First-in-human, Open-label, Dose-escalation Trial With Expansion Cohorts to Evaluate Safety of GEN1029 in Patients With Malignant Solid Tumors
Phase: PHASE1
Conditions: Colorectal Cancer, Non-small Cell Lung Cancer, Triple Negative Breast Cancer, Renal Cell Carcinoma, Gastric Cancer, Pancreatic Cancer, Urothelial Cancer
Sponsor: Genmab

Document Name: GCT1029-01 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
 
1 
PROTOCOL AND SUMMARY OF PROTOCOL 
AMENDMENTS 
First-in-human, open-label, dose-escalation trial with 
expansion cohorts to evaluate safety of GEN1029 in patients 
with malignant solid tumors 
 
Protocol no.: 
GCT1029-01 
Sponsor: 
Genmab* 
Clinical Research 
Organization: 
, 
, 
, USA 
EudraCT No.: 
2017-001394-16 
IND No.: 
134822 
NCT No. 
NCT03576131 
Trial Drug Name: 
GEN1029 (HexaBody-DR5/DR5) 
*Genmab is a global organization that operates through different legal entities in various 
countries. Therefore, the legal entity acting as the sponsor for Genmab trials may vary, such 
as, but not limited to Genmab B.V; or Genmab US, Inc. The term “sponsor” is used 
throughout the protocol to represent these various legal entities; the sponsor is identified on the 
following contact information page. 
 
 

Document Name: GCT1029-01 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
 
2 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................. 2 
1 
OVERVIEW OF PROTOCOL AMENDMENTS .................................................. 3 
2 
SUMMARY OF PROTOCOL AMENDMENTS .................................................... 4 
3 
REDACTED PROTOCOL VERSION 9.0, LATEST VERSION ......................... 8 
 
 
 

Document Name: GCT1029-01 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
 
3 
1 OVERVIEW OF PROTOCOL AMENDMENTS 
 
Protocol/Amendment No; Version  
Issue Date 
Version 9.0 (incorporating protocol amendment 07); 
24-Oct-2019 
Version 8.0 (incorporating protocol amendment 06) 
13-Sep-2019 
Version 7.0 (incorporating protocol amendment 05) 
18-Mar-2019 
Version 6.0 (incorporating protocol amendment 04) 
07-Feb-2019 
Version 5.0 (incorporating protocol amendment 03) 
15-Mar-2018 
Version 4.0 (incorporating protocol amendment 02) 
13-Dec-2017 
Version 3.0 (incorporating protocol amendment 01) 
07-Dec-2017 
Version 2.0  
04-Oct-2017 
 
 
 

Document Name: GCT1029-01 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
 
4 
2 SUMMARY OF PROTOCOL AMENDMENTS 
Seven protocol amendments have been made to the original protocol (dated 04-Oct-2017, protocol 
version 2.0). A summary of key changes with each amendment is provided in Table 1. 
Table 1 
Protocol Amendments 
Amendment Number/ 
Protocol Version 
Document 
Date 
Key Changes 
Amendment 7, v9.0 
24-Oct-2019 
A health authority raised concerns that the current dose levels (0.3, 1.0, 3.0, 
 
 mg/kg) were too steep for dose escalation, which was the main reason for the 
present protocol amendment. As an additional precaution, the proposed optional 
intermediate dose levels 
 2.0,
 mg/kg) were made mandatory.  
• Footnotes on monitoring of liver parameters were edited for clarity. 
• The PK sampling schedule of the Dose Escalation part was aligned with the overall 
visit schedule.  
• For completeness, time to response was added as a secondary endpoint. 
• Because optional intermediate dose levels were no longer applicable, any reference 
to these have been deleted. 
• Clarified to emphasize that the PET scans are exploratory and treatment decisions 
must be made based on the results of the CT portion of the scans according to 
RECIST v1.1.   
• Progression-free survival was redefined according to new guidance. 
Amendment 6, v8.0 
13-Sep-2019 
As of the 20-Aug-2019, 27 subjects had been exposed to GEN1029 at dose levels 
ranging from 0.3 to 3 mg/kg: 24 subjects on the Biweekly Regimen (Q2W) and 3 
subjects on the Intensified Regimen (8×Q1W/Q2W). All 3 subjects exposed in the 
Intensified Regimen experienced DLTs,
 
 
 Consequently, the Intensified Regimen was permanently 
discontinued and, with this amendment, removed from the protocol.  
 
Additional precautionary measures were implemented including: 
• 
Monitoring of liver laboratory parameters at Day 3 of Cycles 1 and 2. To be repeated 
at least once more, ie, at Day 5, if Day 3 AST or ALT ≥grade 1 and >1.5×baseline.  
• 
Restart dosing at 0.3 mg/kg. One subject had been dosed with 0.3 mg/kg and the 
patient showed no signs of transaminase elevations. 
• 
The Priming Regimen was modified so that the priming dose was reduced from 2 
doses to 1 dose, with the full dose administered 14 days after the priming dose. The 
priming regimen was being evaluated as it may mitigate the hepatotoxicity, since 
clinical data from the trial demonstrated that hepatotoxicity was primarily a first dose 
effect, and if hepatotoxicity is observed after the first dose, then it is often absent or 
at least less severe upon re-exposure of the subject.  
• 
PET-CT was implemented to better evaluate anti-tumor activity and allow for a better 
benefit/risk assessment.  
• 
Performing liver ultrasound at Screening to explore potential correlation between 
findings and efficacy/safety. 
 
Diarrhea was reported in more than 40% of the patients and was the most frequently 
reported SAE; the majority of these events were considered to be related to the trial 
drug. Therefore, a guidance on managing diarrhea has been included in the protocol. 

Document Name: GCT1029-01 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
 
5 
Amendment Number/ 
Protocol Version 
Document 
Date 
Key Changes 
Amendment 5, v7.0 
18-Mar-2019 
A detailed evaluation and analysis of transaminase levels for all subjects in the trial led 
to observations regarding the opportunity to introduce steroid premedication in 
potentially mitigating these events. Thus, with the present amendment, a mitigation plan 
to prevent transaminase elevations was introduced. 
• Prophylactic premedication with dexamethasone (10 mg IV) became mandatory for 
at least the first 2 cycles.  
• If a ≥ grade 2 increase of ALT or AST was observed during the second cycle, or at 
any time thereafter, premedication with dexamethasone was to be 
continued/reintroduced.  
• Furthermore, paracetamol (acetaminophen) as premedication was to be considered to 
be omitted and used with caution during all treatment cycles.  
• Antihistamines, diphenhydramine (50 mg po preferred) or dexchlorpheniramine (5 
mg IV), could be part of the premedication regimen as per protocol. 
Amendment 4, v6.0 
07-Feb-2019 
Initial PK data suggested that PK appears to be very similar for the 2 antibodies (1029-
01 and 1029-05). However, human PK predictions based on the nonclinical model 
appear to have significantly underestimated the observed human clearance of both 1029-
01 and 1029-05. Predictions for Cmax have been very accurate and increase of Cmax 
appeared to be dose-proportional. However, since the clearance in humans appeared to 
be significantly higher than predicted, Ctrough values for both GEN1029 component 
antibodies were below the lower level of quantification (based on 14 days dosing 
interval) and AUC0-14days was also below the predicted values. Thus, based on limited 
PK data from 10 subjects at doses of 0.3-3 mg/kg in dose escalation cohorts, plasma 
half-life (T1/2) appeared to be relatively short, ranging from 15 to 63 hours. To achieve 
higher exposures in subjects and potentially provide opportunity to achieve the best 
therapeutic response, 2 additional dose regimens were introduced with this amendment: 
• 
An Intensified Regimen: subjects dosed once weekly for the first 8 weeks then once 
every 14 days thereafter (8×Q1W/Q2W) to obtain higher drug exposures and thereby 
potentially improve the anti-tumor efficacy. 
• 
A Priming Regimen: in the first cycle, subjects received 2 weekly priming doses. 
Thereafter, they were dosed once every 14 days (Priming/Q2W) to potentially enable 
tolerance of increased dose levels and consecutively providing higher exposures. The 
concept of a priming dose has been successfully implemented for multiple drugs to 
desensitize the system to prevent eg, tumor lysis syndrome, cytokine release and 
infusion reactions. This may potentially lead to tolerance of higher dose levels as 
well as increasing the therapeutic window. 
 
The total maximum planned number of subjects was increased from 188 to 549,  partly 
because of the additional dose regimens and partly because of the introduction of a 
Bayesian predictive probability approach for the Expansion.   
Amendment 3, v5.0 
15-Mar-2018 
The original protocol version 2.0 dated 04 October 2017 was submitted to the FDA and 
MHRA. In order to address the recommendations and requests from the FDA, 
amendment 1, dated 06-Dec-2017, was prepared. Similarly, amendment 2, dated 13-
Dec-2017, was prepared to address the comments and requests from MHRA.  
 
The purpose of amendment 3 was to combine the two regional amendments 1 and 2 into 
one global amendment.   

Document Name: GCT1029-01 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
 
6 
Amendment Number/ 
Protocol Version 
Document 
Date 
Key Changes 
Amendment 2, v4.0 
13-Dec-2017 
The original protocol version 2.0 dated 04 October 2017 was submitted to the MHRA. 
In order to address the recommendations and requests from the MHRA, the Amendment 
2 was prepared. 
• The trial objectives and trial design were updated to clarify that only 1 
recommended phase 2 dose will be tested in the expansion part. 
• The investigational and reference therapy were modified to clarify that the absolute 
maximum dose of GEN1029 would be 
 
• Clarified that the safety follow-up visit must be performed 70 days rather than 30 
days after last dosing. 
• Clarified that all AEs would be collected from the time where the subject signed the 
informed consent form. 
• Added rationale for the highest pre-planned dose level. 
• Inclusion criterion #10 was expanded to include recommendations on highly 
effective methods of contraception. 
• Since attribution of an observed toxicity to a new drug can be uncertain, the word 
“related” was modified to “at least possibly related.”   
• Modified DLT definition to clarify that a grade ≥2 AST or ALT elevation with 
concomitant grade ≥2 bilirubin elevation lasting for > 7 days should be considered a 
DLT.  
• Modified DLT definition to clarify that non-hematologic laboratory abnormalities 
that had no clinical consequences and that resolved to grade ≤1 within 7 days should 
not be considered DLTs. 
• Clarified that grade 4 AEs fulfilling the DLT criteria should always lead to IMP 
discontinuation. 

