HIV 
 
 Human Immunodeficiency Virus 
HRT 
 Hormone Replacement Therapy 
ICH 
 International Council for Harmonisation of Technical Requirements for 
 Pharmaceuticals for Human Use 
ICMJE  
 International Committee of Medical Journal Editors 
IgG1  
 Immunoglobulin G1 
IHC 
 
 Immunohistochemistry 
IMP 
 
 Investigational Medicinal Product 
INR 
 
 International Normalized Ratio 
IRB 
 
 Institutional Review Board 
IRR 
 
 Infusion-Related Reaction 
ISF 
 
 Investigator Site File 
IV 
 
 Intravenous 
KRAS  
 Kirsten Rat Sarcoma Viral Oncogene Homolog 
LVEF  
 Left Ventricular Ejection Fraction 
mAb  
 Monoclonal Antibody 
MAD  
 Maximum Administered Dose 
MAPK  
 Mitogen-Activated Protein Kinase 
MedDRA 
 Medical Dictionary for Regulatory Activities 
MRI 
 
 Magnetic Resonance Image/Imaging 
MTD  
 Maximum Tolerated Dose 
MUGA 
 Multi-Gated Acquisition 

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NE 
 
 Not Evaluable 
NOAEL 
 No Observed Adverse Event Level 
NRAS  
 Neuroblastoma RAS Viral Oncogene Homolog 
NSAID 
 Nonsteroidal Anti-Inflammatory Drug 
NSCLC 
 Non-Small Cell Lung Cancer 
NYHA  
 New York Heart Association 
OR 
 
 Objective Response 
OS 
 
 Overall Survival 
PD 
 
 Progressive Disease 
PDF 
 
 Portable Document Format 
PDX  
 Patient-Derived Xenograft 
PET 
 
 Positron Emission Tomography 
PI3K  
 Phosphoinositide 3-Kinase 
PK 
 
 Pharmacokinetic(s) 
PO 
 
 Orally, by mouth 
PR 
 
 Partial Response 
PS 
 
 Performance Status 
PSA 
 
 Prostate-Specific Antigen 
PT 
 
 Prothrombin Time 
PTT 
 
 Partial Thromboplastin Time 
q.s. 
 
 Quantum Sufficit (as much as suffices) 
Q1W  
 Every week, weekly 
Q2W  
 Every second week 
RAS 
 
 Rat Sarcoma 
RECIST v1.1  Response Evaluation Criteria in Solid Tumors (Version 1.1) 
RP2D  
 Recommended Phase 2 Dose 
RTK  
 Receptor Tyrosine Kinase 
SAE 
 
 Serious Adverse Event 
SCCHN 
 Squamous Cell Carcinoma of the Head and Neck  
SD 
 
 Stable Disease 
SMC  
 Safety Monitoring Committee 
SOC  
 System Organ Class 

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SOI 
 
 Start of Infusion 
SOP 
 
 Standard Operating Procedure(s) 
SUSAR 
 Suspected Unexpected Serious Adverse Reaction 
TBD  
 To Be Determined 
TEAE  
 Treatment Emergent Adverse Events 
TKI 
 
 Tyrosine Kinase Inhibitor 
ULN  
 Upper Limit of Normal 
WHO  
 World Health Organization 
WT 
 
 Wild-Type 

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3. 
BACKGROUND AND TRIAL RATIONALE 
3.1 
Disease and Treatment 
3.1.1 
Solid Tumor Malignancies 
Cancers are caused by malignant tumors formed by an abnormal growth of cells and tissue 
leading to organ failure. They fall into two categories: solid and hematological cancers. Solid 
tumors are formed by an abnormal growth of body tissue cells other than blood, bone marrow or 
lymphatic cells. A solid tumor consists of an abnormal mass of cells, which may stem from 
different tissue types such as lung, breast, colon, prostate, stomach and liver, and which initially 
grows in the organ of its cellular origin. In advanced stages of the disease, solid tumors may 
spread to other organs through metastatic tumor growth.   
Cancer is the second-leading cause of death and disability in the world, only surpassed by heart 
disease. In 2012, 14.1 million people were diagnosed with cancer worldwide. An estimated 8.2 
million people died from the disease. The World Health Organization (WHO) projected that by 
2035, these figures could increase to 24 million new cases and 14.6 million cancer deaths 
worldwide. Lung, breast, colorectal, prostate and stomach cancer are the most common 
malignancies (1). 
3.1.2 
Epithelial Malignancies and the Role of the HER Family of Receptors 
Epithelial malignancies or carcinomas are derived from tissues lining both the external (skin) and 
internal (mucosal) surfaces of the body. Carcinomas may differ based on their tissue origin and 
include: (a) adenocarcinomas; (b) squamous cell carcinomas; (c) basal cell carcinomas; and (d) 
transitional cell carcinomas. A variety of inherited or acquired genetic abnormalities may 
underlie the transformation of normal epithelial tissues to bona fide malignancies.  
Although a wide variety of abnormalities may be involved in the genesis or maintenance of 
epithelial malignancies, the human epidermal growth factor receptor (HER) family has been 
shown to be involved in many cases. The HER family consists of four members: EGFR-ErbB1-
HER1, ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4. These receptors play an important role in 
normal cell growth, metabolism, proliferation, survival, and differentiation. However, 
deregulation through mutation, overexpression, or gene amplification of HER family members 
(or their ligands) is commonly associated with development, progression, or acquired resistance 
of many human cancers. Homo- or hetero-dimerization induced by binding of ligands within the 
EGF family of growth factors results in cross-phosphorylation of the dimerization partners, 
ultimately triggering intracellular signaling (2,3). 

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Epidermal Growth Factor Receptor (EGFR) and HER2 are clinically validated targets with 
agents targeted to EGFR active in squamous cell carcinoma of the head and neck (SCCHN), 
colorectal, and squamous cell histology non-small cell lung cancers (NSCLC), and agents 
targeting HER2 approved for the treatment of breast and gastric cancers. There is also preclinical 
evidence suggesting that antibodies to HER3 may prove to be a clinically relevant target in 
combination with agents active against other HER family members (3,4,5,6). In contrast, the role 
of HER4 in cancer pathogenesis is less clear.  
Accumulating evidence shows that the HER family displays a high degree of plasticity and the 
multiple members provide compensatory signaling leading to acquired resistance in response to 
therapeutic intervention to a single target (7,8). Simultaneous targeting of more than one HER 
family receptor is frequently able to reverse the resistance to the initial drug and is often more 
efficacious than single-receptor targeting alone (9,10,11). Inhibiting more than one HER family 
member may thus be critical to limiting acquired resistance and more effectively treating cancer. 
In addition, the cells within a tumor may display extensive heterogeneity and therefore do not 
respond equally to individual therapies. This intra-tumor heterogeneity comprises not only 
clinically important traits such as ability to metastasize and resist therapy, but these cells may 
also express biomarkers suggesting potential alternative therapeutic targets, including the 
members of the HER family (12,13).  
3.1.3 
Current Treatment of Epithelial Malignancies with HER Family Inhibitors 
Both small molecule tyrosine kinase inhibitors (TKI), targeting individual or multiple members 
of the HER family, and therapeutic monoclonal antibodies (mAbs) have been approved for 
treatment of various epithelial tumors. A number of additional therapeutic agents, including 
small molecules, antibody-drug conjugates, bispecific antibodies, and antibody mixtures are also 
being investigated in clinical trials. However, most of these approaches, including bi- or dual-
specific antibody formats currently in development, fail to capture the full complexity of the 
HER family plasticity as only two of the receptors at the most are targeted simultaneously. 
Although small molecule TKIs are often capable of inhibiting multiple kinases simultaneously, 
they are unable to directly address HER3 since very limited kinase activity is associated with this 
member of the HER family.  
HER-targeting TKIs are small molecules that bind either reversibly or irreversibly. They inhibit 
receptor signaling by competing with adenosine triphosphate for binding to the intracellular 
catalytic kinase domain of the receptor, thereby preventing autophosphorylation and activation of 
several downstream signaling pathways (4,5).  

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First-generation EGFR TKIs, such as erlotinib and gefitinib, are oral reversible inhibitors that 
have been shown to be effective in specific subsets of patients with NSCLC. Erlotinib is 
approved for second or third line therapy of NSCLC, for first line therapy of EGFR-activating 
mutation-positive NSCLC and maintenance therapy after first line therapy of this patient 
population. Erlotinib is also approved in combination with gemcitabine for treatment of 
pancreatic carcinoma. Gefitinib is approved for treatment of metastatic NSCLC with activating 
mutations of EGFR. Afatinib is a second generation oral TKI that irreversibly inhibits EGFR, 
HER2 and HER4. Due to the additional activity against HER2, afatinib is being investigated for 
breast cancer as well as other EGFR and HER2 driven cancers. Gefitinib and afatinib are both 
approved for treatment of patients with activating mutations of EGFR, and afatinib has also been 
approved for the treatment of patients with squamous cell histology NSCLC. Osimertinib, a third 
generation EGFR TKI has been approved for the treatment of patients who have developed 
resistance to previous treatment with erlotinib, gefitinib, or afatinib, including patients who 
express EGFR T790M mutations (25).  It has recently been approved for first line therapy of 
patients with activating mutations of EGFR who have not developed resistance to first or second 
generation therapies (26,27). 
Lapatinib is an oral TKI with activity against EGFR and HER2 that has been approved in 
combination with capecitabine for therapy of HER2-overexpressing advanced or metastatic 
breast cancer patients who have received and progressed after prior therapy including 
trastuzumab, an anti-HER mAb. It is also approved in combination with letrozole, an aromatase 
inhibitor, for HER2 overexpressing patients for whom hormonal therapy is indicated. Neratinib 
is an irreversible TKI with activity against EGFR, HER2, and HER4 (28).  It was recently 
approved for adjuvant therapy of HER2-positive breast cancer following therapy with 
trastuzumab (29). 
Since HER3 has only limited kinase activity, it is not effectively targeted directly by TKIs. For 
this reason, therapeutic antibodies are being explored to target HER3 for cancer therapy.  
Therapeutic antibodies are large molecules (proteins) that are designed specifically for binding to 
epitopes displayed on the surface of cells. Antibodies against targets such as the HER family act 
mainly through two mechanisms. They may a) interfere with signal transduction from the cell 
surface and induce cellular events such as growth arrest or apoptosis, or they may b) induce 
effector functions such as antibody-dependent cellular cytotoxicity (ADCC) and complement-
dependent cytotoxicity (CDC) that kill the targeted cell (14). 

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Three anti-EGFR mAbs have received regulatory approval. Cetuximab, a chimeric mouse-human 
anti-EGFR antibody is approved alone and in combination with certain chemotherapy regimens 
for the treatment of first and later lines of therapy of advanced or metastatic Kirsten rat sarcoma 
(KRAS) viral oncogene homolog and neuroblastoma rat sarcoma (NRAS) viral oncogene 
homolog wild-type (WT) colorectal carcinoma. Cetuximab is also approved alone and in 
combination with either radiotherapy or chemotherapy for the treatment of SCCHN. 
Panitumumab is a human anti-EGFR mAb indicated as a single agent for patients with advanced 
or metastatic RAS WT colorectal cancer (CRC) refractory to prior treatment with a 
fluoropyrimidine, irinotecan, and oxaliplatin as well as in combination with FOLFOX for first 
line treatment of RAS WT advanced or metastatic CRC. Necitumumab is a recombinant human 
anti-EGFR antibody that is indicated for first line therapy of squamous cell NSCLC in 
combination with gemcitabine plus cisplatin. 
Trastuzumab is an anti-HER2 mAb indicated for the treatment of patients with HER2-
overexpressing breast cancer as well as HER2-overexpressing metastatic gastric or 
gastroesophageal junction adenocarcinoma. Trastuzumab is approved in a variety of settings 
alone and in combination with chemotherapy for patients with breast carcinoma. Pertuzumab is 
another anti-HER2 antibody that is approved in combination with trastuzumab and docetaxel for 
patients with treatment-naïve HER2-overexpressing metastatic breast cancer. It has also been 
approved in combination with trastuzumab and docetaxel for neoadjuvant treatment of patients 
with locally advanced, inflammatory, or early breast cancer based on improvement of 
pathological complete responses. Ado-trastuzumab emtansine is an antibody drug conjugate 
(ADC) composed of trastuzumab conjugated to a microtubule inhibitor. This ADC is indicated 
for patients with HER2-overexpressing metastatic breast cancer who had recurred within six 
months of having received prior therapy with a taxane and trastuzumab. Additional novel agents 
targeting HER2 are currently in development including mAbs, bispecific antibodies, and ADCs. 
There is currently no approved HER3 targeting therapeutic antibody, but a variety of anti-HER3 
antibodies are at different stages of clinical development. Based on preliminary data, most HER3 
targeting antibodies have limited activity as single agents and are therefore being investigated in 
combination with other HER targeting agents and/or with chemotherapy (6).  
3.2 
Investigational Medicinal Product 
3.2.1 
Sym013 (Pan-HER) 
The investigational medicinal product (IMP) tested in this trial is Sym013, referenced as Pan-
HER. 

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Pan-HER is a recombinant antibody mixture containing 6 humanized immunoglobulin G1 
(IgG1) mAbs, which bind specifically to non-overlapping epitopes on the EGFR (Hu1277 and 
Hu1565), HER2 (Hu4384 and Hu4517) and HER3 (Hu5038 and Hu5082).  
Pan-HER IMP is a clear to opalescent, colorless to slightly yellow liquid to be administered as an 
intravenous (IV) infusion through a peripheral line or indwelling venous access device. 
3.2.2 
Mechanism of Action 
The two antibodies against each receptor in Pan-HER bind to non-overlapping epitopes on their 
target receptor. This allows the pairs of antibodies to bind simultaneously to the receptor and 
effectively induce receptor internalization and degradation thereby inhibiting downstream 
signaling pathways that regulate growth, metabolism, proliferation, and survival. The removal of 
the receptors from the cell surface also prevents interactions between the receptors and other 
proteins, including ligands, and Pan-HER is consequently capable of effectively blocking HER 
ligand-induced proliferation in cancer cell lines (15). Unlike antibodies targeting a single 
member of the HER family, Pan-HER effectively prevents compensatory receptor up-regulation, 
which may allow tumor cells to initiate compensatory signaling and escape treatment. Pan-HER 
also mediates secondary effector functions, such as ADCC and CDC, which may contribute to 
the activity observed in vivo. 
3.2.3 
Summary of Non-clinical Findings 
Results from a number of in vitro experiments demonstrate that Pan-HER effectively inhibits 
proliferation of a range of different cancer cell lines originating from various malignant human 
tissues, including cell lines with intrinsic and acquired resistance to existing HER-targeted 
therapies, such as cetuximab, trastuzumab, or pertuzumab. The fact that not all tested cell lines 
are inhibited to the same degree demonstrates that the activity is not due to a general cytotoxic 
effect (15). 
The superior ability of Pan-HER to down-regulate EGFR, HER2, and HER3 simultaneously in 
cancer cells in vitro also translates into broad and efficacious tumor growth suppression in vivo. 
Pan-HER strongly suppressed tumor growth in seven cell-line based xenograft models of human 
cancer with varying dependency on EGFR, HER2, and HER3. In addition, Pan-HER effectively 
suppressed tumor growth in patient-derived xenograft (PDX) models of various tissue origin, 
including pancreatic, head and neck, squamous lung, ovarian, breast, and colorectal cancer. The 
majority of the models had documented resistance to targeted therapeutics and/or carried mutated 
KRAS and were considered hard-to-treat. Across all indications, Pan-HER had a measurable 

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effect in 81 of the 96 PDX models tested, and induced tumor regression in 23 models of the 96 
tested.  
Collectively, the xenograft studies have shown that there is a clear benefit of combining HER 
family target specificities as compared to single-receptor targeting. All three target specificities 
have been demonstrated to contribute to the efficacy of Pan-HER. The in vivo tumor growth 
inhibition by Pan-HER was superior or equal to that of cetuximab and/or trastuzumab in the 
models where these comparators were included.  
In vivo safety and pharmacokinetics (PK) of Pan-HER were evaluated in non-human primates. 
EGFR, HER2 and HER3 are evolutionarily conserved between cynomolgus monkeys and 
humans, and Pan-HER recognizes both the human and cynomolgus targets with similar, high 
affinity. Thus, the cynomolgus monkey is considered a pharmacologically relevant model in 
which to study toxicity and PK.  
Once-weekly IV infusion of Pan-HER at 3, 6, 12, 18, 24 and 36 mg/kg (non-GLP studies) and at 
5, 10 and 15 mg/kg (pivotal study) was evaluated in the cynomolgus monkeys.  
Following the first administration of Pan-HER in monkeys, Pan-HER showed a rapid clearance 
from serum with short half-lives (T½) ranging from 1 to 3 days over the dose levels tested. A 
trend of increasing half-life with increasing dose was observed.  
Dose-limiting toxicities (DLTs) in the form of diarrhea, dehydration and weight loss as well as 
skin sores/lesions were recorded after the second infusion of Pan-HER at 24 mg/kg and after one 
infusion at 36 mg/kg. The toxicity profile and PK profile indicate target engagement and that the 
toxicity is exaggerated pharmacology reflecting the mode of action of Pan-HER. 
In the pivotal toxicology study, once-weekly IV infusions of Pan-HER to cynomolgus monkeys 
for six weeks at dose levels of 15 mg/kg/week or below were tolerated with no adverse signs of 
toxicity. Microscopically, there were no systemic findings, but locally thrombus formation and 
intimal proliferation within the saphenous veins were observed, and an increase in the 
inflammatory response in and around the infusion sites. These findings are considered as 
secondary toxicity features related to nonclinical immunotoxicity and not a direct target mediated 
toxicity. 
Tissue cross reactivity studies showed specific positive staining with Pan-HER in the majority of 
human and cynomolgus monkey tissues examined. Specific positive staining with Pan-HER was 
observed mainly in tissues with epithelial and/or endothelial components and/or in the 
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An in vitro safety study (i.e., a human whole blood activation assay using blood from six healthy 
donors) indicated that Pan-HER has a low risk of triggering acute immune toxicity in human 
blood as no significant increase in cytokine release was observed. 
In conclusion, data from toxicology, tissue cross reactivity, PK and the in vitro safety study in 
human whole blood indicate that Pan-HER can be safely tested in human cancer patients. Based 
on the data described in the pivotal study, the No Observed Adverse Event Level (NOAEL) is 
considered to be 15 mg/kg. 
For further information, refer to the Investigator’s Brochure. 
3.2.4 
Summary of Clinical Findings 
3.2.4.1 
Protocol Sym013-01 
This is the first clinical trial to study Pan-HER.  As of Amendment 6, a total of 19 patients have 
been entered to Part 1 of this trial: 1 patient each at 1 mg/kg and 2 mg/kg weekly (Q1W), 4 
patients at 4 mg/kg Q1W, 3 patients at 6 mg/kg every second week (Q2W), 7 patients at 9 mg/kg 
Q2W, and with Amendment 5, 3 patients at the recently initiated cohort of 9 mg/kg Q2W + 
mandatory intensive prophylaxis for infusion-related reactions (IRRs) and oropharyngeal 
mucositis. Adverse events (AEs) observed at the 4 mg/kg Q1W dose activated the stopping rule 
of the single-patient dose cohort titration and resulted in transition to a 3+3 trial design. Effective 
with Amendment 3, due to Grade 1-2 oral mucositis, rash, and diarrhea at the 4 mg/kg Q1W 
dose, the dosing interval in this trial was changed from Q1W to Q2W for doses of 6 mg/kg and 
higher. Overall, the most frequently occurring, treatment-related AEs have been IRRs, oral 
mucositis, rash, and diarrhea.   
Regarding IRRs, despite required premedication with a glucocorticoid and an antihistamine, 2 of 
4 patients at 4 mg/kg Q1W experienced Grade 1-2 events, and 2 of 3 patients at 6 mg/kg Q2W 
experienced Grade 2 events.  Per protocol, the occurrence of 2 IRRs in the 6 mg/kg Q2W cohort 
resulted in prolongation of infusion from a minimum duration of 2 hours to 2.5 hours, beginning 
with the 9 mg/kg cohort.  Two (2) of the first 4 patients at 9 mg/kg Q2W experienced Grade 1-2 
IRRs, and a fifth patient experienced a Grade 3 IRR. The Grade 3 event met the protocol-
specified DLT criteria and was reported as a study drug-related serious adverse event (SAE).  
The patient was discontinued from study and the 9 mg/kg Q2W cohort was expanded.  In 
addition, the minimum duration of infusion for subsequent patients was once again extended, 
from 2.5 hours to 3 hours, and as allowed per protocol, additional premedications were 
recommended for all future patients, to include predosing with montelukast and oral 

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dexamethasone, and day-of-dosing administration of an H2 antagonist and acetaminophen. No 
IRRs were observed in the subsequent 2 of 7 total patients entered to the 9 mg/kg cohort, and one 
Grade 1 IRR has been observed in a patient entered to the 9 mg/kg Q2W + prophylaxis cohort. 
Overall, IRRs have occurred on Day 1 of treatment (7 of 16 patients total), with 2 patients at 9 
mg/kg Q2W experiencing a repeat Grade 1 to Grade 2 IRR with the 2nd and 5th dose of Pan-HER, 
respectively.       
Regarding mucositis, Grade 1-2 events were observed in 4 of 4 patients at 4 mg/kg Q1W, in 2 of 
3 patients treated at 6 mg/kg Q2W following recommended prophylaxis (1 patient also with anal 
mucositis), and in 5 of 7 patients at 9 mg/kg Q2W following recommended prophylaxis. 
Furthermore, 1 patient (who had not been premedicated) at 9 mg/kg Q2W experienced Grade 3 
oropharyngeal mucositis meeting the protocol-specified DLT criteria.  The event was also 
reported as a study drug-related SAE. Symptomatic treatment resulted in symptom resolution, 
and the patient was retreated with a reduced dose without recurrence.  Since implementation of 
mandatory prophylaxis, a single case of mucositis, Grade 2, has been observed in the 9 mg/kg 
Q2W + prophylaxis cohort. 
Regarding rash and diarrhea, Grade 1-2 acneiform/maculopapular rash has been reported in 11 
patients at doses of 2 mg/kg and above; and Grade 1-2 diarrhea has been reported in 4 patients 
(i.e. 2 patients at 4 mg/kg Q1W and 2 patients at 6 mg/kg Q2W).   
While data in this ongoing clinical trial have not been fully verified, other study drug-related 
AEs have included Grade 1-2 fatigue, epistaxis, dry skin, and flushing (each in 2 to 3 patients), 
as well as single episodes of nausea, vomiting, dyspepsia, anorexia, weight loss, blurred vision, 
dry eye, paronychia, oral candidiasis, dysgeusia, arthralgia, dysesthesia, and alopecia.  A single 
episode of Grade 3 asymptomatic lipase elevation occurred at the 2 mg/kg Q1W. Dose-escalation 
and accrual to Part 1 continues, under the conditions set forth with Amendment 5; Pan-HER is 
being delivered by 4-hour infusion, and with mandatory intensive prophylaxis to reduce the risk 
of IRRs and oropharyngeal mucositis. 
As of Amendment 5:  As described, 2 events meeting the protocol DLT criteria occurred in the 9 mg/kg 
Q2W cohort, IRR and mucositis, and while increased prophylaxis for each was recommended, it was not 
fully implemented in advance of these events.  For this reason, intensive prophylaxis for both toxicities 
was made mandatory in an effort to facilitate a more accurate evaluation of the safety and tolerability of 
Pan-HER at dose levels likely to be therapeutically active.  Per amendment, patients entered to receive 9 
mg/kg Q2W in Dose Level 5P (P=prophylaxis) and patients entered thereafter must receive intensive 
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mucositis.  Further, to reduce the risk of IRRs the infusion duration of Pan-HER was further prolonged, 
with delivery over a fixed 4-hour period (unless further prolongation is required for an individual patient 
due to the occurrence of an IRR).  Titrated rate increases during infusions and infusion duration 
reductions after C1/D1 were no longer allowed.  
As of Amendment 6: With Amendment 3, Q1W dosing was halted; with Amendment 6, Q1W dosing is 
reintroduced under the prophylaxis and infusion duration conditions outlined in Amendment 5.  All 
patients must receive intensive prophylaxis, as defined herein, on a mandatory basis to reduce the risk of 
IRRs and oropharyngeal mucositis, and must receive Pan-HER infusions over a fixed (at minimum) 4-
hour (+10 min) period, unless further prolongation is required for an individual patient due to the 
occurrence of an IRR.  Reevaluation of Q1W dosing will begin at the 6 mg/kg dose; however, lower 
doses may be explored if indicated based on tolerability.                                                                
3.2.4.2 
Other Anticipated Clinical Findings 
Dermatological toxicities, such as acneiform rash, dry skin, fissures, and paronychia are common 
AEs associated with EGFR inhibitors, in particular EGFR targeting antibodies, such as 
cetuximab and panitumumab (16). Other common side effects often associated with anti-EGFR 
mAbs are electrolyte disturbances, in particular hypomagnesemia, and IRRs. 
Cardiotoxicity in the form of left ventricular dysfunction has been observed in association with 
HER2 inhibition, in particular with trastuzumab treatment (16). The risk increases in 
combination with anthracyclines.  
Diarrhea is a common side effect of many cancer treatments, including chemotherapeutic agents 
and targeted therapeutics (16,17). EGFR-targeted TKIs are associated with high frequencies of 
clinically important diarrhea. Diarrhea is also common with several multi-agent HER2-directed 
regimens used in the treatment of HER2-positive breast cancer. HER3 targeting antibodies do 
not seem to induce much diarrhea or other severe AEs on their own, but increased frequencies of 
diarrhea have been observed in combination with EGFR targeted therapeutics such as erlotinib 
and cetuximab (18,19). Prophylaxis with agents that decrease intestinal motility, such as 
loperamide, appears to effectively reduce the incidence and severity of diarrhea caused by HER 
family targeting (17,20). 
Based on nonclinical results, the AE most likely to be seen with Pan-HER is diarrhea. 
 

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3.3 
Trial Rationale 
As outlined in the previous sections, HER family expression heterogeneity and plasticity in 
response to therapeutic intervention are important drivers of primary and acquired drug 
resistance and pose challenges to effective cancer treatment in the clinic. By targeting three 
receptors of the HER family, Pan-HER effectively inhibits a range of cancers of various tissue 
origin and genetic background, including cell lines and xenograft models with acquired 
resistance to therapeutic antibodies. Importantly, by down modulating all three targets 
simultaneously, Pan-HER prevents compensatory receptor up-regulation and renders the 
receptors unavailable for ligand binding and activation. Pan-HER represents a novel strategy to 
deal with primary and acquired resistance and thus may provide a clinically relevant effect in 
patient populations for which few therapeutic options exist. 
Pan-HER will be developed for the treatment of patients with resistant or refractory epithelial 
malignancies. Initially, the safety and efficacy of Pan-HER will be investigated in advanced 
epithelial malignancies. Future development of Pan-HER may include pancreatic, esophageal, 
gastric, CRC, NSCLC, advanced ovarian, and HER2-postive breast cancer having failed HER2 
targeted therapy.   
3.4 
Dose Rationale 
Data from toxicology, tissue cross reactivity, PK and in vitro safety study in human whole blood 
indicate that Pan-HER can be safely tested in human cancer patients.  
Based on the observed NOAEL (15 mg/kg) during the pivotal toxicology study in monkeys, a 
starting dose of Pan-HER at 1.0 mg/kg in cancer patients has been selected. A safety factor of 15 
is implemented to counterbalance a possible underestimation of the dose-toxicity relationship 
due to the immunogenicity in monkeys. 
3.5 
Overall Benefits/Risk 
As limited clinical information is available for patients treated with Pan-HER (see Section 
3.2.4.1), the benefits and the safety profile of Pan-HER have not been fully established.  
However, definite antitumor activity has been reported in many Phase 1 trials, including trials of 
HER family targeting agents. Results from preclinical studies indicate that Pan-HER may have a 
clear benefit against a number of different cancers, including those with primary or acquired 
resistance to HER family targeted therapeutics. Pan-HER has also been shown to be efficacious 
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During this trial, there will be an ongoing assessment of the risks with periodic evaluation of 
safety data. The trial will be discontinued in the event of any new finding indicating a risk that 
would render continuation of the trial unjustifiable. 
In order to mitigate potential risks, the trial is designed to detect DLTs, if any, and to define a 
maximum tolerated dose (MTD) in accordance with the dose-escalation scheme planned for the 
trial. Enrollment will be staggered by 2 weeks between the first and second patient in each new 
dose level tested where more than 1 patient is to be entered, in order to ensure safety, before 
allowing concurrent enrollment of further patients at the given dose level.  If the dose 
administered in a cohort is well tolerated, dose-escalation may proceed, and enrollment of 
subsequent cohorts may occur in order to establish a recommended phase 2 dose (RP2D).  The 
options to slow infusions, interrupt dosing, decrease the dose administered, and discontinue 
administration of Pan-HER in the event of specific AEs is outlined in this clinical trial protocol. 
In addition, steps to prevent IRRs, and measures to intervene in the event of their occurrence, are 
specified. 

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4. 
TRIAL OBJECTIVES 
4.1 
Objectives of Part 1, Dose-Escalation 
4.1.1 
Primary Objective (Part 1) 
To assess the safety and tolerability of Pan-HER when administered either Q1W or Q2W by IV 
infusion to separate dose-escalation cohorts of patients with advanced epithelial malignancies 
without available therapeutic options.                                                             
4.1.2 
Secondary Objectives (Part 1) 
1. To determine a RP2D and regimen of Pan-HER 
2. To evaluate the PK profile of Pan-HER 
3. To evaluate the immunogenicity of Pan-HER 
4. To evaluate target engagement in skin biopsy tissue (EGFR and HER3) and tumor biopsy 
tissue, if available, (EGFR, HER2 and HER3) 
5. To evaluate other potential pharmacodynamic biomarkers of Pan-HER action, and estimate, 
if feasible, the magnitude of biological activity in peripheral blood and in skin biopsy (and 
tumor biopsy, if available) tissue 
6. To make a preliminary evaluation of the antitumor effect of Pan-HER 
4.2 
Objectives of Part 2, Dose-Expansion 
4.2.1 
Primary Objective (Part 2) 
To evaluate the antitumor effect of Pan-HER when administered at the RP2D and regimen to 
patients with advanced epithelial malignancies without available therapeutic options.  
Four (4) dose-expansion cohorts will be evaluated: Cohort A (HER2+ solid tumor malignancy 
Basket Cohort*), Cohort B (pancreatic carcinoma), Cohort C (to be determined [TBD]), or 
Cohort D (TBD). 
*A Basket Cohort is designed to evaluate the potential antitumor effects of a targeted therapy by enriching for 
patients with a defined genetic alteration (e.g., mutations in or overexpression of a specific gene(s)) regardless of 
the tumor histotype of the enrolled patients’ tumors. 
4.2.2 
Secondary Objectives (Part 2) 
1. To further evaluate the safety and tolerability of Pan-HER 
2. To further evaluate the PK profile of Pan-HER 

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3. To further evaluate the immunogenicity of Pan-HER 
4. To further evaluate target engagement in skin biopsy tissue (EGFR and HER3) and tumor 
biopsy tissue (EGFR, HER2 and HER3) (tumor biopsy required) 
5. To further evaluate other potential pharmacodynamic biomarkers of Pan-HER action, and 
estimate, if feasible, the magnitude of biological activity in peripheral blood and in skin and 
tumor biopsy tissue (tumor biopsy required)

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5. 
TRIAL DESIGN 
5.1 
Overall Design and Plan 
This is an open-label, multicenter trial composed of 2 parts in which Pan-HER will be evaluated 
when administered by IV to patients with advanced epithelial malignancies without available 
therapeutic options: 
• Part 1 is a Phase 1a dose-escalation evaluating Q1W and Q2W schedules of 
administration in separate dose-escalation cohorts to determine the recommended phase 2 
dose (RP2D) and regimen of Pan-HER  
• Part 2 is a Phase 2a dose-expansion at the RP2D and regimen. Four (4) dose-expansion 
cohorts will be evaluated in this part of the trial and will be selected based upon findings 
from Part 1, additional preclinical data, and additional clinical data available at that time 
from other agents inhibiting these targets. Patients will be entered, depending upon either 
a defined molecular profile or profiles, or their underlying malignancy, to 1 of 4 
corresponding expansion cohorts: Cohort A (HER2+ solid tumor malignancy Basket 
Cohort), Cohort B (pancreatic carcinoma), Cohort C (TBD), or Cohort D (TBD). 
During Part 1, cohorts of patients will receive increasing doses of Pan-HER on either a Q1W or a 
Q2W schedule until establishment of the following for each schedule: 
• A maximum administered dose (MAD), the highest dose level administered (in mg/kg). 
• An MTD; a dose level below the MAD, which is evaluated to have a toxicity level of 
<33%. An MTD may or may not be found within the dose levels tested. Dose-escalation 
may be stopped due to toxicity observations other than DLTs and/or results from PK 
and/or target engagement analyses. 
• A RP2D; the RP2D may be equal to or lower than the MTD for the Q1W and/or Q2W 
dosing regimens.  
During Part 2, expansion cohorts of patients will receive the RP2D and regimen. The RP2D and 
regimen ultimately identified for use in this trial may be comprised of a fixed dose and schedule, 
a combination of doses to be administered on either a Q1W or Q2W schedule, or a combination 
dose and regimen.  
The RP2D and regimen will be selected based on tolerability demonstrated with Q1W and Q2W 
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lower than the MTD(s) but between doses investigated in Part 1 may be selected if data indicate 
them to be optimal.  
The Part 1 starting dose of Pan-HER will be 1 mg/kg Q1W.  The following dose levels of Pan-
HER are planned to be evaluated: 
Q1W 
• Dose Level 1:   
1 mg/kg Q1W 
• Dose Level 2:   
2 mg/kg Q1W 
• Dose Level 3:   
4 mg/kg Q1W 
• *Dose Level 4P: 
6 mg/kg Q1W + P (lower doses with prophylaxis may be explored, 
if indicated) 
• *Dose Level 5P:  
9 mg/kg Q1W + P  
• *Dose Level 6P:  
12 mg/kg Q1W + P  
• *Dose Level 7P:  
15 mg/kg Q1W + P 
• *Dose Level 8P:  
18 mg/kg Q1W + P (highest potential dose allowed per protocol) 
Q2W 
• Dose Level 4:   
6 mg/kg Q2W 
• Dose Level 5:   
9 mg/kg Q2W 
• *Dose Level 5P:  
9 mg/kg Q2W+ P   
• *Dose Level 6P:  
12 mg/kg Q2W+ P  
• *Dose Level 7P:  
15 mg/kg Q2W + P 
• *Dose Level 8P:  
18 mg/kg Q2W + P (highest potential dose allowed per protocol) 
*Mandatory intensive IRR and oropharyngeal mucositis prophylaxis; 4-hour infusion (designated “P”) 
Note: Patients entered to Dose Levels 1, 2 and 3 were treated Q1W.  As of Amendment 3, the dosing schedule in 
this trial was changed to Q2W.  Patients entered to the trial prior to implementation of this amendment could 
continue to be treated Q1W. 
Note: As of Amendment 5, patients entered to Dose Level 5P and all patients thereafter must receive intensive 
prophylaxis on a mandatory basis to reduce the risk of IRRs and oropharyngeal mucositis, and must receive Pan-
HER over a fixed (at minimum) 4-hour (+10 min) period unless further prolongation is required for an individual 
patient due to the occurrence of an IRR. For patients entered to the trial prior to Amendment 5, these changes could 
be implemented at the Investigator’s discretion based on the individual patient’s prior experience with Pan-HER 
dosing. 
Note: As of Amendment 6, Q1W dosing is reintroduced under the prophylaxis and infusion duration conditions 
outlined in Amendment 5.  All patients must receive intensive prophylaxis, as defined herein, on a mandatory basis 
to reduce the risk of IRRs and oropharyngeal mucositis, and must receive Pan-HER infusions over a fixed (at 
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occurrence of an IRR.  Reevaluation of Q1W dosing will begin at the 6 mg/kg dose; however, lower doses may be 
explored if indicated based on tolerability. 
Initially, one patient will be treated at each dose level until the occurrence of a toxicity during 
Cycle 1 that activates the stopping rule of the single-patient cohort titration design.  If such a 
toxicity has not occurred in the first 3 cohorts (i.e., cohorts of 1 mg/kg, 2 mg/kg, and 4 mg/kg 
Q1W), the next cohort to open will be a 3-patient cohort and the design will switch to the 3+3 
design. 
Further dose-escalation will follow a standard 3+3 design with a target toxicity level of < 33% as 
determined by DLTs.  
During Part 1, intermediate dose level(s) between 2 planned dose levels may be evaluated to 
further characterize safety and tolerability of Pan-HER, if indicated based on toxicity 
observations and/or results from PK and/or target engagement analyses.     
A safety monitoring committee (SMC) will be established and will include Investigator(s), 
Medical Monitor(s) and Sponsor’s medical representatives. The SMC will review clinical and 
laboratory safety data regularly throughout the trial and will select the RP2D and regimen to be 
used in Part 2 based on safety data, as well as available PK and target engagement results. 
During Part 2, the RP2D and regimen will be evaluated in 4 dose-expansion cohorts of patients 
(Cohort A, Cohort B, Cohort C, or Cohort D). A protocol amendment will be submitted 
specifying the inclusion and exclusion criteria related to each dose-expansion cohort. 
Patients enrolled to dose-expansion cohorts will be treated with IV doses of Pan-HER at the 
RP2D and regimen to investigate the antitumor activity of Pan-HER and to further evaluate 
safety and tolerability. 
The trial design is shown in Figure 1. 