Document Name: GCT1029-01 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
 
7 
Amendment Number/ 
Protocol Version 
Document 
Date 
Key Changes 
Amendment 1, v3.0 
07-Dec-2017 
The original protocol version 2.0 dated 04 October 2017 was submitted to the FDA. In 
order to address the recommendations and requests from the FDA, Amendment 1 was 
prepared. 
• Modified inclusion criterion to clarify that subjects should only be included in the 
Dose Escalation part of the trial if there was no other available therapy likely to 
confer a clinical benefit or if they were not candidates for such therapy. 
• Modified inclusion criterion for clarity by removing “a taxane” from the list of 
acceptable prior treatment failures. 
• Modified inclusion criterion for the urothelial Expansion cohort to more clearly 
state that subjects should have metastatic disease after failure of at least 1 platinum-
containing regimen and a checkpoint inhibitor, since both have a survival advantage 
in this setting. In addition, “a taxane or pemetrexed” was omitted from the end of 
this criterion, as this wording was not appropriate in this setting. 
• Clarified that if a subject was withdrawn prematurely from a cohort without 
experiencing a DLT, another subject should be enrolled in the cohort to bring the 
number to 3 evaluable subjects. 
• Modified DLT definition to clarify that a grade ≥3 thrombocytopenia associated 
with bleeding was considered a DLT. 
• 
Since attribution of an observed toxicity to a new drug can be uncertain, the word 
“related” was modified to “at least possibly related.”   
• 
Modified DLT definition to clarify that grade ≥3 amylase and/or lipase elevations 
with significant clinical symptoms that did not resolve to grade ≤1 or baseline 
within 7 days should be considered a DLT. 
• 
Modified DLT definition to clarify that a grade ≥2 AST or ALT elevation with 
concomitant grade ≥2 bilirubin elevation lasting for > 7 days should be considered a 
DLT.  
• 
Modified DLT definition to clarify that non-hematologic laboratory abnormalities 
that have no clinical consequences and that resolved to grade ≤1 within 7 days 
should not be considered DLTs. 
• 
Modified safety stopping rule related to drug-related grade 4 AEs that did not fulfill 
the DLT criteria, so that if such events did not resolve to grade ≤1 or baseline within 
14 days, this would be considered a safety stopping rule. 
Original protocol v2.0 
04-Oct-2017 
Original protocol, v2.0 distributed 
v1.0 
04-Oct-2017 
Original protocol, v1.0 internal document at Genmab, not distributed 
 
 
 

Document Name: GCT1029-01 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
 
8 
3 REDACTED PROTOCOL VERSION 9.0, LATEST VERSION 

Document Name: GCT1029-01 – Clinical Trial Protocol 
Genmab 
Document Number: TMF-03345 
Version: 9.0 
 
 
1 
CLINICAL TRIAL PROTOCOL 
First-in-human, open-label, dose-escalation trial with 
expansion cohorts to evaluate safety of GEN1029 in patients 
with malignant solid tumors 
 
Protocol no.: 
GCT1029-01 
Sponsor: 
Genmab* 
Clinical Research 
Organization: 
 
, 
, USA 
Coordinating 
Investigator: 
Professor 
 
Newcastle Hospitals NHS Foundation Trust 
Sir Bobby Robson Cancer Trials Research Centre 
Newcastle upon Tyne, NE7 7DN 
England 
EudraCT No.: 
2017-001394-16 
IND No.: 
134822 
Trial Drug Name: 
GEN1029 (HexaBody-DR5/DR5) 
Date of Protocol: 
Version 9.0; 24-Oct-2019 (incorporating protocol amendment 07) 
Version 8.0, 13-Sep-2019 (incorporating protocol amendment 06) 
Version 7.0, 18-Mar-2019 (incorporating protocol amendment 05) 
Version 6.0, 07-Feb-2019 (incorporating protocol amendment 04) 
Version 5.0, 15-March-2018 (incorporating protocol amendment 03) 
Version 4.0, 13-Dec-2017 (incorporating protocol amendment 02) 
Version 3.0, 07-Dec-2017 (incorporating protocol amendment 01) 
Version 2.0, 04-Oct-2017 
*Genmab is a global organization that operates through different legal entities in various 
countries. Therefore, the legal entity acting as the sponsor for Genmab trials may vary, such 
as, but not limited to Genmab B.V; or Genmab US, Inc. The term “sponsor” is used 
throughout the protocol to represent these various legal entities; the sponsor is identified on the 
following contact information page. 
The information in this document is confidential and is proprietary to Genmab. It is understood that information in 
this document shall not be disclosed to any third party, in any form, without prior written consent of an authorised 
officer of Genmab 
 
 

Document Name: GCT1029-01 – Clinical Trial Protocol 
Genmab 
Document Number: TMF-03345 
Version: 9.0 
 
 
2 
Sponsor information for all countries except the USA 
Sponsor 
Genmab B.V. 
Uppsalalaan 15 
3584 CM Utrecht 
The Netherlands 
Sponsor information for the USA 
Sponsor 
Genmab US, Inc. 
902 Carnegie Center 
Suite 301 
Princeton, NJ 08540 
USA 
 
 
 

Document Name: GCT1029-01 – Clinical Trial Protocol 
Genmab 
Document Number: TMF-03345 
Version: 9.0 
 
 
3 
TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ............................................................................................ 7 
ABBREVIATIONS ....................................................................................................................... 8 
TRIAL SYNOPSIS ...................................................................................................................... 11 
1 
VISIT SCHEDULE ............................................................................................. 16 
1.1 
Dose Escalation Part .............................................................................................. 16 
1.2 
Expansion Part ....................................................................................................... 22 
2 
INTRODUCTION ............................................................................................... 26 
2.1 
Background ............................................................................................................ 26 
2.1.1 
Overview of Disease .............................................................................................. 26 
2.1.2 
Introduction to Investigational Treatment ............................................................. 30 
2.1.3 
Summary of Nonclinical Studies ........................................................................... 30 
2.1.4 
Summary of Clinical Trials ................................................................................... 32 
2.2 
Rationale ................................................................................................................ 32 
2.3 
Benefit-Risk Assessment ....................................................................................... 32 
3 
OBJECTIVES AND ENDPOINTS .................................................................... 35 
4 
TRIAL DESIGN .................................................................................................. 37 
4.1 
Description of Trial Design ................................................................................... 37 
4.2 
Dose regimens ....................................................................................................... 38 
4.2.1 
Biweekly Regimen (Q2W) .................................................................................... 38 
4.2.2 
Priming Dose Regimen .......................................................................................... 38 
4.3 
Dose Escalation Part .............................................................................................. 39 
4.4 
Expansion Part ....................................................................................................... 42 
4.5 
Planned Number of Patients .................................................................................. 42 
4.6 
Trial Design Rationale ........................................................................................... 43 
4.7 
First-in-Human Clinical Trial Starting Dose, dose increments and highest pre-
planned dose level.................................................................................................. 43 
4.8 
End of Trial and End of Treatment Definitions ..................................................... 45 
4.8.1 
End of Trial ............................................................................................................ 45 
4.8.2 
End of Treatment ................................................................................................... 45 
4.8.3 
Trial Termination ................................................................................................... 45 
5 
TRIAL POPULATION(S) .................................................................................. 46 
5.1 
Inclusion Criteria ................................................................................................... 46 
5.2 
Exclusion Criteria .................................................................................................. 49 
5.3 
Screen Failures....................................................................................................... 51 
6 
TREATMENT ..................................................................................................... 52 
6.1 
Treatment Assignment ........................................................................................... 52 
6.1.1 
Patient Numbering ................................................................................................. 52 
6.1.2 
Treatment Assignment ........................................................................................... 52 
6.2 
Dosage and Administration ................................................................................... 52 
6.3 
Compliance ............................................................................................................ 53 
6.4 
Concomitant Medications and Therapies .............................................................. 53 
6.4.1 
Prophylactic Concomitant Medication .................................................................. 53 
6.4.2 
Permitted Concomitant Medications and Therapies .............................................. 54 

Document Name: GCT1029-01 – Clinical Trial Protocol 
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Version: 9.0 
 
 
4 
6.4.3 
Prohibited Concomitant Therapy ........................................................................... 54 
6.5 
Trial Drug Information .......................................................................................... 55 
6.5.1 
Physical Description of Trial Drug ........................................................................ 55 
6.5.2 
Packaging ............................................................................................................... 55 
6.5.3 
Labeling ................................................................................................................. 55 
6.5.4 
Preparation, Handling, and Storage ....................................................................... 55 
6.5.5 
Drug Accountability .............................................................................................. 55 
6.6 
Technical Complaint Handling .............................................................................. 55 
6.6.1 
Procedures.............................................................................................................. 55 
6.6.2 
Contacting Sponsor Regarding Product Quality.................................................... 56 
7 
DOSE MODIFICATIONS AND SAFETY MANAGEMENT 
GUIDELINES ...................................................................................................... 57 
7.1 
Dose-limiting Toxicity........................................................................................... 57 
7.2 
Dose Modification Guidance and Mitigation Plans for Specific Adverse Events. 58 
7.2.1 
Dose modification Guidance ................................................................................. 58 
7.2.2 
Mitigation Plan for Specific Adverse Events ........................................................ 60 
7.3 
Safety Stopping Rules ........................................................................................... 63 
8 
DISCONTINUATION, FOLLOW UP AND COMPLETION ........................ 65 
8.1 
Discontinuation of Treatment ................................................................................ 65 
8.2 
Withdrawal from the Trial ..................................................................................... 65 
8.3 
Safety Follow up Evaluations ................................................................................ 66 
8.4 
Lost to Follow-up .................................................................................................. 66 
9 
ASSESSMENTS ................................................................................................... 67 
9.1 
Demography and Baseline Characteristics ............................................................ 67 
9.1.1 
Demographics ........................................................................................................ 67 
9.1.2 
Disease Status ........................................................................................................ 67 
9.1.3 
Medical History ..................................................................................................... 67 
9.1.4 
Concomitant Medication ....................................................................................... 67 
9.1.5 
Prior Cancer Therapy and Surgery ........................................................................ 67 
9.1.6 
Liver Ultrasound .................................................................................................... 68 
9.2 
Efficacy Assessment .............................................................................................. 69 
9.2.1 
Dose Escalation Part .............................................................................................. 69 
9.2.2 
Expansion Part ....................................................................................................... 69 
9.2.3 
PET-CT .................................................................................................................. 70 
9.2.4 
Reading of the Scans ............................................................................................. 71 
9.3 
Pharmacokinetics ................................................................................................... 71 
9.3.1 
Evaluations ............................................................................................................ 71 
9.3.2 
Analytical Procedures ............................................................................................ 71 
9.4 
Clinical Safety Assessments .................................................................................. 71 
9.4.1 
Physical Examination ............................................................................................ 71 
9.4.2 
Vital Signs ............................................................................................................. 72 
9.4.3 
Electrocardiograms ................................................................................................ 72 
9.4.4 
ECOG Performance Status .................................................................................... 72 
9.5 
Clinical Laboratory Assessments .......................................................................... 73 
9.6 
Immunogenicity ..................................................................................................... 74 
9.6.1 
Evaluations ............................................................................................................ 74 
9.6.2 
Analytical Procedures ............................................................................................ 75 

Document Name: GCT1029-01 – Clinical Trial Protocol 
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Document Number: TMF-03345 
Version: 9.0 
 
 
5 
9.6.3 
Immunogenicity Assessments ............................................................................... 75 
9.7 
Biomarkers ............................................................................................................. 75 
9.7.1 
Biomarker assessments in tumor samples ............................................................. 75 
9.7.2 
Biomarker assessments in blood samples .............................................................. 76 
9.7.3 
Additional analyses ................................................................................................ 76 
10 
SAFETY MONITORING AND ADVERSE EVENT REPORTING ............. 78 
10.1 
Adverse Event Definitions ..................................................................................... 78 
10.1.1 
Definition of Adverse Event .................................................................................. 78 
10.1.2 
Definition of Serious Adverse Event ..................................................................... 78 
10.1.3 
Definition of Adverse Events of Special Interest (AESI) ...................................... 78 
10.1.4 
Definition of Infusion-Related Reactions .............................................................. 79 
10.2 
Adverse Event Reporting ....................................................................................... 79 
10.2.1 
Pre-existing Condition ........................................................................................... 80 
10.2.2 
Diagnosis ............................................................................................................... 80 
10.2.3 
Study Disease......................................................................................................... 80 
10.2.4 
Disease Progression or Death ................................................................................ 80 
10.2.5 
Unrelated Procedures ............................................................................................. 80 
10.2.6 
Laboratory test abnormalities ................................................................................ 80 
10.2.7 
Start Date and Time ............................................................................................... 80 
10.2.8 
Information about infusion-related reactions......................................................... 81 
10.2.9 
Seriousness Criteria ............................................................................................... 81 
10.2.10 
Intensity ................................................................................................................. 81 
10.2.11 
Relationship to Investigational Medicinal Product................................................ 81 
10.2.12 
Action Taken with Investigational Medicinal Product .......................................... 81 
10.2.13 
Outcome ................................................................................................................. 81 
10.2.14 
End Date and Time ................................................................................................ 82 
10.3 
Adverse Events of Special Interest ........................................................................ 82 
10.3.1 
Elevation of Transaminases ................................................................................... 82 
10.3.2 
Diarrhea ................................................................................................................. 82 
10.4 
Events Requiring Immediate Reporting ................................................................ 82 
10.4.1 
Serious Adverse Events and Non-Serious   Grade 3 Adverse Events ................. 82 
10.4.2 
Overdose and Medication Errors ........................................................................... 82 
10.4.3 
Pregnancy .............................................................................................................. 83 
10.4.4 
Timelines for Immediate Reporting....................................................................... 83 
10.5 
Suspected Unexpected Serious Adverse Reactions (SUSARs) ............................. 84 
10.6 
Follow-Up on Adverse Events............................................................................... 85 
10.7 
Warnings and Precautions ..................................................................................... 85 
10.8 
Data Monitoring Committee .................................................................................. 85 
11 
STATISTICS ........................................................................................................ 86 
11.1 
Analysis Sets .......................................................................................................... 86 
11.1.1 
Full Analysis Set .................................................................................................... 86 
11.1.2 
Safety Set ............................................................................................................... 86 
11.1.3 
Per-Protocol Set ..................................................................................................... 86 
11.1.4 
Dose-Determining Analysis Set ............................................................................ 86 
11.2 
Patient Demographics and Baseline Characteristics.............................................. 86 
11.3 
Treatments ............................................................................................................. 87 
11.4 
Analysis of Dose Escalation Part ........................................................................... 87 

Document Name: GCT1029-01 – Clinical Trial Protocol 
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Version: 9.0 
 
 
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11.4.1 
Primary Objectives ................................................................................................ 87 
11.4.2 
Secondary Safety Objectives ................................................................................. 87 
11.4.3 
Pharmacokinetics ................................................................................................... 88 
11.4.4 
Immunogenicity of GEN1029 ............................................................................... 89 
11.4.5 
Secondary Efficacy Objective ............................................................................... 89 
11.5 
Analysis of Expansion Part .................................................................................... 91 
11.5.1 
Primary Objective .................................................................................................. 91 
11.5.2 
Secondary Efficacy Objective ............................................................................... 92 
11.5.3 
Secondary Safety Objective ................................................................................... 92 
11.5.4 
Pharmacokinetics ................................................................................................... 92 
11.5.5 
Immunogenicity of GEN1029 ............................................................................... 92 
11.6 
Explorative Analysis .............................................................................................. 93 
11.6.1 
Biomarkers ............................................................................................................. 93 
11.6.2 
Metabolic Response in the Tumors ....................................................................... 93 
11.6.3 
 
11.7 
Interim Analyses .................................................................................................... 93 
11.8 
Sample Size Calculation ........................................................................................ 95 
11.8.1 
Dose Escalation Part .............................................................................................. 95 
11.8.2 
Expansion Cohorts ................................................................................................. 96 
11.8.3 
Statistical Power for Comparing Two Regimens within one Indication ............... 98 
12 
DATA HANDLING AND RECORD KEEPING ............................................. 99 
12.1 
Data Flow............................................................................................................... 99 
12.2 
Source Documentation........................................................................................... 99 
12.3 
Case Report Form Completion ............................................................................ 100 
12.4 
Data Quality Management ................................................................................... 100 
12.5 
Record Retention ................................................................................................. 100 
13 
ETHICS .............................................................................................................. 102 
13.1 
Trial-Specific Design Considerations .................................................................. 102 
13.2 
Regulatory Ethics Compliance ............................................................................ 102 
13.2.1 
Investigator Responsibilities ................................................................................ 102 
13.2.2 
Independent Ethics Committee or Institutional Review Board ........................... 102 
13.2.3 
Informed Consent ................................................................................................ 103 
13.2.4 
Privacy of Personal Data ..................................................................................... 103 
13.2.5 
Long-Term Retention of Samples for Additional Future Analyses..................... 104 
14 
ADMINISTRATIVE PROCEDURES ............................................................. 105 
14.1 
Protocol Amendments ......................................................................................... 105 
14.2 
Regulatory Documentation .................................................................................. 105 
14.2.1 
Regulatory Approval/Notification ....................................................................... 105 
14.3 
Patient Identification, Enrollment, and Screening Logs ...................................... 105 
14.4 
Monitoring ........................................................................................................... 105 
14.5 
On-Site Audits ..................................................................................................... 106 
14.6 
Publication ........................................................................................................... 106 
14.7 
Registration of Clinical Trials and Disclosure of Results ................................... 107 
15 
REFERENCES .................................................................................................. 108 
 

Document Name: GCT1029-01 – Clinical Trial Protocol 
Genmab 
Document Number: TMF-03345 
Version: 9.0 
 
 
7 
STATEMENT OF COMPLIANCE 
GCP Compliance: This trial will be conducted in compliance with International Conference on 
Harmonisation Good Clinical Practice (ICH GCP E6 (R2)), and applicable regulatory 
requirements. 
 
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are 
privileged or confidential and may not be disclosed unless such disclosure is required by applicable 
law or regulations. In any event, persons to whom the information is disclosed must be informed 
that the information is privileged or confidential and may not be further disclosed by them. These 
restrictions on disclosure will apply equally to all future information supplied to you that is 
indicated as privileged or confidential. 

Document Name: GCT1029-01 – Clinical Trial Protocol 
Genmab 
Document Number: TMF-03345 
Version: 9.0 
 
 
8 
ABBREVIATIONS 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALK 
Anaplastic lymphoma kinase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
BOIN 
Bayesian Optimal Interval 
BOR 
Best Overall Response 
 
 
 
 
CFR 
Code of Federal Regulations 
Cmax 
Maximum Concentration 
CMV 
Cytomegalovirus 
CR 
Complete response 
CRC 
Colorectal Cancer 
CRO 
Contract Research Organisation 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DDS 
Dose-Determining Set 
DLT 
Dose limiting toxicity 
DMC 
Data Monitoring Committee 
DoR 
Duration of Response 
DR5 
Death Receptor 5 
DRF 
Dose-range finding 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EGFR 
EoT 
Epidermal growth factor receptor 
End of Trial 
FAS 
Full analysis set 
FDA 
U.S. Food and Drug Administration 
FDG  
Fluoro-Deoxy-Glucose 
FIH 
First-in-human 
FFPE 
Formalin Fixed Paraffin Embedded 

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GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
GFR 
Glomerular filtration rate 
GLP 
Good Laboratory Practice 
HBsAg 
Hepatitis B surface antigen 
HED 
Human equivalent dose 
HNSTD 
Highest Non-Severely Toxic Dose 
i.v. 
Intravenous 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
LD 
Longest Diameter 
mAbs 
monoclonal antibodies 
mBOIN 
modified Bayesian Optimal Interval 
mCRC 
Metastatic colorectal cancer 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOA 
Mode of Action 
MRSD 
Maximum Recommended Starting Dose 
MTD 
Maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute  
NOAEL 
No Observable Adverse Effect Level 
NS 
Non serious 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective Response Rate 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PET 
Positron Emission Tomography 
PERCIST 
Positron Emission Tomography Response Criteria In Solid Tumors 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PR 
Partial response 
RCC 
Renal Cell Carcinoma 
RDFD 
Recommended Dose for Further Development 

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10 
RECIST 
Response Evaluation Criteria In Solid Tumors 
 
 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCC 
Squamous cell carcinomas 
SD 
Stable disease 
SUL 
Standardized uptake volume 
SUSAR 
Serious unexpected suspected adverse reactions 
SUVmax 
Maximum tumor standardized uptake value 
SUVpeak 
Peak tumor standardized uptake value 
TEAE 
Treatment-emergent adverse event 
TLG 
Total lesion glycolysis 
TLS 
Tumor lysis syndrome 
TNBC 
Triple Negative Breast Cancer 
TNFRSF 
Tumor Necrosis Factor Receptor Superfamily 
TNM 
TRAIL 
Tumor Nodes Metastasis 
TNF Related Apopotosis Induced Ligand 
TTR 
Time to response 
ULN 
Upper Limit of Normal 
VEGF 
Vascular Endothelial Growth Factor 
WHO 
World Health Organization 
 

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11 
TRIAL SYNOPSIS 
Title 
First-in-human, open-label, dose-escalation trial with expansion cohorts 
to evaluate safety of GEN1029 in patients with malignant solid tumors. 
Brief Title 
GEN1029 Safety Trial in Patients With Malignant Solid Tumors. 
Clinical Phase 
Phase I/IIa 
Countries and 
Sites 
The Dose Escalation part is planned to be performed in a maximum of 5-
10 sites in Spain, United Kingdom and the US, with up to 20-30 
additional sites to be included in Europe and the US for the Expansion 
part. 
Purpose and 
Rationale 
Death receptor 5 (DR5) is a receptor for TRAIL, which initiates the 
extrinsic apoptosis pathway leading to apoptotic cell death of TRAIL-
sensitive cancer cells. GEN1029 is a mixture of two HexaBody® 
molecules which targets two distinct epitopes on DR5. 
Objectives and 
Endpoints 
Dose Escalation Part 
Objectives 
Endpoints 
Primary 
 
 
Determine the Maximum Tolerated 
Dose 
(MTD) 
and/or 
the 
Recommended Phase 2 Dose (RP2D) 
 
Dose Limiting Toxicities (DLTs) 
 
 
Establish the safety profile of 
GEN1029 
 
Adverse events (AEs) and safety 
laboratory parameters (hematology 
and biochemistry) 
Secondary 
 
 
Establish the pharmacokinetic (PK) 
profile and evaluate immunogenicity 
of 
GEN1029 
after 
single 
and 
multiple infusions 
 
PK parameters (clearance, volume of 
distribution 
and 
area-under-the-
concentration-time curve [AUC0-Clast 
and 
AUC0-∞], 
AUC0_14d, 
CL. 
maximum concentration [Cmax], time 
of Cmax [Tmax], pre-dose values, and 
half-life of GEN1029) 
 
Immunogenicity of GEN1029 
 
Evaluate the anti-tumor activity of 
GEN1029 
 
Anti-tumor activity measured by tumor 
shrinkage (based on computerized 
tomography [CT]-scan evaluations)  
 
Objective Response, Progression-Free 
Survival (PFS), Overall Survival (OS), 
Duration of Response (DoR), and 
Time to Response (TTR)  
Exploratory 
 