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Figure 1  Overall Trial Design  
 
The number of investigational trial sites, hereafter called “trial sites”, expected to participate will 
be approximately 3 in Part 1 and 25 in Part 2. 
5.2 
Discussion of Trial Design 
5.2.1 
Rationale for Trial Design 
During Part 1 of this trial, patients will be enrolled to single-patient cohorts until occurrence of a 
toxicity that triggers switching to a standard 3+3 dose-escalation design (21). The trial is 
designed to select a safe and well-tolerated dose of Pan-HER during Part 1 and to investigate the 
selected dose in 4 groups of patients with epithelial malignancies without available therapeutic 
options during Part 2 of the trial. Four (4) dose-expansion cohorts to be evaluated in Part 2 will 
be selected based upon findings from Part 1, additional preclinical data, and additional clinical 
data from other agents inhibiting these targets available at that time. A protocol amendment will 
be submitted specifying the inclusion and exclusion criteria related to each dose-expansion 
cohort. 

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5.2.2 
Rationale for Trial Population 
In Part 1, patients with epithelial malignancies without available therapeutic options will be 
entered to evaluate the safety, tolerability and preliminary antitumor effect of Pan-HER. Results 
from preclinical studies indicate that Pan-HER is likely to be efficacious in this population. The 
patient population has been selected to optimize conditions for selecting tumor types for Part 2. 
In addition, it offers an opportunity to observe clinical benefit, if any, in patients during the 
initial escalation portion of the study.  
In Part 2, the RP2D and regimen will be investigated in patients with epithelial malignancies 
without available therapeutic options (4 cohorts; patients to be entered to Cohort A [HER2+ solid 
tumor malignancy Basket Cohort], Cohort B [pancreatic carcinoma], Cohort C [TBD], or Cohort 
D [TBD], collectively called “dose-expansion cohorts”). The selection of expansion cohorts in 
Part 2 will be based upon findings from Part 1, additional preclinical data, and additional clinical 
data from other agents inhibiting these targets available at that time. A rationale for the 4 tumor 
types selected will be provided prior to opening Part 2 of the trial. 
5.3 
Schedule of Events 
The overall trial plan is introduced in Table 1 and further defined in the following sections. 

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Table 1   Overall Trial Plan 
Screening Period 
Screening 
14 days within first dose of Pan-HER 
Treatment Period 
Treatment Allocation 
The allocated dose and schedule of Pan-HER will depend upon cohort assignment 
and will be confirmed by Sponsor or designee on the Screening and Allocation Form. 
Pan-HER 
Pan-HER will be initiated on C1/D1 and, based on cohort assignment, will be 
administered either Q1W or Q2W to separate dose-escalation cohorts of patients by 
IV infusion in cycles of treatment: 
• 
Q1W: Dosing on Day 1, 8, 15, and 22 of each 28-day cycle (±2 days) 
• 
Q2W: Dosing on Day 1and 15 of each 28-day cycle (±2 days) 
The duration of infusion will be (effective with Amendment 5): 
• 
Minimum of 4 hours (+10 min) for all infusions.  Titrated rate increases during 
infusions, and infusion duration reductions after C1/D1, will no longer be 
allowed         
For Part 1 of the trial, Pan-HER will be administered following delivery of intensive 
prophylaxis, as defined herein, on a mandatory basis to reduce the risk of IRRs and 
oropharyngeal mucositis. 
For Part 2, IRR and oropharyngeal mucositis prophylaxis is mandatory during Cycle 
1 and 2. If the patient is without evidence of IRRs or oropharyngeal mucositis after 
Cycle 2, the Investigator may choose to withdraw related medications with 
subsequent dosing. Gradual withdrawal of medications is recommended. 
Discontinuation of Pan-
HER 
Treatment will continue until unacceptable toxicity or other conditions preventing 
further treatment, PD, termination of the trial, or patient’s decision to withdraw.  
End of Treatment  
End of Treatment Visit 
 
Within 10 days after the decision to discontinue Pan-HER, an EOT Visit should be 
performed. 
Follow-up 
1-Month Follow-up 
Visit 
Follow-up continues until 1 month (30+7 days) after the last dose of Pan-HER. At 
that time, a 1M FUP Visit should be performed. This visit constitutes the end of trial 
participation for the patient. 
Part 2 ONLY: 
Continued follow-up for 
response and/or for OS 
After the 1M FUP Visit, the Investigator will make every effort to obtain follow-up 
information on response assessment and/or OS every 2 months. Response assessment 
follow-up is required in the event of an ongoing SD, PR or CR at the 1M FUP Visit, 
until PD or another therapeutic intervention is initiated. Survival follow-up is 
required until death, withdrawal of consent, or termination of the trial. The continued 
follow-up does not require an in-person visit at the trial site, but may be obtained by 
collection of data/documentation. 
Abbreviations (in alphabetical order): C1/D1, Cycle1/Day1; CR, complete response; EOT, End of Treatment Visit; IRR, infusion 
related reaction; IV, intravenous; 1M FUP, 1-Month Follow-up Visit; OS, overall survival; PD, progressive disease; PR, partial 
response; SD, stable disease 
 

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5.3.1 
Screening 
When the trial site identifies a patient suitable for screening, the Sponsor or designee should be 
contacted to ensure that a cohort is open for inclusion. Once confirmed, the patient may be 
approached for informed consent. Screening activities may begin only once written informed 
consent has been obtained. 
All patients giving informed consent to participate in the trial will receive a unique patient 
number. This number is composed of a five-digit prefix (which identifies the country and site), 
and a three-digit number, allocated sequentially starting from 001 for the first patient screened at 
the site, 002 for the second patient screened, etc. 
The trial site staff must complete a Screening and Allocation Form, stating the allocated patient 
number along with the planned dates of screening and first scheduled Pan-HER administration 
(Cycle 1/Day 1, in the following C1/D1). The planned date of C1/D1 will need to be agreed upon 
in collaboration with the Sponsor or designee for the dose-escalation cohorts in order to ensure 
adequate time between dosing of the first patient and dosing of any subsequent patients within 
each cohort. The completed Screening and Allocation Form will then be sent to the Sponsor or 
designee prior to or on the day of Screening. 
All screening activities must be performed within 14 days prior to C1/D1, unless otherwise 
specified. Individual screening assessments may be repeated prior to C1/D1, if justified and 
documented by the Investigator.  
Once eligibility has been confirmed in accordance with the inclusion and exclusion criteria 
(Sections 6.1 and 6.2, respectively), the Screening and Allocation Form will be fully completed 
and signed by the Investigator and resent to the Sponsor or designee. Sponsor or designee will 
approve each patient for start of treatment. A copy of the fully executed Screening and 
Allocation Form will be returned to the trial site for archiving. This form documents the 
allocated dose and schedule of Pan-HER. 
Furthermore, once eligibility is confirmed: 
• All patients in Part 1 and 2 will have a blood sample taken for exploratory biomarker analysis 
• All patients in Part 1 and 2 will have a skin biopsy performed 
• Patients included in Part 1 of the trial and consenting to the optional tumor biopsy procedure 
will have a tumor biopsy performed, unless it is confirmed that suitable archival tissue is 
available for central analysis. 

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• All Patients in Part 2 will have a tumor biopsy performed, unless it is confirmed that suitable 
archival tissue is available for central analysis 
5.3.2 
Screening Failures 
A patient found not eligible for the trial after giving informed consent is considered a screening-
failure. The Screening and Allocation Form must be completed and sent to the Sponsor or 
designee to confirm the outcome of the screening process. 
Re-screening of a patient will be allowed, if justified and documented by the Investigator. 
5.3.3 
Treatment 
On the day of the first scheduled Pan-HER infusion (C1/D1), and prior to the start of infusion 
(SOI), the Investigator must assess whether any changes have occurred in the clinical state of the 
patient, which would exclude the patient from the trial.  
Pan-HER will be administered by IV infusion on either a Q1W or a Q2W schedule: 
• Q1W: dosing will be every 7 (±2) days. Four (4) doses of Pan-HER administered Q1W 
constitute 1 cycle. 
• Q2W: dosing will be every 14 (±2) days. Two (2) doses of Pan-HER administered Q2W 
constitute 1 cycle.  
Patients in Part 1 will be enrolled to either Q1W or Q2W dose-escalation cohorts until 
establishment of an MAD, an MTD, and/or a RP2D for each schedule.   
During Part 2, all patients will receive the RP2D and regimen of Pan-HER. 
For all patients, the dose and schedule to be administered will be documented on the Screening 
and Allocation Form. Patients will receive the allocated dose and schedule according to their 
cohort assignment until treatment withdrawal. There will be no intra-patient dose-escalation. 
Dose-delays of Pan-HER and/or intra-patient dose-reduction(s) may be required upon occurrence 
of specific toxicities, as described in Section 7.1.4. 
Treatment will continue until unacceptable toxicity or other conditions preventing further 
treatment, progressive disease (PD), termination of the trial, or patient’s decision to withdraw. 
Disease status evaluation will be by computed tomography (CT) or magnetic resonance imaging 
(MRI) according to Response Evaluation Criteria in Solid Tumors (Version 1.1) (RECIST v1.1) 
(22). 

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5.3.4 
End of Treatment and Follow-up Visit 
An End of Treatment (EOT) Visit will be performed for all patients within 10 days from the 
decision to discontinue treatment. 
The patient will return for a 1-Month Follow-up Visit (1M FUP) 30 (+7) days after the last dose 
of Pan-HER. 
Part 2 ONLY: After the 1M FUP Visit, the Investigator will make every effort to obtain follow-
up information on response assessment and/or overall survival (OS) every 2 months. Response 
assessment follow-up is required in the event of an ongoing stable disease (SD) or objective 
response (OR, defined as partial response [PR] or complete response [CR]), as per RECIST v1.1 
at the 1M FUP Visit, until PD or another therapeutic intervention is initiated. Survival follow-up 
is required until death, withdrawal of consent, or termination of the trial. This continued follow-
up does not require an in-person visit at the trial site but may be obtained by collection of 
data/documentation. 
5.3.5 
Schedule of Assessments 
Schedule of Assessments are provided in Table 2 (Q1W dosing) and Table 3 (Q2W dosing). 
Visit windows are included. The projection of visit days within each cycle must be made from 
Day 1 of the respective cycle. Furthermore, each new cycle must be initiated as soon as possible 
after completion of the previous cycle to maintain the dosing schedule. 
All individual assessments are to be performed on or about the indicated visit day (i.e., ±2 days) 
unless otherwise stated. All efforts should be made to perform assessments as close as possible to 
the scheduled time points. 

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Table 2   Schedule of Assessments: Q1W Dosing  
Pre-Treatment Period 
Treatment Period1 
Post-Treatment Period2 
 
Screening 
Cycle 1 
Cycle 2, 4, 6 etc. 
Cycle 3, 5, 7 etc. 
EOT 
1M FUP 
Day within Cycle 
Visit Window (± days) 
D-14 to  
D-1 
D1 
D3 
D8 
(±2) 
D15 
(±2) 
D22 
(±2) 
D1 
(±2) 
D8 
(±2) 
D15 
(±2) 
D22 
(±2) 
End of 
Cycle 
D1 
(±2) 
D8 
(±2) 
D15 
(±2) 
D22 
(±2) 
≤ 10 d from the 
decision of trial 
treatment 
withdrawal 
1 month after 
last dose of trial 
treatment 
(30+7d) 
Informed Consent3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline Characteristics4/Eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
Medication/Procedure Survey 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(S)AE Survey and Reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DLT Evaluation5 
Part 1 only 
 
X 
X 
X 
X 
X 
C2 
only 
 
 
 
 
 
 
 
 
 
 
Vital Signs and Body Measurements 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
ECOG PS6 
X 
X6 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
Physical Examination6 
X 
X6 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
ECG7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
ECHO or MUGA scan8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Safety blood samples6,9 
X 
X6 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Urinalysis6,9 
X 
X6 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Complement Panel10 Part 2 only 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Assessments 
Disease Status Evaluation by CT/ MRI11,12 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X12 
X12 
Tumor Marker Evaluation, if applicable13 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
Archival Tumor Tissue14 
Part 1: Submit if available (optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional Assessments 
PK Samples15 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
ADA Sample 
 
X 
 
 
 
 
C2 
only 
 
 
 
 
X 
 
 
 
X 
X 
Skin Biopsy16 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Biopsy17 
Part 1: Optional 
Part 2: Required 
X 
 
 
 
 
 
 
 
 
 
C2 only 
 
 
 
 
 
 
Biomarker Blood Sample18 
X 
 
 
 
 
 
 
 
 
 
C2 only 
 
 
 
 
X 
 
Trial Treatment 
Pan-HER Premedication19 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
Pan-HER Infusion 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
Post-Infusion Monitoring 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
Abbreviations (in alphabetical order): ADA, anti-drug antibody; C, Cycle; CT, computed tomography; D/d, day(s); DLT, dose-limiting toxicity; EOT, End of Treatment; ECG, electrocardiogram; 
ECHO, echocardiogram; ECOG PS, Eastern Cooperative Oncology Group performance status; MRI, magnetic resonance imaging; MUGA, multi-gated acquisition; 1M FUP, 1-Month Follow-up; 
PK, pharmacokinetic; (S)AE, (serious) adverse event 

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1) 
The treatment period continues until the patient is withdrawn from Pan-HER. 
2) 
Applicable for Part 2 only: After the 1M FUP Visit, the Investigator will make every effort to obtain follow-up information on response assessment and/or OS every 2 
months. Response assessment follow-up is required in the event of an ongoing SD, PR or CR at the 1M FUP Visit, until PD or another therapeutic intervention is initiated. 
Survival follow-up is required until death, withdrawal of consent, or termination of the trial. This continued follow-up does not require an in-person visit at the trial site, but 
may be obtained by collection of data/documentation. 
3) 
Informed consent may be obtained outside the 14-day screening period prior to C1/D1, but is recommended to be obtained no earlier than 4 weeks prior to the planned C1/D1. 
4) 
Screening assessments/baseline characteristics include demographics, medical history, tumor histology, mutation status, extent of disease, prior anti-cancer treatment etc. 
5) 
DLT evaluation, Applicable for Part 1 only: DLTs are reported during Cycle 1 with final assessment 7 days after the last dose of Cycle 1 or prior to dosing on C2/D1. 
6) 
Does not need to be performed on C1/D1 if performed during screening ≤ 7 days from C1/D1. 
7) 
In addition to the scheduled timepoints, an ECG should be performed in the event of cardiac symptoms. 
8) 
In addition to the scheduled timepoints, an ECHO/MUGA should be performed in the event of cardiac symptoms. 
9) 
Local laboratory results must be available and assessed prior to each Pan-HER infusion for all infusions during Cycle 1, and for every second infusion from Cycle 2 onwards. 
Refer to Section 8.2.9 for further details 
10) Complement sampling, Applicable for Part 2 only, will be done C1/D1and in the event of an IRR. Refer to Section 8.2.10 for further details. 
11) CT or MRI imaging schedule and conditions, applying to all cohorts: 
• 
A CT/MRI performed within 28 days prior to C1/D1 can be used for evaluation of eligibility and as baseline scan, provided that the CT/MRI has been performed 
according to the clinical trial protocol requirements. 
• 
The first CT/MRI assessment for response is done at the end of Cycle 2 and thereafter repeated at the end of every second cycle (in the week prior to Day 1 of the next 
cycle). 
• 
In the event of suspected PD, a CT/MRI is to be performed as soon as possible.  
• 
In the event of CR/PR, a confirmatory CT/MRI is to be performed 28 (+7) days after the first assessment of CR/PR.   
12) A CT/MRI at EOT should only be performed if the previous CT/MRI has been performed >3 weeks before; a CT/MRI scan at 1M FUP should only be performed if no 
CT/MRI documents disease progression before or at EOT. 
13) Tumor marker evaluation to include tumor markers that are part of the trial site standard practices as indicated by tumor type, if applicable. 
14) Archival tumor tissue, applicable for patients in Part 1 only if tissue is available: To be assessed locally, preferably by immunohistochemistry (IHC). Does not need to be 
repeated if EGFR and HER2 status have been assessed previously and the pathology report is available to document findings. 
15) Extended PK sampling for PK profiling will be done starting C1/D1 and C1/D22. Refer to Table 11 for further details. 
16) Skin biopsy: All patients enrolled will undergo skin biopsies. Sample is to be obtained during screening after patient eligibility has been confirmed. Sampling is to be repeated 
Cycle 1/Day 8 (prior to dosing) and Cycle 1/Day 15 (prior to dosing).  
17) Tumor biopsy, Optional for patients in Part 1. Required for all patients in Part 2: To be assessed centrally. Tumor biopsy is to be performed after patient eligibility has 
been confirmed. Archival tissue may be accepted at screening if suitable for central analysis. Sampling is repeated at the end of Cycle 2 or upon PD, whichever occurs first. 
Refer to Section 8.7 for further details. 
18) Biomarker blood sample: To be obtained during screening after patient eligibility has been confirmed. Sampling is to be repeated at the end of Cycle 2 or upon PD, whichever 
occurs first, and at EOT. 
19) Premedication: For Part 1, premedication is mandatory prior to each dose of Pan-HER. For Part 2, premedication is mandatory prior to each dose of Pan-HER during Cycle 1. 
In Part 2, premedication may be withdrawn after Cycle 2 on a patient-by-patient basis, if the patient is without evidence of IRRs. Refer to Section 7.2.1 for details. 

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Table 3   Schedule of Assessments: Q2W Dosing 
Pre-Treatment Period 
Treatment Period1 
Post-Treatment Period2 
 
Screening 
Cycle 1 
Cycle 2, 4, 6 etc. 
Cycle 3, 5, 7 etc. 
EOT 
1M FUP 
Day within Cycle 
Visit Window (± days) 
D-14 to  
D-1 
D1 
D3 
D8 
(±2) 
D15 
(±2) 
D22 
(±2) 
D1 
(±2) 
D15 
(±2) 
End of Cycle 
D1 
(±2) 
D15 
(±2) 
≤ 10 d from the 
decision of trial 
treatment 
withdrawal 
1 month after 
last dose of trial 
treatment 
(30+7d) 
Informed Consent3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline Characteristics4/Eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
Medication/Procedure Survey 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(S)AE Survey and Reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DLT Evaluation5  Part 1 only 
 
X 
X 
X 
X 
X 
C2 only 
 
 
 
 
 
 
Vital Signs and Body Measurements 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
ECOG PS6 
X 
X6 
 
 
 
 
X 
 
 
X 
 
X 
X 
Physical Examination6 
X 
X6 
 
 
 
 
X 
 
 
X 
 
X 
X 
ECG7 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
ECHO or MUGA scan8 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Safety blood samples6,9 
X 
X6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis6,9 
X 
X6 
 
 
X 
 
X 
 
 
X 
 
X 
X 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Complement Panel10  Part 2 only 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Disease Assessments 
Disease Status Evaluation by CT/ MRI11,12 
X 
 
 
 
 
 
 
 
X 
 
 
X12 
X12 
Tumor Marker Evaluation, if applicable13 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Archival Tumor Tissue14 
Part 1: Submit if available (optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Additional Assessments 
PK Samples15 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
ADA Sample 
 
X 
 
 
 
 
C2 only 
 
 
X 
 
X 
X 
Skin Biopsy16 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
Tumor Biopsy17 
Part 1: Optional / Part 2: Required 
X 
 
 
 
 
 
 
 
C2 only 
 
 
 
 
Biomarker Blood Sample18 
X 
 
 
 
 
 
 
 
C2 only 
 
 
X 
 
Trial Treatment 
Pan-HER Premedication19 
 
X 
 
 
X 
 
X 
X 
 
X 
X 
 
 
Pan-HER Infusion 
 
X 
 
 
X 
 
X 
X 
 
X 
X 
 
 
Post-Infusion Monitoring 
 
X 
 
 
X 
 
X 
X 
 
X 
X 
 
 
Abbreviations (in alphabetical order): ADA, anti-drug antibody; C, Cycle; CT, computed tomography; D/d, day(s); DLT, dose-limiting toxicity; EOT, End of Treatment Visit; 
ECG, electrocardiogram; ECHO, echocardiogram; ECOG PS, Eastern Cooperative Oncology Group performance status; MRI, magnetic resonance imaging; MUGA, multi-gated 
acquisition; 1M FUP, 1-Month Follow-up Visit; PK, pharmacokinetic; (S)AE, (serious) adverse event 
 
 

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1) 
The treatment period continues until the patient is withdrawn from Pan-HER 
2) 
Applicable for Part 2 only: After the 1M FUP Visit, the Investigator will make every effort to obtain follow-up information on response assessment and/or OS every 2 
months. Response assessment follow-up is required in the event of an ongoing SD, PR or CR at the 1M FUP Visit, until PD or another therapeutic intervention is initiated. 
Survival follow-up is required until death, withdrawal of consent, or termination of the trial. This continued follow-up does not require an in-person visit at the trial site, but 
may be obtained by collection of data/documentation 
3) 
Informed consent may be obtained outside the 14-day screening period prior to C1/D1, but is recommended to be obtained no earlier than 4 weeks prior to the planned C1/D1 
4) 
Screening assessments/baseline characteristics include demographics, medical history, tumor histology, mutation status, extent of disease, prior anti-cancer treatment etc. 
5) 
DLT evaluation, Applicable for Part 1 only: DLTs are reported during Cycle 1 with final assessment 7 days after the last dose of Cycle 1 or prior to dosing on C2/D1 
6) 
Does not need to be performed on C1/D1 if performed during screening ≤ 7 days from C1/D1 
7) 
In addition to the scheduled timepoints, an ECG should be performed in the event of cardiac symptoms 
8) 
In addition to the scheduled timepoints, an ECHO/MUGA should be performed in the event of cardiac symptoms 
9) 
Local laboratory results must be available and assessed prior to each Pan-HER infusion for all infusions during Cycle 1, and for every second infusion from Cycle 2 onwards. 
Refer to Section 8.2.9 for further details 
10) Complement sampling, Applicable for Part 2 only, will be done C1/D1and in the event of an IRR. Refer to Section 8.2.10 for further details 
11) CT or MRI imaging schedule and conditions, applying to all cohorts: 
• 
A CT/MRI performed within 28 days prior to C1/D1 can be used for evaluation of eligibility and as baseline scan, provided that the CT/MRI has been performed 
according to the clinical trial protocol requirements 
• 
The first CT/MRI assessment for response is done at the end of Cycle 2 and thereafter repeated at the end of every second cycle (in the week prior to Day 1 of the next 
cycle) 
• 
In the event of suspected PD, a CT/MRI is to be performed as soon as possible  
• 
In the event of CR/PR, a confirmatory CT/MRI is to be performed 28 (+7) days after the first assessment of CR/PR   
12) A CT/MRI at EOT should only be performed if the previous CT/MRI has been performed >3 weeks before; a CT/MRI scan at 1M FUP should only be performed if no 
CT/MRI documents disease progression before or at EOT 
13) Tumor marker evaluation to include tumor markers that are part of the trial site standard practices as indicated by tumor type, if applicable 
14) Archival tumor tissue, applicable for patients in Part 1 only if tissue is available: To be assessed locally, preferably by immunohistochemistry (IHC). Does not need to be 
repeated if EGFR and HER2 status have been assessed previously and the pathology report is available to document findings 
15) Extended PK sampling for PK profiling will be done starting C1/D1 and C2/D1. Refer to Table 11 for further details 
16) Skin biopsy: All patients enrolled will undergo skin biopsies. Sample is to be obtained during screening after patient eligibility has been confirmed. Sampling is to be repeated 
Cycle 1/Day 8 and Cycle 1/Day 15 (prior to dosing)   
17) Tumor biopsy, Optional for patients in Part 1. Required for all patients in Part 2: To be assessed centrally. Tumor biopsy is to be performed after patient eligibility has 
been confirmed. Archival tissue may be accepted at screening if suitable for central analysis. Sampling is repeated at the end of Cycle 2 or upon PD, whichever occurs first. 
Refer to Section 8.7 for further details 
18) Biomarker blood sample: To be obtained during screening after patient eligibility has been confirmed. Sampling is to be repeated at the end of Cycle 2 or upon PD, whichever 
occurs first, and at EOT. For those timepoints where both a blood sample and a tumor biopsy are to be obtained, blood sample to be collected first. 
19) Premedication:  For Part 1, intensive prophylaxis, as defined herein, on a mandatory basis is required to reduce the risk of IRRs and oropharyngeal mucositis. For Part 2, 
prophylaxis is mandatory during Cycle 1 and Cycle 2. Thereafter, if the patient is without evidence of IRRs or mucositis, the Investigator may choose to withdraw related 
medications with subsequent dosing. Refer to Sections 7.2.1 and 7.2.2 for details 

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5.4 
Recruitment Period 
Part 1 of the trial is expected to begin Q4 2016.  
Patients will be sequentially enrolled to dose-escalation cohorts on either a Q1W or a Q2W 
schedule until establishment of a RP2D and regimen, expectedly Q1 2019.   
Enrollment to the expansion cohorts in Part 2 of the trial will commence upon approval of a 
protocol amendment defining the expansion cohorts to be further explored. Enrollment is 
expected to be from Q1 2019 to Q3 2020. 
5.5 
Number of Patients 
In total, approximately 134 patients will be included in this trial. 
It is estimated that approximately 34 patients will be enrolled to receive increasing doses of Pan-
HER during Part 1. The exact number of patients will depend upon the observed tolerability of 
Pan-HER and the potential for adding additional patients to a cohort to ensure a sufficient 
number of evaluable patients per cohort. For details, refer to Section 7.1.3.2. 
It is planned to enroll and treat approximately 100 patients during Part 2. 
For details regarding the sample size considerations, please refer to Section 10.1. 
5.6 
End of Trial 
The end of trial will be reached at the latest 1 month (30 +7 days) after the last patient has 
discontinued Pan-HER. During Part 2, patients will continue to be followed to assess duration of 
disease stabilization, response and/or overall survival. 
Once all patients have discontinued Pan-HER, or 6 months after the last patient has started 
treatment with Pan-HER, whichever occurs first, the trial objectives will be considered to have 
been met. Thereafter, patients still in treatment with Pan-HER, if any, will be given the 
opportunity to continue their treatment. However, while the Sponsor still needs to collect certain 
data to meet its regulatory obligations (AEs, SAEs, dosing of Pan-HER, reason for withdrawal, 
etc.), the Sponsor may elect to reduce the efficacy assessments and other assessments required, 
as well as scale down data collection, and/or switch patients to an extension/rollover protocol. 