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 
To assess biomarkers predictive of 
response or resistance to GEN1029 
 
To assess potential 
pharmacodynamic biomarkers of 
GEN1029   
 
 
To assess the metabolic response in 
the tumors 
 
 
 
 
DR5 expression (protein, 
) 
in tumor biopsies 
 
Circulating protein profiles  
 
Immune cells levels 
 
Biomarker profile 
 
Standardized uptake volume corrected 
for body lean mass (SUL)  
 
 
Expansion Part 
Objectives 
Endpoints 
Primary 
 
 
To evaluate the Objective Response 
Rate (ORR) by indication 
 
ORR 
Secondary 
 
 
Evaluate the anti-tumor activity of 
GEN1029  
 
Anti-tumor activity measured by tumor 
shrinkage (based on computerized 
tomography [CT]-scan evaluations)  
 
Objective Response, Progression-Free 
Survival (PFS), Overall Survival (OS), 
Duration of Response (DoR), and 
Time to Response (TTR)  
 
To further describe the safety profile 
of GEN1029 
 
Adverse events (AEs) and safety 
laboratory parameters (hematology 
and biochemistry) 
 
Evaluate the pharmacokinetic (PK) 
profile 
as 
feasible, 
evaluate 
immunogenicity of GEN1029 after 
single and multiple infusions 
 
PK parameters  
 
Immunogenicity of GEN1029 
Exploratory 
 
 
To assess biomarkers predictive of 
response or resistance to GEN1029 
 
To 
assess 
potential 
pharmacodynamic 
biomarkers 
of 
GEN1029   
 
DR5 expression (protein, 
) 
in tumor biopsies 
 
Circulating protein profiles  
 
Immune cells levels 
 
Biomarker profile  
 
To assess the metabolic response in 
the tumors 
 
 
 
Standardized uptake volume corrected 
for body lean mass (SUL) 
 

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Trial Design 
This is an open-label, multi-center phase I/IIa safety trial of GEN1029 in 
patients with malignant solid tumors. The trial consists of two parts; a 
dose-escalation part (phase I, first-in-human (FIH)) and an expansion part 
(phase IIa). The expansion part of the trial will be initiated once the MTD 
or the Recommended Phase 2 Dose (RP2D) has been determined.  
In the dose escalation part, up to 2 dose regimens may be evaluated: 
 The Biweekly Regimen: patients are dosed once every 14 days 
(Q2W). 
 The Priming Regimen: in the first cycle, patients receive a priming 
dose. After 14 days and thereafter, they are dosed with the maximum 
starting dose once every 14 days (Priming/Q2W). 
These regimens may also be evaluated in the expansion part. If two 
regimens are available for patients with a specific indication they will be 
randomized in a 1:1 fashion. Randomization will be stratified by the 
Eastern Cooperative Oncology Group performance status at screening (0 
or 1). 
Planned Number 
of Patients 
Up to 520 patients can be enrolled in this trial. 
The dose escalation part will enroll up to approximately 100 patients, 
shared between the Biweekly and Priming Regimens. Three patients were 
exposed in an Intensified Regimen (8×Q1W/Q2W) all of whom 
experienced DLTs and, consequently, this dosing regimen was 
permanently discontinued. 
In the expansion part, each cohort will enroll between 10 and 60 patients. 
If all seven cohorts are opened, between 70 and 420 patients may be 
enrolled. 
Population 
Patients with the following indications: patients with advanced and/or 
metastatic colorectal cancer (CRC), non-small cell lung cancer (NSCLC), 
triple negative breast cancer (TNBC), renal cell carcinoma (RCC), gastric 
(incl. esophagogastric junction) cancer, pancreatic cancer or urothelial 
cancer who have failed available standard therapy or who are not 
candidates for standard therapy, and for whom, in the opinion of the 
investigator, experimental therapy with GEN1029 may be beneficial. 
The following indication specific cohorts are considered for the 
expansion part: CRC, NSCLC, TNBC, RCC, gastric, pancreas or 
urothelial cancer who have failed anticancer therapy for metastatic 
disease (as defined in the inclusion criteria). 
Key Inclusion 
Criteria 
 
Patients with advanced and/or metastatic CRC, NSCLC, TNBC, 
RCC, gastric (incl. esophagogastric junction), pancreas or urothelial 
cancer who have no available standard therapy or who are not 
candidates for available standard therapy, and for whom, in the 
opinion of the investigator, experimental therapy with GEN1029 
may be beneficial. 
 
Patient must be ≥ 18 years of age 

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14 
 
Patients must have measurable disease according to Response 
Evaluation Criteria In Solid Tumors (RECIST) version 1.1 
 
In the dose escalation part all patients must provide a tumor tissue 
sample (Formalin Fixed Paraffin Embedded (FFPE) blocks/slides) 
from either archival tissue (preferably derived from advanced 
disease stage) or a fresh biopsy collected before Cycle 1, Day 1. In 
the expansion part a mandatory fresh biopsy (FFPE tissue 
blocks/slides) at screening (aspirates are not acceptable) is to be 
provided for all patients which is taken after failure/stop of last prior 
treatment, unless not clinically feasible as documented by the 
investigator. In case it is not feasible to meet the required criteria for 
a fresh tumor biopsy, the sponsor medical officer’s approval of 
enrollment is needed. Furthermore, the latest available archival 
tumor tissue sample has to be collected if available. 
 
Have an acceptable hematological status 
 
Have an acceptable renal function 
 
Have an acceptable liver function 
 
Have an Eastern Cooperative Oncology Group performance status 
of 0 or 1  
 
Body weight ≥ 40 kg 
Key Exclusion 
Criteria 
 
Acute deep vein thrombosis or clinically relevant pulmonary 
embolism, not stable for at least 8 weeks prior to first IMP 
administration 
 
Have clinically significant cardiac disease 
 
Uncontrolled hypertension defined as systolic blood pressure 
≥160 mmHg and/or diastolic blood pressure ≥100 mmHg, despite 
optimal medical management 
 
Any history of intracerebral arteriovenous malformation, cerebral 
aneurysm, new (younger than 6 months) or progressive brain 
metastases or stroke 
 
History of organ allograft (except for corneal transplant) or 
autologous or allogeneic bone marrow transplant, or stem cell rescue 
within 3 months prior to the first dose of IMP 
 
Have received a cumulative dose of corticosteroid ≥ 150 mg 
prednisone (or equivalent doses of corticosteroids) within two weeks 
before the first IMP administration 
 
History of ≥ grade 3 allergic reactions to monoclonal antibody 
therapy as well as known or suspected allergy or intolerance to any 
agent given in the course of this trial 
 
Radiotherapy within 14 days prior to first IMP administration 
 
Any prior therapy with a compound targeting DR4 or DR5 
Investigational 
and Reference 
Therapy 
GEN1029 at dose levels: 0.3, 
, 1.0, 2.0, 3.0, 
 
 mg/kg.  

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Statistics 
MTD and/or RP2D will be determined using a modified (mBOIN) 
algorithm. 
Patients eligible for an expansion cohort will be entered in a stage-wise 
fashion. For each stage, the success of the stage is predicted. If the 
predictive probability of success is less than 10% the stage is not further 
explored. Success is evaluated on the basis of the objective responder 
rate. 
Adverse events will be presented using summary statistics 
Individual curves of plasma/serum concentration of each component of 
GEN1029 including information on actual dose, will be presented for all 
patients. 
PK parameters will be calculated based on non-compartmental methods 
and will be calculated separately for Cycle 1, Cycle 2 and Cycle 3. 
RECIST criteria (v1.1) will be used to define response. Summaries of 
objective response, best overall tumor response and disease control will 
be presented by dose cohort/indication and total. 
PFS, OS, and DoR will be summarized using survival analysis methods. 
The number of events may be small, and thereby limit use of the Kaplan 
Meier method to provide reliable information. In this case, descriptive 
statistics (e.g., n, mean, standard deviation, median, minimum and 
maximum) will be presented. TTR will be summarized using descriptive 
statistics. 
 

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16 
1 
VISIT SCHEDULE 
1.1 
Dose Escalation Part 
In the dose escalation part, up to 2 dose regimens may be evaluated: 
 The Biweekly Regimen: patients are dosed once every 14 days (Q2W). 
 The Priming Regimen: in the first cycle, patients receive a priming dose. After 14 days and 
thereafter, they are dosed with the maximum starting dose once every 14 days (Priming/Q2W). 
An overview of the dosing frequency as well as treatment cycle duration and dose limiting toxicity 
(DLT) period duration, and scanning frequency is shown in Figure 1-1. A cycle is always 14 days 
and the DLT period is always 28 days, irrespective of which dose regimen the patients are 
following. 
Further details on when the 2 dose regimens will be available and open for enrollment are 
described in Section 4.2. 
Table 1-1 lists all of the assessments in the dose escalation part and indicates with an “X” the visits 
at which they are performed. All data obtained from these assessments must be supported in the 
patient’s source documentation. 
Table 1-2 shows the timing of the ECG assessments, Table 1-3 shows the timing of the PK 
sampling, Table 1-4 shows the timing of cytokine and complement sampling, and Table 1-5 shows 
the timing for measurement of vital signs in relation to infusions. 
 

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*: Mandatory PET-CT scans must be taken at screening and, if avid at screening, also at Cycle 2 Day 2, and week 12 (±7 days). If PET-CT at screening showed no 
avidity, a CT scan has to be done instead of a PET-CT in week 12 (±7 days). 
**: A CT scan must be performed at Cycle 3, Day 8-14 after first dose. From week 18 (±7 days) until week 50 after first dosing, CT scans must be performed every 
6 weeks (±7 days), and every 12 weeks (±7 days) thereafter. Imaging assessments should follow calendar days and should not be adjusted for delays in cycle starts. 
***: Only if a patient, who has been exposed to GEN1029, did not have any PET-CT scans while on treatment and displayed avidity at screening.  
Figure 1-1 Overview of Dosing and Scanning Frequency, DLT and Cycle Duration – Dose Escalation Part  
 
 

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Table 1-1 Visit evaluation schedule Dose Escalation Part – Biweekly Regimen (Q2W) and Priming Regimen (Priming/Q2W) 
Treatment Cycle 
Screening 
Cycle 1-31 
Cycle 4-PD1 
End of 
treatment2 
Safety Follow-up21 
Patient follow-up 
End of 
trial 
Unscheduled 
Day 
≤ 21 days 
prior to Visit 
C1-D1 
1d 
2d 
3d24,28 
8d 
1d 
8d22 
- 
30 days 
after last 
dosing 
70 days 
after last 
dosing 
13W, 26W, 39W 
+ 52W after last 
dosing 
- 
- 
Visit window3 
 
±1d 
- 
- 
±1d 
±3d 
±1d 
- 
±7d 
±7d 
±14d 
- 
- 
Informed Consent4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, disease status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior cancer therapy/surgery 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight6 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
Physical Examination25 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
Vital Signs7 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
X14 
Liver ultrasound 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
Please see Table 1-2 for details of ECG assessments 
PET-CT scan29 
X29 
X8 
X8 
 
 
 
 
X30 
 
Efficacy assessment (CT-Scan) 
 
X9 
X9 
X23 
 
 
 
 
X14 
ECOG status 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
X14 
Adverse Events5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X18 
 
X14 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X19 
X19 
X19 
 
X14 
Pre-medication33 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
IMP administration 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
End of trial 
 