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6. 
PATIENT SELECTION AND WITHDRAWAL 
Questions regarding patient eligibility must be addressed and resolved by the Investigator in 
consultation with the Sponsor or designee prior to enrollment. All referenced toxicity grading 
within this protocol will be according to the Common Terminology Criteria for Adverse Events 
(Version 4.03) (CTCAE v4.03). 
6.1 
Inclusion Criteria  
For inclusion in the trial, all of the following criteria must be fulfilled: 
1. Written informed consent given before any trial-specific procedure is initiated 
2. Male or female, at least 18 years of age at the time of informed consent 
3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 
4. Life expectancy >3 months assessed during Screening 
5. Documented (histologically- or cytologically-proven) epithelial tumor malignancy that is 
locally advanced or metastatic, having received all therapy known to confer clinical benefit   
6. If female and of childbearing potential, a negative pregnancy test 
Note: Women are considered of childbearing potential unless they have been hysterectomized, have undergone 
tubal ligation or have been postmenopausal for at least one year. 
7. Not of childbearing potential or agrees to use a medically effective method of contraception 
as per institutional standards during the trial and for 3 months after the last dose of trial drug 
Note: Women are considered of childbearing potential unless they have been hysterectomized, have undergone 
tubal ligation or have been postmenopausal for at least one year. 
8. Part 2 ONLY: 
a. Epithelial malignancy (HER2+ solid tumor malignancy Basket Cohort, pancreatic 
carcinoma, and 2 other tumor types to be specified in a protocol amendment), 
measurable according to RECIST v1.1 that has been confirmed by CT or MRI within 
4 weeks prior to C1/D1 
Note: Measurable disease is defined as 1 or more target lesions assessed by CT or MRI. A tumor lesion 
situated in a previously irradiated area is considered measurable only if subsequent disease progression 
has been documented in the lesion 
b. Willingness to undergo a pre-and post-dosing biopsy (total of 2 biopsies) from 
primary or metastatic tumor site(s) considered safe for biopsy 
Note: For patients on anticoagulant therapy at the time of biopsy, it must be deemed safe by the 
Investigator to have anticoagulant therapy held prior to the procedure 

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6.2 
Exclusion Criteria 
Patients meeting any of the following criteria will not be permitted to enter the trial: 
1. Any antineoplastic agent for the primary malignancy (standard or investigational) without 
delayed toxicity within 4 weeks or 5 plasma half-lives, whichever is shortest, prior to C1/D1 
except: 
• Nitrosoureas and mitomycin C within 6 weeks prior to C1/D1 
2. Part 2 ONLY: Radiotherapy against target lesions within 4 weeks prior to C1/D1, unless 
there is documented progression of the lesion following the radiotherapy 
Note: Radiotherapy for pain control against non-target lesions is allowed, as long as it does not influence bone 
marrow function. 
3. Immunosuppressive or systemic hormonal therapy (> 10 mg daily prednisone equivalent) 
within 2 weeks prior to C1/D1 with the exception of the following allowed therapies: 
a. Hormonal therapy (e.g., Megace) for appetite stimulation 
b. Nasal, ophthalmic, inhaled, and topical glucocorticoid preparations 
c. Hormone replacement therapy at standard doses for end-organ failure 
d. Steroid therapy as prophylaxis for contrast reactions 
e. Intra-articular steroid injections  
f. Hormonal therapy for ovarian suppression*, hormonal contraceptive therapy, post-
menopausal hormone replacement therapy (HRT)  
g. Gonadotropin-releasing hormone (GnRH) analogs in patients with prostate cancer* 
h. Low-dose maintenance steroid therapy for other conditions (excluding steroid tapers 
for brain edema/metastases/radiation) 
i. Higher dose steroid therapy for treatment of an acute intercurrent illness in patients 
with stable disease or an ongoing response.  In such situations, study drug treatment 
should be interrupted for the duration of immunosuppressive therapy 
*Patients must have been on a stable dose for at least 3 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). 
4. Use of hematopoietic growth factors within 2 weeks prior to C1/D1 
5. Active second malignancy or history of another malignancy within the last 3 years, with the 
exception of: 
a. Treated, non-melanoma skin cancers 

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b. Treated carcinoma in situ of the breast or cervix 
c. Controlled, superficial carcinoma of the urinary bladder 
d. T1a or b carcinoma of the prostate treated according to local standard of care, with 
prostate-specific antigen (PSA) within normal limits for the institution 
6. Central nervous system (CNS) malignancies including:  
a. Primary malignancies of the CNS 
b. Known, untreated CNS or leptomeningeal metastases, or spinal cord compression; 
patients with any of these not controlled by prior surgery or radiotherapy, or 
symptoms suggesting CNS metastatic involvement for which treatment is required 
Note: Patients with treated CNS metastases will be eligible if they are asymptomatic, do not require 
corticosteroids, and have confirmation of at least stable brain disease status as assessed by 2 imaging 
studies performed at least 4 weeks apart with the most recent study performed within 4 weeks prior to first 
trial drug administration. Prophylactic anticonvulsant medications are allowed.   
Patients with newly identified CNS metastases during study will be considered to have PD and will be 
discontinued from treatment. 
7. Inadequate recovery from an acute toxicity associated with any prior antineoplastic therapy 
Note: With the exception of persistent Grade 2 alopecia, peripheral neuropathy, decreased hemoglobin, and/or 
end-organ failure being adequately managed by hormone replacement therapy, patients must have recovered 
from acute toxicity by C1/D1; any Grade 1 residual toxicity may be acceptable. 
8. Major surgical procedure within 4 weeks prior to C1/D1 or inadequate recovery from any 
prior surgical procedure 
9. Non-healing wounds on any part of the body 
10. Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within 1 
month prior to C1/D1, unless adequately treated and stable 
11. Active uncontrolled bleeding or a known bleeding diathesis 
12. Significant gastrointestinal abnormalities, including but not limited to: 
a. History of inflammatory bowel disease (e.g., ulcerative colitis, Crohn’s disease) 
b. Diarrhea ≥ Grade 2 within 2 weeks prior to C1/D1 
13. Significant cardiovascular disease or condition, including: 
a. Congestive heart failure currently requiring therapy 
b. Class III or IV cardiovascular disease according to the New York Heart Association's 
(NYHA) functional criteria (23) 
c. Left ventricular ejection fraction (LVEF) ≤50% by Multi-Gated Acquisition (MUGA) 
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d. Need for antiarrhythmic medical therapy for a ventricular arrhythmia 
e. Severe conduction disturbance (e.g., 3rd degree heart block) 
f. Unstable angina pectoris (last episode within 6 months prior to C1/D1)  
g. Uncontrolled hypertension (per the Investigator's discretion) 
h. Myocardial infarction within 6 months prior to C1/D1 
14. Abnormal hematologic, renal or hepatic function as defined by the following criteria: 
a. Absolute neutrophil count (ANC) <1.5 ×109/L (1500/mm3) 
b. Hemoglobin ≤8 g/dL 
c. Platelet count <100 ×109/L (100,000/mm3)  
d. Serum creatinine >1.5 × upper limit of normal (ULN) for the institution 
e. Aspartate aminotransferase (AST) >3.5 × ULN for the institution or AST >5 × ULN 
for the institution in case of known liver metastases 
f. Alanine aminotransferase (ALT) >3.5 × ULN for the institution or ALT >5 × ULN 
for the institution in case of known liver metastases 
g. Total bilirubin >1.5 × ULN for the institution 
h. Prothrombin time (PT) as assessed by International Normalized Ratio (INR) >1.5 × 
ULN for the institution* 
i. Partial thromboplastin time (PTT) >1.5 × ULN for the institution* 
*Unless on a stable dose (per the Investigator’s discretion) of anticoagulant therapy 
for a prior thrombotic event 
15. Any of the following within 2 weeks prior to C1/D1: 
a. Any serious or uncontrolled infection 
b. Any infection requiring parenteral antibiotics 
c. Unexplained fever >38.0 °C 
16. Known or suspected hypersensitivity to any of the excipients of the Pan-HER drug product 
17. Any other life-threatening illness, significant organ system dysfunction, or clinically 
significant laboratory abnormality, which in the opinion of the Investigator, would either 
compromise the patient’s safety or interfere with the evaluation of the safety of the trial drug 
18. Any disorder that compromises the ability of the patient to give written informed consent 
and/or to comply with trial procedures or is unwilling or unable to comply with trial 
requirements at the discretion of the Investigator  

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19. Breast feeding, or plans by the patient (or the patient’s partner) to become pregnant during 
treatment or within 3 months after the EOT 
6.3 
Withdrawal from Treatment and Trial 
The visit schedule for the treatment period will apply until Pan-HER has been discontinued. 
Once this has occurred, an EOT Visit will be performed within 10 days from the decision to 
discontinue Pan-HER. 
After EOT, the patient will continue to be followed until 1 month (30 +7 days) after the last dose 
of Pan-HER, when the 1M FUP Visit must be completed. 
6.3.1 
Withdrawal from Treatment  
The patient must be withdrawn from treatment with Pan-HER in the event of any of the 
following: 
• A DLT considered by the Investigator to require treatment discontinuation (Part 1 only) (See 
Section 9.5)  
• Occurrence of an AE considered by the Investigator to require treatment discontinuation 
• Need for more than three dose-reductions of Pan-HER 
• Patients with hepatotoxicity that cannot be explained by factors not related to Pan-HER, i.e., 
Hy’s Law criteria (24) 
Note: Patients meeting all three of the following are considered to have met Hy’s Law criteria: 
• 
Hepatocellular injury, generally shown by a higher incidence of 3-fold or greater elevations above 
ULN of ALT or AST (or > 3 × baseline if elevated at study entry due to hepatic involvement by 
tumor). 
• 
Elevation of serum total bilirubin to ≥2×ULN, without findings of cholestasis (elevated serum alkaline 
phosphatase [ALP] < 2×ULN). 
• 
No other reason to explain the combination of increased aminotransferase and serum total bilirubin, 
such as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of causing 
the observed injury. 
• PD, verified by CT/MRI according to RECIST v1.1 
• Treatment failure not meeting the criteria for PD, but considered by the Investigator to 
require treatment discontinuation 
• Requirement for a significant surgical procedure  
Note: Patients requiring a minor surgical procedure (e.g., port placement, skin abscess drainage) may continue 
at the Investigator's discretion following discussion with the Sponsor or designee. A brief interruption in therapy 
may be considered. 

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• An intercurrent illness which, in the opinion of the Investigator, would prevent completion of 
trial-related evaluations 
• Use of prohibited concomitant medication, as defined in Section 7.5.2 
• Pregnancy 
• Significant deviation from the eligibility criteria may require discontinuation after discussion 
with the Sponsor 
• Noncompliance with trial procedures may require discontinuation after discussion with the 
Sponsor 
• Patient election to discontinue treatment  
• Termination of the trial by the Sponsor 
6.3.2 
Withdrawal from Trial 
The patient must be withdrawn from trial in the event of any of the following: 
• Patient election to discontinue from trial (patients may leave the trial at any time for any 
reason if they wish to do so, without any consequences) 
• The Investigator judges it necessary due to medical reasons 
The EOT and the 1M FUP visits should be performed to the extent possible and the Investigator 
should ensure any SAE is followed as described in Section 9.3. 
Part 2 ONLY: After the 1M FUP Visit, the Investigator will make every effort to obtain follow-
up information on response assessment and/or OS every 2 months. Response assessment follow-
up is required in the event of an ongoing SD, PR or CR, as per RECIST v1.1 at the 1M FUP 
Visit, until PD or another therapeutic intervention is initiated. Survival follow-up is required 
until death, withdrawal of consent, or termination of the trial. This continued follow-up does not 
require an in-person visit at the trial site, but may be obtained by collection of 
data/documentation. 
6.4 
Replacement of Patients 
6.4.1 
Part 1, Dose-Escalation Cohorts 
Patients in Part 1, who do not complete Cycle 1 as defined in Section 9.5.2, for reasons other 
than drug toxicity, will be replaced.  
Data from these patients will be included in the safety analysis, but will not contribute to the 
determination of the MTD. 

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6.4.2 
Part 2, Dose-Expansion  
It is not planned to replace any patients in Part 2.

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7. 
TREATMENT 
7.1 
Investigational Medical Product/Sym013/Pan-HER 
The IMP in this trial is Sym013/Pan-HER. 
Pan-HER IMP is a clear to opalescent, colorless to slightly yellow liquid, formulated at 12 
mg/mL to be administered as an IV infusion through a peripheral line or indwelling venous 
access device.  
The IMP is provided in clear glass vials with a nominal fill volume of 10 mL. The closure 
system for the IMP vials consists of FluroTec®-coated Bromobutyl rubber stoppers, secured with 
a flip-off seal cap. The materials used are of pharmacopeial quality and considered suitable for 
storage of sterile injectable solutions. Please refer to Table 4 for a full list of excipients. 
Table 4   Description of Investigational Medicinal Product/Sym013/Pan-HER 
Ingredients 
Quantity per mL 
Function 
Pan-HER drug substance 
12.0 mg 
Active pharmaceutical ingredient 
Acetic acid  
0.12 mg 
Buffering agent 
Sodium acetate trihydrate 
2.45 mg 
Buffering agent 
Sodium chloride 
7.01 mg 
Tonicity modifier 
Trehalose dihydrate  
22 mg 
Stabilizer 
Polysorbate 20 (Tween®20) 
0.1 mg 
Stabilizer 
Water for injection 
q.s. 1.0 mL 
Diluent 
Abbreviations (in alphabetical order): q.s., quantum sufficit (as much as suffices)  
 
7.1.1 
Packaging and Labeling of Pan-HER 
Pan-HER IMP will be provided as 10 mL clear glass vials, Type 1. 
Labeling will be in accordance with all applicable local regulatory requirements. 
7.1.2 
Handling, Storage and Preparation of Pan-HER 
All handling, storage, and preparation of IMP should take place at the trial site pharmacy. The 
Investigator is responsible for informing the pharmacy of the dose of Pan-HER to be 
administered to a given patient, taking into account the patient’s body weight.  
Pan-HER is to be stored in a refrigerator at 2-8ºC (36-46 ºF), protected from direct sunlight, and 
may not be frozen. 
Pan-HER will be diluted in saline to effect a total infusion volume of 250 mL. The infusion must 
be completed within 24 hours after preparation of the infusion bag. 

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A detailed pharmacy guide, specifying handling, storage, and preparation of Pan-HER, will be 
provided to the trial sites. 
7.1.3 
Administration of Pan-HER 
7.1.3.1 
Treatment Schedule 
All patients will be administered IV infusions of Pan-HER, dosed according to body weight, 
through a peripheral line or indwelling venous access device, and with the use of an infusion 
pump and an inline filter. Pan-HER will be administered on either a Q1W or a Q2W schedule:  
• Q1W: dosing will be every 7 (±2) days. Four (4) doses of Pan-HER administered Q1W 
constitute 1 cycle 
• Q2W: dosing will be every 14 (±2) days. Two (2) doses of Pan-HER administered Q2W 
constitute 1 cycle   
For all Pan-HER infusions, a complete dosing history will be recorded: 
• Total dose and volume administered 
• Start and stop time of infusion 
• Infusion interruption or termination, including times, and reason for such actions 
7.1.3.2 
Part 1, Dose-Escalation 
Single-Patient Cohorts and Stopping Rule 
The starting dose of Pan-HER will be 1 mg/kg Q1W. The following dose levels of Pan-HER are 
planned to be evaluated: 
Q1W 
• Dose Level 1:   
1 mg/kg Q1W 
• Dose Level 2:   
2 mg/kg Q1W 
• Dose Level 3:   
4 mg/kg Q1W 
• *Dose Level 4P:  
6 mg/kg Q1W + P (lower doses with prophylaxis may be explored, 
if indicated) 
• *Dose Level 5P:  
9 mg/kg Q1W + P 
• *Dose Level 6P:  
12 mg/kg Q1W + P 
• *Dose Level 7P:  
15 mg/kg Q1W + P 
• *Dose Level 8P:  
18 mg/kg Q1W + P (highest potential dose allowed per protocol) 
Q2W 

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• Dose Level 4:   
6 mg/kg Q2W 
• Dose Level 5:   
9 mg/kg Q2W 
• *Dose Level 5P:  
9 mg/kg Q2W + P 
• *Dose Level 6P:  
12 mg/kg Q2W + P 
• *Dose Level 7P:  
15 mg/kg Q2W + P 
• *Dose Level 8P:  
18 mg/kg Q2W + P (highest potential dose allowed per protocol) 
*Mandatory intensive IRR and oropharyngeal mucositis prophylaxis; 4-hour infusion (designated “P”) 
Note: Patients entered to Dose Levels 1, 2 and 3 treated Q1W.  As of Amendment 3, the dosing schedule in this trial 
was changed to Q2W.  Patients entered to the trial prior to implementation of this amendment could continue to be 
treated Q1W. 
Note: As of Amendment 5, patients entered to Dose Level 5P and all patients thereafter must receive intensive 
prophylaxis on a mandatory basis to reduce the risk of IRRs and oropharyngeal mucositis, and must receive Pan-
HER over a fixed (at minimum) 4-hour (+10 min) period unless further prolongation is required for an individual 
patient due to the occurrence of an IRR. For patients entered to the trial prior to Amendment 5, these changes could 
be implemented at the Investigator’s discretion based on the individual patient’s prior experience with Pan-HER 
dosing. 
As of Amendment 6: Q1W dosing is reintroduced under the prophylaxis and infusion duration conditions 
outlined in Amendment 5.  All patients must receive intensive prophylaxis, as defined herein (Section 
7.2.1 and Section 7.2.2), on a mandatory basis to reduce the risk of IRRs and oropharyngeal mucositis 
and must receive Pan-HER infusions over a fixed (at minimum) 4-hour (+10 min) period (Section 
7.1.3.4) unless further prolongation is required for an individual patient due to the occurrence of an IRR 
(Section 7.1.3.7). Reevaluation of Q1W dosing will begin at the 6 mg/kg dose; however, lower doses may 
be explored if indicated based on tolerability. 
In the initial portion of dose-escalation, patients will be sequentially enrolled to single-patient 
cohorts of increasing doses of Pan-HER. One patient will be treated at each dose level until the 
occurrence of a toxicity* during Cycle 1 that activates the stopping rule of the single-patient 
cohort titration design. The cohort will expand to 3 patients and the design switch to a classical 
3+3 dose-escalation design.  
*Grade 2 toxicity, assessed by the Investigator as possibly, probably, or related to Pan-HER with the 
exception of Grade 2 alopecia, nausea, anemia, lymphopenia, and/or eosinophilia. Toxicity grading will 
be according to the CTCAE v4.03. 
If a toxicity that activates the stopping rule of the single-patient cohort design has not occurred in 
the first 3 cohorts (i.e., 1 mg/kg, 2 mg/kg, and 4 mg/kg), the next cohort to open will be a 3-
patient cohort and the design will switch to the 3+3 design. 

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Note:  The transition from single patient cohorts to 3+3 dose-escalation design occurred beginning with Dose Level 
3 (4 mg/kg Q1W). All Dose Levels evaluated thereafter are to be comprised of a minimum of 3 patients. 
Each patient enrolled will receive Pan-HER at the allocated dose and schedule, unless dose-
reduction is necessary as specified in Section 7.1.4. There will be no intra-patient dose-
escalation. 
The SMC will review safety data and make decisions regarding the advisability of continuing 
accrual to a particular dose cohort, and dose-escalation and accrual of patients to a higher dose 
cohort.  
Classical 3+3 Dose-Escalation Design 
During the 3+3 design portion of dose-escalation, at least 3 patients will be treated per dose 
level. 
Staggered Dosing: Enrollment will be staggered between the first and second patient in each 
new dose level tested. The first patient must have completed and tolerated the first 2 doses of 
Pan-HER with Q1W dosing, or the first dose of Pan-HER with Q2W dosing, including follow-up 
until Day 15 of Cycle 1 (C1/D15) in order to allow for review of clinical and laboratory 
assessments. Thereafter patients within a cohort may be added concurrently. 
Additional Patients: There is the potential for additional patients to be enrolled in the dose-
escalation portion of the trial to ensure a sufficient number of evaluable patients per cohort by 
entering an additional patient to a cohort (e.g., increase a 1 patient cohort to 2 patients, a 3 
patient cohort to 4 patients, or a 6 patient cohort to 7 patients).  
Note: Should this action be taken, cohort tolerability assessment and subsequent dose-escalation will occur when the 
minimum number of patients required to evaluate tolerability have completed Cycle 1. However, if any additional 
patient experiences an event that would, per protocol, result in either cohort expansion or the halting of dose-
escalation, protocol rules as outlined herein will be followed. 
Escalation Rules: Escalation from a current dose level to the next will only proceed following 
evaluation of tolerability of the current dose level. Thus, dosing of the first patient at any new 
dose level will commence only after all patients to be treated at the current dose level have 
completed Cycle 1, and the current dose level has been found to be tolerable. The dose-
escalation decision points are listed below: 
• If no DLTs are encountered in any of the first 3 patients completing Cycle 1 within a dose 
level, dose-escalation may continue to the next level 
• If 1 of 3 patients within a dose level experiences a DLT, 3 more patients will be enrolled at 
the same dose level (to a total of 6 patients). If no DLTs are encountered in the 3 additional 

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patients, dose-escalation may continue to the next level when all patients have completed and 
tolerated Cycle 1 
• If ≥2 patients within a dose level (of up to 6 patients) experience a DLT, then that dose will 
be considered to have exceeded the MTD and the dose level just below this MAD will be 
considered to be the potential MTD 
• Once the potential MTD has been declared, the MTD dose level will be completed to a total 
of 6 patients, if not already accomplished. In order to confirm the MTD, ≤1 of 6 patients 
within a dose level may have experienced a DLT 
• An MTD may or may not be found within the dose levels tested. Dose-escalation may be 
stopped due toxicity observations other than DLTs and/or results from PK and/or target 
engagement analyses  
Each patient enrolled will receive Pan-HER at the allocated dose and schedule, unless dose-
reduction is necessary as specified in Section 7.1.4. There will be no intra-patient dose-
escalation. 
During Part 1, intermediate dose level(s) between 2 planned dose levels may be evaluated to 
further characterize safety and tolerability of Pan-HER, if indicated based on toxicity 
observations and/or results from PK and/or target engagement analyses.     
The SMC will review safety data and make decisions regarding the advisability of continuing 
accrual to a particular dose cohort, dose-escalation and accrual of patients to a higher dose 
cohort, and the RP2D to be used in Part 2. 
RP2D: The RP2D may include a dose or a combination of doses equal to or lower than the MTD 
for the Q1W and/ or Q2W dosing regimens.  A dose or doses between tolerated doses 
investigated in Part 1 may also be selected if data indicate this to be optimal. Furthermore, the 
RP2D and regimen ultimately identified for use in Part 2 of this trial may be a dose or a 
combination of doses to be administered on a Q1W schedule, a Q2W schedule, or a combination 
thereof. The selection will be based on tolerability demonstrated with Q1W and Q2W dosing, as 
well as available PK and target engagement results, as applicable. 
7.1.3.3 
Part 2, Dose-Expansion Cohorts 
Once the RP2D and regimen have been established during dose-escalation, enrollment into the 4 
separate dose-expansion cohorts will commence (Cohort A, Cohort B, Cohort C, or Cohort D). 
All patients enrolled will be treated with Pan-HER at the established RP2D and regimen.  

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7.1.3.4 
Duration of Infusion for Administration of Pan-HER 
Pan-HER will be administered following delivery of premedication as specified in Section 7.2.1 
and Section 7.2.2. 
Prior to Amendment 5 
As the risk of an IRR is highest for the first administration of a mAb and diminishes with 
subsequent infusions, the minimum duration of the infusion is required to be approximately 2 
hours (+10 minutes) for the first infusion of Pan-HER, approximately 1.5 hours (+10 minutes) 
for the second infusion and approximately 1 hour (+10 minutes) for all subsequent infusions. 
For the first infusion, the infusion rate will start at 1 mL/minute. The infusion rate will be 
increased at reasonable intervals throughout the 2-hour infusion period according to the trial site 
practices for IV infusion of mAbs. For subsequent infusions, the infusion rate will be adjusted in 
order to reach an infusion time of 1.5 and 1 hour respectively. 
Recommended guidelines for infusion rates are provided in Table 5, Table 6, and Table 7. 
Table 5   Infusion Rate for First Infusion of Pan-HER 
Infusion Time Interval 
Infusion Rate 
Approximate Volume 
Infused during interval 
0-30 min 
1 mL/min = 60 mL/h 
30 mL 
31-60 min 
1.5 mL/min = 90 mL/h 
45 mL 
61-90 min 
2 mL/min = 120 mL/h 
60 mL 
91- approx. 120 min 
4 mL/min = 240 mL/h 
115 mL 
 
 
Total = 250 mL 
Abbreviations (in alphabetical order): h, hour; min, minutes 
 
Table 6   Infusion Rate for Second Infusion of Pan-HER 
Infusion Time Interval 
Infusion Rate 
Approximate Volume 
Infused during interval 
0-30 min 
1 mL/min = 60 mL/h 
30 mL 
31-60 min 
2.5 mL/min = 150 mL/h 
75 mL 
61- approx. 90 min 
5 mL/min = 300 mL/h 
145 mL 
 
 
Total = 250 mL 
Abbreviations (in alphabetical order): h, hour; min, minutes 
 

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Table 7   Infusion Rate for Third and Subsequent Infusions of Pan-HER 
Infusion Time Interval 
Infusion Rate 
Approximate Volume 
Infused during interval 
0-30 min 
2.5 mL/min = 150 mL/h 
75 mL 
31- approx. 60 min 
5.8 mL/min =350 mL/h 
175 mL 
 
 
Total = 250 mL 
Abbreviations (in alphabetical order): h, hour; min, minutes 
 
The duration of Pan-HER-infusion will be prolonged by 0.5 hours (or longer, if indicated) for all 
subsequent patients entered to the trial in the following situations: 
• In the event of a Grade 2 IRR in ≥ two thirds of the patients entered to a cohort 
• In the event of a Grade 3 or greater IRR in any patient within a cohort 
These same criteria will be applied in the event IRRs occur on an extended infusion schedule.  
Amendment 5 Note:  Prolongation of Pan-HER infusions by 0.5 hours was implemented on 2 occasions: 
• 
Beginning with Dose Level 5 (9 mg/kg Q2W), and due to Grade 2 IRRs in ≥ two thirds of patients entered to 
Dose Level 4 (6 mg/kg Q2W), the minimum duration of infusion was prolonged by 0.5 hours to approximately 
2.5 hours (+10 min) for the first infusion of Pan-HER, approximately 2 hours (+10 min) for the second infusion, 
and approximately 1.5 hours (+10 min) for all subsequent infusions.   
• 
During Dose Level 5 (9 mg/kg Q2W), and due to a Grade 3 IRR in a patient entered to Dose Level 5 (9 mg/kg 
Q2W), the minimum duration of infusion was prolonged by 0.5 hours to approximately 3 hours (+10 min) for 
the first infusion of Pan-HER, approximately 2.5 hours (+10 min) for the second infusion, and approximately 2 
hours (+10 min) for all subsequent infusions. 
Effective with Amendment 5 
Beginning with Dose Level 5P (9 mg/kg Q2W with intensive prophylaxis) and all patients 
thereafter, the duration of the infusion is required to be at minimum 4 hours (+10 min) for all 
infusions of Pan-HER (unless further prolongation is required for an individual patient due to the 
occurrence of an IRR).  Titrated rate increases during infusions, and infusion duration reductions 
after C1/D1, will no longer be allowed.         
Recommendations for management of an IRR in individual patients can be found in Section 
7.1.3.7. 
7.1.3.5 
Patient Monitoring During and After Infusion of Pan-HER 
Patients will be treated on an outpatient basis. 

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Pan-HER infusions must be administered under the close supervision of an experienced 
physician in an environment where full resuscitation facilities are immediately available.  
Patients will be carefully observed for a minimum of 2 hours following completion of the first 
administration of Pan-HER and a minimum of 1 hour following completion of subsequent 
administrations. 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. 
7.1.3.6 
Infusion-Related Reactions to Pan-HER 
An IRR is defined as an AE occurring during the Pan-HER infusion and up to 2 hours after the 
end of infusion (EOI), which is assessed by the Investigator as possibly, probably, or related to 
Pan-HER. Signs of IRRs may include but are not limited to facial flushing and swelling, 
shortness of breath, headache, diaphoresis, tachycardia, hypotension, chills, rigors, chest and 
throat tightness, as well as chest, back and/or abdominal discomfort. 
7.1.3.7 
Handling of Infusion-Related Reactions to Pan-HER 
Recommended guidelines for management of IRRs are shown in Table 8. In all cases, the 
Investigator should use best clinical judgment in managing such reactions. 

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Table 8   Infusion-Related Reactions Management Guidelines 
CTCAE Grade 
Management/Treatment 
Grade 1 
Mild transient reaction; 
infusion interruption not indicated; 
intervention not indicated 
• 
Continue infusion; consider slowing to 50% of the prior rate 
• 
Monitor closely 
• 
If infusion is extended, administer subsequent infusions during 
Cycle 1 at the prolonged rate 
• 
Thereafter, if vital signs remain stable and symptoms do not 
recur, at the discretion of the Investigator an attempt may be 
made to slowly increase the rate of infusion. Final infusion 
duration should not be briefer than the initial rate attempted in 
the patient 
Grade 2 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(e.g., antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications indicated for 
≤ 24 h 
• 
Interrupt infusion for a minimum of 30 minutes 
• 
Administer symptomatic treatment (e.g., antihistamines, 
NSAIDs, etc.) and appropriate supportive care (e.g., 
bronchodilator, oxygen, etc.), as indicated 
• 
When symptoms have resolved or decreased to Grade 1, restart 
infusion at 50% of the prior rate  
• 
Monitor closely 
• 
If symptoms recur, stop the infusion, institute remedial therapy, 
monitor closely and evaluate whether the patient can continue 
the trial 
• 
Administer subsequent infusions during Cycle 1 at the 
prolonged rate 
• 
Thereafter, if vital signs remain stable and symptoms do not 
recur, at the discretion of the Investigator an attempt may be 
made to slowly increase the rate of infusion. Final infusion 
duration should not be briefer than the initial rate attempted in 
the patient 
Grade 3 
Prolonged (e.g., not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae 
• 
Discontinue the infusion 
• 
Administer symptomatic treatment (e.g., antihistamines, 
NSAIDs, glucocorticoid etc.) and appropriate supportive care 
(e.g., bronchodilator, oxygen, IV fluid etc.), as indicated 
• 
Do not resume infusion 
• 
Patient will either be discontinued from further treatment or 
receive subsequent treatments at a reduced dose (if >6 hours in 
duration) ; if treatment is continued administer subsequent 
infusions during Cycle 1 at 50% of the prior rate 
• 
Thereafter, if vital signs remain stable and symptoms do not 
recur, at the discretion of the Investigator an attempt may be 
made to slowly increase the rate of infusion. Final infusion 
duration should not be briefer than the initial rate attempted in 
the patient. 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated 
• 
Discontinue infusion 
• 
Administer necessary life-support measures, as indicated 
• 
Discontinue from further treatment 
Abbreviations (in alphabetical order): CTCAE, Common Terminology Criteria for Adverse Events v4.03; h, hours; IV, 
intravenous; ; NSAID, nonsteroidal anti-inflammatory drug 

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7.1.4 
Dose Adjustment and Delays of Pan-HER 
The dose of Pan-HER in mg/kg assigned to the individual patient, will be confirmed by the 
Sponsor or designee prior to C1/D1.  
Based on the body weight of the patient, the trial site will calculate the nominal dose of Pan-HER 
to be administered in mg.  
Weight changes (≥ ±10%) for a patient during trial should be accompanied by recalculation of 
the dose (Section 7.1.4.1). 
Furthermore, dose-delays of Pan-HER and intra-patient dose-reduction(s) may also be required 
upon occurrence of specific toxicities (Section 7.1.4.2). 
7.1.4.1 
Dose-Adjustment for Body Weight 
Pan-HER is dosed in mg/kg and the dose to be administered will be calculated based on the 
actual body weight of the patient. The dose calculated may be used for subsequent infusions, 
unless body weight changes of ≥ ±10%, in which case the dose should be adjusted according to 
the change in body weight. Recalculation for lower weight changes is allowed if required by trial 
site standard practices. 
7.1.4.2 
Dose-Delays for Pan-HER-Related or Disease-Related Toxicities 
Clinical judgment will be used when determining whether it is advisable to continue a patient on 
to the next dosing.  In order to dose a patient, the following retreatment criteria must be met. 
Evaluations must occur at minimum prior to each Cycle 1 dose and prior to D1 and D15 doses 
each cycle thereafter: 
1. ANC >1.5 ×109/L (1500/mm3) 
2. Platelet count >75 ×109/L (75,000/mm3) 
3. Any ongoing AEs should NOT meet the criteria for DLT, during the DLT-observation period 
4. Any ongoing AEs, assessed as possibly, probably, or related to Pan-HER, should have either 
ameliorated to ≤ Grade 1 severity, returned to baseline status, or resolved with the exception 
of Grade 2 clinical events that are being adequately controlled with best supportive care (e.g., 
nausea, vomiting, diarrhea, fatigue) and asymptomatic laboratory abnormalities that are 
considered clinically insignificant or that are resolving with medical therapy 
Should any one of the criteria above not be met, dosing of Pan-HER must be delayed until the 
patient meets the above criteria. All per protocol assessments must be done. 

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7.1.4.3 
Dose-Reduction for Pan-HER-Related Toxicities 
Patients experiencing any of the following toxicities, assessed as possibly, probably, or related to 
Pan-HER, will have their dose reduced in accordance with the reduction schedule outlined in 
Table 9: 
1. Grade 3 non-hematologic toxicity regardless of duration, with the exception of:  
a. Grade 3 nausea, vomiting, diarrhea, or fatigue lasting ≤2 days with best supportive 
care  
b. Grade 3 asymptomatic electrolyte abnormality that is not considered clinically 
significant by the Investigator and that is controlled with medical therapy 
2. Grade 4 non-hematologic toxicity, with the exception of: 
a. Grade 4 asymptomatic electrolyte abnormalities that is not considered clinically 
significant by the Investigator and that is controlled with medical therapy 
3. Neutropenia that is: 
a. Grade 3-4 febrile neutropenia 
b. Grade 4 and sustained (i.e., ANC <0.5 ×109/L [500/mm3], duration >5 days) 
4. Thrombocytopenia that is  
a. Grade 3 with clinically significant hemorrhage 
b. Grade 4 (platelets <25 ×109/L [25,000/mm3]) 
5. AST/ALT elevation >3×ULN (or >3× baseline if elevated at study entry due to hepatic 
involvement by tumor) with bilirubin elevation >2×ULN without evidence of cholestasis that 
cannot be explained by factors not related to Pan-HER 
6. Evidence of cardiac toxicity as defined by either: 
a. ≥16% absolute decrease in LVEF from baseline, or 
b. LVEF below the institutional lower limit of normal and ≥10% absolute decrease in 
LVEF from baseline 
Need for more than three dose-reductions of Pan-HER will lead to withdrawal from treatment. 

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Table 9   Pan-HER Dose-Reduction Schedule 
Dose Level 
First Reduction 
Second Reduction 
Third Reduction 
Dose level 1 
1.0 mg/kg 
0.5 mg/kg 
0.25 mg/kg 
0.125 mg/kg 
Dose level 2 
1 mg/kg 
0.5 mg/kg 
0.25 mg/kg 
Dose level 3 
Dose level 2 
1 mg/kg 
0.5 mg/kg 
Dose level 4 
Dose level 3  
Dose level 2 
1 mg/kg 
Continue as 
above 
Next lower tolerated 
dose 
Next lower tolerated 
dose 
Next lower tolerated 
dose 
Dose-reductions will be to the next lower tolerated dose (one level per dose-reduction step). If dose-reduction below a 
previously tested dose level is warranted, the dose will be reduced by 50% (i.e., to ½ the previous dose) in any subsequent 
stepwise reduction(s). Need for more than three dose-reductions of Pan-HER will lead to withdrawal from treatment. 
 
7.2 
Other Drugs to be Used in the Trial 
7.2.1 
Pre-Medication for Pan-HER Infusion-Related Reactions 
There is an inherent risk for IRRs with the administration of mAbs. A premedication schedule 
will therefore be implemented for all patients treated. 
For Part 1, premedication is mandatory prior to each dose of Pan-HER. 
For Part 2, premedication is mandatory prior to each dose of Pan-HER during Cycle 1 and 2. 
As of Amendment 5, all patients must be premedicated as described with standard therapies that 
include each of the following.  The recommended premedication doses are as follows: 
• Montelukast (selective leukotriene receptor antagonist) 10 mg PO daily × 7 prior to each 
Pan-HER infusion (schedule may be extended to daily throughout study at the Investigator’s 
discretion); plus approx. 0.5 hours prior to the start of Pan-HER infusion  
• Dexamethasone 10 mg PO, approx. 12 and 6 hours prior to the start of Pan-HER infusion 
• Glucocorticoid therapy equivalent to 80-100 mg IV methylprednisolone, approx. 0.5 to 2 
hours prior to the start of Pan-HER infusion 
• Antihistamine (H1 antagonist) equivalent to 25-50 mg IV diphenhydramine, approx. 0.5 
hours prior to the start of Pan-HER infusion 
• Antihistamine (H2) antagonist such as 50 mg IV ranitidine or 30 mg famotidine, approx. 0.5 
hours prior to the start of Pan-HER infusion 

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• Acetaminophen such as 1000 mg IV or PO (orally), approx. 0.5 hours prior to the start of 
Pan-HER infusion 
In Part 2, if a patient is without evidence of IRRs after Cycle 2, the Investigator may choose 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 those patients who experienced symptoms suggestive of an IRR after Cycle 1, consideration 
should be given to continuing premedication for at minimum 1 to 2 additional doses before any 
future attempt to withdraw. 
7.2.2 
Treatment of Toxicities (Other Than IRRs) 
7.2.2.1 
Mandatory Prophylactic Treatment 
Oropharyngeal Mucositis 
As of Amendment 5, for prophylaxis against Pan-HER-associated oropharyngeal mucositis, the 
following management is mandatory throughout the Pan-HER treatment period during Part 1, 
and throughout the Cycle 1 and 2 Pan-HER treatment period during Part 2: 
• Use of alcohol-free dexamethasone-containing oral solution; recommended 10 mL 
containing 0.5 mg/5 mL dexamethasone, 4× per day (swish/gargle for approximately 2 
minutes then spit)    
• Avoidance of alcohol- or peroxide-containing mouthwashes 
• In addition, patients to be provided with instructions by the site on how best to prevent 
and manage oral symptoms, including but not limited to instruction to rinse mouth 
frequently with water (may add salt or baking-soda), use saliva substitutes if needed, 
apply lip moisturizer, maintain good oral hygiene, dietary restrictions, etc.   
In Part 2, if a patient is without evidence of mucositis after Cycle 2, the Investigator may choose 
to withdraw prophylaxis 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 prophylactic therapy be done in a gradual fashion. 
Other Toxicities 
Mandatory prophylactic treatment will be implemented for all patients treated in this trial should 
an increased incidence begin to occur of other mild-to-moderate Pan-HER-related reactions that 

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are amenable to prophylaxis with standard agents. Such actions will occur following discussions 
within the SMC. 
7.2.2.2 
Therapeutic Treatment 
Oropharyngeal Mucositis 
As of Amendment 5, in the event of development of Pan-HER-associated oropharyngeal 
mucositis, appropriate standard supportive care measures are to be implemented and should 
include: 
• Application of topical or local analgesic agents such as oral benzocaine preparations 
• Protective barrier-based combination mouthwash (e.g., Magic Mouthwash or similar 
preparation) 
• Hydration, nutritional support, as needed 
• Systemic analgesia, as needed 
• Antibiotic, antifungal, antiviral support, as needed 
• Other methods of support, per institutional standards 
Cardiac Toxicity 
Recent studies administering anti-HER2 drugs have confirmed the potential for cardiac toxicity, 
specifically dilated cardiomyopathy. Patients will be scheduled for an ECHO at screening to 
exclude enrollment of patients with insufficient LVEF; alternatively, a MUGA scan of the heart 
can be performed. Follow-up cardiac evaluations will also be performed at the EOT visit. 
In the event of cardiac symptoms (e.g., shortness of breath, edemas) an electrocardiogram (ECG) 
and an ECHO or MUGA is to be performed as soon as possible to ensure clinically relevant 
cardiac AEs are detected, including but not limited to left ventricular systolic dysfunction and 
LVEF decrease. 
Gastrointestinal Toxicity 
Recent studies with anti-HER drugs have confirmed the potential for gastrointestinal toxicity, 
including diarrhea, stomatitis, nausea and vomiting. Appropriate standard supportive care 
measures are recommended for symptomatic patients. 

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Integument Toxicity 
AEs of skin and subcutaneous tissues are a hallmark of anti-EGFR drugs and, to a lesser degree, 
of anti-HER2/HER3 drugs. The toxicity studies in cynomolgus monkeys have revealed limited 
signs of skin toxicity. Therefore, it is considered appropriate to remain reactive to symptoms 
with standard supportive care measures; however, preemptive skin care measures or treatment 
(including, topical or oral antibiotics and corticosteroids) remain at the Investigator’s discretion.   
Fatigue 
Recent studies with anti-HER3 drugs have revealed the potential of chronic fatigue following 
administration. A causal treatment of chronic fatigue is unknown and therefore a treatment 
program managing the physical and emotional effects of chronic fatigue symptoms should be 
considered at the Investigator’s discretion. 
Other Potential Toxicities 
Recent studies with anti-HER drugs have revealed further potential toxicities as listed below: 
• Hepatotoxicity 
o Regular serum chemistry samples will be analyzed to address potential increase in 
liver function tests 
• Pulmonary tissue toxicity 
o It is considered appropriate to remain reactive, e.g., symptomatic patients should be 
scheduled for thoracic X-ray or thoracic CT to address potential interstitial lung 
disease or acute interstitial pneumonitis 
• Metabolic deteriorations  
o Regular blood samples will be analyzed to assess hyperglycemia, hypomagnesemia, 
and hypokalemia  
• Musculoskeletal and connective tissue disorders 
o It is considered appropriate to remain reactive, e.g., joint pain requiring supportive 
care measures 
7.3 
Blinding 
Not applicable. 

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7.4 
Drug Accountability and Compliance Check 
The Investigator is responsible for ensuring accountability for the IMP, including maintenance of 
IMP accountability records. 
IMP accountability records will include a full inventory of the IMP including: 
• Confirmation of IMP delivery to the trial site 
• Record of each dose dispensed 
• The return of unused IMP to the Sponsor or designee 
• Record of any on-site destruction of unused IMP, as agreed with the Sponsor or designee  
Records will specify dates, quantities, batch numbers, use-by dates and patient numbers, as 
applicable. 
The Investigator, or designee, should maintain records that adequately document: 
• That the patients were provided the doses specified by the protocol, and 
• That all IMP provided by the Sponsor was fully reconciled 
7.5 
Concomitant Medication/Therapy 
7.5.1 
Allowed Medication/Therapy and Procedures During the Trial 
Patients may receive their current concomitant medication and any medication considered 
necessary for the welfare of the patient during trial, except if listed in Section 7.5.2.  
Furthermore, the following are permitted during the trial: 
• Premedication with standard therapies prior to Pan-HER administration to reduce the risk of 
IRRs 
• Prophylaxis and treatment of Pan-HER-related toxicities 
• Radiotherapy for pain control against non-target lesions, as long as it does not influence bone 
marrow function 
7.5.2 
Prohibited Medication/Therapy and Procedures During the Trial 
The following medications and procedures are not allowed from C1/D1, or as specified in the 
inclusion/exclusion criteria, until the EOT Visit: 
• Anti-cancer treatment, including cytotoxic or cytostatic agents, hormonal therapy (except as 
physiologic hormone replacement) and EGFR/HER-targeting therapies 

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• Radiotherapy against target lesion(s) (Part 2 only) 
• Systemic immunosuppressive or systemic hormonal therapy (> 10 mg daily prednisone 
equivalent) with the exception of the following allowed therapies: 
o Hormonal therapy (e.g., Megace) for appetite stimulation 
o Nasal, ophthalmic, inhaled, and topical glucocorticoid preparations 
o Hormone replacement therapy at standard doses for end-organ failure 
o Steroid therapy as prophylaxis for contrast reactions 
o Intra-articular steroid injections 
o Hormonal therapy for ovarian suppression, hormonal contraceptive therapy, post-
menopausal HRT  
o GnRH analogs in patients with prostate cancer 
o Low-dose maintenance steroid therapy for other conditions (excluding steroid tapers 
for brain edema/metastases/radiation) 
o Higher dose steroid therapy for treatment of an acute intercurrent illness in patients 
with stable disease or an ongoing response.  In such situations, study drug treatment 
should be interrupted for the duration of immunosuppressive therapy 
• Prophylactic use of hematopoietic growth factors during Cycle 1 
• Use of alcohol- or peroxide-containing mouthwashes 
• Major surgery that would preclude the patient from complying with the requirements of the 
protocol 
If any one of the above listed medications/procedures becomes necessary during the trial, the 
patient must be withdrawn from Pan-HER and the EOT Visit should be performed. The 1M FUP 
Visit should then be performed, no less than 1 month (30+7 days) after the last dose of Pan-HER. 
7.6 
Medical Care of Patients after End of Trial Participation 
After completing participation in this trial, patients will be offered standard of care treatment in 
accordance with generally accepted medical practice and depending on the patient’s individual 
medical need. During Part 2, patients will continue to be followed for survival.

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8. 
TRIAL ASSESSMENTS 
All trial assessments are considered mandatory for all patients included in the trial, unless 
otherwise stated. All assessments are to be performed on or about the indicated visit day (e.g., ±2 
days) unless otherwise stated.  
8.1 
Baseline Characteristics / Eligibility Assessments 
8.1.1 
Signing of Informed Consent 
Prior to any trial-related procedure, unless such testing was performed previously as part of the 
routine clinical management of the patient. 
• Screening 
Note: Informed consent may be obtained outside the 14-day screening period prior to C1/D1, but is 
recommended to be obtained no earlier than 4 weeks prior to the planned C1/D1. 
 
8.1.2 
Demographics 
To include date of birth (or year of birth/age in regions where applicable), sex, race and 
ethnicity. 
• Screening 
8.1.3 
Medical History 
To include prior and ongoing medical illnesses and conditions and prior surgical procedures not 
related to the primary diagnosis. 
• Screening 
8.1.4 
Tumor Characteristics and Extent of Disease 
To include diagnosis and date of initial diagnosis, staging at time of initial diagnosis and at 
screening, tumor histology, mutational status, current location of metastases, and date of most 
recent disease progression. 
• Screening 
8.1.5 
Prior Cancer Treatments 
To include prior surgical procedures for the primary diagnosis, as well as prior radiotherapy, 
chemotherapy and/or biological targeted therapy, investigational treatments, and/or procedures.  
Include dates of treatments, numbers of cycles, and best response to such treatments.  

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• Screening 
• C1/D1 (prior to dosing) 
8.2 
Safety Assessments 
To be performed within 14 days of C1/D1 (first dose of Pan-HER), unless otherwise specified. 
Details on the safety assessments, including assessment timepoints, are presented in the 
following subsections. 
8.2.1 
Medication/Procedure Survey 
To include all medications taken other than Pan-HER and all procedures performed during trial. 
For medications: Include generic name or brand name, indication for use, dose and frequency, 
route of administration, start and stop dates or if ongoing at 1M FUP Visit. For procedures: 
Include date and reason for procedure. 
• Starting from date of screening 
• Until the date of the 1M FUP 
8.2.2 
Adverse Events Survey  
For details about (S)AEs and (S)AE reporting, refer to Section 9.  
• Starting from signing of informed consent for participation in the trial 
• Until the date of the 1M FUP 
Note: Patients who sign informed consent and are subsequently deemed to be screening failures will be 
followed for the occurrence of SAEs/AEs until it is determined that they will not be participating in the trial. 
8.2.3 
Dose-Limiting Toxicities Evaluation (Part 1 Only) 
For details about AEs meeting DLT criteria, refer to Section 9.5. 
• Starting from the first dose of Pan-HER (C1/D1) 
• Reported during Cycle 1 with final assessment 7 days after the last dose of Cycle 1 for Q1W 
dosing, 14 days after the last dose of Cycle 1 for Q2W dosing, or prior to dosing on Day 1 of 
Cycle 2 (C2/D1) 
8.2.4 
Vital Signs and Body Measurements 
To include temperature, heart rate, blood pressure, height (screening only), and body weight.   
• Screening 
• Prior to each dosing 

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• EOT 
• 1M FUP  
• As clinically indicated 
8.2.5 
ECOG Performance Status 
To be assessed by ECOG PS score. 
• Screening 
• Day 1 of each cycle (prior to dosing)  
Note: Does not need to be assessed prior to C1/D1, if assessed during screening ≤ 7 days from C1/D1. 
• EOT 
• 1M FUP 
• As clinically indicated 
8.2.6 
Physical Examination 
Full physical examination at Screening to include evaluation of the following: general 
appearance, skin, head, ears, eyes, nose, throat, neck/thyroid, chest, cardiovascular system, 
abdomen, musculoskeletal system, lymph nodes, neurologic status and mental status. Thereafter, 
a targeted physical examination may be performed as indicated. 
• Screening 
• Day 1 of each cycle (prior to dosing)  
Note: Does not need to be assessed prior to C1/D1, if assessed during screening ≤ 7 days from C1/D1. 
• EOT 
• 1M FUP 
• As clinically indicated 
8.2.7 
Electrocardiogram (ECG) 
To include standard 12-lead ECG. The Investigator, or qualified designee, should document the 
evaluation of the ECG, including specification of any abnormality as clinically significant or not 
clinically significant. 
• Screening 
• EOT 

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• As clinically indicated. In the event of cardiac symptoms (e.g., shortness of breath, edemas) 
an ECG should be performed as soon as possible 
8.2.8 
Echocardiogram (ECHO) or Multi-Gated Acquisition (MUGA) Scan 
Patients will be scheduled for an ECHO at screening to exclude enrollment of patients with 
evidence of insufficient cardiac function (LVEF ≤50%); alternatively, a radionuclide 
angiography, i.e., MUGA scan, of the heart may be performed.  
• Screening 
• EOT 
• As clinically indicated. In the event of cardiac symptoms (e.g., shortness of breath, edemas) 
an ECHO or MUGA is to be performed as soon as possible  
8.2.9 
Laboratory Assessments and Pregnancy Test 
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 taken at the scheduled visits and analyzed for the following parameters as 
per Table 10 and as clinically indicated. Results must be available and assessed prior to dosing 
of Pan-HER, when sampling is scheduled on days of dosing. All individual assessments are to be 
performed on or about the indicated visit day (i.e., ±2 days) unless otherwise stated. 
Table 10   Schedule of Safety Blood and Urine Samples 
Sample Analysis 
Screening 
Cycle 1 
Cycles 
Thereafter 
EOT 
1M 
FUP 
Day within Cycle 
 
D1 
D3 
D8 
D15 
D22 
D1 
D15 
 
 
Hematology Panel 
X 
X1 
X 
X 
X 
X 
X 
X 
X 
Biochemistry Panel 
X 
X1 
X 
X 
X 
X 
X 
X 
X 
Coagulation Panel 
X 
X1 
 
X 
 
X 
 
X 
X 
Urinalysis 
X 
X1 
 
X 
 
X 
 
X 
X 
Pregnancy Test 
X 
 
 
 
 
 
 
X 
 
Abbreviations (in alphabetical order): D, day; EOT, End of Treatment Visit; 1M FUP, 1-Month Follow-up Visit 
1) 
Does not need to be performed prior to C1/D1, if performed during screening ≤7 days from C1/D1 
 

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8.2.9.1 
Hematology Panel 
To include complete blood count with differential, ANC, and platelet count. 
• Screening 
• Cycle 1 
o Weekly (prior to dosing if on dosing days) 
Note: Does not need to be performed prior to C1/D1, if performed during screening ≤7 days from C1/D1. 
o Day 3 
• Each cycle thereafter 
o Day 1 and 15 (prior to dosing) 
• EOT 
• 1M FUP 
• As clinically indicated  
In the event of hematologic toxicity, the evaluation frequency should be increased to include 
additional evaluations between scheduled assessments, as clinically indicated. 
8.2.9.2 
Biochemistry Panel  
To include sodium, potassium, chloride, bicarbonate or carbon dioxide, blood urea nitrogen 
(BUN), creatinine, glucose, bilirubin [total and direct], AST, ALT, ALP, calcium, magnesium, 
phosphorus, albumin, total protein, uric acid, amylase, lipase, and creatine kinase (fasting not 
required). Clinically significant electrolyte abnormalities should be corrected prior to dosing. 
• Screening 
• Cycle 1 
o Weekly (prior to dosing if on dosing days) 
Note: Does not need to be performed prior to C1/D1, if performed during screening ≤7 days from C1/D1. 
o Day 3 
• Each cycle thereafter 
o Day 1 and 15 (prior to dosing) 
• EOT 
• 1M FUP 

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• As clinically indicated  
In the event of significant biochemistry abnormalities, the evaluation frequency should be 
increased to include additional evaluations between the scheduled assessments, as clinically 
indicated. In the event of creatine kinase abnormalities, isoenzyme analysis should be performed. 
8.2.9.3 
Coagulation Panel 
To include PT, PTT and INR 
• Screening 
• Cycle 1 
o Day 1 and Day 15 (prior to dosing) 
Note: Does not need to be performed prior to C1/D1, if performed during screening ≤7 days from C1/D1. 
• Each cycle thereafter 
o Day 1 (prior to dosing) 
• EOT 
• 1M FUP 
• As clinically indicated  
8.2.9.4 
Urinalysis 
Multi-parameter chemical test strips are acceptable and should include assessment of: Specific 
gravity, pH, protein, glucose, ketones, occult blood, leukocyte esterase, nitrite, bilirubin, and 
urobilinogen. 
• Screening 
• Cycle 1 
o Day 1 and Day 15 (prior to dosing) 
Note: Does not need to be performed prior to C1/D1, if performed during screening ≤7 days from C1/D1. 
• Each cycle thereafter 
o Day 1 (prior to dosing) 
• EOT 
• 1M FUP 
• As clinically indicated 

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8.2.9.5 
Pregnancy Test 
Serum human Chorionic Gonadotropin (β-hCG) at screening, urine β-hCG thereafter, in women 
of childbearing potential 
• Screening 
• EOT 
• As clinically indicated 
Women are considered of childbearing potential unless they have been hysterectomized, have 
undergone tubal ligation or have been postmenopausal for at least one year. 
8.2.10 
Complement Panel (Part 2 only) (Central Laboratory) 
To include total complement hemolytic activity (CH50), C3, C4, C3a, and C4a 
• Cycle 1 (timepoints coincide with PK sampling) 
o Day 1 
▪ Prior to SOI (- 4h) 
▪ 4 hours after EOI (±30 min) 
• In the event of an IRR 
Note: A detailed laboratory manual specifying sample collection, handling, storage, and shipment will be provided 
to the trial sites. 
8.3 
Disease Assessments 
8.3.1 
Disease Status Evaluation by CT or MRI 
The anti-tumor activity of Pan-HER will be assessed by the Investigator, or qualified designee, 
according to RECIST v1.1. Refer to Appendix 1. 
Patients will undergo imaging by CT or MRI of neck, chest, abdomen and pelvis as indicated 
based on tumor type and clinical judgment in order to follow the underlying malignancy. The use 
of CT or MRI must be consistent per patient throughout the trial.  Use of contrast is preferred but 
is at the discretion of the Investigator, as medically indicated.  
• Screening 
Note: A CT/MRI performed within 28 days prior to Day 1 may be used for evaluation of eligibility and as 
baseline scan, provided that the CT/MRI has been performed according to the protocol requirements. 

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• End of Cycle 2 and end of every second cycle thereafter, i.e., Cycle 4, 6, 8 etc. 
Note: End of cycle assessments may be conducted at any time during the week prior to Day 1 of the next cycle. 
• Suspected PD (as soon as possible) 
• Confirmation of response, to be performed 28 (+7) days after the first assessment of CR/PR   
• EOT (if >3 weeks since previous CT/MRI)  
• At 1M FUP (if PD was not documented before or at EOT) 
If PD is documented at any time, no further disease assessments will be required. Patients with 
documented PD will be discontinued from Pan-HER so that alternative management of their 
malignancy may be considered. 
To be assigned a status of confirmed PR or CR, changes in disease status must be confirmed by 
repeat imaging studies performed no less than 28 days (4 weeks) after the criteria for response 
are first met.  In the case of SD, follow-up measurements must have met the SD criteria at least 
once after trial entry at a minimal interval in general no less than 6-8 weeks from first dose of 
Pan-HER. 
Imaging data (imaging studies and derived assessments) will be stored by the trial sites and 
will be available upon request for potential review by the Sponsor or an independent radiology 
reviewer. For Part 2 only: In addition, imaging studies will be sent to an imaging facility for 
storage to ensure central availability and readiness for read at a future time upon Sponsor or 
Health Authority (HA) request. 
For all imaging time points, the following will be recorded as per RECIST v1.1: Target lesions 
including size, location, and type (nodal/non-nodal); sum of diameters of target lesions; any new 
lesions noted during trial, including size, location, and type (nodal/non-nodal); final response 
assessment at each visit (PD, SD, PR, CR or Not Evaluable [NE]). 
8.3.2 
Tumor Marker Evaluation (as per standard practice of a trial site) 
To include tumor markers that are part of the trial site standard practices, as indicated by tumor 
type. 
It is recommended that tumor markers are evaluated at timepoints coinciding with the CT/MRI 
imaging studies as listed in Section 8.3.1. 

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8.3.3 
Archival Tumor Tissue for EGFR, HER2 Assessment (Part 1 only) 
To be assessed locally, preferably by immunohistochemistry (IHC) for EGFR and HER2 
expression level, if tissue is available. Only applicable to patients included in Part 1. Does not 
need to be repeated if previously assessed and the pathology report is available to document 
findings. 
• Screening 
8.4 
Pharmacokinetic Assessments (Central Laboratory) 
PK samples will be taken according to the schedules shown in Table 11 and Table 12 and 
analyzed centrally. Actual time will be recorded for all samples taken. 
Note:  Comprehensive collection of clinical samples is critical to the conduct of this study.  In situations where 
collection of the EOI + 8h samples is logistically difficult due to clinic staff availability, the observation period may 
be shortened and an "end of day" sample may be obtained at the latest practical time.  Such an option (if to be 
routinely employed) is available only after previous discussion with and approval by the Sponsor. 
Table 11   Schedule of Pharmacokinetic (PK) Assessments: Q1W Dosing 
 
Cycle 1 
Cycle 2 Onward 
EOT 
1M 
FUP 
Sampling Time 
Window 
D1-
D3 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
 
 
Prior to SOI 
- 4 h 
X 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
 
 
EOI 
+ 10 min 
X 
X1 
X1 
X 
X1 
X1 
X1 
X1 
 
 
EOI + 2 h 
±30 min 
X 
 
 
X 
 
 
 
 
 
 
EOI + 4 h 
±30 min 
X 
 
 
X 
 
 
 
 
 
 
EOI + 8 h2 
±90 min 
X 
 
 
X 
 
 
 
 
 
 
EOI + 24 h 
 
±6 h 
X 
 
 
X 
 
 
 
 
 
 
EOI + 48 h 
-12 h to + 24 h 
X 
 
 
X 
 
 
 
 
 
 
During Visit 
NA 
 
 
 
 
 
 
 
 
X 
X 
Abbreviations (in alphabetical order): D, day; EOI, End of Infusion, EOT, End of Treatment Visit; NA, Not Applicable; h, hour; min, minutes; 
1M FUP, 1-Month Follow-up Visit; SOI, Start of Infusion 
1) 
If Pan-HER dosing is delayed, only one PK sample should be taken during the visit. 
2) 
Effective with Amendment 6, sampling at this timepoint is optional. 
 

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Table 12   Schedule of Pharmacokinetic (PK) Assessments: Q2W Dosing 
 
Cycle 1 
Cycle 2 
Cycle 3 
Onward 
EOT 
1M 
FUP 
Sampling Time 
Window 
D1-
D3 
D8 
D15 
D22 
D1- 
D3 
D15 
D1 
D15 
 
 
Prior to SOI 
- 4 h 
X 
 
X1 
 
X 
X1 
X1 
X1 
 
 
EOI 
+ 10 min 
X 
 
X1 
 
X 
X1 
X1 
X1 
 
 
EOI + 2 h 
±30 min 
X 
 
 
 
X 
 
 
 
 
 
EOI + 4 h 
±30 min 
X 
 
 
 
X 
 
 
 
 
 
EOI + 8 h2 
±90 min 
X 
 
 
 
X 
 
 
 
 
 
EOI + 24 h 
 
±6 h 
X 
 
 
 
X 
 
 
 
 
 
EOI + 48 h 
-12 h to + 24 h 
X 
 
 
 
X 
 
 
 
 
 
During Visit 
NA 
 
X 
 
X 
 
 
 
 
X 
X 
Abbreviations (in alphabetical order): D, day; EOI, End of Infusion, EOT, End of Treatment Visit; NA, Not Applicable; h, hour; min, minutes; 
1M FUP, 1-Month Follow-up Visit; SOI, Start of Infusion 
1) 
If Pan-HER dosing is delayed, only one PK sample should be taken during the visit. 
2) 
Effective with Amendment 6, sampling at this timepoint is optional. 
 
A detailed laboratory manual specifying sample collection, handling, storage, and shipment will 
be provided to the trial sites. 
Serum concentrations of each of the 6 mAbs that comprise Pan-HER will support the PK 
endpoints of the trial.  The serum concentrations may also be used in an exploratory population 
PK analysis which will be reported separately from the clinical trial report. 
In the event that a collected serum sample is inadequate or insufficient for PK analysis, the 
analysis of PK may be performed using an anti-drug antibody (ADA) serum sample from the 
same time point, if available. 
8.5 
Anti-Drug Antibody Testing (Central Laboratory) 
To assess formation of ADA. All samples must be taken prior to the Pan-HER infusion of that 
visit. Analysis of ADA and residual serum levels of Pan-HER will be performed at a central 
laboratory. A detailed laboratory manual specifying sample collection, handling, storage, and 
shipment will be provided to the trial sites. In the event that a collected serum sample is 
inadequate or insufficient for ADA analysis, the analysis of ADA can be done using a PK serum 
sample from the same time point, if available. 
• C1/D1 

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• C2/D1 
• Prior to every second cycle thereafter, i.e., Cycle 3, 5, 7 etc.  
• EOT 
• 1M FUP 
8.6 
Skin Biopsy (Central Laboratory) 
To be performed only after eligibility has been confirmed.  
All patients enrolled will undergo 3 skin biopsies for evaluation of target engagement (EGFR 
and HER3). Analysis of skin biopsy samples will be performed at a central laboratory. Biopsy 
specimens will be obtained using standard techniques and formalin-fixed, paraffin-embedded 
according to standard laboratory practice. A detailed laboratory manual specifying sample 
collection, handling, storage, and shipment will be provided to trial sites.  
Skin biopsies are requested from a rash-free area. 
• Screening, after confirmation of eligibility 
• C1/D8 (prior to dosing if on dosing day)  
• 
C1/D15 (prior to dosing) 
8.7 
Tumor Biopsy (Central Laboratory) 
Part 1: Optional (requires separate informed consent) and only applicable for patients where a 
tumor lesion is considered safe for biopsy. To be performed after eligibility has been confirmed.  
Part 2: Required. Patients must have tumor lesion considered safe for biopsy. To be performed 
after eligibility has been confirmed. 
• Screening, after confirmation of eligibility  
Note: Archival tissue may be accepted, if suitable for central analysis as specified in the laboratory manual. 
It must be ensured that the archived biopsy can be made available to the central laboratory prior to deciding 
to omit the tumor biopsy procedure at time of screening. 
• End of Cycle 2 (prior to dosing Cycle 3) or upon PD, whichever occurs first 
Note: End of cycle assessments may be conducted at any time during the week prior to Day 1 of the next 
cycle. If feasible, it is preferred that the second biopsy is taken from the same tumor site from which the 
first biopsy was taken. 
To include a tumor biopsy performed by a core biopsy of a locally recurrent or metastatic lesion. 
The procedure at time of screening will take place after eligibility has been confirmed and prior 

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to first Pan-HER administration. The tumor biopsy must 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 formalin-fixed, 
paraffin-embedded according to standard laboratory practice. All tumor tissue samples should be 
reviewed by a pathologist to confirm the presence of tumor cells before the tissue sample (block 
or slides) is sent to the central laboratory for analysis. A detailed laboratory manual specifying 
sample collection, handling, storage, and shipment will be provided to the trial sites. 
Analysis of tumor biopsies will include target engagement (EGFR, HER2 and HER3) and may 
furthermore include proteins and genes that are unknown or have not been included in the 
scientific hypotheses at the present time of trial, but that, during the collection of data from this 
trial, may evolve as new candidate genes and markers related to Pan-HER safety, efficacy, or 
mechanism of action.  
All analyses will be related to and used in connection with the data collected in the present trial 
and Pan-HER program, and the identity of the patient will remain confidential. The analyses will 
not have any medical consequences for the patient. 
Tumor biopsy samples will be stored for up to 15 years after completion of the trial, where after 
all samples will be destroyed.  
8.8 
Biomarker Blood Sample (Central Laboratory) 
To be performed only after eligibility has been confirmed. 
Peripheral blood samples are taken for subsequent biomarker analysis. Analysis of all samples 
will be performed at a central laboratory. A detailed laboratory manual specifying sample 
collection, handling, storage, and shipment will be provided to the trial sites.  
• Screening, after confirmation of eligibility 
• End of Cycle 2 (prior to dosing Cycle 3) or upon PD, whichever occurs first 
Note: End of cycle assessments may be conducted at any time during the week prior to Day 1 of the next 
cycle. For those timepoints where both a blood sample and a tumor biopsy are to be obtained, blood sample 
to be collected first. 
• EOT 

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The purpose of the pharmacodynamic biomarker analysis is to develop an approach for the 
identification and validation of genes or proteins that may predict which patients are likely to 
respond to Pan-HER, and that may change with the possible development of acquired resistance 
to Pan-HER. Potential biomarkers of interest include genes, gene transcripts, and proteins of the 
HER family receptors and molecules of the mitogen-activated protein kinase (MAPK) and 
phosphoinositide 3-kinase (PI3K) pathways involved in HER signaling. 
Analysis of biomarker samples may include genes and/or proteins 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 evolve as new candidate genes and markers related to Pan-HER 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 identity of the patient will remain confidential. The analyses will not have any 
medical consequences for the patient. 
Biomarker samples will be stored for up to 15 years after completion of the trial where after all 
samples will be destroyed. 
8.9 
Handling of Biological Samples  
All biological samples to be analyzed locally will be collected and handled according to 
institutional practices. 
All biological samples to be analyzed centrally will be collected and handled according to a 
detailed laboratory manual. 
Retention time for biologic specimens will be specified in the laboratory manual. 
8.10 Follow-up Assessments 
Assessments at the 1M FUP Visit include disease status and subsequent cancer therapy. 
Part 2 ONLY: After the 1M FUP Visit, the Investigator will make every effort to obtain follow-
up information on response assessment and/or OS every 2 months. Response assessment follow-
up is required in the event of an ongoing SD, PR or CR, as per RECIST v1.1 at the 1M FUP 
Visit, until PD or another therapeutic intervention is initiated. Survival follow-up is required 
until death, withdrawal of consent, or termination of the trial. This continued follow-up does not 
require an in-person visit at the trial site, but may be obtained by collection of 
data/documentation. 

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8.11 Appropriateness of Measurements 
Standardized methods for assessments of efficacy and safety variables will be used. 

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9. 
ADVERSE EVENTS 
9.1 
Definitions of Adverse Events 
9.1.1 
Adverse Event 
An AE is any untoward medical occurrence in a patient or a clinical investigation subject 
administered a pharmaceutical product, and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an IMP, whether or not considered related to the IMP.  
Causality for the above-mentioned AE will be assessed appropriately as: Not Related to IMP, 
Unlikely Related to IMP, Possibly Related to IMP, Probably Related to IMP, or Related to IMP. 
In addition, any AE, regardless of causality, that also meets the seriousness criteria, will be 
reported on an SAE form. 
9.1.2 
Events Not to be Considered as Adverse Events 
A pre-existing condition (i.e., a disorder that is present before the AE recording period starts and 
is noted on the medical history/physical examination form) should not be recorded as an AE 
unless the condition worsens, or episodes increase in frequency during the AE recording period. 
Refer to Section 9.2.1. 
PD will not be captured as an AE 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 AE in the case of patient death, with death being the outcome of the event. 
An abnormal laboratory value or an abnormality in physiological testing (such as ECGs) per se 
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 Pan-HER (dose-reduction and/or withdrawal) 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
recorded as AEs. A medical condition for which an unscheduled procedure was performed, 
should however be recorded if it meets the definition of an AE. For example, an acute 
appendicitis should be recorded as the AE and not the appendectomy. 

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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. 
9.1.3 
Adverse Events of Medical Interest 
Not applicable. 
9.1.4 
Serious Adverse Events 
An SAE is an AE that meets one or more of the following regulatory outcomes criteria: 
• Results in death 
Note: 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 event (SAE), unless the cause of the 
death is unknown (e.g., in case of unexplained or sudden death).  
• Is life-threatening 
Note: The term "life-threatening" in this definition refers to an event in which the patient is at immediate 
risk of death at the time of the event; it does not refer to an event which hypothetically might cause death if 
it was more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is medically important  
Note: Medical and scientific judgment must be exercised in deciding whether an AE is believed to be 
“medically important”. Medically important events may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above. 
9.1.5 
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 is considered 
serious.  

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Hospitalization for observation or convenience following the Pan-HER infusions without an 
SAE occurring should not be recorded as an SAE, e.g., if a patient is hospitalized merely for 
observation, or if a patient finalizes the infusion at a time of day requiring a convenience 
overnight stay in the hospital.  
If procedures to support the treatment regimens require hospitalization, they should not be 
recorded as SAEs. However, in cases where a procedure results in complications 
requiring/prolonging hospitalization this must be recorded and reported as an SAE. 
9.2 
Adverse Event Recording and Reporting Instructions 
9.2.1 
Adverse Event Recording Period 
All AEs will be recorded from signing of informed consent for participation in the trial. The 
recording period ends at the time of the 1M FUP Visit.  
Note: Patients who sign informed consent and are subsequently deemed to be screening failures will be followed for 
the occurrence of SAEs/AEs until it is determined that they will not be participating in the trial. 
The Investigator must record all directly observed AEs and all AEs spontaneously reported by 
the patient. A general, open-ended type of question should be used to elicit a response from the 
patient, such as, “How have you been feeling?” or “Have you had any health problems since 
your last visit?”. 
All AEs that occur in patients during the AE recording period must be recorded/entered on the 
AE section of the Case Report Form (CRF), whether or not the event is assessed as related to 
Pan-HER. If the AE is serious, the SAE report forms must also be completed and submitted (see 
Section 9.3). 
9.2.2 
Diagnosis 
A diagnosis should be recorded if possible. If no diagnosis is available, signs and symptoms 
should be recorded instead. 
9.2.3 
Intensity 
All referenced toxicity grading within this protocol will be according to the CTCAE v4.03. If the 
severity of an AE is not specifically graded by the CTCAE guidance document, the Investigator 
should use the general definitions of Grades 1 to 5 as per the following, and use his/her best 
medical judgment to describe the severity of the AE: 
• Grade 1: Mild 

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• Grade 2: Moderate 
• Grade 3: Severe 
• Grade 4: Life-threatening or disabling 
• Grade 5: Death caused by the event 
Changes in severity of AEs will be recorded. 
Generally, an AE of Grade 4 or 5 qualifies for SAE reporting to the Sponsor or designee; 
however, the definition of Grade 4 does not necessarily always meet the regulatory definition of 
“life-threatening”.  As an example, a laboratory abnormality of Grade 4 does not need to be 
reported as an SAE, unless it meets one of the seriousness criteria in Section 9.1.4.  
9.2.4 
Relationship to Investigational Medicinal Product/Pan-HER 
The Investigator must assess causal relationship to the IMP, Pan-HER. Relatedness has to be 
assessed and recorded within the initial report (CRF and SAE report form). 
The causal relationship is an assessment of whether or not the event is related to the use of the 
IMP. It is not an evaluation of whether or not the event could hypothetically occur in the 
investigational patient population. 
The causal relationship of an AE to the IMP, Pan-HER, will be rated as follows: 
Not Related: The AE is not related to the IMP, which means the event: 
• Does not follow a reasonable temporal sequence from drug administration  
• Is readily explained by the patient’s clinical state or by other modes of therapy 
administered to the patient 
• The AE is clearly NOT related to the IMP 
Unlikely Related: The AE is considered not related to the IMP based on the following: 
• Does not follow a reasonable temporal sequence from administration of drug 
• Could readily be a result of the patient’s clinical state, environmental, or toxic factors, or 
other modes of therapy 
• Does not follow a known response pattern to the suspected drug 
• Does not reappear or worsen when the drug is re-administered 

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Possibly Related: The AE might not be related, but possibility cannot be ruled out with certainty 
and therefore would be considered related based on: 
• Follows a reasonable temporal sequence from administration of drug 
• Could readily have been a result of the patient’s clinical state, environmental or toxic 
factors, or other modes of therapy 
• Follows a known response pattern to the suspected drug 
Probably Related: It has been determined with a high degree of certainty that the AE is 
associated with administration of IMP based on: 
• Follows a reasonable, temporal sequence 
• Cannot be reasonably explained by known characteristics of the patient’s clinical state, 
environmental, or toxic factors, or other modes of administered therapy 
• The AE disappears or decreases in severity upon cessation of drug, or reduction in dose. 
• Follows a known response pattern to the suspected drug 
Related: The AE is related to the IMP, which means the event: 
• Follows a reasonable temporal sequence from drug administration  
• Abates upon discontinuation of the IMP (de-challenge)  
• Is confirmed by reappearance of the reaction on repeat exposure (re-challenge)  
• Cannot be reasonably explained by the known characteristics of the patient’s clinical state  
• Is not likely to have been produced by the patient’s clinical state or by other modes of 
therapy administered to the patient 
9.2.5 
Outcome 
Outcome of the AE must be assessed by the Investigator utilizing one of the following terms: 
• Recovered 
• Recovered with sequelae (if recovered with sequelae, specify sequelae) 
• Not recovered 
• Fatal 
• Unknown 
Instructions for reporting changes in an ongoing AE during a patient's participation in the trial 
are provided in the instructions that accompany the AE CRF pages. 