 
 
 
 
 
 
 
 
 
 
X20 
 
Laboratory assessments10 
 
Hematology 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X14 
Biochemistry26 
X 
X 
X 
X27 
X 
X 
X 
X 
X 
X 
 
 
X14 
Urinalysis 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
 
X14 
Pregnancy Test11 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
X14 
ADA (Immunogenicity) 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
 
X14 
Hepatitis B, C, CMV12 
X 
 
 
 
 
 
 
X 
 
 
 
 
X14 
PK Sampling 
Please see Table 1-3 for details of PK sampling 
Tumor biopsy 
X13 
 
 
 
 
 
 
X14 
 
 
 
 
X14 
Immunophenotyping 
 
X15 
 
 
X15 
 
X17 
X 
 
 
 
 
X14 
Cytokine and circulating factors  
Please see Table 1-4 for details of cytokine and complement sampling 
 

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19 
Footnotes to Trial Flowchart: Dose Escalation Part - Biweekly Regimen (Q2W) and Priming Regimen (Priming/Q2W) 
1 The duration of one cycle is 14 days. Treatment can continue until PD. 
2 If the patient shows PD, starts a new anti-cancer treatment or withdraws from treatment due to another reason,  the end of treatment visit should be performed as soon as possible after decision of 
discontinuation. 
3 The specified visit windows are in accordance with the previous visit. However, within 28 days from treatment start (corresponding to the DLT period), max. 2 doses of GEN1029 in the Q2W regimen and 
in the priming regimen can be administered. At Cycles 2 and 3, Day 1 of the next cycle should be performed 7 days ± 1 day after Day 8 of the previous cycle and from Cycle 4 and onwards, Day 1 of the 
next cycle should be performed 7 days ± 3 days after Day 8 of the previous cycle. 
4 Informed consent must be obtained before or at Screening prior to making any screening assessments. 
5 Adverse Events should be reported from the time the informed consent is signed. 
6 During the trial, body weight is measured on the dosing day, as part of the dose calculation. Please see section 9.4.1. 
7 Temperature, blood pressure and heart rate. Please see Table 1-5 and section 9.4.2. 
8 Mandatory PET-CT scans must be taken at screening and, if avid at screening, also at Cycle 2 Day 2, and week 12 (±7 days). Please see section 9.2.  
9 A CT scan must be performed at Cycle 3, Day 8-14 after first dose. If PET-CT at screening showed no avidity, a CT scan has to be done instead of a PET-CT in week 12 (±7 days). From week 18 (±7 days) 
until week 50 after first dosing, CT scans must be performed every 6 weeks (±7 days), and every 12 weeks (±7 days) thereafter until disease progression is assessed by the investigator, the start of new anti-
cancer therapy, withdrawal of consent, or death, whichever occurs first. Imaging assessments should follow calendar days and should not be adjusted for delays in cycle starts.  
10 All laboratory parameters will be analyzed centrally, except urinalysis. In the first 3 cycles, all biochemistry safety parameters must be assessed locally as well to monitor liver function. At treatment visits, 
laboratory parameters will also be analyzed at local laboratory prior to treatment of IMP please see section 9.5.  
11 Serum (beta-hCG) laboratory test should be taken at screening. A urine pregnancy test should be taken before every treatment of IMP. 
12 HbsAg, anti-HBs and anti-HBc, Hepatitis C and antibodies to CMV antigen will be assessed at screening for all patients. At end of treatment, only antibodies to CMV antigen will be assessed. Please see 
section 9.5 for further details. 
13 The latest archived biopsy can be used preferably derived from advanced disease stage. If no sample is available, a new tumor biopsy must be obtained.  
14 Optional. 
15 All patients must have a sample taken at Day 1 and 8 of Cycle 1 and at Day 8 of Cycle 3. If the visit occurs on an infusion day, the sample must be taken before IMP treatment. 
16 Sample to be taken at Cycle 3. 
17 Sample to be taken at Cycle 6. 
18 Only non-serious AEs ≥ 3 possibly related to IMP and SAEs (independent of causality). 
19 Only new anticancer treatments. 
20 Patient status at withdrawal. 
21 If the patient withdraws sooner than 70 days after the last dosing, the safety follow-up visit should take place at the time of withdrawal unless there has been a safety follow-up visit within the last 14 days. 
22 The day 8 visit can be omitted after approval by the sponsor medical monitor if there have been no AEs fulfilling the DLT criteria in the previous 6 cycles. 
23 To be completed as indicated to confirm response, new symptoms, end of treatment visit or at the physician discretion, see Section 9.2. 
24 Cytokine, complement and PK sampling to be taken at Cycles 1 and 2 Day 3 after infusion, see Table 1-3 and Table 1-4. 
25 A complete, general physical examination will be done at the screening and Cycle 1 Day 1 visits. At subsequent visits and as clinically indicated, limited symptom-directed physical examinations should be 
performed. 
26 Any AST, ALT, and/or bilirubin ≥ grade 2 needs to be checked 2×/week for up to 4 weeks and until resolution or return to baseline. 
27 Repeat at least once more, i.e. on Day 5 if AST, ALT, or bilirubin ≥ grade 1 and > 1.5×baseline.  
28 If no AST, ALT, and/or bilirubin ≥ grade 2 elevations are observed in Cycle 1 and 2, the visit at Cycle 3 Day 3 can be omitted 
29 The PET must be combined with CT and the CT portion must be of similar diagnostic quality to CT alone. The PET-CT must be performed before any optional tumor biopsy to avoid potential false positive 
findings. The baseline PET-CT assessment during screening should be performed at the closest date as possible from start of trial treatment, at least one week before tumor biopsy. Of note, if tumor lesions 
showed no avidity at baseline, no further PET scans should be performed, but CT scans only. 
30 To be performed only if a patient, who has been exposed to GEN1029, did not have any PET-CT scans while on treatment and displayed avidity at screening. 
 
 
 33  Dexamethasone 4 mg/p.o. one day before dosing at Cycles 1 and 2 and 10 mg. i.v. at Day 1 before dosing and at Day 2 in Cycles 1 and 2. If a drug-related ≥ grade 2 elevation of ALT and/or AST is observed 
during the second cycle or thereafter, Dexamethasone pre-medication should be continued/re-introduced. In this case, Dexamethasone can be given orally on the day after the dosing day (Section 6.4.1). 
 

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Table 1-2 ECG Assessments in Dose Escalation Part – Applicable for Both Regimens 
Treatment Cycle 
Screening 
Cycle 1-3 
Cycle 4-PD 
End of 
Treatment 
Unscheduled 
Day 
- 
1d 
2d 
8d 
1d 
- 
 
Before Infusion 
(on infusion days) 
1 
3 
3 a 
3 
3 
1 
1b 
End of infusion  
(+15 minutes) 
 
3 
 
 
3 
 
 
End of infusion + 2 
hours  (± 15 minutes) 
 
3 
 
 
 
 
 
End of infusion + 4 
hours (± 30 minutes) 
 
3 
 
 
 
 
 
1 – Single ECG assessment 
3 – Triplicate ECG assessments 
a Time window for the Day 2 sampling in the dose escalation part is 24 hours ± 2 hours after the end of infusion on Day 1 
b Optional 
 
Table 1-3 PK Sampling in Dose Escalation Part – Applicable for Both Regimens 
Treatment Cycle 
Screening 
Cycle 1-3 
Cycle 4-PD 
Unscheduled 
Day/Week 
- 
1d 
2d 
3d 
8d 
1d 
 
Before Infusion 
(on infusion days) 
X 
X 
X1 
X2 
X 
X 
X3 
End of infusion  
(+15 minutes) 
 
X 
 
 
X 
X 
 
End of infusion + 2 
hours  
(± 15 minutes) 
 
X 
 
 
 
 
 
End of infusion + 4 
hours (± 30 minutes) 
 
X 
 
 
 
 
 
1 Time window for the Day 2 sampling in the dose escalation part is 24 hours ± 2 hours after the end of infusion on Day 1  
2 Sample to be taken at Day 3 of Cycles 1 and 2. If a patient comes for a visit at Day 5 to have safety laboratory samples taken, a sample for PK 
assessments should also be taken. 
3 Optional 
 
 
Table 1-4 Cytokine and Circulating Factors Sampling in Dose Escalation Part – Applicable 
for Both Regimens 
Treatment Cycle 
Cycle 1-3 
Unscheduled 
Day 
1d 
2d 
3d 
8d 
 
Before infusion 
(on infusion days) 
X 
X 
X2 
X 
X3 
End of infusion + 4 
hours ( 30 minutes) 
X 
 
 
 
 
1 Time window for the Day 2 sampling in the dose escalation part is 24 hours ± 2 hours after the end of infusion on Day 1  
2 Sample to be taken at Cycles 1 and 2 Day 3  
3 Optional 
 

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Table 1-5 Vital Signs during the Dose Escalation Part – Applicable for Both Regimens 
Pre-infusion (up to 30 min before infusion) 
15 min after start of infusion (± 5 min)*  
At the end of infusion (± 5 min)  
15 min after end of infusion (± 5 min)  
30 min after end of infusion (± 5 min)  
1 hour after end of infusion (± 10 min)  
2 hours after end of infusion (± 10 min)  
4 hours after end of infusion (± 30 min)  (first 3 cycles) 
*If infusion lasts for more than 60 minutes, vital signs should be assessed every 15 minutes (± 5 minutes) for the remaining duration of the infusion. 
 

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1.2 
Expansion Part 
In the expansion part, up to 2 dose regimens may be evaluated: 
 The Biweekly Regimen: patients are dosed once every 14 days (Q2W). 
 The Priming Regimen: in the first cycle, patients receive a priming dose. After 14 days and 
thereafter, they are dosed with the maximum starting dose once every 14 days (Priming/Q2W). 
An overview of the dose, dosing frequency, and cycle duration is shown in Figure 1-2. A cycle is 
always 14 days, irrespective of which dose regimen the patients are following. 
 
Figure 1-2 Overview of Dosing Frequency and Cycle Duration – Expansion Part 
Further details on when the 2 dose regimens are available and open for enrollment are described 
in Section 4.2. 
Table 1-6 lists all of the assessments in the expansion part and indicates with an “X” the visits at 
which they are performed. All data obtained from these assessments must be supported in the 
patient’s source documentation. 
Table 1-7 shows the timing of the ECG assessments, Table 1-8 shows the timing of the PK 
sampling and Table 1-9 shows the timing for measurement of vital signs in relation to infusions. 
 