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9.2.6 
Follow-up of Adverse Events 
All AEs should be followed until resolution or until the 1M FUP Visit, whichever comes first. 
Note: Patients who sign informed consent and are subsequently deemed to be screening failures will be followed for 
the occurrence of SAEs/AEs until it is determined that they will not be participating in the trial. 
9.3 
Serious Adverse Event Recording and Reporting 
9.3.1 
Timeframes for Reporting to the Sponsor 
All SAEs occurring at any time from signing of informed consent for participation in the trial 
and until 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 screening 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 first awareness of the event, report 
the SAE to the Sponsor or designee by fax 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. 
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 has been resolved or until the Investigator 
assesses it as chronic or stable. The Sponsor or designee will pursue sufficient information and 
will return to the trial sites for such information as deemed required. 
If the Investigator becomes aware of an SAE that occurred after the 1M FUP Visit and finds it to 
be related to the IMP (possibly-, probably-, or related to Pan-HER) or trial conduct, it must be 
recorded and reported to the Sponsor or designee as an SAE. These SAEs considered related to 
the IMP and occurring after the 1M FUP Visit will not be reported in the CRF but only on an 
SAE Report Form instead for recording in the safety database. 
The Investigator should be aware of local reporting regulations to the Institutional Review Board 
(IRB)/Ethics Committee (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. 

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9.4 
Safety Reporting to Health Authorities, Institutional Review Boards/Ethics 
Committees, 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 HAs and central 
IRBs/ECs, as well as participating investigators. Reporting of SUSARs to local IRBs/ECs will be 
handled by the Investigator.  
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.  
Additionally, the annual Development Safety Update Report (DSUR) will be submitted by the 
Sponsor or designee to all appropriate HAs and central IRBs/ECs as per ICH Guidelines. 
Submission of the DSUR to local IRBs/ECs will be handled as per local regulations and/or 
requests. 
9.5 
Dose-Limiting Toxicities (Part 1 Only) 
9.5.1 
Definition of Dose-Limiting Toxicities 
A DLT is defined as any of the following toxicities that occur during the DLT-observation 
period, if considered related (causality rating of possibly, probably, or related) to Pan-HER:   
1. Grade 3 non-hematologic toxicity regardless of duration, with the exception of:  
a. Grade 3 nausea, vomiting, diarrhea, or fatigue lasting ≤2 days with best 
supportive care  
b. Grade 3 asymptomatic electrolyte abnormality that is not considered clinically 
significant by the Investigator and that is controlled with medical therapy 
2. Grade 4 non-hematologic toxicity, with the exception of: 
a. Grade 4 asymptomatic electrolyte abnormalities that is not considered clinically 
significant by the Investigator and that is controlled with medical therapy 
3. Neutropenia that is: 
a. Grade 3-4 febrile neutropenia 
b. Grade 4 and sustained (i.e., ANC <0.5 ×109/L [500/mm3], duration >5 days) 
4. Thrombocytopenia that is  
a. Grade 3 with clinically significant hemorrhage 

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b. Grade 4 (platelets <25 ×109/L [25,000/mm3]) 
5. AST/ALT elevation >3×ULN with bilirubin elevation >2×ULN without evidence of 
cholestasis that cannot be explained by factors not related to Pan-HER 
6. Evidence of cardiac toxicity as defined by either: 
a. ≥16% absolute decrease in LVEF from baseline, or 
b. LVEF below the institutional lower limit of normal and ≥10% absolute decrease 
in LVEF from baseline 
7. Inability to complete Cycle 1 at the assigned dose due to ≥ Grade 3 toxicity 
8. Treatment delays >2 weeks from the scheduled next dose due to ≥ Grade 3 toxicity 
9.5.2 
Observation Period for Dose-Limiting Toxicities 
The decision to dose-escalate will be based on close monitoring of safety during the observation 
period for DLTs, defined as the initial 28-day period (±2 days) from first treatment of Pan-HER 
(i.e., Cycle 1) and including 7 days of follow-up (Q1W dosing) or 14 days of follow-up (Q2W 
dosing) from the last dose of Cycle 1. 
A minimum of 4 Pan-HER infusions (Q1W dosing) or 2 Pan-HER infusions (Q2W dosing) must 
have been administered at the assigned dose for a patient to have completed the DLT-observation 
period. 
9.5.3 
Reporting of Dose-Limiting Toxicities 
All presumed DLTs must be reported to the Sponsor or designee within 24 hours after the 
Investigator or designee have become aware of the event. In addition, DLTs fulfilling the SAE 
criteria must be reported according to the procedure for SAEs, as outlined in Section 9.3. 
9.6 
Reporting of Infusion-Related Reactions 
The definition of an IRR is included in Section 7.1.3.6. 
All IRRs must be reported in the CRF as an AE with the term “Infusion-related Reaction” 
followed by a specification of symptoms (e.g., “Infusion-related Reaction with dyspnea and 
flushing”).  
To facilitate ongoing safety review throughout the course of this trial, the occurrence of ≥ Grade 
2 IRRs must be reported to the Sponsor or designee within 24 hours of occurrence. As always, 
any IRR fulfilling the SAE criteria must be reported as per Section 9.3. 

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9.7 
Pregnancy 
If any trial patient becomes pregnant during the course of the trial, the patient must be 
discontinued from Pan-HER immediately and the pregnancy must be reported to the Sponsor or 
designee according to the same timelines as for an SAE. While pregnancy is not considered an 
AE, all pregnancies are tracked as SAEs within the safety database in order to follow-up on 
exposure to the fetus/infant.  
Pregnancies reported in female partners of male trial patients must also be 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 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 Pan-HER 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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10. STATISTICS 
10.1 Sample Size Considerations 
The primary endpoint of Part 1 is occurrence of DLTs during Cycle 1 for each of the Pan-HER 
dosing regimens. The number of enrolled patients will depend on the extent of observed DLTs 
independently in each cohort. Please refer to Section 7.1.3.2 for a description of planned dose 
levels and decision points for dose-escalation. Based on the dose-escalation design, it is planned 
to enroll approximately 34 patients during the dose-escalation part of the trial. 
In Part 2 of the trial, the primary endpoint is documented OR, defined as documented PR or CR 
assessed by RECIST v1.1 at any time during trial participation, with radiologic evaluation to be 
performed locally. 
During Part 2, it is planned to enroll and treat approximately 100 patients. The planned number 
of patients to be enrolled might be adjusted when the 4 dose-expansion cohorts (i.e., based on 
defined molecular profiles(s) and tumor types) have been selected. The protocol amendment 
defining the dose-expansion cohorts will contain a detailed sample size calculation covering the 
four expansion cohorts, including expected range of OR. 
10.2 Analysis Population 
Two analysis sets will be defined in accordance with the consolidated ICH E9 GCP guidelines.  
The Full Analysis Set (FAS) will comprise all enrolled patients who have received at least one 
dose of Pan-HER. The FAS will be used for evaluation of all endpoints except evaluation of 
DLTs. The patients in the FAS will contribute to the analyses as allocated to treatment. For the 
evaluation of PK endpoints, patients, full profiles, or single measurements can be excluded from 
the analyses. The decision of excluding patients, full profiles, or part of profiles will be described 
in the clinical trial report (CTR). 
The DLT Analysis Set will comprise all patients in the FAS enrolled in Part 1, except patients 
who did not complete Cycle 1 for reasons other than drug toxicity. The DLT Analysis Set will be 
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10.3 Primary Endpoint and Analysis 
10.3.1 
Part 1, Dose-Escalation 
The primary objective of the dose-escalation part is to assess the safety and tolerability of Pan-
HER. This will be assessed by the primary endpoint for Part 1: occurrence of DLTs during Cycle 
1 for each of the Pan-HER dose regimens. 
All DLT events will be listed by dose cohort and patient. A summary table of DLTs across dose 
cohorts by System Organ Class (SOC) and preferred term will be presented, if applicable. The 
summaries will include number of DLTs, number, and percentages of patients experiencing a 
DLT. The definition of a DLT is included in Section 9.5.1.  
The MTD is defined as the highest dose with a maximum of 1 out of 6 patients experiencing a 
DLT. The MTD may or may not be found within the dose levels tested. Based on an overall 
evaluation of the dose-escalation part, the RP2D to be used in Part 2 will be selected. The RP2D 
may be equal to or lower than the MTD. 
10.3.2 
Part 2, Dose-Expansion 
The primary objective of Part 2 is to evaluate the antitumor effect of Pan-HER when 
administered at the RP2D and regimen to patients with advanced epithelial malignancies without 
available therapeutic options. Four (4) dose-expansion cohorts will be evaluated. This will be 
assessed by the primary endpoint for Part 2: documented OR, defined as documented PR or CR 
assessed by RECIST v1.1 at any time during trial participation, with radiologic evaluation to be 
performed locally. 
Number and percentages of patients with documented OR will be presented including 
corresponding 95% exact Clopper-Pearson Confidence Intervals (CI) for binomial proportion. 
The summaries will be presented for each tumor type separately. 
10.4 Secondary and Exploratory Endpoint and Analysis 
All statistical analyses of the secondary and exploratory endpoints for both phases will be 
descriptive unless otherwise specified. Details will be specified in a separate statistical analysis 
plan. 
In the following sections, ‘cohort’ refers to dose cohort for Part 1 and tumor type for Part 2. 
Thus, summaries by trial part and cohort will be presented by dose cohorts within Part 1 and 
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10.4.1 
Efficacy Endpoints and Analyses 
All statistical analysis of the secondary endpoints will be presented using the FAS.  
The following anti-tumor response endpoints will be measured in Part 1: 
• Documented OR, defined as documented PR or CR, from baseline to end of trial 
participation (in patients with measurable disease only) 
The following anti-tumor response endpoints will be measured in Part 2: 
• Changes in sum of diameters of target lesions from baseline to end of trial participation 
• SD for >16 weeks from baseline 
• Time to documented PD, death, patient withdrawal or end of trial participation, 
whichever comes first 
• Overall survival (OS) 
Best overall response by RECIST v1.1 will be summarized by trial part and cohort by means of 
counts and percentages for the categories CR, PR, SD, PD, and NE. 
Number and percentages of patients with documented OR in the dose-escalation part will be 
presented including corresponding 95% exact Clopper-Pearson CI. All documented ORs (Part 1 
and Part 2) will be listed including duration (in days) of OR, measured from time of first PR or 
CR to PD. 
Duration of SD is calculated from baseline until first measurement of PD. The number and 
percentages of patients with SD for more than 16 weeks will be presented by trial part and tumor 
type. 
Time to documented PD, death, patient withdrawal or end of trial participation, whichever comes 
first, will be presented in a Kaplan-Meier plot. The median progression free survival time, 
including 95% CI, will be derived. There will be one plot for Part 1, and plots for each of the 4 
tumor types in Part 2. 
10.4.2 
Other Efficacy Assessments 
Tumor markers will be listed and summarized as appropriate. 

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10.4.3 
Safety Endpoints and Analyses 
The safety endpoints are presented below and will all be presented for the FAS by trial part and 
tumor type. Safety data will only be presented descriptively, and no formal statistical analyses 
will be performed. 
In Part 1 and Part 2 of the trial, the following safety endpoints will be assessed: 
• Nature, incidence and severity of AEs measured from baseline to end of trial participation  
• AEs leading to dose-reductions, dose delays and permanent treatment cessation 
• Changes in safety laboratory values from baseline to end of trial participation 
• Changes in vital signs and physical examinations from baseline to end of trial 
participation 
• Occurrence of ADA to Pan-HER measured in serum at selected timepoints from baseline 
to end of trial participation 
10.4.3.1 
Adverse Events 
The AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) current 
version. AEs will be regarded as treatment emergent AEs (TEAEs) if they occur after first 
treatment. Non-treatment emergent AEs (non-TEAEs) are defined as AEs collected before 
dosing. TEAEs will be presented by SOC and preferred term unless stated otherwise. The 
frequencies of TEAEs will be presented including number and percentages of patients having 
experienced an event and the total number of events. 
AEs including SAEs are reported from signing of the informed consent for participation in the 
trial and until the end of trial participation. SAEs reported outside the required reporting window 
are only entered into the safety database and will be described separately in the report.  
Note: Patients who sign informed consent and are subsequently deemed to be screening failures will be followed for 
the occurrence of SAEs/AEs until it is determined that they will not be participating in the trial. 
All AEs will be listed. The AEs will be presented using summary tables by trial phase including: 
• AEs, in total and sorted by frequency  
• AEs by relationship 
• AEs by Grade and maximum Grade 
• SAEs, in total, and by relationship 

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• AEs leading to withdrawal from treatment 
• AEs leading to trial drug interruption or dose reduction 
• Fatal AEs 
10.4.3.2 
Clinical Laboratory Values 
Biochemistry, hematology, and coagulation parameters will be presented using box plots by 
visits and by trial part and tumor type. In addition, individual patient biochemistry, hematology, 
and coagulation parameters during the trial will be presented graphically using longitudinal plots. 
Urinalysis parameters will be summarized using descriptive statistics. 
Laboratory values outside normal range will be flagged, and all laboratory values will be listed 
including grading of abnormal values. 
10.4.3.3 
Other Safety Assessments 
Change in vital signs from baseline to end of trial participation will be summarized by visit, trial 
part and tumor type. Normal and abnormal findings in physical examination and ECG 
measurements will be presented in shift tables by visit, trial part and tumor type. 
ECOG PS, body weight and ADA results will be listed. 
10.4.4 
Pharmacokinetic Endpoints and Analyses 
The PK endpoints with Q1W dosing will be derived based on the concentration time curves of 
Pan-HER after the first and fourth infusion of Pan-HER in both parts of the trial, as applicable.  
The PK endpoints with Q2W dosing will be derived based on the concentration time curves of 
Pan-HER after the first and third infusion of Pan-HER in both parts of the trial, as applicable. 
Refer to Table 13. The serum concentration of total Pan-HER will be derived as the sum of the 
serum concentration of all six constituting antibodies. Supporting plots and PK parameters for 
the individual antibodies will also be generated. 
 

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Table 13   Pharmacokinetic (PK) Endpoints, Definitions, and Derivations 
Symbol 
Definition and derivation 
Ctrough 
Trough concentration (i.e., concentration of Pan-HER measured pre-infusion) 
AUCτ 
 
Area under the concentration-time curve in a dosing interval (i.e., from time 
zero (end of infusion) up to 168 hours). AUCτ will be calculated using the 
linear trapezoidal method and interpolated in case of measurements after 168 
hours, or extrapolated using terminal rate constant and the last quantifiable 
concentration 
AUCτ0 
Area under the concentration-time curve from start of infusion up to 168 hours. 
AUCτ0 will be calculated similar to AUCτ 
AUCnorm, τ 
 
Dose normalized area under the concentration-time curve in a dosing interval, 
calculated as AUC τ divided by the dose infused 
Cmax 
Maximum concentration 
Tmax 
Time to reach maximum concentration 
CEOI 
Concentration at End of Infusion 
λz 
Terminal rate constant (negative of the slope of an ln-linear regression of the 
un-weighted data considering the terminal phase of the concentration-time 
curve ≥ limit of quantification). λz is not an endpoint, but is used for derivation 
of endpoints 
T½ 
Terminal elimination half-life, calculated as ln(2)/ λz 
CLS 
Clearance after first dose, calculated as Dose/AUCinf for C1/D1, where AUCinf 
will be calculated as the sum of the area from time zero to time of last 
quantifiable concentration, tz, and the area from tz to infinity. The second area 
will be estimated using the observed concentration at tz and the terminal rate 
constant  
CLSS 
Clearance after 4th dose, calculated as Dose/AUCτ 
VS 
Volume of distribution during the terminal phase after first dose (CLS/ λz) 
VSS 
Volume of distribution during the terminal phase after 4th dose (CLSS/ λz) 
 
Cmax, CEOI, Ctrough and Tmax will be derived from observed data while AUCτ, AUCτ0, AUCnorm, τ, 
CLS, CLSS, VS, VSS, and T½ will be estimated using non-compartmental methods and actual time 
points. 
Individual curves of serum concentration of total Pan-HER versus time after the first and fourth 
infusion of Pan-HER with Q1W dosing, and after the first and third infusion of Pan-HER with 
Q2W dosing, will be presented on log- and linear scale for all patients in the FAS. Furthermore, 
trough serum concentrations for the period from first dose to EOT will be presented on linear 
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scale using nominal time point by cohort and trial part. All PK endpoints will be listed and 
summarized by trial part and cohort. 
10.4.5 
Additional Endpoints and Analyses 
The following additional endpoints will be assessed in Part 1 and Part 2 of the trial: 
• EGFR and HER3 receptor down modulation in skin biopsies, measured by percentage 
and nominal difference in target expression from baseline to end of Cycle 2 
• EGFR, HER2 and HER3 receptor down modulation in tumor biopsies (may not be 
available in Part 1), measured by percentage and nominal difference in target expression 
from baseline to end of Cycle 2 
• Biomarkers relevant to Pan-HER activity 
• Tumor genetics, drug target genes, and other biomarker genes that are known to be 
involved in the development and progression of epithelial malignancies 
The additional endpoints, outlined above may include genes and/or proteins that are unknown or 
have not been included in the scientific hypotheses at the present time of trial, but that, during 
the collection of data from this trial, may evolve as new candidate genes and markers related to 
Pan-HER safety, efficacy, or mechanism of action. 
Percentage and nominal change in target expression from baseline to end of Cycle 2 or PD 
(whichever comes first) in skin and tumor biopsy samples will be presented by trial part and 
tumor type using descriptive statistics including scatter plots of values at end of Cycle 2 versus 
baseline. 
Potential biomarkers include genes, gene transcripts and proteins of the receptor tyrosine kinases 
(RTKs) and molecules of the EGFR signaling pathway. All biomarkers will be listed. 
Exploratory analysis using the biomarkers might be performed. 
10.5 Interim Analysis 
No interim analysis is planned for this trial. 
All relevant safety, PK and toxicity data will be reviewed on an ongoing basis throughout the 
trial. Please refer to Section 12. 
Based on an overall evaluation of Part 1 of the trial, the RP2D will be chosen. 

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10.6 Deviations from the Statistical Plan 
Any deviation(s) from the original analysis plan will be described in a protocol amendment 
and/or in a statistical analysis plan and/or in the final CTR, as appropriate. 
10.7 Modelling of Pharmacokinetics and Pharmacodynamics 
PK samples will be analyzed on an on-going basis during the trial. These preliminary data will 
be evaluated by non-compartmental and/or compartmental methods. 
All data collected in this trial may be used for modelling of PK and pharmacodynamics to 
support the planning and dose setting within the current trial as well as for future trials. 
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. 

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11. ETHICS 
11.1 Institutional Review Board/Ethics Committee 
An IRB/EC will review the protocol and any amendments and advertisements used for 
recruitment, as well as the informed consent documents, their updates (if any), and any other 
written materials given to the patients. The CTR will include a list of all IRBs/ECs to which the 
protocol has been submitted and the name of the committee chair. 
11.2 Patient Information and Informed Consent 
The Investigator or his/her designee must obtain written informed consent from each patient 
before any trial related procedures are performed. Each patient must receive full patient 
information before giving consent. The patient information must contain full and adequate verbal 
and written information regarding the objective and procedures of the trial and the possible risks 
involved. 
Before signing the informed consent form the patient must be given sufficient time to consider 
his/her possible participation. Each patient must also be informed about his/her right to withdraw 
from the trial at any time. 
Each patient must sign the informed consent form. The informed consent form must be signed 
and dated both by the patient and by the Investigator or designee providing the information to the 
patient. The patient receives a copy of the signed form and the original is retained in the 
Investigator Site File (ISF).  
 
 

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12. SAFETY SURVEILLANCE SET-UP 
12.1 Safety Review 
An SMC will be established. This committee will include Investigator(s), Medical Monitor(s), 
and Sponsor’s medical representatives. The SMC will review clinical and laboratory safety data 
regularly throughout the trial and make decisions regarding the advisability of continuing accrual 
to a particular dose cohort, and/or escalating the dose and allowing accrual to a higher dose 
cohort. In order to do so, the Investigator must ensure to report safety data to the Sponsor or 
designee in a timely manner. This includes, but is not limited to: 
• SAEs must be reported within 24 hours of awareness (SAE report form) 
• DLTs must be reported within 24 hours of occurrence 
• IRRs of ≥ Grade 2 must be reported within 24 hours of occurrence 
• All AEs will be reported in the CRF in a timely manner 
• Dose-modifications (i.e., dose-reduction, temporary interruptions regardless of cause) 
will be reported in a timely manner 
• Local laboratory data will be reported in the CRF in a timely manner 
Availability of these data will enable the Sponsor to act promptly in response to safety signals 
and to ensure that HAs, as well as Investigators, who may be participating in other Pan-HER 
clinical trials, are informed of events occurring during this trial.  
Regular safety teleconferences will be held between the trial site(s) and the Sponsor and/or 
designee. Such safety teleconferences may fluctuate in frequency based on accrual and trial 
activity, as indicated. 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 trial. 
12.2 Other Safety Surveillance Activities 
At least one Medical Monitor is assigned to review and evaluate relevant clinical/safety 
information concerning the clinical trial. The responsibilities of the Medical Monitor include, but 
are not limited to: 
• Evaluation of 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 

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

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13. MONITORING AND QUALITY ASSURANCE 
13.1 Compliance with Good Clinical Practice 
The responsibilities of the Sponsor, the Monitor, and the Investigator are defined in ICH E6(R2) 
GCP, and applicable regulatory requirements in the country where the trial takes place. The 
Investigator is responsible for adhering to the ICH E6(R2) GCP responsibilities of the 
Investigators, and for dispensing IMP only in accordance with this protocol or a signed 
amendment, and for its storage and safe handling throughout the trial. 
13.2 Source Documents 
The Investigator will maintain adequate and accurate records for each patient treated with study 
drug.  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 HAs 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 
authorized regulatory agencies, to have direct access to source data that support data in the CRF 
(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. 
13.3 Monitoring 
Monitoring visits to the trial sites will be made periodically during the trial to ensure that all 
aspects of the protocol are followed. The Investigator must give the Sponsor and/or their 
representatives direct access to all relevant source documents to confirm consistency with the 
CRF entries. Source Data Verification will be conducted according to Sponsor or designee 

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Standard Operating Procedures (SOPs) and requirements will be specified in a trial specific 
monitoring plan.  
It is important that the Investigator and their relevant personnel are available during monitoring 
visits and possible audits and that sufficient time is devoted to the process. 
 
 

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14. HANDLING AND PROCESSING OF DATA 
14.1 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).  
14.2 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. 
A CRF is required to be submitted for every patient who receives any amount of study drug.  
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. 
14.3 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.   
14.4 Data Protection 
The Investigator, Sponsor, and Sponsor designee(s) will ensure that the confidentiality of the 
patients’ data is preserved. Each participating site will maintain appropriate medical and research 
records for this trial in compliance with ICH E6(R2) GCP and regulatory and institutional 
requirements for the protection of confidentiality of patients. 

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14.5 Data Transactions and Access 
The trial data and any other documents transferred to the Sponsor or designee will not contain 
patient names or other confidential personal data, but patients will be identified using the 
assigned trial specific patient numbers. 
When data are transferred to the Sponsor or designee, access will be limited to relevant persons. 
The Investigator will maintain documents that are not for collection by the Sponsor, e.g., patient 
identification list and the signed informed consent forms. 
14.6 Case Report Form 
The Investigator or designee will be responsible for entering trial data in the CRF provided. It is 
the responsibility of the Investigator to ensure the accuracy of the data entered in the CRF. 
All collected data will be entered into a validated database. 
14.7 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 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 14.3. Data 
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 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. 

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14.8 Retention of Trial Documents at Site 
The Investigator at each trial site must make arrangements to store the essential trial documents 
(including the ISF) after the end of trial according to ICH E6(R2) GCP and local requirements. 
In addition, the Investigator is responsible for archiving all relevant source documents so that the 
trial data can be compared against source data after completion of the trial, e.g., in case of 
inspection from authorities. 
The Investigator is required to ensure the continued storage of the documents, even if the 
Investigator should leave the clinic/practice or retire before the end of the required storage 
period. 
14.9 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 
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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15. REGISTRATION AND COMMUNICATION OF RESULTS 
15.1 Use of Information 
All unpublished information relating to this trial and the IMP is considered confidential by the 
Sponsor and shall remain the sole property of the Sponsor. The Investigator must accept that the 
Sponsor may use information from this trial in connection with the development of the IMP, and 
therefore, may disclose it as required to Investigators, government-licensing authorities, HAs of 
other governments, stock exchange market and commercial partners. 
15.2 Registration and Publication 
The trial will be registered in one or more public trial registries and results will be reported 
according to current legislation. The trial results will be posted in the same clinical trial registries 
as the initial registration(s) in accordance with the latest International Committee of Medical 
Journal Editors (ICMJE) recommendations (URL: www.icmje.org). 
The Sponsor acknowledges the Investigators’ rights to publish the full results of the trial, 
regardless of the outcome, in accordance with the latest ICMJE recommendations. 
The Coordinating Investigator and the Sponsor will decide on the publication strategy. The 
Coordinating Investigator has 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 a number of persons who have contributed 
substantially to the trial. The Sponsor will have representation in the list of authors. 
Publication is subject to the following conditions: 
• No publication before the completion of the trial at all participating trial sites without 
preceding written approval from the Sponsor 
• Publications shall not disclose any Sponsor confidential information and property (not 
including the trial results) 
• The Sponsor reserves the right to review results communications prior to public release 
and can embargo communications regarding trial results for a period that is less than or 
equal to 60 days. The Sponsor cannot require changes to the communication and cannot 
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16. INSURANCE AND LIABILITY 
The Sponsor will take out Human Clinical Trials Insurance for its legal liability in accordance 
with laws and regulations, and with limits customary or required by law in the territory in 
question. 
 

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

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

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19. REFERENCE LIST 
1. WHO World Cancer Report 2014. Edited by Bernard W. Stewart and Christopher P. 
Wild 
2. Bublil EM, Yarden Y. The EGF receptor family: spearheading a merger of signaling and 
therapeutics. Curr Opin Cell Biol. 2007; 19:124-134  
3. Baselga J, Swain, SM. Novel anticancer targets: revisiting ERBB2 and discovering 
ERBB3. Nat Rev Cancer. 2009; 9:463-75  
4. Seshacharyulu P, Ponnusamy MP, Haridas D, et al. Targeting the EGFR signaling 
pathway in cancer therapy. Expert Opin Ther Targets. 2012; 16(1):15-31 
5. Tebbutt N, Pedersen MW, Johns TG. Targeting the ERBB family in cancer: couples 
therapy. Nat Rev Cancer 2013; 9:663-73 
6. Zhang N, Chang Y, Rios A, et al. HER3/ErbB3, and emerging cancer therapeutic target. 
Acta Biochim Biophys Sin. 2016; 48(1):39-48 
7. Vlacich G, Coffey RJ. Resistance to EGFR-targeted therapy: a family affair. Cancer Cell. 
2011; 20:423-25 
8. Brand TM, Iida M, Wheeler DL. Molecular mechanisms of resistance to the EGFR 
monoclonal antibody cetuximab. Cancer Biol Ther. 2011; 11(9):777-92 
9. Garrett JT, Olivares MG, Rinehart C, et al. Transcriptional and posttranslational up-
regulation of HER3 (ERbB3) compensates for inhibition of the HER2 tyrosine kinase. 
Proc Natl Acad Sci U.S.A. 2011; 108(12):5021-6 
10. Yonesaka K, Zejnullahu K, Okamoto I, et al. Activation of ERBB2 signaling causes 
resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med. 2011; 
3(99):99ra86, 1-11 
11. Garrett JT, Sutton CR, Kuba MG, et al. Dual blockade of HER2 in HER2-overexpressing 
tumor cells does not completely eliminate HER3 function. Clin Cancer Res. 2013; 
19(3):610-19 
12. Marusyk A, Almendro V, Polyak K. Intra-tumour heterogeneity: a looking glass for 
cancer? Nat Rev Cancer. 2012; 12(5):323-34 
13. Almendro V, Marusyk A, Polyak K. Cellular heterogeneity and molecular evolution in 
cancer. 2013; 8:277-302 

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14. Carvalho S, Levi-Schaffer F, Sela M, et al. Immunotherapy of cancer: from monoclonal 
to oligoclonal cocktails of anti-cancer antibodies: IUPHAR review 18. Br J Pharmacol. 
2016; 173(9):1407-24 
15. Jacobsen HJ, Poulsen TT, Dahlman A, et al. Pan-Her, an antibody mixture 
simultaneously targeting EGFR, HER2, and HER3, effectively overcomes tumor 
heterogeneity and plasticity. Clin Cancer Res. 2015; 21(18):4110-22 
16. Gharwan H, Groninger H. Kinase inhibitors and monoclonal antibodies in oncology: 
clinical implications. Nat Rev Clin Oncol. 2016; 13(4):209-27 
17. Ustaris F, Saura C, Di Palma J, et al. Effective management and prevention of neratinib-
induced diarrhea. Am J Hemat Oncol. 2015;11(11):13-22 
18. LoRusso P, Jänne PA, Oliveira M, et al. Phase I study of U3-1287, a fully human anti-
HER3 monoclonal antibody, in patients with advanced solid tumors. Clin Cancer Res. 
2013; 19(11):3078-87 
19. Lassen UN, Cervantes Ruiperez A, Fleitas T, et al. Phase Ib trial of RG7116, a 
glycoengineered monoclonal antibody targeting HER3, in combination with cetuximab or 
erlotinib in patients with advanced/metastatic tumors of epithelial cell origin expressing 
HER3 protein. Ann Oncol 25 (suppl 4):iv147 
20. Inman S. Prophylactic loperamide reduces neratinib-related diarrhea in HER2+ breast 
cancer. http://global.onclive.com/web-exclusives/prophylactic-loperamide-reduces-
neratinib-related-diarrhea-in-her2-breast-cancer 2015; Published online: Tuesday, 
December 22, 2015 cited 09 May 2016 
21. Simon R, Friedlin B, Rubinstein et al. Accelerated titration designs for phase I clinical 
trials in oncology. J Natl Cancer Inst, 1997;89(15):1138-47 
22. Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid 
tumors: Revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228-247 
23. The Criteria Committee of the New York Heart Association. Nomenclature and criteria 
for diagnosis of diseases of the heart and great vessles. 9th ed. Boston, Mass:Little, 
Brown & Co; 1994:253-6 
24. Hy’s Law. Drug–induced liver injury: premarketing clinical evaluation. Guidance for 
Industry. U.S. Department of HHS, FDA, CDER, CBER, 2009 
25. Mok TS, Wu Y-L, Ahn M-J, et al. Osimertinib or platinum-pemetrexed in EGFR 
T790M-positive lung cancer. N Engl J Med. 2017; 376:629-640 

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26. Soria J-C, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated 
advanced non-small-cell lung cancer. N Engl J Med. 2018; 378(2):113-125 
27. Popat S. Osimertinib as first-line treatment in EGFR-mutated non-small-cell lung cancer. 
N Engl J Med. 2018; 378:192-193 
28. Nerlynx (neratinib) [package insert]. Los Angeles, CA: Puma Biotechnology, Inc., 2017 
29. Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant 
therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, 
double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017; 18:1688-1700 
 

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20. APPENDICES 
Appendix 1:  Summary of Response Evaluation Criteria in Solid Tumors (RECIST v1.1) 
For details, see Eisenhauer EA, Therasse P, Bogaerts J, et al (2009). New response evaluation 
criteria in solid tumours: Revised RECIST guideline (version 1.1) (22). 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows: 
Measurable: 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
• 20 mm by chest X-ray 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. See also notes below on “Baseline documentation of target and non-
target lesions” for information on lymph node measurement. 
Non-measurable: 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with 10 to <15 mm short axis) as well as truly non-measurable lesions. Lesions considered truly 
non-measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
Special considerations regarding lesion measurability: 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 

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Bone lesions 
• Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques to measure bone lesions. However, these techniques can be 
used to confirm the presence or disappearance of bone lesions 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above 
• Blastic bone lesions are non-measurable. 
Cystic lesions 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts 
• “Cystic lesions” thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions 
Lesions with prior local treatment 
• Tumor lesions situated in a previously irradiated area, or other loco-regional therapy area, 
are usually not considered measurable unless there has been demonstrated progression in 
the lesion. Study protocols should detail the conditions under which such lesions would 
be considered measurable 
Methods of Measurement 
Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
Method of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 

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• Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥10 mm diameter as assessed using calipers (e.g., skin nodules). For the 
case of skin lesions, documentation by color photography including a ruler to estimate the 
size of the lesion is suggested. As noted above, when lesions can be evaluated by both 
clinical exam and imaging, imaging evaluation should be undertaken since it is more 
objective and may also be reviewed at the end of the study 
• Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung 
• CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion should 
be twice the slice thickness. MRI is also acceptable in certain situations (e.g., for body 
scans) 
• Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement 
• Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following CR or surgical resection is an endpoint 
• Tumor markers: Tumor markers alone cannot be used to assess objective tumor response 
• Cytology, histology: These techniques can be used to differentiate between PR and CR in 
rare cases if required by protocol (for example, residual lesions in tumor types such as 
germ cell tumors, where known residual benign tumors can remain). When effusions are 
known to be a potential adverse effect of treatment (e.g., with certain taxane compounds 
or angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any 
effusion that appears or worsens during treatment can be considered if the measurable 
tumor has met criteria for response or SD in order to differentiate between response (or 
SD) and PD 
Tumor response evaluation 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Only patients with 
measurable disease at baseline should be included in protocols where objective tumor response is 

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the primary endpoint. Measurable disease is defined by the presence of at least one measurable 
lesion. Response criteria are listed in Table 14 and Table 15. 
Table 14   Response Criteria for Evaluation of Target Lesions 
 
Evaluation of Target Lesions 
Complete Response 
(CR) 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm 
Partial Response 
(PR) 
At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters 
Progressive Disease 
(PD) 
At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study). In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at least 5 mm.   
(Note: the appearance of one or more new lesions is also considered progression) 
Stable Disease  
(SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on 
study 
 
Table 15   Response Criteria for Evaluation of Non-Target Lesions 
 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size 
(<10 mm short axis) 
Progressive Disease (PD) 
Unequivocal progression of existing non-target lesions.  
(Note: the appearance of one or more new lesions is also considered 
progression) 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits 
 

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Evaluation of Best Overall Response 
It is assumed that at each protocol specified time point, a response assessment occurs. Table 16 
provides a summary of the overall response status calculation at each time point for patients who 
have measurable disease at baseline. 
Table 16   Overall Response Status for Patients with Baseline Measurable Disease 
Target Lesions 
Non-target Lesions 
New 
Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviation: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease 
 
The best overall response is determined once all the data for the patient is known. 
Best response determination in trials where confirmation of CR or PR is NOT required:  
Best response in these trials is defined as the best response across all time points (for example, a 
patient who has SD at first assessment, PR at second assessment, and PD on last assessment has 
a best overall response of PR). When SD is believed to be best response, it must also meet the 
protocol specified minimum time from baseline. If the minimum time is not met when SD is 
otherwise the best time point response, the patient’s best response depends on the subsequent 
assessments. For example, a patient who has SD at first assessment, PD at second and does not 
meet minimum duration for SD, will have a best response of PD. The same patient lost to follow-
up after the first SD assessment would be considered NE. 
Best response determination in trials where confirmation of CR or PR is required:  
Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point as specified in the protocol (generally 4 weeks later). In this circumstance, 
the best overall response can be interpreted as shown in Table 17. 

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Table 17   Best Overall Response when Confirmation of CR and PR Required  
Overall Response  
First Time Point 
Overall Response  
Subsequent Time Point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR1 
CR 
SD 
SD provided minimum criteria for SD 
duration met, otherwise PD 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise PD 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise PD 
PR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise NE 
NE 
NE 
NE 
Abbreviation: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease 
1) 
If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR criteria relative to 
baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best response would depend on whether 
minimum duration for SD was met. However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were 
likely still present and in fact the patient had PR, not CR at the first time point. Under these circumstances, the original CR should be 
changed to PR and the best response is PR. 

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21. SUMMARY OF CHANGES 
21.1 Protocol Amendment 1 dated 03-Oct-2016 
• Modified inclusion criteria for Part 1 and 2 to clarify that patients must have received all therapy known to confer clinical 
benefit in order to be eligible for inclusion 
• Modified withdrawal criteria to include that the need for more than three dose-reductions of Pan-HER will lead to treatment 
withdrawal 
• Modified dose-delay criteria  
• Modified dose-reduction criteria  
• Modified the definition of dose-limiting toxicities (Part 1 only) by removing the exception of Grade 3 IRR that is transient 
 
Refer to Table 18 for the changes in Protocol Amendment 1. 
Table 18   Protocol Amendment 1 
SECTION 
ORIGINAL TEXT  
NEW TEXT 
1. Synopsis 
Main Inclusion 
and Exclusion 
Criteria 
Documented (histologically- or cytologically-proven) epithelial malignancy 
that is locally advanced or metastatic and that is refractory to standard 
therapy or for which no standard therapy is available 
 
Documented (histologically- or cytologically-proven) epithelial malignancy 
that is locally advanced or metastatic, having received all therapy known to 
confer clinical benefit 
6.1 Inclusion 
Criteria 
Documented (histologically- or cytologically-proven) epithelial malignancy 
that is locally advanced or metastatic and that is refractory to standard 
therapy or for which no standard therapy is available 
Documented (histologically- or cytologically-proven) epithelial malignancy 
that is locally advanced or metastatic, having received all therapy known to 
confer clinical benefit 
6.3.1 Withdrawal 
from Treatment 
Not applicable 
 
Added withdrawal criteria: 
Need for more than three dose-reductions of Pan-HER 
7.1.4.2 Dose-
Delays for Pan-
HER-Related or 
Disease-Related 
Toxicities 
1.   ANC >1.0 ×109/L (1000/mm3) 
2. Platelet count >60 ×109/L (60,000/mm3) 
1.   ANC >1.5 ×109/L (1500/mm3) 
2. Platelet count >75 ×109/L (75,000/mm3) 
7.1.4.3 Dose-
Reduction for 
Pan-HER-Related 
Toxicities 
c. Grade 3 IRR that is transient (resolving ≤6 hours from onset) 
Removed 
New text added: Need for more than three dose-reductions of Pan-HER will 
lead to withdrawal from treatment. 
Table 8 and footnote updated 

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9.5.1 Definition 
of Dose-Limiting 
Toxicities 
c. Grade 3 IRR that is transient (resolving ≤6 hours from onset) 
Removed 
 
 
21.2 Protocol Amendment 2 dated 14-Nov-2016 
• Clarified exclusion criteria #2 by allowing radiotherapy against target lesions within 4 weeks prior to C1/D1, provided there is 
documented progression of the lesion following the radiotherapy 
• Clarified exclusion criteria #12a by providing specific examples of inflammatory bowel disease that would exclude the patient 
• Clarified exclusion criteria #14i that the Investigator will decide whether the patient can be considered to be on a stable dose of 
anticoagulant therapy 
• Deleted exclusion criteria related to HIV and hepatitis B or C 
• For Part 2 ONLY: included continued follow-up for response and/or overall survival after the 1M FUP Visit and added related 
secondary endpoint of overall survival 
• Clarified that the retreatment criteria must be evaluated at minimum prior to each Cycle 1 dose and prior to D1 and D15 doses 
each cycle thereafter.  
• Modified retreatment criteria #4 by allowing Grade 2 clinical events that are being adequately controlled with best supportive 
care and asymptomatic laboratory abnormalities that are considered clinically insignificant or that are resolving with medical 
therapy 
• Recommended that informed consent be obtained no earlier than 4 weeks prior to the planned C1/D1 
• Clarified that the local assessment of archival tumor tissue for EGFR and HER2 is preferred done by immunohistochemistry 
(IHC) 
• Updated events not to be considered as AEs to include PD, unless the nature of the PD is different than expected 
• Updated timelines for reporting of SAE Follow-up information 
• Included other minor updates and clarifications 
 
Refer to Table 19 for the changes in Protocol Amendment 2. 

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Table 19   Protocol Amendment 2 
SECTION 
ORIGINAL TEXT  
NEW TEXT 
1. Synopsis:  
Trial Periods 
 
5.3.4 End of 
Treatment and 
Follow-up Visit 
 
6.3.2 Withdrawal 
from Trial 
 
8.10 Follow-up 
Assessments 
Not applicable 
Part 2 ONLY, continued follow-up for response and/or overall 
survival:  
After the 1M FUP Visit, the Investigator will make every effort to obtain 
follow-up information on response assessment and/or overall survival (OS) 
every 2 months. Response assessment follow-up is required in the event of 
an ongoing stable disease (SD) or objective response (OR, defined as PR or 
CR), as per RECIST v1.1 at the 1M FUP Visit, until progressive disease 
(PD) or another therapeutic intervention is initiated. Survival follow-up is 
required… 
1. Synopsis: 
Number of Patients 
 
5.5 Number of 
Patients 
The exact number of patients will depend upon the observed tolerability of 
Pan-HER and occurrence of discontinuation of patients during the DLT-
observation period for reasons other than toxicity. 
The exact number of patients will depend upon the observed tolerability of 
Pan-HER and the potential for adding additional patients to a cohort to 
assure a sufficient number of evaluable patients per cohort. 
1. Synopsis:  
Main Inclusion and 
Exclusion Criteria 
 
6.2 Exclusion 
Criteria 
Main exclusion criteria: 
• 
Part 2 ONLY: Radiotherapy against target lesions within 4 weeks prior 
to C1/D1 
• 
History of inflammatory bowel disease 
• 
Abnormal hematologic, renal or hepatic function as defined by the 
following criteria: 
i. Partial thromboplastin time (PTT) >1.5 ULN for the institution* 
*Unless on a stable dose of anticoagulant therapy for a prior 
thrombotic event 
• 
Known history of human immunodeficiency virus (HIV) infection 
• 
Known active hepatitis B or C virus infection 
 
Main exclusion criteria: 
• 
Part 2 ONLY: Radiotherapy against target lesions within 4 weeks prior 
to C1/D1, unless there is documented progression of the lesion 
following the radiotherapy 
• 
History of inflammatory bowel disease (e.g. ulcerative colitis, Crohn’s 
disease) 
• 
Abnormal hematologic, renal or hepatic function as defined by the 
following criteria: 
i. Partial thromboplastin time (PTT) >1.5 ULN for the institution* 
*Unless on a stable dose (per the investigator’s discretion) of 
anticoagulant therapy for a prior thrombotic event 
Removed known history of HIV infection 
Removed known active hepatitis B or C virus infection 
5.6 End of Trial 
Not applicable 
During Part 2, patients will continue to be followed to assess duration of 
disease stabilization, response and/or overall survival. 

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7.1.3.2 Part 1, 
Dose-Escalation: 
Classical 3+3 
Dose-Escalation 
Design 
Not applicable 
There is the potential for additional patients to be enrolled in the dose-
escalation portion of the trial to ensure a sufficient number of evaluable 
patients per cohort by entering an additional patient to a cohort (e.g. 
increase a 1 patient cohort to 2 patients, a 3 patient cohort to 4 patients, or a 
6 patient cohort to 7 patients)… 
7.1.4.2 Dose-
Delays for Pan-
HER-Related or 
Disease-Related 
Toxicities 
In order to dose a patient, the following criteria must be met:… 
4. Any ongoing AEs, assessed as possibly, probably, or related to Pan-HER, 
should have either ameliorated to ≤ Grade 1 severity, returned to baseline 
status, or resolved with the exception of laboratory abnormalities that are 
considered clinically insignificant 
 
In order to dose a patient, the following retreatment criteria must be met. 
Evaluations must occur at minimum prior to each Cycle 1 dose and prior to 
D1 and D15 doses each cycle thereafter:… 
4. Any ongoing AEs, assessed as possibly, probably, or related to Pan-HER, 
should have either ameliorated to ≤ Grade 1 severity, returned to baseline 
status, or resolved with the exception of Grade 2 clinical events that are 
being adequately controlled with best supportive care (e.g. nausea, 
vomiting, diarrhea, fatigue) and asymptomatic laboratory abnormalities that 
are considered clinically insignificant or that are resolving with medical 
therapy 
7.6 Medical Care 
of Patients after 
End of Trial 
Participation 
Not applicable 
During Part 2, patients will continue to be followed for survival. 
8.1.1 Signing of 
Informed Consent 
Note: Informed consent may be obtained outside the 14-day screening 
period prior to C1/D1 
 
Note: Informed consent may be obtained outside the 14-day screening 
period prior to C1/D1, but is recommended to be obtained no earlier than 4 
weeks prior to the planned C1/D1 
8.2.1 Medication/ 
Procedure Survey 
To include all medications and/or treatments taken other than Pan-HER. 
Include generic name or brand name, indication for use, dose and 
frequency, route of administration, start and stop dates or if ongoing at 1M 
FUP Visit. 
To include all medications taken other than Pan-HER and all procedures 
performed during trial. For medications: Include generic name or brand 
name, indication for use, dose and frequency, route of administration, start 
and stop dates or if ongoing at 1M FUP Visit. For procedures: Include date 
and reason for procedure. 
8.2.6 Physical 
Examination 
Full physical examination at Screening to include… 
Removed breasts, lungs, pulses 
8.3.3 Archival 
Tumor Tissue for 
EGFR, HER2 
Assessment (Part 1 
only) 
To be assessed locally for EGFR and HER2 expression level, if tissue is 
available. 
To be assessed locally, preferably by immunohistochemistry (IHC) for 
EGFR and HER2 expression level, if tissue is available. 

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9.1.1 Adverse 
Event 
PD will be captured as an AE. Events associated with the actual PD will 
also be captured, as determined by the Investigator. Additionally, AEs 
occurring simultaneously with PD, but which may not be related to the 
actual PD, will also be captured. 
Removed 
9.1.2 Events Not to 
be Considered as 
Adverse Events 
 
9.1.5 Events that 
Do Not Meet the 
Definition of 
Serious Adverse 
Events 
Not applicable 
PD will not be captured as an AE/SAE unless the nature of the PD is 
different than expected (i.e. other diagnosis and/or signs/symptoms that are 
not typical of PD). PD may be reported as an AE/SAE in the case of patient 
death, with death being the outcome of the event. 
An abnormal laboratory value or an abnormality in physiological testing 
(such as ECGs) per se 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 Pan-HER (dose-reduction 
and/or withdrawal) 
10.4.1 Efficacy 
Endpoints and 
Analyses 
The following anti-tumor response endpoints will be measured in Part 2:… 
The following anti-tumor response endpoints will be measured in Part 2:… 
• 
Overall survival (OS) 
 
21.3 Protocol Amendment 3 dated 26-Apr-2017 
• Changed the dosing schedule from Q1W to Q2W due to AEs seen on the 4 mg/kg and to further explore the safety and 
tolerability of Pan-HER when given Q2W 
• Clarified that patients entered to the study prior to implementation of Amendment 3 will continue to be treated on the Q1W 
schedule 
• Revised the PK collection timepoints for the Q2W dosing schedule 
• Changed dose-escalation from a modified Fibonacci scheme to fixed dose levels 
• Included a PET expansion cohort to evaluate the effects on tumor metabolism of Pan-HER when administered at the RP2D  
• Modified inclusion criteria to include the criteria for patients participating in the PET expansion cohort 
• Extended the number of cohorts in the dose-expansion part of the trial and increased the overall number of patients and number 
of participating sites accordingly 
• Added the option for investigators to include an H2 antagonist and/or acetaminophen premedication, where indicated 

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Refer to Table 20 for the changes in Protocol Amendment 3. 
Table 20   Protocol Amendment 3 
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1. Synopsis:  
Overall Trial 
Design 
 
5.1 Overall 
Design and Plan 
 
7.1.3.2 Part 1, 
Dose-Escalation 
 
7.1.3.3 Part 2, 
Dose-Expansion 
Cohorts 
Not applicable 
 
As of Amendment 3: A total of 6 patients entered Part 1 of this trial: 1 
patient each at Dose Level 1 and 2, and 4 patients at dose Level 3 (1, 2, and 
4 mg/kg, respectively) were treated on a weekly schedule (Q1W; 4 doses 
equaling 1 cycle)… 
This is an open-label, multicenter trial… on a weekly schedule… Four (4) 
doses of Pan-HER administered weekly constitute 1 cycle. 
This is an open-label, multicenter trial… on a Q2W (previously Q1W) 
schedule… With the change in dosing schedule, 2 doses of Pan-HER 
administered Q2W constitute 1 cycle. 
Not applicable 
Once the RP2D is selected, an expansion cohort of patients with 
fluorodeoxyglucose (FDG)-avid tumors will undergo pre- and post-dosing 
fluorine-18 radiolabeled FDG (18F-FDG) positron emission tomography 
(PET) imaging…  
Two tumor types to be evaluated in this part of the trial will be selected 
based upon findings from Part 1… Patients will be entered, depending upon 
their underlying malignancy, to one of 2 corresponding expansion cohorts: 
Cohort A or Cohort B. 
Four tumor types to be evaluated in this part of the trial will be selected 
based upon findings from Part 1… Patients will be entered, depending upon 
their underlying malignancy, to 1 of 4 corresponding expansion cohorts: 
Cohort A, Cohort B, Cohort C, or Cohort D. 
From starting dose n0, dose-escalation of Pan-HER will adhere to the 
following: Doses are initially escalated by 100% at each step n1, n2 etc. until 
a G2T occurs or completion… 
Text removed.  
Figure updated. 
Part 1/Dose-escalation:  
The starting dose of Pan-HER will be 1.0 mg/kg.  
  
Initially, patients will be sequentially enrolled to single-patient cohorts of 
increasing doses of Pan-HER with 100% increase in dose from the previous 
dose level tested. One patient will be treated at each dose level until the 
occurrence of a toxicity* during Cycle 1...  
 
If such a toxicity has not occurred in the first 3 cohorts… the next cohort to 
open will be a 3-patient cohort at 8 mg/kg and the design will switch to the 
3+3 design. 
The increase in dose between dose levels will follow a modified Fibonacci 
scheme. At the first dose-escalation step, approximately 67% will be added 
to the previous dose… 
Part 1/Dose-escalation: 
The starting dose of Pan-HER will be 1.0 mg/kg.  The following dose levels 
of Pan-HER potentially will be evaluated… 
Initially, one patient will be treated at each dose level until the occurrence 
of a toxicity* during Cycle 1…  
 
 
If such a toxicity has not occurred in the first 3 cohorts… the next cohort to 
open will be a 3-patient cohort and the design will switch to the 3+3 design. 
 
Removed modified Fibonacci scheme text. 
 

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Enrollment will be staggered between the first and second patient in each 
new higher 3+3 dose level tested. The first patient must have completed and 
tolerated the first 2 doses of Pan-HER… 
 
Not applicable 
 
Enrollment will be staggered between the first and second patient in each 
new dose level tested. The first patient must have completed and tolerated 
the first dose (previously the first 2 doses with Q1W dosing) of Pan-HER…  
 
Once the RP2D is selected, enrollment to the PET Expansion Cohort may 
begin. 
Part 2/Dose-expansion: 
…enrollment into the 2 separate dose-expansion cohorts will commence 
(Cohort A and Cohort B). All patients enrolled will be treated with weekly 
doses… 
Part 2/Dose-expansion: 
…enrollment into the 4 separate dose-expansion cohorts will commence 
(Cohort A, Cohort B, Cohort C, or Cohort D). All patients enrolled will be 
treated with Q2W doses… 
1. Synopsis:  
Trial Sites 
 
5.1 Overall 
Design and Plan 
Part 2/Dose-expansion: Approximately 10 trial sites 
Part 2/Dose-expansion: Approximately 20 trial sites 
1. Synopsis:  
Planned Trial 
Period 
 
5.4 Recruitment 
Period 
…establishment of a RP2D, expectedly Q3-Q4 2017.  
Enrollment to Part 2 is expected to be from Q1 2018 to Q2 2019. 
…establishment of a RP2D, expectedly beginning of 2018.  Enrollment to 
the PET Expansion Cohort may follow. 
Enrollment to Part 2 is expected to be from second half of 2018 to second 
half of 2019. 
1. Synopsis: 
Primary and 
Secondary 
Objectives 
4.1.1 Primary 
Objective 
4.1.3 Exploratory 
Objective  
4.2.1 Primary 
Objective 
Primary objective of Part 1/Dose-escalation: To assess the safety and 
tolerability of Pan-HER when administered weekly…   
Primary objective of Part 1/Dose-escalation: To assess the safety and 
tolerability of Pan-HER when administered weekly and Q2W…   
Not applicable 
Exploratory objective of Part 1/Dose-escalation:  To evaluate by 18F-
FDG PET the effects on tumor metabolism of Pan-HER when administered 
Q2W at the RP2D in an expansion cohort of patients with FDG-avid tumors  
Primary objective of Part 2/Dose-expansion: To evaluate the antitumor 
effect of Pan-HER when administered weekly at the RP2D to patients with 
advanced epithelial malignancies (2 tumor types to be selected). 
Primary objective of Part 2/Dose-expansion: To evaluate the antitumor 
effect of Pan-HER when administered Q2W at the RP2D to patients with 
advanced epithelial malignancies (4 tumor types to be selected). 
1. Synopsis: 
Trial Periods 
Treatment period: Patients in the trial will receive weekly… 
Treatment period: Patients in the trial will receive Q2W (previously 
Q1W)… 

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1. Synopsis: 
Number of 
Patients 
 
5.5 Number of 
Patients 
In total, approximately 75 patients will be included in this trial. 
In total, approximately 131 patients will be included in this trial. 
Not applicable 
 
It is estimated that approximately 6 patients will be enrolled to the PET 
Expansion Cohort.  The exact number of patients will depend… 
It is planned to enroll and treat approximately 50 patients during Part 2 with 
25 patients in each dose-expansion cohort. 
It is planned to enroll and treat approximately 100 patients during Part 2 
with 25 patients in each dose-expansion cohort. 
1. Synopsis: 
Main Inclusion 
and Exclusion 
Criteria 
 
6.1 Inclusion 
Criteria 
Not applicable 
Main inclusion criteria all patients, Part 1 and Part 2: 
• 
PET Expansion Cohort:  Epithelial malignancy, measurable according 
to RECIST v1.1 that has been confirmed by 18F-FDG-PET imaging to 
be FDG-avid within 28 days prior to C1/D1 
1. Synopsis: 
Investigational 
Medicinal 
Product: 
Dose(s) and 
Treatment 
Schedule 
Pan-HER will be initiated on C1/D1 and will be administered weekly by IV 
infusion in cycles of treatment: 
• 
Dosing on Day 1, 8, 15 and 22 of each 28-day cycle (±2 days) 
 
Pan-HER will be initiated on C1/D1 and will be administered Q2W 
(previously Q1W) by IV infusion in cycles of treatment: 
• 
Dosing on Day 1 and 15 of each 28-day cycle (±2 days) 
As of Amendment 3: Doses previously administered on Days 8 and 22 are 
omitted. 
1. Synopsis: 
Dose-Limiting 
Toxicities 
(Part 1 only) 
 
9.5.2 Observation 
Period for Dose-
Limiting 
Toxicities 
A minimum of 4 infusions of Pan-HER must have been administered at the 
assigned dose for a patient to have completed the DLT-observation period. 
A minimum of 2 infusions (previously 4 infusions with Q1W dosing) of 
Pan-HER must have been administered at the assigned dose for a patient to 
have completed the DLT-observation period. 
1. Synopsis: 
Trial 
Assessments 
Not applicable 
Disease Assessments: 
• 
Evaluation of tumor metabolic activity by 18F-FDG PET 
1. Synopsis: 
Statistical 
It is planned to enroll and treat approximately 50 patients during Part 2: 25 
patients in each dose-expansion cohort, selected by underlying malignancy. 
It is estimated that approximately 6 patients will be enrolled to the PET 
Expansion Cohort… 

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Methods and 
Sample Size 
Considerations 
 
10.1 Sample Size 
Considerations 
The planned number of patients to be enrolled may be adjusted when the 
two… 
It is planned to enroll and treat approximately 100 patients during Part 2: 25 
patients in each dose-expansion cohort, selected by underlying malignancy. 
The planned number of patients to be enrolled may be adjusted when the 
four… 
3.2.4.1 Protocol 
Sym013-01 
Text previously under 3.2.4 Summary of Clinical Findings 
This is the first clinical trial to study Pan-HER. 
Added subheading 3.2.4.1 
This is the first clinical trial to study Pan-HER.  As of Amendment 3, a total 
of 6 patients have been entered to Part 1 of this trial… 
3.2.4.2 Other 
Anticipated 
Clinical Findings 
Not applicable 
Added subheading 3.2.4.2 
3.5 Overall 
Benefits/Risk 
Enrollment will be staggered by 2 weeks between the first and second 
patient in each new higher dose level tested… 
Enrollment will be staggered by 2 weeks between the first and second 
patient in each new dose level tested… 
5.2.1 Rationale 
for Trial Design 
The trial is designed to select a safe and well-tolerated dose of Pan-HER 
during Part 1 and to investigate the selected dose in 2 groups… 
The trial is designed to select a safe and well-tolerated dose of Pan-HER 
during Part 1 and to investigate the selected dose in 4 groups… 
5.2.2 Rationale 
for Trial 
Population 
In Part 2, the RP2D will be investigated in patients with epithelial 
malignancies (2 tumor types to be selected; patients to be entered to Cohort 
A or Cohort B, collectively called “dose-expansion cohorts”)... A rationale 
for the 2 tumor types… 
In Part 2, the RP2D will be investigated in patients with epithelial 
malignancies (4 tumor types to be selected; patients to be entered to Cohort 
A, Cohort B, Cohort C, or Cohort D, collectively called “dose-expansion 
cohorts”)… A rationale for the 4 tumor types… 
5.3.3 Treatment 
 
7.1.3.1 Treatment 
Schedule 
Pan-HER will be administered by IV infusion on a weekly schedule, i.e. 
dosing will be every 7 (±2) days. Four (4) doses of Pan-HER administered 
weekly constitute 1 cycle.  
Pan-HER will be administered by IV infusion on a Q2W (previously Q1W) 
schedule, i.e. dosing will be every 14 (±2) days. Two (2) doses of Pan-HER 
administered Q2W constitute 1 cycle.  
 
As of Amendment 3: With the previous Q1W schedule, dosing was every 7 
(±2) days.  Four (4) doses of Pan-HER administered Q1W constituted 1 
cycle. 
Enrollment to the PET Expansion Cohort may follow. 
5.3.5 Schedule of 
Assessments 
A schedule of assessments for Part 1 and Part 2 is provided in Table 2. 
Schedule of assessments for Part 1 and Part 2 are provided in Table 2 (Q1W 
dosing) and Table 3 (Q2W dosing). 
6.2 Exclusion 
Criteria 
Exclusion Criteria #7: 
NOTE: With the exception of alopecia, patients must have recovered… 
Exclusion Criteria #7: 
NOTE: With the exception of persistent Grade 2 alopecia and/or peripheral 
neuropathy, patients must have recovered… 
7.1.3.2 Part 1, 
Does-Escalation 
The increase in dose between dose levels will follow a modified Fibonacci 
scheme… 
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When calculating the doses for each new dose level, the following approach 
will be applied…  
7.2.1 Pre-
Medication for 
Pan-HER 
Infusions 
Not applicable 
All patients must be premedicated as described 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… 
8.2.3 Dose-
Limiting 
Toxicities 
Evaluation (Part 1 
Only) 
 
9.5.2 Observation 
Period for Dose-
Limiting 
Toxicities 
• 
Reported during Cycle 1 with final assessment 7 days after the last 
dose of Cycle 1 or prior to dosing on Day 1 of Cycle 2 (C2/D1) 
• 
Reported during Cycle 1 with final assessment 14 days (previously 7 
days with Q1W dosing) after the last dose of Cycle 1 or prior to dosing 
on Day 1 of Cycle 2 (C2/D1) 
8.3.4 18F-FDG 
PET Imaging 
(PET Expansion 
Cohort Only) 
Not applicable 
Added section. 
8.4 
Pharmacokinetic 
Assessments 
Serum concentrations of total Pan-HER will support the PK endpoints of 
the trial. A subset of the PK samples will be analyzed for the serum levels 
of each of the six mAbs constituting Pan-HER. These results will be 
reported separately from the clinical trial report. 
Table 11 is for PK samples for Q1W dosing and Table 12 is for PK samples 
for Q2W dosing. 
Note:  Comprehensive collection of clinical samples is critical to the 
conduct of this study… 
Serum concentrations of each of the 6 mAbs that comprise Pan-HER will 
support the PK endpoints of the trial.  The serum concentrations may also 
be used in an exploratory population PK analysis which will be reported 
separately from the clinical trial report. 
10.4 Secondary 
and Exploratory 
Endpoint and 
Analysis 
All statistical analyses of the secondary endpoints for both phases will be 
performed after completion of Part 2 of the trial. 
All statistical analyses of the secondary and exploratory endpoints for both 
phases will be descriptive unless otherwise specified. Details will be 
specified in a separate statistical analysis plan. 
10.4.4 
Pharmacokinetic 
The PK endpoints will be derived based on the concentration time curves of 
Pan-HER, after the first and fourth infusion…  
The PK endpoints with Q2W dosing will be derived based on the 
concentration time curves of Pan-HER, after the first and third infusion…  

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Endpoints and 
Analyses 
As of Amendment 3:  For patients entered to Dose Level 1, 2 and 3 (1, 2, 
and 4 mg/kg, respectively) treated on a Q1W schedule…  
10.4.5 Additional 
Endpoints and 
Analyses 
Not applicable 
• 
Changes in tumor metabolism as evaluated by 18F-FDG PET 
 
21.4 Protocol Amendment 4 dated 04-May-2017 
• Modified the biomarker blood sample section to clarify that the collected biomarker sample is not plasma only 
• Clarified that the pre-medication dose for acetaminophen is recommended 
• Minor typographical error has been corrected 
 
Refer to Table 21 for the changes in Protocol Amendment 4. 
 
Table 21   Protocol Amendment 4 
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3.5 Overall 
Benefits/Risk 
As Pan-HER has not been investigated in humans, the benefits and the 
safety profile of Pan-HER cannot be established.   
As limited clinical information is available for patients treated with Pan-
HER (see Section 3.2.4.1), the benefits and the safety profile of Pan-HER 
have not been fully established.   
7.2.1 Pre-
Medication for 
Pan-HER 
Infusions 
Acetaminophen (optional) 1000 mg IV or PO (orally), approx. 0.5 hours 
prior to the start of Pan-HER infusion 
 
Acetaminophen (optional) such as 1000 mg IV or PO (orally), approx. 0.5 
hours prior to the start of Pan-HER infusion 
 
8.8 Biomarker 
Blood Sample 
Peripheral blood samples are taken for preparation of plasma and 
subsequent biomarker analysis. Analysis of all plasma samples will be 
performed at a central laboratory…  
 
Analysis of biomarker plasma samples may include genes…  
 
Aliquots of plasma samples will be stored… 
Peripheral blood samples are taken for subsequent biomarker analysis. 
Analysis of all samples will be performed at a central laboratory…  
 
Analysis of biomarker samples may include genes…  
 
Biomarker samples will be stored…  

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21.5 Protocol Amendment 5 dated 23-Jan-2018 
• Prophylaxis for both IRR and mucositis made mandatory in Part 1 (dose-escalation) to facilitate a more accurate evaluation of 
the safety and tolerability of Pan-HER at dose levels likely to be therapeutically active. 
• Added mandatory prophylactic treatment for both IRR and mucositis as well as supportive care measures in the event of Pan-
HER associated mucositis. 
• Prolonged the infusion of Pan-HER with delivery over a fixed infusion period of 4 hours to reduce the risk of IRRs. 
• Specified that increased infusion rate and reduced infusion duration after C1/D1 will no longer be allowed. 
• Modified exclusion criteria and prohibited medication to specify when the use of steroid therapy is allowed. 
• Added collection of blood samples for complement hemolytic activity analysis. 
• Specified the process for data recording, validation, review, and query resolution. 
• Included other minor updates, clarifications, and structural reformatting. 
 
Refer to Table 22 for the changes in Protocol Amendment 5. 
 
Table 22   Protocol Amendment 5 
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1 Synopsis: Overall 
Trial Design 
 
5.1 Overall Design 
and Plan 
 
7.1.3.2 Part 1, 
Dose-Escalation 
• Dose Level 1: 1 mg/kg  
• Dose Level 2: 2 mg/kg 
• Dose Level 3: 4 mg/kg 
• Dose Level 4: 6 mg/kg 
• Dose Level 5: 9 mg/kg 
• Dose Level 6: 12 mg/kg 
• Dose Level 7: 15 mg/kg 
• Dose Level 8: 18 mg/kg (highest potential dose allowed per protocol) 
 
Q1W 
• Dose Level 1: 1 mg/kg  
• Dose Level 2: 2 mg/kg 
• Dose Level 3: 4 mg/kg 
Q2W 
• Dose Level 4: 6 mg/kg 
• Dose Level 5: 9 mg/kg 
Q2W with mandatory intensive IRR and mucositis prophylaxis; 4h infusion 
(designated “P”) 
• Dose Level 5P: 9 mg/kg 
• Dose Level 6P: 12 mg/kg 
• Dose Level 7P: 15 mg/kg 
• Dose Level 8P: 18 mg/kg (highest potential dose allowed per protocol) 
As of Amendment 5, patients entered to Dose Level 5P and all patients 
thereafter must receive intensive prophylaxis…          
1 Synopsis: 
For Part 1 of the trial, Pan-HER will be administered following delivery of 
For Part 1 of the trial, Pan-HER will be administered following delivery of 

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Investigational 
Medicinal Product: 
Dose(s) and 
Treatment Schedule 
mandatory premedication prior to each infusion. 
 
For Part 2, premedication is mandatory prior to each dose of Pan-HER 
during Cycle 1. If the patient is without evidence of infusion-related 
reactions (IRRs) after Cycle 1, the Investigator may choose to withdraw 
premedication with subsequent dosing. Gradual withdrawal of 
premedication is recommended. 
 
The duration of infusion will be: 
• Approximately 2 hours (+10 min) for the 1st infusion 
• Approximately 1.5 hours (+10 min) for the 2nd infusion 
• Approximately 1 hour (+10 min) for subsequent infusions 
intensive prophylaxis, as defined herein, on a mandatory basis to reduce the 
risk of IRRs and oropharyngeal mucositis.    
 
For Part 2, IRR and mucositis prophylaxis is mandatory during Cycle 1 and 
Cycle 2. If the patient is without evidence of IRRs or mucositis after Cycle 
2, the Investigator may choose to withdraw related medications with 
subsequent dosing. Gradual withdrawal of medications is recommended. 
 