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Table 1-6 Visit Evaluation Schedule in Expansion Part – Biweekly Regimen (Q2W) and Priming Regimen (Priming/Q2W) 
Treatment Cycle 
Screening 
Cycle 1-31 
Cycle 4-PD1 
End of treatment2 
Safety Follow-up20 
Patient 
follow-up 
End of 
trial 
Un-
scheduled 
Day 
≤ 21 days prior 
to Visit 
C1-V1 
1d 
3d31 
8d 
1d 
8d21 
- 
30 days 
after last 
dosing 
70 days 
after last 
dosing 
13W, 26W, 
39W + 
52W after 
last dosing 
- 
- 
Visit window3 
 
±1d 
- 
±1d 
±1d 
±1d 
- 
±7d 
±7d 
±14d 
- 
- 
Informed Consent4 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics, Disease status 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior cancer therapy/surgery 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
Body Weight6 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
Physical Examination24 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
Vital Signs7 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
X15 
Liver ultrasound 
X 
 
 
 
 
 
 
 
 
 
 
 
ECG 
Please see Table 1-7 for details of ECG assessments 
Efficacy assessment 
([PET]-CT-Scan/MRI) 
X8 
X9 
X22 
 
 
 
 
X15 
ECOG status 
X 
X 
 
 
X 
 
X 
 
 
 
 
X15 
Adverse Events5 
X 
X 
 
X 
X 
X 
X 
X 
X 
X17 
 
X15 
Concomitant Medication 
X 
X 
 
X 
X 
X 
X 
X18 
X18 
X18 
 
X15 
IMP administration 
 
X 
 
 
X 
 
 
 
 
 
 
 
Pre-medication30 
 
X 
 
 
 
 
 
 
 
 
 
 
End of trial 
 
 
 
 
 
 
 
 
 
 
X19 
 
Laboratory assessments10 
 
 
 
Hematology 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X15 
Biochemistry23 
X 
X 
X25 
X 
X 
X 
X 
X 
X 
 
 
X15 
Urinalysis  
X 
X 
 
 
X 
 
X 
X 
X 
 
 
X15 
Pregnancy Test11 
X 
X 
 
 
X 
 
X 
 
 
 
 
X15 
ADA (Immunogenicity) 
X 
X 
 
 
X 
 
X 
X 
X 
 
 
X15 
Hepatitis B, C, CMV12 
X 
 
 
 
 
 
X 
 
 
 
 
X15 
PK Sampling 
Please see Table 1-8 for details of PK sampling 
Tumor biopsy 
X13 
 
 
 
 
 
X15 
 
 
 
 
X15 
Immunophenotyping and PBMC 
 
X28 
 
X28 
 
X16 
X 
 
 
 
 
X15 
Cytokines and circulating factors 
 
X 
X27 
X 
X14 
X14 
 
 
 
 
 
X15 

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Footnotes to Trial Flowchart: Expansion Part - Biweekly Regimen (Q2W) and Priming Regimen (Priming/Q2W) 
1 The duration of one cycle is 14 days. Treatment can continue until PD. 
2 If the patient shows PD, is starting new anti-cancer treatment or withdraws from treatment due to another reason the end of treatment visit should be performed as soon as possible after decision of 
discontinuation. 
3 The specified visit windows are in accordance with the previous visit. From Cycle 2-12, Day 1 of the next cycle should be performed 7 days ± 1 day after Day 8 of the previous cycle and from Cycle 13 and 
onwards, Day 1 of the next cycle should be performed 7 days ± 3 days after Day 8 of the previous cycle. 
4 Informed consent must be obtained before or at Screening  prior to making any screening assessments. 
5  Adverse Events should be reported from the time the informed consent is signed. 
6 During the trial, body weight is measured on the dosing day as part of the dose calculation. If body weight is assessed ≤ 7 days before the first day of the planned dosing in a cycle, this value can be used to 
calculate dose. 
7 Temperature, blood pressure and heart rate. Please see Table 1-9 and Section 9.4.2 
8 Within 4 weeks prior to Cycle 1 Day 1. If a (PET)-CT-scan/MRI has been performed within 4 weeks prior to Cycle 1 Day 1 as part of standard procedure, it is acceptable as screening CT-scan/MRI for the 
trial. If there is suggestion of brain metastases/tumors, a (PET)-CT-scan/MRI of the head and neck will be performed before inclusion. Please see section 9.2. At the discretion of the investigators and after 
approval of the sponsor, combined PET-CT may be performed for tumor assessments. 
9  On-trial imaging will be performed at Week 6 (-7 days), every 6 weeks (±7 days) for 50 weeks, and every 12 weeks (±7 days) thereafter from the date of first dose until disease progression is assessed by 
the investigator, the start of new anti-cancer therapy, withdrawal of consent, or death, whichever occurs first. Imaging assessments should follow calendar days and should not be adjusted for delays in 
cycle starts. 
10 All laboratory parameters will be analyzed centrally, except urinalysis. In the first 3 cycles, all biochemistry safety parameters must be assessed locally as well to monitor liver function. At infusion visits 
laboratory parameters will be analyzed at local laboratory prior to IMP  treatment please see section 9.5. 
11Serum (beta-hCG) laboratory test should be taken at screening. A urine pregnancy test should be taken before every treatment of IMP. 
12 HBsAg, anti-HBs and anti-HBc, Hepatitis C and antibodies to CMV antigen will be assessed at screening for all patients. At end of treatment, only antibodies to CMV antigen will be assessed. 
13 A mandatory fresh biopsy (FFPE tissue blocks/slides) at screening (aspirates are not acceptable) is to be provided for all patients which is taken after failure/stop of last treatment, unless not clinically 
feasible as assessed and documented by investigator. In case it is not feasible to meet the required criteria for fresh tumor biopsy, the sponsor medical officer’s approval of enrollment is needed. Furthermore 
the latest available archival tumor tissue sample has to be collected if available.   
14 All patients must have a sample taken at Day 1 and 8 of Cycles 4, 5 and 6. If the visit occurs on an infusion day, the sample must be taken before IMP treatment. If the Day 8 visit on Cycle 4 and/or 5 is 
omitted according to footnote 21, the sample does not need to be taken (sample at Cycle 6 Day 8 is mandatory). 
15 Optional. 
16 Sample to be taken Cycles 3 and 6. 
17 Suspected IMP related AEs only. 
18 Only new anticancer treatments. 
19 Patient status at withdrawal. 
20 If the patient withdraws sooner than 70 days after the last dosing, the safety follow-up visit should take place at the time of withdrawal unless there has been a safety follow-up visit within the last 14 days. 
21 The Day 8 visit can be omitted after approval by the sponsor medical monitor if there have been no AEs fulfilling the DLT criteria in the previous 3 cycles. 
22 To be completed as indicated to confirm response, new symptoms, end of treatment visit or at the physician discretion, see Section 9.2. 
23 Any AST, ALT, and/or bilirubin ≥ grade 2 needs to be checked 2×/week for up to 4 weeks and until resolution or return to baseline. 
24 A complete, general physical examination will be done at the screening and Cycle 1 Day 1 visits. At subsequent visits and as clinically indicated, limited symptom-directed physical examinations should be 
performed. 
25 Repeat at least once more, i.e. on Day 5 if AST, ALT, or bilirubin ≥ grade 1 and > 1.5×baseline. 
27 Only required at Cycles 1 and 2 
28 All patients must have a sample taken at Day 1 and 8 of Cycle 1 and at Day 8 of Cycle 3. If the visit occurs on an infusion day, the sample must be taken before IMP treatment. 
 
30 Dexamethasone 4 mg/p.o. one day before dosing at Cycles 1 and 2 and 10 mg. i.v. at Day 1 before dosing and orally at Day 2 in Cycles 1 and 2. If a drug-related ≥ grade 2 elevation of ALT and/or AST is 
observed during the second cycle or thereafter, Dexamethasone pre-medication should be continued/re-introduced. In this case, Dexamethasone can be given orally on the day after the dosing day (Section 
6.4.1). 
31 If no AST, ALT, and/or bilirubin ≥ grade 2 elevations are observed in Cycle 1 and 2, the visit at Cycle 3 Day 3 can be omitted. 
 

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Table 1-7 ECG Assessments in Expansion Part – Applicable for Both Regimens 
Treatment Cycle 
Screening 
Cycle 1-3 
Cycle 4-PD 
End of 
Treatment 
Unscheduled 
Day 
- 
1d 
8d 
1d 
- 
 
Before Infusion 
(on infusion days) 
1 
3 
3 
3 
1 
1a 
End of infusion  
(+15 minutes) 
 
3 
 
3 
 
 
1 – Single ECG assessment 
3 – Triplicate ECG assessments 
a Optional. 
 
Table 1-8 PK Sampling in Expansion Part – Applicable for Both Regimens 
Treatment Cycle 
Screening 
Cycle 1-3 
Cycle 4-PD 
Unscheduled 
Day/Week 
- 
1d 
8d 
1d 
 
Before Infusion 
(on infusion days) 
X 
X 
X 
X 
X1 
End of infusion  
(+15 minutes) 
 
X 
 
X 
 
1 Optional. 
 
Table 1-9 Vital Signs during the Expansion Part – Applicable for Both Regimens 
Pre-infusion  (up to 30 min before infusion) 
At the end of infusion (± 10min)* 
1 hour after end of infusion (± 10 min) 
2 hours after end of infusion (± 15 min) 
*If infusion lasts for more than 60 minutes, vital signs should be assessed every 30 minutes (± 5 minutes) for the remaining duration of infusion. 

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2 
INTRODUCTION 
2.1 
Background 
GEN1029 is being developed primarily for intravenous (i.v.) treatment of selected malignant solid 
tumors. The medical need is high for innovative anti-cancer therapies with improved efficacy and 
safety profiles, including therapies for patients with advanced and/or metastatic Colorectal Cancer 
(CRC), Non-small Cell Lung Cancer (NSCLC), Triple Negative Breast Cancer (TNBC), Renal 
Cell Carcinoma (RCC), gastric, pancreas or urothelial cancer. Additional tumor types might be 
selected based on ongoing preclinical research and initial experience to be generated in this first-
in-human trial, primarily focusing on the safety and tolerability of GEN1029 being administered 
as a monotherapy. 
GEN1029 targets DR5 (TRAILR2, CD262), which is expressed in a variety of human cancer 
tissues (Burvenich et al., 2013; Ichikawa et al., 2001; Koornstra et al., 2003; Wang et al., 2003). 
DR5 is a member of the Death Receptor subgroup of the Tumor Necrosis Factor Receptor 
Superfamily (TNFRSF) (MacFarlane et al., 1997; Pan et al., 1997; Schneider et al., 1997; Walczak 
et al., 1997). The mechanism of action of GEN1029 resembles DR5 activation by its natural ligand, 
trimeric TNF-related apoptosis-inducing (TRAIL, Apo-2L) (Sessler et al., 2013), resulting in DR5 
hyperclustering and induction of caspase-dependent apoptosis.  
The level of DR5 protein expression on the cell surface required for efficacy of GEN1029 is not 
known. Preclinical activity of GEN1029 was observed at low levels of DR5 expression, and there 
was no correlation between DR5 expression levels and GEN1029 preclinical efficacy. The 
threshold of DR5 expression for clinical efficacy may be well below the detection limit of 
immunohistochemical methods, and target expression could thus not be used as a basis for 
indication selection. Instead, indication selection for this FIH trial was based on a comprehensive 
preclinical efficacy data package. In an in vitro screening of a cell line panel consisting of 240 
DR5-positive cell lines representing 16 different tumor types, GEN1029 induced strong inhibition 
of tumor cell viability in cell lines representing renal, colorectal, gastric, urothelial and pancreatic 
cancer as well as TNBC, NSCLC and brain tumors. These in vitro screening results were validated 
in vivo in a patient-derived xenograft (PDX) clinical trial, in which large sets of CRC and NSCLC 
PDX models were screened for sensitivity to GEN1029.  
Based on these in vitro and in vivo efficacy screenings for GEN1029, CRC, NSCLC, TNBC, RCC, 
gastric, pancreas and urothelial cancer have been selected to be explored in this trial. For more 
comprehensive information regarding the cytotoxicity of GEN1029 in vitro and in vivo, please 
refer to the Investigator's Brochure. 
2.1.1 Overview of Disease 
2.1.1.1 Colorectal Cancer 
In the US, 134,490 new cases of colorectal cancer and 49,190 deaths due to/related to CRC are 
estimated in 2016. Five-year relative survival rates in the US were 71% for patients with regional 
disease at diagnosis and only 13% for patients with distant disease at diagnosis (rates are adjusted 
for normal life expectancy and are based on cases diagnosed in the SEER 18 areas from 2005-
2011, all followed through 2012).  
The current management of metastatic colorectal cancer involves various drugs, either in 
combination or as single agents: 5-FU/LV, capecitabine, irinotecan, oxaliplatin, bevacizumab, 
cetuximab, panitumumab, ziv-aflibercept, ramucirumab, regorafenib, trifluridine-tipiracil, 

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pembrolizumab, and nivolumab. Recommended initial therapy options for advanced or metastatic 
disease depend on whether the patient is appropriate for intensive therapy. The more intensive 
initial therapy options include FOLFOX, FOLFIRI, CapeOx, and FOLFOXIRI. Addition of a 
biological agent (e.g., bevacizumab, cetuximab, panitumumab) is an option in combination with 
some of these regimens. Systemic therapy options for patients with progressive disease depend on 
the choice of initial therapy. The NCCN panel endorses the concept that treating patients in a 
clinical trial has priority over standard treatment regimens. In the currently established treatment 
algorithm clinical trials are at least to be considered in the fourth line setting. The approval of 
targeted agents, like Avastin and Erbitux, has  improved outcomes for patients with metastatic 
colorectal cancer (mCRC). However, all targeted agents currently approved to treat mCRC patients 
either target the Vascular Endothelial Growth Factor (VEGF) pathway or the Epidermal Growth 
Factor Receptor (EGFR) pathway. This highlights the need for new agents with novel mechanisms 
of action. The medical need appears to be given especially for patients with RAS (KRAS, NRAS) 
or BRAF mutant disease, and those patients who have failed all available treatment options. 
2.1.1.2 Lung Cancer - NSCLC 
In the US, 224,390 new cases and 158,080 deaths from lung and bronchial cancer are estimated in 
2016. At least 57% of patients had metastatic disease at initial diagnosis. Five-year relative 
survival rates in the US are 27% for patients with regional disease at diagnosis and only 4% for 
patients with distant disease at diagnosis (rates are adjusted for normal life expectancy and are 
based on cases diagnosed in the SEER 18 areas from 2005-2011, all followed through 2012). 
NSCLC represents approximately 80% of lung cancers and includes adenocarcinomas which 
account for approximately 50% of lung cancers, squamous cell carcinomas (SCC) which account 
for approximately 20% and large cell carcinomas which account for approximately 10% of lung 
cancers. 
Several drugs are approved for treatment of NSCLC including alkylators, antimetabolites, tubulin 
inhibitors and monoclonal antibodies. Bevacizumab (anti-VEGF), ramucirumab (anti-VEGFR-2) 
and tyrosine kinase inhibitors are reserved for patients who are EGFR or Anaplastic lymphoma 
kinase (ALK) positive. Recently the immune checkpoint inhibitor nivolumab and pembrolizumab 
(a human and humanized IgG4 monoclonal antibodies, respectively) that target PD-1 have both 
gained approval as 2nd line therapy for SCCs and as subsequent therapy for patients with metastatic 
non-squamous NSCLC which has progressed on or after first-line chemotherapy or targeted 
agents. In patients with sensitizing EGFR mutations, erlotinib is recommended as 1st line treatment 
(gefitinib and afatinib are also indicated in this patient population); and for patients with an ALK 
mutation crizotinib is 1st line therapy. For other patients diagnosed with NSCLC stage III or IV, 
chemotherapy is 1st line treatment and tubulin inhibitors, paclitaxel, docetaxel, vinorelbine and 
nab-paclitaxel, in combination with platinum based chemotherapy is standard of care treatment.  
Despite multiple treatment options, patients with stage IV NSCLC ultimately have a poor 
prognosis - lung cancer is the leading cause of cancer death for both men and women. The 
treatment rate diminishes with each line of therapy, as patients succumb to their cancer or 
experience deterioration of their health that makes further treatment impossible. This poor 
prognosis highlights the need for more effective agents, across all lines of therapy and especially 
in later lines. Squamous histology patients are the least likely to receive multiple lines of treatment, 
while those with EGFR or ALK mutations are more likely to receive additional lines, reflecting 
differences in the availability of approved treatment options for each population. 

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2.1.1.3 Breast Cancer - TNBC 
In the US, 249,260 new cases and 40,890 deaths from breast cancer are estimated in 2016. Five-
year relative survival rates in the US are 85% for patients with regional disease at diagnosis and 
only 26% for patients with distant disease at diagnosis (rates are adjusted for normal life 
expectancy and are based on cases diagnosed in the SEER 18 areas from 2005-2011, all followed 
through 2012). Overall, about 12% of breast cancers are triple negative.  
Metastatic breast cancer patients generally have a number of treatment options. Breast cancer is 
particularly sensitive to cytotoxic therapy, with several types of agents with different mode of 
actions (MOA), active for first-line therapy including anthracyclines and taxanes. Median survival 
with chemotherapy is approximately two and a half years. Long-term responses to 1st line therapy 
are rare; however, breast cancer is sensitive to later lines of therapy as well. Slightly fewer than 
three-quarters of patients receive 2nd line therapy, and approximately two-thirds of these 2nd line 
patients receive 3rd line therapy. Classes of agents such as fluoropyrimidines, antimetabolites, and 
vincaalkaloids are common agents for the chemotherapy backbone in later lines of therapy. Nearly 
two-thirds of patients overexpress one of the hormone receptors, estrogen (ER) or progesterone 
(PR), making them sensitive to endocrine therapy. With at least five endocrine agents available, 
combined with the recent successes of the mTOR inhibitor everolimus and the CDK4/6 inhibitor 
palbociclib in this setting, physicians are able to treat patients sequentially through multiple lines 
of therapy. The medical need for patients that overexpress HER2 is partially addressed by 
trastuzumab, lapatinib, pertuzumab, and T-DM1. HER2-positive patients represent approximately 
one-third of all breast cancers. With the recent introduction of novel HER2-targeted agents in the 
1st line and relapsed setting, sequencing and combinations of agents in later lines of therapy 
appears to provide promising options. 
A huge unmet medical need remains for women with metastatic TNBC, as this disease usually 
progresses rapidly following three to five lines of chemotherapy. To date, only one targeted drug, 
bevacizumab, has been registered in this setting, however bevacizumab has limited clinical value 
as no overall survival gain was demonstrated. Considerable interest has been generated by the 
encouraging results obtained with the immune-checkpoint inhibitors pembrolizumab and 
atezolizumab in heavily pre-treated women with advanced-stage TNBC. The overall response rate 
to these agents remains modest (~18%), but the median duration of response had not been reached 
at the time of publication, indicating sustained responses rarely observed in patients with heavily 
pre-treated TNBC (Piccart et al., 2016).  
2.1.1.4 Renal Cell Cancer 
In the US, 62,700 new cases and 14,240 deaths from renal cell cancer are estimated in 2016. Five-
year relative survival rates in the US were 65% for patients with regional disease at diagnosis and 
only 13% for patients with distant disease at diagnosis (rates are adjusted for normal life 
expectancy and are based on cases diagnosed in the SEER 18 areas from 2005-2011, all followed 
through 2012). Approximately 90% of renal tumors are RCC, and approximately 80% of these are 
clear cell tumors.  
For the treatment of RCC, multiple targeted agents (two mTOR inhibitors, i.e. everolimus and 
temsirolimus; six VEGF pathway inhibitors, i.e. bevacizumab, cabozantinib, axitinib, sorafenib, 
sunitinib, and pazopanib) and the immune checkpoint inhibitor nivolumab are available. There are 
numerous treatment possibilities through multiple lines of therapy. With so many options, 
prognosis is relatively good: in the 1st line setting, median survival of -2-3 years is achieved, and 

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most patients achieve a PFS of approximately a year. The relatively long survival obscures the fact 
that, even with best therapy, patients are not cured. 
2.1.1.5 Gastric Cancer 
In the US, 26,370 new cases of stomach cancer and 10,730 deaths are estimated in 2016. 
Approximately 50% of patients present with advanced disease at diagnosis and have a poor 
outcome. Five-year relative survival rates in the US are 30% for patients with regional disease at 
diagnosis and only 5% for patients with distant disease at diagnosis (rates are adjusted for normal 
life expectancy and are based on cases diagnosed in the SEER 18 areas from 2005-2011, all 
followed through 2012).  
In HER2-negative patients cytotoxic regimens such as FOLFOX (folinic acid, 5-fluorouracil 
(5-FU), oxaliplatin) and EOX (epirubicin, oxaliplatin, capecitabine) are established treatments for 
1st line. In HER2-positive patients, trastuzumab, has become the standard of care, either in 
combination with cisplatin plus 5-FU or with cisplatin plus capecitabine. Ramucirumab, as single 
agent or in combination with paclitaxel is an option for 2nd line therapy. However, with 
approximately a one-year survival reported in the 1st line setting for either HER2-negative or 
HER2-positive patients, there is a significant unmet need for more efficacious therapies for 
metastatic gastric cancer patients. 
2.1.1.6 Pancreas Cancer 
Pancreatic cancer is the third leading cause of cancer-related deaths in the United States and 
expected to become the second by 2020. In the US, 53,070 new cases of pancreatic cancer and 
41,780 deaths are estimated in 2016. Five-year relative survival rates in the US are 27% for patients 
with local disease at diagnosis and only 2% for patients with distant disease at diagnosis (rates are 
adjusted for normal life expectancy and are based on cases diagnosed in the SEER 18 areas from 
2005-2011, all followed through 2012). 
FOLFIRINOX and gemcitabine alone or in combination with albumin-bound paclitaxel, are the 
predominant systemic therapeutic regimens used as 1st line treatments in this setting, although 
other regimens containing agents such as irinotecan liposome injection (combined with 5-FU and 
leucovorin), bevacizumab, or erlotinib and FOLFOX may be utilized as 2nd and 3rd line treatments. 
The use of FOLFIRINOX in patients with good performance status has significantly increased in 
recent years. However, despite the increased number of treatments available in this setting, many 
patients continue to opt for no therapy at this stage. The low objective response rate and lack of 
survival benefit with current chemotherapy and combined modalities indicate that clinical trials 
are crucial options for newly diagnosed, late-stage patients. 
2.1.1.7 Urothelial Cancer 
In US, 76,900 new urinary bladder cancer cases and 16,390 deaths are estimated in 2016. Five-
year relative survival rates in the US are 34% for patients with regional disease at diagnosis and 
only 5% for patients with distant disease at diagnosis (rates are adjusted for normal life expectancy 
and are based on cases diagnosed in the SEER 18 areas from 2005-2011, all followed through 
2012). 
Treatment for advanced bladder cancer has historically included gemcitabine- or taxane-based 
chemotherapy regimens besides DDMVAC and chemoradiotherapy. A clear unmet need is the 
paucity of approved targeted agents for the treatment of bladder cancer. That has started to change 
with the recent approval of atezolizumab as well as several other novel agents currently in pivotal 