The duration of infusion will be (prior to Amendment 5): 
• Approximately 2 hours (+10 min) for the 1st infusion 
• Approximately 1.5 hours (+10 min) for the 2nd infusion 
• Approximately 1 hour (+10 min) for subsequent infusions 
 
The duration of infusion will be (effective with Amendment 5): 
• Minimum of 4 hours (+10 min) for all infusions. Titrated rate increases 
during infusions, and infusion duration reductions after C1/D1, will no 
longer be allowed.         
3.2.4.1 Protocol 
Sym013-01 
This is the first clinical trial to study Pan-HER.  As of Amendment 3, a 
total of 6 patients have been entered to Part 1 of this trial… 
As of Amendment 3:  Due to the occurrence of Grade 1-2 oral mucositis, 
rash, and diarrhea at the 4 mg/kg dose, the dosing interval in this trial has 
been changed from Q1W to every second week (Q2W; 2 doses equaling 1 
cycle)...   
This is the first clinical trial to study Pan-HER.  As of Amendment 5, a 
total of 16 patients have been entered to Part 1 of this trial…  
Regarding IRRs, despite required premedication with a glucocorticoid and 
an antihistamine, 2 of 4 patients at 4 mg/kg experienced Grade 1-2 
events…  
Regarding mucositis, Grade 1 to 2 events were observed in 4 of 4 patients 
at 4 mg/kg on the Q1W schedule, and on the Q2W schedule following 
recommended prophylaxis…   
Regarding rash and diarrhea, Grade 1-2 acneiform/maculopapular rash has 
been reported in 11 patients at 2 mg/kg and above; and Grade 1-2 diarrhea 
has been reported in 4 patients at 4 mg/kg and above.   
While data in this ongoing clinical trial have not been fully verified, other 
study drug-related AEs have included… 
As of Amendment 5:  As described, 2 events meeting the protocol DLT 
criteria have occurred in the 9 mg/kg cohort, IRR and mucositis, and while 
increased prophylaxis for each was recommended, it was not fully 
implemented in advance of these events...                                                          

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6.2 Exclusion 
Criteria 
3. Immunosuppressive or systemic hormonal therapy within 2 weeks prior 
to C1/D1 with the exception of the following allowed therapies: 
a. Hormonal therapy (e.g., Megace) for appetite stimulation 
b. Nasal, ophthalmic, inhaled, and topical glucocorticoid preparations 
c. Oral replacement glucocorticoid therapy for adrenal insufficiency 
d. Low-dose maintenance steroid therapy for other conditions 
(excluding steroid tapers for brain edema/metastases/radiation) 
e. Steroid therapy as prophylaxis for contrast reactions 
f. Hormonal contraceptive therapy  
g. Gonadotropin-releasing hormone (GnRH) analogs in patients with 
prostate cancer 
 
 
 
 
 
 
 
 
 
 
 
6. Known central nervous system (CNS) or leptomeningeal metastases not 
controlled by prior surgery or radiotherapy, or symptoms suggesting CNS 
involvement for which treatment is required 
 
7. Inadequate recovery from an acute toxicity associated with any prior 
antineoplastic therapy 
NOTE: With the exception of persistent Grade 2 alopecia and/or peripheral 
neuropathy, patients must have recovered from acute toxicity by C1/D1; 
any Grade 1 residual toxicity may be acceptable 
3. Immunosuppressive or systemic hormonal therapy (> 10 mg daily 
prednisone equivalent) within 2 weeks prior to C1/D1 with the exception of 
the following allowed therapies: 
a. Hormonal therapy (e.g. Megace) for appetite stimulation 
b. Nasal, ophthalmic, inhaled, and topical glucocorticoid preparations 
c. Hormone replacement therapy at standard doses for end-organ failure 
d. Steroid therapy as prophylaxis for contrast reactions 
e. Intra-articular steroid injections  
f. Hormonal therapy for ovarian suppression*, hormonal contraceptive 
therapy, post-menopausal hormone replacement therapy (HRT)  
g. Gonadotropin-releasing hormone (GnRH) analogs in patients with 
prostate cancer* 
h. Low-dose maintenance steroid therapy for other conditions 
(excluding steroid tapers for brain edema/metastases/radiation) 
i. Higher dose steroid therapy for treatment of an acute intercurrent 
illness in patients with stable disease or an ongoing response.  In such 
situations, study drug treatment should be interrupted for the duration 
of immunosuppressive therapy 
*Patients must have been on a stable dose for at least 3 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). 
 
6. Central nervous system (CNS) malignancies; known, untreated CNS or 
leptomeningeal metastases, or spinal cord compression, any of the above 
not controlled by prior surgery or radiotherapy, or symptoms suggesting 
CNS involvement for which treatment is required 
 
7. Inadequate recovery from an acute toxicity associated with any prior 
antineoplastic therapy 
NOTE: With the exception of persistent Grade 2 alopecia, peripheral 
neuropathy, decreased hemoglobin, and/or end-organ failure being 
adequately managed by hormone replacement therapy, patients must have 
recovered from acute toxicity by C1/D1; any Grade 1 residual toxicity may 
be acceptable 
6.3.1 Withdrawal 
NOTE: Patients meeting all three of the following are considered to have 
NOTE: Patients meeting all three of the following are considered to have 

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from Treatment 
met Hy’s Law criteria: 
• Hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above ULN of ALT or AST 
• Elevation of serum total bilirubin to ≥2×ULN, without findings of 
cholestasis (elevated serum alkaline phosphatase [ALP])… 
met Hy’s Law criteria: 
• Hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above ULN of ALT or AST (or > 3 × baseline if elevated 
at study entry due to hepatic involvement by tumor) 
• Elevation of serum total bilirubin to ≥2×ULN, without findings of 
cholestasis (elevated serum alkaline phosphatase [ALP] < 2×ULN)… 
7.1.3.4 Duration of 
Infusion for 
Administration of 
Pan-HER 
Not applicable 
Amendment 5 Note:  Prolongation of Pan-HER infusions by 0.5 hours was 
implemented on 2 occasions: 
• Beginning with Dose Level 5 (9 mg/kg), and due to Grade 2 IRRs in ≥ 
two thirds of patients entered to Dose Level 4 (6 mg/kg)…   
• During Dose Level 5 (9 mg/kg), and due to a Grade 3 IRR in a patient 
entered to Dose Level 5 (9 mg/kg)… 
Effective with Amendment 5 
Beginning with Dose Level 5P (9 mg/kg with intensive prophylaxis) and all 
patients thereafter, the duration of the infusion is required to be...         
7.1.4 Dose 
Adjustment and 
Delays of Pan-HER 
Weight changes (≥ ±10%) for a patient during trial will require 
recalculation of the dose. 
Weight changes (≥ ±10%) for a patient during trial should be accompanied 
by recalculation of the dose. 
7.1.4.1 Dose-
Adjustment for 
Body Weight 
The dose calculated may be used for subsequent infusions, unless body 
weight changes of ≥ ±10%, in which case the dose must be adjusted 
according to the change in body weight. 
The dose calculated may be used for subsequent infusions, unless body 
weight changes of ≥ ±10%, in which case the dose should be adjusted 
according to the change in body weight. 
7.1.4.3 Dose-
Reduction for Pan-
HER-Related 
Toxicities 
5. AST/ALT elevation >3×ULN with bilirubin elevation >2×ULN without 
evidence of cholestasis that cannot be explained by factors not related to 
Pan-HER 
5. AST/ALT elevation >3×ULN (or >3× baseline if elevated at study entry 
due to hepatic involvement by tumor) with bilirubin elevation >2×ULN 
without evidence of cholestasis that cannot be explained by factors not 
related to Pan-HER 
7.2.1 Pre-
Medication for Pan-
HER Infusion-
Related Reactions 
For Part 2, premedication is mandatory prior to each dose of Pan-HER 
during Cycle 1. 
All patients must be premedicated as described 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.  The recommended premedication doses are as follows: 
• Glucocorticoid therapy equivalent to 80-100 mg IV 
methylprednisolone, approx. 0.5 to 2 hours prior to the start of Pan-
HER infusion 
• Antihistamine (H1 antagonist) equivalent to 25-50 mg IV 
For Part 2, premedication is mandatory prior to each dose of Pan-HER 
during Cycle 1 and 2. 
As of Amendment 5, all patients must be premedicated as described with 
standard therapies that include each of the following.  The recommended 
premedication doses are as follows: 
• Montelukast (selective leukotriene receptor antagonist) 10 mg PO 
daily × 7 prior to each Pan-HER infusion…  
• Dexamethasone 10 mg PO, approx. 12 and 6 hours prior to the start of 
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diphenhydramine, approx. 0.5 hours prior to the start of Pan-HER 
infusion 
• Antihistamine (H2) antagonist (optional) such as 50 mg IV ranitidine 
or 30 mg famotidine, approx. 0.5 hours prior to the start of Pan-HER 
infusion 
• Acetaminophen (optional) such as 1000 mg IV or PO (orally), approx. 
0.5 hours prior to the start of Pan-HER infusion 
In Part 2, if a patient is without evidence of IRRs after Cycle 1… 
• Glucocorticoid therapy equivalent to 80-100 mg IV 
methylprednisolone, approx. 0.5 to 2 hours prior to the start of Pan-
HER infusion 
• Antihistamine (H1 antagonist) equivalent to 25-50 mg IV 
diphenhydramine, approx. 0.5 hours prior to the start of Pan-HER 
infusion 
• Antihistamine (H2) antagonist such as 50 mg IV ranitidine or 30 mg 
famotidine, approx. 0.5 hours prior to the start of Pan-HER infusion 
• Acetaminophen such as 1000 mg IV or PO (orally), approx. 0.5 hours 
prior to the start of Pan-HER infusion 
In Part 2, if a patient is without evidence of IRRs after Cycle 2… 
7.2.2.1 Mandatory 
Prophylactic 
Treatment 
Mandatory prophylactic treatment will be implemented for all patients 
treated in this trial should an increased incidence begin to occur… 
Oropharyngeal Mucositis 
As of Amendment 5, for prophylaxis against Pan-HER-associated 
oropharyngeal mucositis, the following management is mandatory 
throughout the Pan-HER treatment period… 
In Part 2, if a patient is without evidence of mucositis after Cycle 2, the 
Investigator may choose to withdraw prophylaxis… 
 
Other Toxicities 
Mandatory prophylactic treatment will be implemented for all patients 
treated in this trial should an increased incidence begin to occur… 
7.2.2.2 Therapeutic 
Treatment 
Not applicable 
Oropharyngeal Mucositis 
As of Amendment 5, in the event of development of Pan-HER-associated 
oropharyngeal mucositis, appropriate standard supportive care measures are 
to be implemented and should include… 
7.5.2 Prohibited 
Medication/Therapy 
and Procedures 
During the Trial 
• Systemic immunosuppressive or systemic hormonal therapy with the 
exception of the following allowed therapies: 
o Hormonal therapy (e.g., Megace) for appetite stimulation 
o Nasal, ophthalmic, inhaled, and topical glucocorticoid preparations 
o Oral replacement glucocorticoid therapy for adrenal insufficiency 
o Low-dose maintenance steroid therapy for other conditions 
(excluding steroid tapers for brain edema/metastases/radiation) 
o Steroid therapy as prophylaxis for contrast reactions 
o Hormonal contraceptive therapy  
o GnRH analogs in patients with prostate cancer 
o Low-dose maintenance steroid therapy for other conditions 
• Systemic immunosuppressive or systemic hormonal therapy (> 10 mg 
daily prednisone equivalent) with the exception of the following 
allowed therapies: 
o 
Hormonal therapy (e.g. Megace) for appetite stimulation 
o 
Nasal, ophthalmic, inhaled, and topical glucocorticoid 
preparations 
o 
Hormone replacement therapy at standard doses for end-organ 
failure 
o 
Steroid therapy as prophylaxis for contrast reactions 
o 
Intra-articular steroid injections 
o 
Hormonal therapy for ovarian suppression, hormonal 

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(excluding steroid tapers for brain edema/metastases/radiation) 
• Prophylactic use of hematopoietic growth factors during Cycle 1 
• Major surgery that would preclude the patient from complying with the 
requirements of the CTP 
contraceptive therapy, post-menopausal HRT  
o 
GnRH analogs in patients with prostate cancer 
o 
Low-dose maintenance steroid therapy for other conditions 
(excluding steroid tapers for brain edema/metastases/radiation) 
o 
Higher dose steroid therapy for treatment of an acute intercurrent 
illness in patients with stable disease or an ongoing response.  In 
such situations, study drug treatment should be interrupted for the 
duration of immunosuppressive therapy 
• Prophylactic use of hematopoietic growth factors during Cycle 1 
• Use of alcohol- or peroxide-containing mouthwashes 
• Major surgery that would preclude the patient from complying with the 
requirements of the CTP 
8.2.10 Complement 
Panel 
Not applicable 
To include total complement hemolytic activity (CH50), C3, C4, C3a, and 
C4a… 
Note:  Comprehensive collection of clinical samples is critical to the 
conduct of this study... 
A detailed laboratory manual specifying sample collection, handling, 
storage, and shipment will be provided to the trial sites in Part 2. 
8.7 Tumor Biopsy 
All analyses will be related to and used only in connection with the data 
collected in the present trial, and the identity of the patient will remain 
confidential. 
All analyses will be related to and used in connection with the data 
collected in the present trial and Pan-HER program, and the identity of the 
patient will remain confidential. 
8.8 Biomarker 
Blood Sample 
Note: End of cycle assessments may be conducted at any time during the 
week prior to Day 1 of the next cycle.  
Note: End of cycle assessments may be conducted at any time during the 
week prior to Day 1 of the next cycle. For those timepoints where both a 
blood sample and a tumor biopsy are to be obtained, blood sample to be 
collected first. 
14.2 Recording of 
Data 
Not applicable 
Clinical trial data for this study will be captured in an electronic format… 
A CRF is required to be submitted for every patient who receives any 
amount of study drug… 
All collected data will be entered into a validated database. 
14.3 Data Review 
During this Study 
Not applicable 
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.   
14.7 Data 
Processing 
The process of entering or uploading of data from trial sites will assure the 
accuracy of data entry into the database and include a validation at data 
entry time (real time validation). Entry or electronic transfer of other data 
The Sponsor or designee will be responsible for data processing in 
accordance with the applicable Data Management SOPs. A Data 
Management Plan will be generated for this trial. 

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than those directly from trial sites (e.g. imports of laboratory results) will 
follow the Sponsor requirements for data flow and transfer. 
 
The Sponsor or designee will be responsible for data processing in 
accordance with the applicable data management SOPs. A Data 
Management Plan will be generated for this trial. 
 
Database lock will occur once quality control procedure, and quality 
assurance procedures (if applicable) have been completed.  
 
The Portable Document Format (PDF) files of the CRFs will be provided to 
the Investigator before access to the CRF is revoked. 
 
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… 
  
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… 
 
Database lock will occur once quality control and quality assurance 
procedures (if applicable) have been completed upon reaching the data cut-
off for primary analysis.  
 
Portable Document Format (PDF) files of the CRFs will be provided to the 
Investigator before access to the CRF system is revoked. 
 
21.6 Protocol Amendment 6 dated 14-Jun-2018 
• Reintroduced Q1W dosing in Part 1 dose-escalation (previously halted with Amendment 3); all current and future patients to 
be treated under the prophylaxis and infusion duration conditions outlined in Amendment 5.   
• With reintroduction of Q1W dosing in Part 1, separate dose-escalation cohorts will be entered to assess the safety and 
tolerability of Pan-HER when administered either Q1W or Q2W; potential doses for evaluation are as previously listed. 
• Stated that the RP2D and regimen ultimately identified for use in Part 2 of this trial may be comprised of a fixed dose and 
schedule, a combination of doses to be administered on either a Q1W schedule or a Q2W schedule, or a combination dose and 
regimen. 
• Omitted expansion cohort of patients with fluorodeoxyglucose (FDG)-avid tumors planned to undergo pre- and post-dosing 
fluorine-18 radiolabeled FDG (18F-FDG) positron emission tomography (PET) for evaluation of effects of Pan-HER on tumor 
metabolism.   
• Identified populations to be evaluated in 2 of the 4 planned Part 2 dose-expansion cohorts; Cohort A will be a HER2+ solid 
tumor malignancies Basket Cohort and Cohort B will be pancreatic carcinoma. The composition of Cohort C and Cohort D 
remains TBD.  A protocol amendment detailing all expansion cohorts will follow. 
• Increased the number of trial sites and number of patients planned for this trial. 
• Modified the washout period between the end of prior therapy and dosing in this trial.  
• Specified that patients with primary CNS malignancies are not eligible for participation. 

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• Increased the total number of skin biopsies per patient from 2 to 3; the schedule for these procedures has been updated. 
• Limited Complement sampling to Part 2 only. 
• Clarified timeframes for reporting initial SAEs and follow-up SAE information to the Sponsor or designee are within 24 hours 
of awareness. 
• Modified the information to be collected with respect to pregnancies. 
• Updated the protocol background to include more recent scientific and clinical experience data. 
• Guidelines pertaining to the General Data Protection Regulation have been added. 
• Tables and Figure have been updated based on changes described. 
• Formatting adjustments, outline modifications, cross-reference link corrections, and other minor typographical corrections and 
slight wording changes are included. 
 
Refer to Table 23 for the changes in Protocol Amendment 6. 
 
Table 23   Protocol Amendment 6 
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ORIGINAL TEXT  
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1 Synopsis: 
Overall Trial 
Design 
 
 
As of Amendment 3: A total of 6 patients entered Part 1 of this trial: 1 
patient each at Dose Level 1 and 2, and 4 patients at dose Level 3 (1, 2, and 
4 mg/kg, respectively) were treated on a weekly schedule (Q1W; 4 doses 
equaling 1 cycle)…  Due to the occurrence of Grade 1-2 oral mucositis, rash, 
and diarrhea at the 4 mg/kg dose, the dosing interval in this trial has been 
changed from Q1W to every second week (Q2W; 2 doses equaling 1 
cycle)… 
Deleted; this text has been removed. 
This is an open-label, multicenter trial composed of 2 parts in which Pan-
HER will be evaluated when administered by the intravenous (IV) route on a 
Q2W (previously Q1W) schedule in patients with advanced epithelial 
malignancies without available therapeutic options. With the change in 
dosing schedule, 2 doses of Pan-HER administered Q2W constitute 1 cycle. 
Part 1 is a Phase 1a dose-escalation designed to determine the recommended 
phase 2 dose (RP2D). 
Part 2 is a Phase 2a dose-expansion at the RP2D. Four tumor types to be 
evaluated in this part of the trial will be selected based upon findings from 
Part 1, additional preclinical data, and additional clinical data available at 
that time from other agents inhibiting these targets… 
This is an open-label, multicenter trial composed of 2 parts in which Pan-
HER will be evaluated when administered by the intravenous (IV) route to 
patients with advanced epithelial malignancies without available therapeutic 
options.  
• Part 1 is a Phase 1a dose-escalation evaluating weekly (Q1W ) and every 
second week (Q2W) schedules of administration in separate dose-escalation 
cohorts to determine the recommended phase 2 dose (RP2D) and regimen of 
Pan-HER.  
• Part 2 is a Phase 2a dose-expansion at the RP2D and regimen. Four (4) 
dose-expansion cohorts will be evaluated in this part of the trial…  
The RP2D and regimen ultimately identified for use in Part 2 may be 
comprised of a fixed dose and schedule, a combination of doses to be 
administered on either a Q1W or Q2W schedule, or a combination dose and 
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Once the RP2D is selected, an expansion cohort of patients with 
fluorodeoxyglucose (FDG)-avid tumors will undergo pre- and post-dosing 
fluorine-18 radiolabeled FDG (18F-FDG) positron emission tomography 
(PET) imaging to evaluate the effects on tumor metabolism of Pan-HER 
when administered at this dose… 
Deleted; the PET Expansion Cohort has been removed. 
Patients entered to Dose Level 1, 2, and 3 (1, 2, and 4 mg/kg, respectively) 
were treated Q1W.  As of Amendment 3, the dosing schedule in this trial has 
been changed to Q2W.  Patients entered to the trial prior to implementation 
of this amendment will continue to be treated Q1W. 
As of Amendment 5, patients entered to Dose Level 5P and all patients 
thereafter must receive intensive prophylaxis…          
As of Amendment 6  
At the time of Amendment 3 to this protocol, a total of 6 patients had been 
entered to Part 1; 1 patient each at Dose Levels 1 and 2 (1 mg/kg and 2 
mg/kg, respectively), and 4 patients at Dose Level 3 (4 mg/kg) had been 
treated weekly (Q1W; 4 doses equaling 1 cycle)... 
Per Amendment 5, all patients must receive intensive prophylaxis, as 
defined herein, on a mandatory basis to reduce the risk of IRRs and 
oropharyngeal mucositis… 
With Amendment 6, Q1W dosing is reintroduced under the prophylaxis and 
infusion duration conditions outlined in Amendment 5… 
1 Synopsis: 
Overall Trial 
Design 
(continued) 
Part 1/Dose-escalation: The starting dose of Pan-HER will be 1.0 mg/kg.  
The following dose levels of Pan-HER potentially will be evaluated: 
Q1W 
• Dose Level 1: 1 mg/kg  
• Dose Level 2: 2 mg/kg 
• Dose Level 3: 4 mg/kg 
Q2W 
• Dose Level 4: 6 mg/kg 
• Dose Level 5: 9 mg/kg 
Q2W with mandatory intensive IRR and mucositis prophylaxis; 4h infusion 
(designated “P”) 
• Dose Level 5P: 9 mg/kg 
• Dose Level 6P: 12 mg/kg 
• Dose Level 7P: 15 mg/kg 
• Dose Level 8P: 18 mg/kg (highest potential dose allowed per protocol)  
Part 1/Dose-escalation 
The starting dose of Pan-HER will be 1 mg/kg Q1W.  The following dose 
levels of Pan-HER are planned to be evaluated: 
Q1W 
• Dose Level 1:        1 mg/kg Q1W  
• Dose Level 2:        2 mg/kg Q1W 
• Dose Level 3:        4 mg/kg Q1W 
• *Dose Level 4P:    6 mg/kg Q1W + P (lower doses with prophylaxis may 
be explored, if indicated) 
• *Dose Level 5P:    9 mg/kg Q1W + P  
• *Dose Level 6P:    12 mg/kg Q1W + P  
• *Dose Level 7P:    15 mg/kg Q1W + P 
• *Dose Level 8P:    18 mg/kg Q1W + P (highest potential dose allowed per 
protocol) 
Q2W 
• Dose Level 4:        6 mg/kg Q2W 
• Dose Level 5:        9 mg/kg Q2W 
• *Dose Level 5P:    9 mg/kg Q2W + P 
• *Dose Level 6P:    12 mg/kg Q2W + P 
• *Dose Level 7P:    15 mg/kg Q2W + P 
• *Dose Level 8P:    18 mg/kg Q2W + P (highest potential dose allowed per 
protocol) 
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infusion (designated “P”) 
The RP2D may be equal to or lower than the MTD. The RP2D will be 
selected based on safety data, as well as available PK and target engagement 
results, as applicable. 
 
 
RP2D: The RP2D may include a dose or a combination of doses (e.g., initial 
loading dose followed by a lower maintenance dose) equal to or lower than 
the MTD for the Q1W and/or Q2W dosing regimens.  A dose or doses 
between tolerated doses investigated in Part 1 may also be selected if data 
indicate this to be optimal… 
Once the RP2D is selected, enrollment to the PET Expansion Cohort may 
begin. 
Deleted; the PET Expansion Cohort has been removed. 
Part 2/Dose-expansion: Once the RP2D has been established during dose-
escalation, enrollment into the 4 separate dose-expansion cohorts will 
commence (Cohort A, Cohort B, Cohort C, or Cohort D). All patients 
enrolled will be treated with Q2W doses of Pan-HER at the established 
RP2D. 
Part 2/Dose-expansion  
Once the RP2D and regimen have been established during dose-escalation, 
enrollment into the 4 separate dose-expansion cohorts will commence 
(Cohort A, Cohort B, Cohort C, or Cohort D). All patients enrolled will be 
treated with Pan-HER at the established RP2D and regimen. 
1 Synopsis: Trial 
Sites 
Part 1/Dose-escalation: 2 to 3 investigational trial sites… 
Part 2/Dose-expansion: Approximately 20 trial sites 
Part 1/Dose-escalation: Approximately 3 investigational trial sites… 
Part 2/Dose-expansion: Approximately 25 trial sites 
1 Synopsis: 
Planned Trial 
Period 
Part 1 of the trial is expected to begin Q4 2016.  
Patients will be sequentially enrolled to dose-escalation cohorts until 
establishment of a RP2D, expectedly beginning of 2018.  Enrollment to the 
PET Expansion Cohort may follow. 
Enrollment to the expansion cohorts in Part 2 of the trial will commence 
upon approval of a clinical trial protocol (CTP) amendment defining the 
expansion cohorts as well as the RP2D to be further explored. Enrollment to 
Part 2 is expected to be from second half of 2018 to second half of 2019. 
Part 1 of the trial is expected to begin Q4 2016.  
Patients will be sequentially enrolled to dose-escalation cohorts on either a 
Q1W or a Q2W schedule until establishment of a RP2D and regimen, 
expectedly Q1 2019.   
Enrollment to the expansion cohorts in Part 2 of the trial will commence 
upon approval of a protocol amendment defining the expansion cohorts to be 
further explored. Enrollment to Part 2 is expected to be from Q1 2019 to Q3 
2020. 
1 Synopsis: 
Primary and 
Secondary 
Objectives 
Primary objective of Part 1/Dose-escalation: To assess the safety and 
tolerability of Pan-HER when administered Q1W and Q2W by IV infusion 
to patients with advanced epithelial malignancies without available 
therapeutic options.   
Secondary objectives of Part 1/Dose-escalation:  
1. To determine a RP2D of Pan-HER 
Primary objective of Part 1/Dose-escalation: To assess the safety and 
tolerability of Pan-HER when administered either Q1W or Q2W by IV 
infusion to separate dose-escalation cohorts of patients with advanced 
epithelial malignancies without available therapeutic options.   
Secondary objectives of Part 1/Dose-escalation:  
1. To determine a RP2D and regimen of Pan-HER 
Exploratory objective of Part 1/Dose-escalation:  To evaluate by 18F-
FDG PET the effects on tumor metabolism of Pan-HER when administered 
Q2W at the RP2D in an expansion cohort of patients with FDG-avid tumors 
Deleted; the PET Expansion Cohort has been removed. 
 
Primary objective of Part 2/Dose-expansion: To evaluate the antitumor 
effect of Pan-HER when administered Q2W at the RP2D to patients with 
advanced epithelial malignancies (4 tumor types to be selected). 
 
Primary objective of Part 2/Dose-expansion: To evaluate the antitumor 
effect of Pan-HER when administered at the RP2D and regimen to patients 
with advanced epithelial malignancies without available therapeutic options. 
Four (4) dose-expansion cohorts will be evaluated. 
1 Synopsis: Trial 
Periods 
Treatment period: Patients in the trial will receive Q2W (previously Q1W) 
IV infusions of Pan-HER until occurrence of any of the following: 
Treatment period: Patients in the trial will receive either Q1W or Q2W IV 
infusions of Pan-HER, depending upon cohort assignment, until occurrence 

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unacceptable toxicity or other conditions preventing further treatment, 
disease progression, termination of the trial, or patient’s decision to 
withdraw. 
of any of the following: unacceptable toxicity or other conditions preventing 
further treatment, disease progression, termination of the trial, or patient’s 
decision to withdraw. 
1 Synopsis: 
Number of 
Patients 
In total, approximately 131 patients will be included in this trial. 
It is estimated that approximately 25 patients will be enrolled to receive 
increasing doses of Pan-HER during Part 1... 
In total, approximately 134 patients will be included in this trial. 
It is estimated that approximately 34 patients will be enrolled to receive 
increasing doses of Pan-HER during Part 1… 
It is estimated that approximately 6 patients will be enrolled to the PET 
Expansion Cohort.  The exact number of patients will depend upon 
identification of patients with FDG-avid tumors. 
Deleted; the PET Expansion Cohort has been removed. 
 
It is planned to enroll and treat approximately 100 patients during Part 2 
with 25 patients in each dose-expansion cohort. 
It is planned to enroll and treat approximately 100 patients during Part 2. 
1 Synopsis: Main 
Inclusion and 
Exclusion 
Criteria 
Main inclusion criteria all patients, Part 1 and Part 2: 
• PET Expansion Cohort:  Epithelial malignancy, measurable according to 
RECIST v1.1 that has been confirmed by 18F-FDG-PET imaging to be 
FDG-avid within 28 days prior to C1/D1 
Deleted; the PET Expansion Cohort has been removed. 
 
Additional inclusion criteria applicable to Part 2 ONLY: 
• Epithelial malignancy (types to be specified in a CTP amendment), 
measurable according to RECIST v1.1 that has been confirmed by computed 
tomography (CT) or magnetic resonance imaging (MRI) within 4 weeks 
prior to C1/D1 
Additional inclusion criteria applicable to Part 2 ONLY: 
• Epithelial malignancy (HER2+ solid tumor malignancies, pancreatic 
carcinoma, and 2 other tumor types to be specified in a protocol 
amendment), measurable according to RECIST v1.1 that has been confirmed 
by computed tomography (CT) or magnetic resonance imaging (MRI) within 
4 weeks prior to C1/D1 
Main exclusion criteria: 
• Any antineoplastic agent (standard or investigational) within 4 weeks prior 
to C1/D1 
Main exclusion criteria: 
• Any antineoplastic agent for the primary malignancy (standard or 
investigational) without delayed toxicity within 4 weeks or 5 plasma half-
lives, whichever is shortest, prior to C1/D1except: 
a. Nitrosoureas and mitomycin C within 6 weeks prior to C1/D1 
Main exclusion criteria: 
• Known central nervous system (CNS) or leptomeningeal metastases not 
controlled by prior surgery or radiotherapy, or symptoms suggesting CNS 
involvement for which treatment is required 
Main exclusion criteria: 
• Central nervous system (CNS) malignancies including:   
a. Primary malignancies of the CNS 
b. Known, untreated CNS or leptomeningeal metastases, or spinal cord 
compression; patients with any of these not controlled by prior surgery or 
radiotherapy, or symptoms suggesting CNS metastatic involvement for 
which treatment is required 
1 Synopsis: 
Investigational 
Medicinal 
Product: Dose(s) 
and Treatment 
Pan-HER will be initiated on C1/D1 and will be administered Q2W 
(previously Q1W) by IV infusion in cycles of treatment: 
• Dosing on Day 1 and 15 of each 28-day cycle (±2 days) 
As of Amendment 3:  Doses previously administered on Days 8 and 22 are 
omitted. 
All patients will receive the allocated dose of Pan-HER until treatment 
Pan-HER will be initiated on C1/D1 and, based on cohort assignment, will 
be administered either Q1W or Q2W to separate dose-escalation cohorts of 
patients by IV infusion in cycles of treatment: 
• Q1W: Dosing on Day 1, 8, 15, and 22 of each 28-day cycle (±2 days)  
• Q2W: Dosing on Day 1 and 15 of each 28-day cycle (±2 days) 
All patients will receive the allocated dose and schedule of Pan-HER until 

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Schedule 
withdrawal… 
treatment withdrawal… 
The duration of infusion will be (prior to Amendment 5): 
• Approximately 2 hours (+10 min) for the 1st infusion 
• Approximately 1.5 hours (+10 min) for the 2nd infusion 
• Approximately 1 hour (+10 min) for subsequent infusions 
Deleted; infusion duration information prior to Amendment 5 has been 
removed. 
1 Synopsis: 
Dose-Limiting 
Toxicities (Part 1 
only) 
A minimum of 2 infusions (previously 4 infusions with Q1W dosing) of 
Pan-HER must have been administered at the assigned dose for a patient to 
have completed the DLT-observation period. 
A minimum of 4 infusions with Q1W dosing, and 2 infusions with Q2W 
dosing must have been administered at the assigned dose for a patient to 
have completed the DLT-observation period. 
1 Synopsis: Trial 
Assessments 
Safety Assessments: 
Not applicable 
Disease Assessments: 
• Evaluation of tumor metabolic activity by 18F-FDG PET 
Additional Assessments: 
• PK sampling with extended PK-profiling after the first and fourth infusion 
of Pan-HER (C1/D1 and C1/D22, respectively) 
Safety Assessments: 
• Complement Panel, applicable for Part 2 
Disease Assessments: 
Deleted; the PET Expansion Cohort has been removed. 
Additional Assessments: 
• PK sampling with extended PK-profiling after the first and fourth infusion 
of Pan-HER (C1/D1 and C1/D22, respectively) for Q1W dosing, and after 
the first and third infusion of Pan-HER (C1/D1 and C2/D1, respectively) for 
Q2W dosing 
1 Synopsis: 
Statistical 
Methods and 
Sample Size 
Considerations 
…Based on the dose-escalation design, it is planned to enroll approximately 
25 patients during the first part of the trial. 
…Based on the dose-escalation design, it is planned to enroll approximately 
34 patients during the first part of the trial. 
It is estimated that approximately 6 patients will be enrolled to the PET 
Expansion Cohort.  The exact number of patients will depend upon 
identification of patients with FDG-avid tumors.  Observations regarding 
changes in tumor metabolism will be described. 
Deleted; the PET Expansion Cohort has been removed. 
It is planned to enroll and treat approximately 100 patients during Part 2: 25 
patients in each dose-expansion cohort, selected by underlying malignancy. 
The planned number of patients to be enrolled may be adjusted when the 
four tumor types have been selected... 
It is planned to enroll and treat approximately 100 patients during Part 2. 
The planned number of patients to be enrolled may be adjusted when the 4 
expansion cohorts (i.e., based on defined molecular profile(s) and tumor 
types) have been selected… 
3.1.2 and 3.1.3 
Not applicable 
Sections 3.1.2 and 3.1.3 have been updated to include more recent scientific 
and clinical experience data, including new citations from new references 
25-29. 
3.2.4.1 Protocol 
Sym013-01 
This is the first clinical trial to study Pan-HER.  As of Amendment 5, a total 
of 16 patients have been entered to Part 1 of this trial: 1 patient each at Dose 
Level 1 and 2, and 4 patients at Dose Level 3 (1, 2, and 4 mg/kg, 
respectively) dosed on a weekly (Q1W) schedule, followed by 3 patients at 
Dose Level 4 and 7 patients at Dose Level 5 (6 and 9 mg/kg, respectively) 
dosed on an every second week (Q2W) schedule. 
This is the first clinical trial to study Pan-HER.  As of Amendment 6, a total 
of 19 patients have been entered to Part 1 of this trial: 1 patient each at 1 
mg/kg and 2 mg/kg weekly (Q1W), 4 patients at 4 mg/kg Q1W, 3 patients at 
6 mg/kg every second week (Q2W), 7 patients at 9 mg/kg Q2W, and with 
Amendment 5, 3 patients at the recently initiated cohort of 9 mg/kg Q2W + 
mandatory intensive prophylaxis for infusion-related reactions (IRRs) and 
oropharyngeal mucositis… 

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Additional text has been revised throughout this entire section. 
As of Amendment 6: With Amendment 3, Q1W dosing was halted; with 
Amendment 6, Q1W dosing is reintroduced under the prophylaxis and 
infusion duration conditions outlined in Amendment 5…                                   
4.1.1 Primary 
Objective (Part 1) 
To assess the safety and tolerability of Pan-HER when administered Q1W 
and Q2W by IV infusion to patients with advanced epithelial malignancies 
without available therapeutic options.   
As of Amendment 3:  The dosing interval in this trial has been changed from 
Q1W to Q2W (2 doses equaling 1 cycle)…   
To assess the safety and tolerability of Pan-HER when administered either 
Q1W or Q2W by IV infusion to separate dose-escalation cohorts of patients 
with advanced epithelial malignancies without available therapeutic options.    
4.1.2 Secondary 
Objectives 
1. To determine a RP2D of Pan-HER 
1. To determine a RP2D and regimen of Pan-HER 
4.1.3 Exploratory 
Objective 
To evaluate by fluorine-18 radiolabeled fluorodeoxyglucose (18F-FDG) 
positron emission tomography (PET) the effects on tumor metabolism of 
Pan-HER when administered Q2W at the RP2D in an expansion cohort of 
patients with FDG-avid tumors. 
Deleted; the PET Expansion Cohort has been removed. 
4.2.1 Primary 
Objective (Part 2) 
To evaluate the antitumor effect of Pan-HER when administered Q2W at the 
RP2D to patients with advanced epithelial malignancies without available 
therapeutic options (4 tumor types to be selected). 
To evaluate the antitumor effect of Pan-HER when administered at the 
RP2D and regimen to patients with advanced epithelial malignancies 
without available therapeutic options.  
Four (4) dose-expansion cohorts will be evaluated: Cohort A (HER2+ solid 
tumor malignancy Basket Cohort*), Cohort B (pancreatic carcinoma), 
Cohort C (to be determined [TBD]), or Cohort D (TBD)… 
5.1 Overall 
Design and Plan 
This is an open-label, multicenter trial composed of 2 parts in which Pan-
HER will be evaluated when administered by the IV route on a Q2W 
(previously Q1W) schedule in patients with advanced epithelial 
malignancies without available therapeutic options: 
• Part 1 is a Phase 1a dose-escalation designed to determine the RP2D 
• Part 2 is a Phase 2a dose-expansion at the RP2D. Four tumor types to be 
evaluated in this part of the trial will be selected based upon findings from 
Part 1, additional preclinical data, and additional clinical data available at 
that time from other agents inhibiting these targets. Patients will be entered, 
depending upon their underlying malignancy, to one of 4 corresponding 
expansion cohorts, Cohort A, Cohort B, Cohort C, or Cohort D. 
 
This is an open-label, multicenter trial composed of 2 parts in which Pan-
HER will be evaluated when administered by IV to patients with advanced 
epithelial malignancies without available therapeutic options: 
• Part 1 is a Phase 1a dose-escalation evaluating Q1W and Q2W schedules 
of administration in separate dose-escalation cohorts to determine the 
recommended phase 2 dose (RP2D) and regimen of Pan-HER  
• Part 2 is a Phase 2a dose-expansion at the RP2D and regimen. Four (4) 
dose-expansion cohorts will be evaluated in this part of the trial and will be 
selected based upon findings from Part 1, additional preclinical data, and 
additional clinical data available at that time from other agents inhibiting 
these targets. Patients will be entered, depending upon either a defined 
molecular profile or profiles, or their underlying malignancy, to 1 of 4 
corresponding expansion cohorts: Cohort A (HER2+ solid tumor 
malignancy Basket Cohort), Cohort B (pancreatic carcinoma), Cohort C 
(TBD), or Cohort D (TBD). 
During Part 1, cohorts of patients will receive increasing doses of Pan-HER 
until establishment of: 
• A maximum administered dose (MAD); a dose, which is evaluated during 
dose-escalation but demonstrates toxicity above the target toxicity level of 
During Part 1, cohorts of patients will receive increasing doses of Pan-HER 
on either a Q1W or a Q2W schedule until establishment of the following for 
each schedule: 
• A maximum administered dose (MAD), the highest dose level 

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33% 
• An MTD; a dose level below the MAD, which is evaluated to have a 
toxicity level of 33% or less (An MTD may or may not be found within the 
dose levels tested. Dose-escalation may be stopped due to toxicity 
observations other than DLTs and/or results from PK and/or target 
engagement analyses) 
• A RP2D to be used in Part 2 (The RP2D may be equal to or lower than the 
MTD. The RP2D will be selected based on safety data, as well as available 
PK and target engagement results, as applicable) 
administered (in mg/kg). 
• An MTD; a dose level below the MAD, which is evaluated to have a 
toxicity level of <33%. An MTD may or may not be found… 
• A RP2D; the RP2D may be equal to or lower than the MTD for the Q1W 
and/or Q2W dosing regimens. 
During Part 2, expansion cohorts of patients will receive the RP2D and 
regimen...  
The RP2D and regimen will be selected based on tolerability demonstrated 
with Q1W and Q2W dosing during Part 1… 
The starting dose of Pan-HER will be 1.0 mg/kg.  The following dose levels 
of Pan-HER potentially will be evaluated: 
Q1W 
• Dose Level 1: 1 mg/kg 
• Dose Level 2: 2 mg/kg 
• Dose Level 3: 4 mg/kg 
Q2W 
• Dose Level 4: 6 mg/kg 
• Dose Level 5: 9 mg/kg 
Q2W with mandatory intensive IRR and mucositis prophylaxis; 4h infusion 
(designated “P”) 
• Dose Level 5P: 9 mg/kg  
• Dose Level 6P: 12 mg/kg 
• Dose Level 7P: 15 mg/kg 
• Dose Level 8P: 18 mg/kg (highest potential dose allowed per protocol) 
Patients entered to Dose Level 1, 2 and 3 (1, 2, and 4 mg/kg, respectively) 
were treated Q1W.  As of Amendment 3, the dosing schedule in this trial has 
been changed to Q2W.  Patients entered to the trial prior to implementation 
of this amendment will continue to be treated Q1W. 
As of Amendment 5, patients entered to Dose Level 5P and all patients 
thereafter must receive intensive prophylaxis, as defined herein… 
The Part 1 starting dose of Pan-HER will be 1 mg/kg Q1W.  The following 
dose levels of Pan-HER are planned to be evaluated: 
Q1W 
• Dose Level 1:  
1 mg/kg Q1W 
• Dose Level 2:  
2 mg/kg Q1W 
• Dose Level 3:  
4 mg/kg Q1W 
• *Dose Level 4P: 6 mg/kg Q1W + P (lower doses with prophylaxis may be 
explored, if indicated) 
• *Dose Level 5P:  9 mg/kg Q1W + P  
• *Dose Level 6P:  12 mg/kg Q1W + P  
• *Dose Level 7P:  15 mg/kg Q1W + P 
• *Dose Level 8P:  18 mg/kg Q1W + P (highest potential dose allowed per 
protocol) 
Q2W 
• Dose Level 4:  
6 mg/kg Q2W 
• Dose Level 5:  
9 mg/kg Q2W 
• *Dose Level 5P:  9 mg/kg Q2W+ P   
• *Dose Level 6P:  12 mg/kg Q2W+ P  
• *Dose Level 7P:  15 mg/kg Q2W + P 
• *Dose Level 8P:  18 mg/kg Q2W + P (highest potential dose allowed per 
protocol) 
*Mandatory intensive IRR and oropharyngeal mucositis prophylaxis; 4-hour 
infusion (designated “P”) 
Note: Patients entered to Dose Levels 1, 2 and 3 were treated Q1W.  As of 
Amendment 3, the dosing schedule in this trial was changed to Q2W.  
Patients entered to the trial prior to implementation of this amendment could 
continue to be treated Q1W. 
Note: As of Amendment 5, patients entered to Dose Level 5P and all 
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to reduce the risk of IRRs and oropharyngeal mucositis, and must receive 
Pan-HER over a fixed (at minimum) 4-hour (+10 min) period… 
Note: As of Amendment 6, Q1W dosing is reintroduced under the 
prophylaxis and infusion duration conditions outlined in Amendment 5… 
5.1 Overall 
Design and Plan 
(continued) 
Once the RP2D is selected, an expansion cohort of patients with FDG-avid 
tumors will undergo pre- and post-dosing 18F-FDG PET imaging to evaluate 
the effects on tumor metabolism of Pan-HER when administered at this 
dose.  Imaging to be paired with computed tomography (CT)/ magnetic 
resonance imaging (MRI) conducted for Disease Status Evaluation.  Accrual 
to this cohort may occur concurrent with accrual to Part 2 of the study. 
Deleted; the PET Expansion Cohort has been removed. 
During Part 2, the RP2D will be evaluated in 4 dose-expansion cohorts of 
patients with distinct types of epithelial malignancies. The 4 types of 
malignancies will be defined based upon findings from Part 1, additional 
preclinical data, and additional clinical data available at that time from other 
agents inhibiting these targets… 
Patients enrolled to dose-expansion cohorts will be treated with Q2W 
(previously Q1W) IV doses of Pan-HER at the RP2D to investigate the 
antitumor activity of Pan-HER and to further evaluate safety and 
tolerability… 
During Part 2, the RP2D and regimen will be evaluated in 4 dose-expansion 
cohorts of patients (Cohort A, Cohort B, Cohort C, or Cohort D). A protocol 
amendment will be submitted specifying the inclusion and exclusion criteria 
related to each dose-expansion cohort. 
Patients enrolled to dose-expansion cohorts will be treated with IV doses of 
Pan-HER at the RP2D and regimen to investigate the antitumor activity of 
Pan-HER and to further evaluate safety and tolerability… 
The number of investigational trial sites, hereafter called “trial sites”, 
expected to participate will be approximately 2 to 3 in Part 1 and 20 in Part 
2. 
The number of investigational trial sites, hereafter called “trial sites”, 
expected to participate will be approximately 3 in Part 1 and 25 in Part 2. 
5.2.1 Rationale 
for Trial Design 
Four (4) tumor types to be evaluated in Part 2 will be selected based upon 
findings from Part 1, additional preclinical data, and additional clinical data 
from other agents inhibiting these targets available at that time. A CTP 
amendment will be submitted, detailing the MTD (if found within the dose 
levels tested), the RP2D, and further specifying the inclusion and exclusion 
criteria related to each dose-expansion cohort. 
Four (4) dose-expansion cohorts to be evaluated in Part 2 will be selected 
based upon findings from Part 1, additional preclinical data, and additional 
clinical data from other agents inhibiting these targets available at that time. 
A protocol amendment will be submitted specifying the inclusion and 
exclusion criteria related to each dose-expansion cohort. 
5.2.2 Rationale 
for Trial 
Population 
In Part 2, the RP2D will be investigated in patients with epithelial 
malignancies (4 tumor types to be selected; patients to be entered to Cohort 
A, Cohort B, Cohort C, or Cohort D, collectively called “dose-expansion 
cohorts”) without available therapeutic options. The selection of tumor types 
in Part 2 will be based upon findings from Part 1, additional preclinical data, 
and additional clinical data from other agents inhibiting these targets 
available at that time. A rationale for the 4 tumor types selected will be 
provided prior to opening Part 2 of the trial. 
In Part 2, the RP2D and regimen will be investigated in patients with 
epithelial malignancies without available therapeutic options (4 cohorts; 
patients to be entered to Cohort A [HER2+ solid tumor malignancy Basket 
Cohort], Cohort B [pancreatic carcinoma], Cohort C [TBD], or Cohort D 
[TBD], collectively called “dose-expansion cohorts”). The selection of 
expansion cohorts in Part 2 will be based upon findings from Part 1, 
additional preclinical data, and additional clinical data from other agents 
inhibiting these targets available at that time. A rationale for the 4 tumor 
types selected will be provided prior to opening Part 2 of the trial. 
5.3.1 Screening 
A copy of the fully executed Screening and Allocation Form will be returned 
to the trial site for archiving. This form documents the allocated dose of Pan-
HER. 
A copy of the fully executed Screening and Allocation Form will be returned 
to the trial site for archiving. This form documents the allocated dose and 
schedule of Pan-HER. 

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5.3.3 Treatment 
Pan-HER will be administered by IV infusion on a Q2W (previously Q1W) 
schedule, i.e. dosing will be every 14 (±2) days. Two (2) doses of Pan-HER 
administered Q2W constitute 1 cycle.  
As of Amendment 3: With the previous Q1W schedule, dosing was every 7 
(±2) days.  Four (4) doses of Pan-HER administered Q1W constituted 1 
cycle. 
Patients in Part 1 will be enrolled to dose-escalation cohorts until 
establishment of an MAD, an MTD and/or a RP2D.  Enrollment to the PET 
Expansion Cohort may follow. 
During Part 2, all patients will receive the RP2D of Pan-HER. 
For all patients, the dose to be administered will be documented on the 
Screening and Allocation Form. Patients will receive the allocated dose 
according to the assigned dose level until treatment withdrawal.  
Pan-HER will be administered by IV infusion on either a Q1W or a Q2W 
schedule: 
• Q1W: dosing will be every 7 (±2) days. Four (4) doses of Pan-HER 
administered Q1W constitute 1 cycle. 
• Q2W: dosing will be every 14 (±2) days. Two (2) doses of Pan-HER 
administered Q2W constitute 1 cycle.  
Patients in Part 1 will be enrolled to either Q1W or Q2W dose-escalation 
cohorts until establishment of an MAD, an MTD, and/or a RP2D for each 
schedule.   
During Part 2, all patients will receive the RP2D and regimen of Pan-HER. 
For all patients, the dose and schedule to be administered will be 
documented on the Screening and Allocation Form. Patients will receive the 
allocated dose and schedule according to their cohort assignment until 
treatment withdrawal.  
5.4 Recruitment 
Period 
Patients will be sequentially enrolled to dose-escalation cohorts until 
establishment of a RP2D, expectedly beginning of 2018.  Enrollment to the 
PET Expansion Cohort may follow. 
Enrollment to the expansion cohorts in Part 2 of the trial will commence 
upon approval of a CTP amendment, defining the expansion cohorts as well 
as the RP2D to be further explored. Enrollment is expected to be from 
second half of 2018 to second half of 2019. 
Patients will be sequentially enrolled to dose-escalation cohorts on either a 
Q1W or a Q2W schedule until establishment of a RP2D and regimen, 
expectedly Q1 2019.   
Enrollment to the expansion cohorts in Part 2 of the trial will commence 
upon approval of a protocol amendment defining the expansion cohorts to be 
further explored. Enrollment is expected to be from Q1 2019 to Q3 2020. 
5.5 Number of 
Patients 
In total, approximately 131 patients will be included in this trial. 
It is estimated that approximately 25 patients will be enrolled to receive 
increasing doses of Pan-HER during Part 1. 
In total, approximately 134 patients will be included in this trial. 
It is estimated that approximately 34 patients will be enrolled to receive 
increasing doses of Pan-HER during Part 1. 
It is estimated that approximately 6 patients will be enrolled to the PET 
Expansion Cohort.  The exact number of patients will depend upon 
identification of patients with FDG-avid tumors. 
Deleted; the PET Expansion Cohort has been removed. 
It is planned to enroll and treat approximately 100 patients during Part 2: 25 
patients in each dose-expansion cohort. 
It is planned to enroll and treat approximately 100 patients during Part 2. 
6.1 Inclusion 
Criteria 
8. PET Expansion Cohort: 
Epithelial malignancy, measurable according to RECIST v1.1 that has been 
confirmed by 18F-FDG-PET imaging to be FDG-avid within 28 days prior 
to C1/D1 
NOTE: Measurable disease is defined as 1 or more target lesions assessed by 
CT or MRI. A tumor lesion situated in a previously irradiated area is 
considered measurable only if subsequent disease progression has been 
documented in the lesion 
Deleted; the PET Expansion Cohort has been removed. 
Part 2 ONLY: 
a. Epithelial malignancy (types to be specified in a CTP amendment), 
measurable according to RECIST v1.1 that has been confirmed by computed 
Part 2 ONLY: 
a. Epithelial malignancy (HER2+ solid tumor malignancy Basket Cohort, 
pancreatic carcinoma, and 2 other tumor types to be specified in a protocol 

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tomography (CT) or magnetic resonance imaging (MRI) within 4 weeks 
prior to C1/D1 
amendment), measurable according to RECIST v1.1 that has been confirmed 
by CT or MRI within 4 weeks prior to C1/D1 
6.2 Exclusion 
Criteria 
1. Any antineoplastic agent (standard or investigational) within 4 weeks 
prior to C1/D1 
1. Any antineoplastic agent for the primary malignancy (standard or 
investigational) without delayed toxicity within 4 weeks or 5 plasma half-
lives, whichever is shortest, prior to C1/D1 except: 
• Nitrosoureas and mitomycin C within 6 weeks prior to C1/D1 
6. Central nervous system (CNS) malignancies; known, untreated CNS or 
leptomeningeal metastases, or spinal cord compression, any of the above not 
controlled by prior surgery or radiotherapy, or symptoms suggesting CNS 
involvement for which treatment is required 
NOTE: Patients with treated CNS metastases will be eligible if they are 
asymptomatic, do not require corticosteroids or anticonvulsants, and have 
confirmation of at least stable brain disease status as assessed by 2 imaging 
studies performed at least 4 weeks apart with the most recent study 
performed within 4 weeks prior to first trial drug administration 
6. Central nervous system (CNS) malignancies including:  
a. Primary malignancies of the CNS 
b. Known, untreated CNS or leptomeningeal metastases, or spinal cord 
compression; patients with any of these not controlled by prior surgery or 
radiotherapy, or symptoms suggesting CNS metastatic involvement for 
which treatment is required 
Note: Patients with treated CNS metastases will be eligible if they are 
asymptomatic, do not require corticosteroids, and have confirmation of at 
least stable brain disease status as assessed by 2 imaging studies performed 
at least 4 weeks apart with the most recent study performed within 4 weeks 
prior to first trial drug administration. Prophylactic anticonvulsant 
medications are allowed.   
Patients with newly identified CNS metastases during study will be 
considered to have PD and will be discontinued from treatment. 
7.1.3.1 Treatment 
Schedule 
All patients will be administered IV infusions of Pan-HER, dosed according 
to body weight, through a peripheral line or indwelling venous access 
device, and with the use of an infusion pump and an inline filter. Pan-HER 
will be administered on a Q2W (previously Q1W) schedule, i.e. dosing will 
be every 14 (±2) days. Two (2) doses of Pan-HER administered Q2W 
constitute 1 cycle. 
As of Amendment 3: With the previous Q1W schedule, dosing was every 7 
(±2) days.  Four (4) doses of Pan-HER administered Q1W constituted 1 
cycle. 
All patients will be administered IV infusions of Pan-HER, dosed according 
to body weight, through a peripheral line or indwelling venous access 
device, and with the use of an infusion pump and an inline filter. Pan-HER 
will be administered on either a Q1W or a Q2W schedule:  
• Q1W: dosing will be every 7 (±2) days. Four (4) doses of Pan-HER 
administered Q1W constitute 1 cycle 
• Q2W: dosing will be every 14 (±2) days. Two (2) doses of Pan-HER 
administered Q2W constitute 1 cycle   
7.1.3.2 Part 1, 
Dose-Escalation 
The starting dose of Pan-HER will be 1.0 mg/kg. The following dose levels 
of Pan-HER will be potentially evaluated: 
Q1W 
• Dose Level 1: 1 mg/kg 
• Dose Level 2: 2 mg/kg 
• Dose Level 3: 4 mg/kg 
Q2W 
• Dose Level 4: 6 mg/kg 
• Dose Level 5: 9 mg/kg 
Q2W with mandatory intensive IRR and mucositis prophylaxis; 4h infusion 
The starting dose of Pan-HER will be 1 mg/kg Q1W. The following dose 
levels of Pan-HER are planned to be evaluated: 
Q1W 
• Dose Level 1:  
1 mg/kg Q1W 
• Dose Level 2:  
2 mg/kg Q1W 
• Dose Level 3:  
4 mg/kg Q1W 
• *Dose Level 4P:  6 mg/kg Q1W + P (lower doses with prophylaxis may be 
explored, if indicated) 
• *Dose Level 5P:  9 mg/kg Q1W + P 
• *Dose Level 6P:  12 mg/kg Q1W + P 

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(designated “P”) 
• Dose Level 5P: 9 mg/kg 
• Dose Level 6P: 12 mg/kg 
• Dose Level 7P: 15 mg/kg 
• Dose Level 8P: 18 mg/kg (highest potential dose allowed per protocol) 
Patients entered to Dose Level 1, 2 and 3 (1, 2, and 4 mg/kg, respectively) 
were treated Q1W.  As of Amendment 3, the dosing schedule in this trial has 
been changed to Q2W.  Patients entered to the trial prior to implementation 
of this amendment will continue to be treated Q1W. 
As of Amendment 5, patients entered to Dose Level 5P and all patients 
thereafter must receive intensive prophylaxis… 
• *Dose Level 7P:  15 mg/kg Q1W + P 
• *Dose Level 8P:  18 mg/kg Q1W + P (highest potential dose allowed per 
protocol) 
Q2W 
• Dose Level 4:  
6 mg/kg Q2W 
• Dose Level 5:  
9 mg/kg Q2W 
• *Dose Level 5P:  9 mg/kg Q2W + P 
• *Dose Level 6P:  12 mg/kg Q2W + P 
• *Dose Level 7P:  15 mg/kg Q2W + P 
• *Dose Level 8P:  18 mg/kg Q2W + P (highest potential dose allowed per 
protocol) 
*Mandatory intensive IRR and oropharyngeal mucositis prophylaxis; 4-hour 
infusion (designated “P”) 
Note: Patients entered to Dose Levels 1, 2 and 3 treated Q1W.  As of 
Amendment 3, the dosing schedule in this trial was changed to Q2W.  
Patients entered to the trial prior to implementation of this amendment could 
continue to be treated Q1W. 
Note: As of Amendment 5, patients entered to Dose Level 5P and all 
patients thereafter must receive intensive prophylaxis on a mandatory basis 
to reduce the risk of IRRs and oropharyngeal mucositis, and must receive 
Pan-HER over a fixed (at minimum) 4-hour (+10 min) period… 
As of Amendment 6: Q1W dosing is reintroduced under the prophylaxis and 
infusion duration conditions outlined in Amendment 5… 
7.1.3.2 Part 1, 
Dose-Escalation 
(continued) 
Enrollment will be staggered between the first and second patient in each 
new dose level tested. The first patient must have completed and tolerated 
the first dose of Pan-HER including follow-up until Day 15 of Cycle 1 
(C1/D15)… 
Staggered Dosing: Enrollment will be staggered between the first and 
second patient in each new dose level tested. The first patient must have 
completed and tolerated the first 2 doses of Pan-HER with Q1W dosing, or 
the first dose of Pan-HER with Q2W dosing, including follow-up until Day 
15 of Cycle 1 (C1/D15)… 
The RP2D may be equal to or lower than the MTD. The RP2D will be 
selected based on safety data, as well as available PK and target engagement 
results, as applicable. 
 
RP2D: The RP2D may include a dose or a combination of doses equal to or 
lower than the MTD for the Q1W and/ or Q2W dosing regimens.  A dose or 
doses between tolerated doses investigated in Part 1 may also be selected if 
data indicate this to be optimal… 
Once the RP2D is selected, enrollment to the PET Expansion Cohort may 
begin. 
Deleted; the PET Expansion Cohort has been removed. 
8.2.3 Dose-
Limiting 
Toxicities 
Evaluation (Part 
1 Only) 
• Reported during Cycle 1 with final assessment 14 days (previously 7 days 
with Q1W dosing) after the last dose of Cycle 1 or prior to dosing on Day 1 
of Cycle 2 (C2/D1) 
• Reported during Cycle 1 with final assessment 7 days after the last dose of 
Cycle 1 for Q1W dosing, 14 days after the last dose of Cycle 1 for Q2W 
dosing, or prior to dosing on Day 1 of Cycle 2 (C2/D1) 

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8.2.9 Laboratory 
Assessments and 
Pregnancy Test 
Not applicable 
All individual assessments are to be performed on or about the indicated 
visit day (i.e., ±2 days) unless otherwise stated. 
8.2.10 
Complement 
Panel (Part 2 
only) (Central 
Laboratory) 
 
8.2.10 Complement Panel 
To include total complement hemolytic activity (CH50), C3, C4, C3a, and 
C4a 
• Cycle 1 Day 1 (timepoints coincide with PK sampling) 
Day 1 
-Prior to SOI (- 4h) 
-EOI (+ 10 min) 
-4 hours after EOI (±30 min) 
-8 hours after EOI (±90 min) 
Day 2 
-24 hours after EOI (±6 h) 
•In the event of an IRR 
Note:  Comprehensive collection of clinical samples is critical to the conduct 
of this study.  In situations where collection of the EOI + 8h samples is 
logistically difficult due to clinic staff availability… 
A detailed laboratory manual specifying sample collection, handling, 
storage, and shipment will be provided to the trial sites in Part 2. 
8.2.10 Complement Panel (Part 2 only) (Central Laboratory) 
To include total complement hemolytic activity (CH50), C3, C4, C3a, and 
C4a 
• Cycle 1 (timepoints coincide with PK sampling) 
Day 1 
-Prior to SOI (- 4h) 
-4 hours after EOI (±30 min) 
• In the event of an IRR 
Note: A detailed laboratory manual specifying sample collection, handling, 
storage, and shipment will be provided to the trial sites. 
8.3.4 18F-FDG 
PET Imaging 
(PET Expansion 
Cohort Only) 
8.3.4 18F-FDG PET Imaging (PET Expansion Cohort Only) 
An expansion cohort of patients with FDG-avid tumors will undergo 18F-
FDG PET imaging to evaluate the effects on tumor metabolism of Pan-HER 
when administered Q2W at the RP2D…   
Entire section deleted; the PET Expansion Cohort has been removed. 
8.6 Skin Biopsy 
All patients enrolled will undergo skin biopsies for evaluation of target-
engagement (EGFR and HER3)...  
Skin biopsies are requested from a rash-free area. 
• Screening, after confirmation of eligibility 
• End of Cycle 2 (prior to dosing Cycle 3) or upon PD, whichever occurs 
first 
Note: End of cycle assessments may be conducted at any time during the 
week prior to Day 1 of the next cycle 
All patients enrolled will undergo 3 skin biopsies for evaluation of target 
engagement (EGFR and HER3)…  
Skin biopsies are requested from a rash-free area. 
• Screening, after confirmation of eligibility 
• C1/D8 (prior to dosing if on dosing day)  
• C1/D15 (prior to dosing) 
9.3.1 Timeframes 
for Reporting to 
the Sponsor 
In case of an SAE, the Investigator must, within 24 hours of first awareness 
of the event, report the SAE to the Sponsor or designee by fax or e-mail. Fax 
number(s) and e-mail address will be stated in the SAE report form and the 
SAE report form instructions. 
Timelines for reporting of SAEs and SAE follow-up information are shown 
in Table 13. 
In case of an SAE, the Investigator must, within 24 hours of first awareness 
of the event, report the SAE to the Sponsor or designee by fax 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. 

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Removed Table: Timelines for Reporting Serious Adverse Events and 
Follow-up 
9.5.2 Observation 
Period for Dose-
Limiting 
Toxicities 
The decision to dose-escalate will be based on close monitoring of safety 
during the observation period for DLTs, defined as the initial 28-day period 
(±2 days) from first treatment of Pan-HER (i.e. Cycle 1) and including 14 
days (previously 7 days with Q1W dosing) of follow-up from the last dose 
of Cycle 1. 
A minimum of 2 infusions (previously 4 infusions with Q1W dosing) of 
Pan-HER must have been administered at the assigned dose for a patient to 
have completed the DLT-observation period. 
The decision to dose-escalate will be based on close monitoring of safety 
during the observation period for DLTs, defined as the initial 28-day period 
(±2 days) from first treatment of Pan-HER (i.e., Cycle 1) and including 7 
days of follow-up (Q1W dosing) or 14 days of follow-up (Q2W dosing) 
from the last dose of Cycle 1. 
A minimum of 4 Pan-HER infusions (Q1W dosing) or 2 Pan-HER infusions 
(Q2W dosing) must have been administered at the assigned dose for a 
patient to have completed the DLT-observation period. 
9.7 Pregnancy 
Pregnancies reported in female partners of male trial patients must also be 
included in the database; therefore, a pregnant partner of a trial participant 
must provide informed consent before information can be collected. 
All pregnancies must be followed up every third month to determine 
outcome (including premature termination) and status of mother and child. 
Pregnancy complications and elective terminations for medical reasons must 
be reported as AEs or SAEs as appropriate (trial patients only). Elective 
terminations for non-medical reasons should not be reported as AEs. 
Spontaneous abortion must be reported as an SAE. 
Any SAE occurring in association with a pregnancy brought to the 
Investigator’s attention after the patient has completed the trial and 
considered by the Investigator as possibly related to the IMP (possibly, 
probably, or related to Pan-HER), must be promptly reported to the Sponsor 
or designee. 
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 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 Pan-
HER must be promptly reported to the Sponsor or designee. 
10.1 Sample Size 
Considerations 
Based on the dose-escalation design, it is planned to enroll approximately 25 
patients during the dose-escalation part of the trial. 
Based on the dose-escalation design, it is planned to enroll approximately 34 
patients during the dose-escalation part of the trial. 
It is estimated that approximately 6 patients will be enrolled to the PET 
Expansion Cohort.  The exact number of patients will depend upon 
identification of patients with FDG-avid tumors. 
Deleted; the PET Expansion Cohort has been removed. 
During Part 2, it is planned to enroll and treat approximately 25 patients in 
each dose-expansion cohort, selected by underlying malignancy. The 
planned number of patients to be enrolled might be adjusted when the four 
tumor types have been selected… 
During Part 2, it is planned to enroll and treat approximately 100 patients. 
The planned number of patients to be enrolled might be adjusted when the 4 
dose-expansion cohorts (i.e., based on defined molecular profiles(s) and 
tumor types) have been selected… 
10.3.2 Part 2, 
Dose-Expansion 
The primary objective of Part 2 is to evaluate the antitumor effect of Pan-
HER when administered Q2W (previously Q1W) at the RP2D to patients 
with advanced epithelial malignancies (4 tumor types to be selected). 
The primary objective of Part 2 is to evaluate the antitumor effect of Pan-
HER when administered at the RP2D and regimen to patients with advanced 
epithelial malignancies without available therapeutic options. Four (4) dose-
expansion cohorts will be evaluated. 
10.4.4 
Pharmacokinetic 
The PK endpoints with Q2W dosing will be derived based on the 
concentration time curves of Pan-HER, after the first and third infusion of 
Pan-HER in both parts of the trial. 
The PK endpoints with Q1W dosing will be derived based on the 
concentration time curves of Pan-HER after the first and fourth infusion of 
Pan-HER in both parts of the trial, as applicable.  

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Endpoints and 
Analyses 
As of Amendment 3:  For patients entered to Dose Level 1, 2 and 3 (1, 2, 
and 4 mg/kg, respectively) treated on a Q1W schedule, PK endpoints will be 
derived based on the concentration time curves of Pan-HER after the first 
and fourth infusion of Pan-HER.   
The PK endpoints with Q2W dosing will be derived based on the 
concentration time curves of Pan-HER after the first and third infusion of 
Pan-HER in both parts of the trial, as applicable. The serum concentration of 
total Pan-HER will be derived as the sum of the serum concentration of all 
six constituting antibodies. Supporting plots and PK parameters for the 
individual antibodies will also be generated. 
Individual curves of serum concentration of total Pan-Her versus time after 
the first and fourth infusion of Pan-HER will be presented on log- and linear 
scale for all patients in the FAS. 
Individual curves of serum concentration of total Pan-HER versus time after 
the first and fourth infusion of Pan-HER with Q1W dosing, and after the 
first and third infusion of Pan-HER with Q2W dosing, will be presented on 
log- and linear scale for all patients in the FAS. 
10.4.5 Additional 
Endpoints and 
Analyses 
• Changes in tumor metabolism as evaluated by 18F-FDG PET 
Deleted; the PET Expansion Cohort has been removed. 
13.2 Source 
Documents 
Source data are all information, original records of clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Examples of these original 
documents and data records include, but are not limited to: Hospital records, 
clinical and office charts, laboratory notes, memoranda… 
 
The Investigator must maintain source documentations for each patient in 
the trial and all information in the CRF must be traceable to these source 
documents in the patient’s file. Data not requiring a separate written record, 
i.e. data, which may be recorded directly in the CRF, will be defined before 
trial start. 
The Investigator will maintain adequate and accurate records for each 
patient treated with study drug.  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.  
 
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 authorized regulatory agencies, to have direct access to 
source data that support data in the CRF (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. 
14.1 Data 
Handling 
Data will be handled according to good data management practices, all 
applicable data protection regulations, and will comply with ICH GCP 
E6(R2). 
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… 
14.2 Recording of 
Data 
Corrections to entered data will be tracked within the EDC system. 
Corrections to entered data will be identified and tracked by audit trails 
within the EDC system.  
14.7 Data 
Processing 
The Sponsor or designee will be responsible for data processing in 
accordance with the applicable Data Management SOPs. A Data 
Management Plan will be generated for this trial. 
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. 

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Database lock will occur once quality control and quality assurance 
procedures (if applicable) have been completed upon reaching the data cut-
off for primary analysis.  
 
Portable Document Format (PDF) files of the CRFs will be provided to the 
Investigator before access to the CRF system is revoked. 
 
Database Lock will occur upon reaching the predefined data cut-off for 
primary analysis and completion of Sponsor’s (or designee’s) quality control 
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. 
14.9 Compliance 
with the General 
Data Protection 
Regulation 
Not applicable (this is a new section) 
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 data 
subjects, as well as the obligations and rights of the data controller...