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clinical development for advanced disease. Atezolizumab’s accelerated approval came along with 
a Breakthrough Therapy Designation and priority review from the U.S. FDA, highlighting the need 
for new treatment options in bladder cancer. 
2.1.2 Introduction to Investigational Treatment 
GEN1029 is an equimolar mixture of two non-competing DR5-specific humanized IgG1 
antibodies, with an E430G HexaBody® mutation in their Fc domains. This is the first time that an 
antibody product exploiting Genmab’s HexaBody technology will be tested in humans. HexaBody 
molecules are monomeric IgG1 antibodies that have an engineered Fc-region harboring a single 
mutation, such as E430G, that significantly enhances the natural process of forming ordered 
hexameric antibody structures through intermolecular Fc-Fc interactions upon cell surface antigen 
binding (de Jong et al., 2016; Diebolder et al., 2014). In the case of GEN1029, this results in DR5 
hyperclustering and activation of the cell death inducing signaling pathway, leading to 
programmed cell death of the target cells. 
The mechanism of GEN1029-mediated DR5 clustering through antibody hexamerization is 
different from conventional, bivalent DR5-specific IgG1 antibodies, such as conatumumab, 
tigatuzumab, drozitumab, lexatumumab, and LBY-135 that depend on additional FcR-mediated 
crosslinking in order to induce DR5 hyperclustering and apoptosis. Despite promising preclinical 
activity and a generally good safety profile (for the majority of the compounds, the MTD was not 
reached – please also refer to the benefit-risk assessment in Section 2.3), these conventional IgG1 
antibodies against DR5 failed to show convincing anti-tumor efficacy in clinical trials (Amarante-
Mendes et al., 2015; Ashkenazi, 2015). The low efficacy of conventional anti-DR5 antibodies has 
been attributed to lack of proper FcR-mediated crosslinking, for example due to competition with 
endogenous serum IgG and/or absence of FcR-expressing cells in the tumor microenvironment 
(Gieffers et al., 2013). 
Of note, TAS266 is a particular multivalent anti-DR5 antibody fragment-based compound that 
was tested in humans. TAS266 is a tetravalent Nanobody®, consisting of four humanized llama-
derived VHH antibody fragments linked through 35-aa linkers (Huet et al., 2014). The TAS266 
study was terminated after three out of four patients showed reversible liver toxicity at starting 
dose, which correlated with the presence of pre-existing anti-drug antibodies (ADA), suggesting 
that TAS266 toxicity was caused by an atypical antigenicity of the tetravalent Nanobody 
(Papadopoulos et al., 2015). 
The unique concept and mechanism of action of GEN1029 supports the notion that GEN1029 is a 
promising therapeutic agent with potential anti-tumor effect in many different cancer types. 
2.1.3 Summary of Nonclinical Studies 
A comprehensive nonclinical data package is available supporting the mechanism of action (MoA) 
of GEN1029 to induce cell killing of DR5-positive cancer cells by DR5 hyperclustering and 
downstream caspase activation.  
The individual antibody components of GEN1029, drug substances 1029-01 and 1029-05, bind 
different epitopes on DR5 but have comparable apparent binding affinities with EC50 values in 
the high picomolar/low nanomolar range. It was shown both in vitro and in vivo that GEN1029 
induced more potent cytotoxicity compared to the single HexaBody molecules and to the mixture 
of wild type (WT) antibodies without the E430G mutation. These data demonstrated that both the 
mixture of the two different HexaBody molecules and the HexaBody format were required for the 
efficacy of GEN1029. Furthermore, it was demonstrated both in vitro and in vivo that the efficacy 

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of GEN1029 was independent of secondary FcR-mediated crosslinking, which was in contrast to 
the conventional DR5-targeting antibody conatumumab. GEN1029 induced cytotoxicity in vitro 
in a range of cell lines derived from different solid cancers, with loss of cell viability starting at a 
median concentration (IC20) of 0.083 g/mL (0.554 nM). In vivo, GEN1029 showed potent anti-
tumor activity in a broad range of human cancer cell line-derived xenograft (CDX) models and 
consistently outperformed conatumumab in all responsive models. Maximal anti-tumor activity 
was observed at doses of 2 mg/kg or higher, and 0.5 mg/kg was the lowest dose at which anti-
tumor activity was observed. Importantly, GEN1029 also showed strong anti-tumor activity in 
patient-derived xenograft (PDX) models, which are thought to represent the genetic and 
histological heterogeneity observed in human tumors. 
The cytotoxic activity of GEN1029 was shown to be caspase-mediated. GEN1029 induced rapid 
and potent caspase-3/7 activation in DR5-positive cancer cells.  
In vitro studies indicated that GEN1029 did not induce antibody-dependent cellular cytotoxicity 
(ADCC) or complement-dependent cytotoxicity (CDC) on tumor cell lines, and did not induce 
fluid-phase complement activation in vitro.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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For more comprehensive information regarding nonclinical studies for GEN1029, please refer to 
the current version of Investigator's Brochure. 
2.1.4 Summary of Clinical Trials 
This will be the first administration of GEN1029 in humans; therefore, no clinical experience is 
available. 
2.2 
Rationale 
Death Receptor 5 (DR5) is a receptor for Tumor Necrosis Factor Related Apoptosis-Inducing 
Ligand (TRAIL), which upon binding to the ligand, initiates an ‘outside-in’ signaling pathway 
leading to apoptotic cell death of TRAIL-sensitive cancer cells. While previously tested human 
DR5 monoclonal antibodies (mAbs) showed compelling pre-clinical anti-tumor activity, human 
DR5 mAbs did not perform well in clinical trials. 
Receptor clustering and activation of apoptosis by human DR5 mAbs appeared not to be potent 
enough in patients, possibly due to insufficient crosslinking of DR5 via FcR expressing immune 
cells in the tumor micro-environment. FcR-mediated crosslinking is considered to be a key factor 
for the anti-tumor activity of human DR5 mAbs. Therefore, GEN1029 targeting of two distinct 
epitopes on DR5 with a mixture of two DR5-specific HexaBody molecules that organize into 
hexameric antibody structures upon surface target binding to increase FcR-independent clustering 
is a rational novel approach to overcome this issue for the therapy of cancer patients. 
Based on promising pre-clinical results this trial is planned to explore the safety, PK and biomarker 
profile as well as the anti-tumor activity of GEN1029 in patients with advanced and/or metastatic 
CRC, NSCLC, TNBC, RCC, gastric, pancreas or urothelial cancer who have failed available 
standard therapy or who are not candidates for standard therapy, and for whom, in the opinion of 
the investigator, experimental therapy with GEN1029 may be beneficial. 
2.3 
Benefit-Risk Assessment 
Several human DR5 mAbs have been clinically tested but their anti-tumor effect has been rather 
limited presumably as a consequence of insufficient FcR-immune cell-mediated crosslinking of 
DR5 and a less potent apoptosis triggering signal (Micheau et al., 2013; Forero et al., 2017; 
Gieffers et al., 2013). GEN1029 targets two distinct epitopes on DR5 and enhances hexamer 
formation/receptor clustering in an FcR-independent manner and is therefore a rational novel 
approach to overcome this issue. 
Previous clinically tested human DR5 mAbs have as described above generally been well tolerated 
and most adverse events (AEs) have been mild to moderate (CTCAE grade 1-2). The most 
frequently reported AEs across human DR5 mAb mono-therapy trials (Herbst et al., 2010; Doi et 
al., 2011; Camidge et al., 2010; Forero-Torres et al., 2010; Plummer et al., 2007; Wakelee et al., 
2010; Forero et al., 2017) conducted in adult patients with advanced cancer disease are listed below 
(order reflecting reported frequency (x out of 7 trials)), independent of CTCAE grading: 

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• 
Fatigue (among the most frequent reported AEs in 7/7 clinical trials) 
• 
Nausea (6/7) 
• 
Vomiting (6/7) 
• 
Pyrexia (5/7) 
• 
Anorexia (4/7) 
• 
Anemia (3/7) 
• 
Chills (3/7) 
• 
Constipation (3/7) 
• 
Cough (3/7) 
• 
Diarrhea (3/7) 
• 
Dyspnea (3/7) 
• 
Headache (3/7) 
The most frequent reported clinical significant and possibly drug related adverse event ≥ grade 3 
has been elevation of amino transferase liver enzymes (Camidge et al., 2010; Plummer et al., 
2007). A mitigation plan for handling AEs of elevated liver parameters has been prepared for this 
trial in order to closely monitor, dose-delay, dose-reduce or withdraw patients with liver enzyme 
elevations (please see Section 7.2.2.1). 
There are so far no specific experimental observations or knowledge about the reproductive or 
fetal developmental toxicity of GEN1029. However, DR5 mRNA has been described to be 
expressed in the reproductive system and reproductive effects of GEN1029 in humans can 
therefore not be ruled out. More detailed information about DR5 receptor expression, nonclinical 
and clinical results as well as potential safety aspects of GEN1029 therapy can be found in the 
Investigator’s Brochure. 
Based on nonclinical and clinical data available to date, and published data from other human DR5 
mAbs, the conduct of the trial GCT1029-01 is regarded as justifiable. Furthermore, the patient 
population eligible for the current trial is patients with selected advanced and/or metastatic cancer, 
who have failed available standard therapy or who are not candidates for standard therapy, and for 
whom in the opinion of the investigator, experimental therapy with GEN1029 may be beneficial. 
All patients enrolled in this trial will be controlled frequently by qualified health care 
professional(s) who will provide care and closely monitor and evaluate the patient’s response to 
the trial drug, in terms of its safety and efficacy.  
As of the 20-Aug-2019, 27 patients have been exposed to GEN1029 at dose levels ranging from 
0.3 to 3 mg/kg: 24 patients on the Biweekly Regimen (Q2W) and 3 patients on the Intensified 
Regimen (8×Q1W/Q2W). Based on this experience, two AEs have been identified as risks and 
AEs of special interest (AESIs). These are elevated transaminase levels and diarrhea (Section 
10.3). As a result, a mitigation plan for handling AEs of diarrhea has been prepared for this trial 
to guide diagnostic steps and treatment.  
Of note, all 3 patients exposed in the Intensified Regimen experienced DLTs due to transaminase 
elevations, 
 
 Consequently, the Intensified 
Regimen is permanently discontinued. 

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More detailed information about the known and expected benefits and risks including reasonably 
expected AEs of GEN1029 can be found in the Investigator’s Brochure. 

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3 
OBJECTIVES AND ENDPOINTS 
Objectives and related endpoints are described in Table 3-1. 
Table 3-1 Objectives and Endpoints 
Dose Escalation Part 
Objectives 
Endpoints 
Primary 
 
 
Determine the MTD and/or  the recommended Phase 2 
dose (RP2D) 
 
Establish the safety profile of GEN1029 
 
Dose limiting Toxicities (DLTs) 
 
Adverse 
events 
(AEs) 
and 
safety 
laboratory 
parameters (hematology and biochemistry)  
 
Secondary 
 
 
Establish the PK profile and evaluate immunogenicity 
of GEN1029 after single and multiple infusions 
 
PK parameters (clearance, volume of distribution and 
area-under-the-concentration-time curve [AUC0-Clast 
and 
AUC0-∞], 
AUC0_14d, 
CL. 
maximum 
concentration [Cmax], time of Cmax [Tmax], pre-dose 
values, and half-life of GEN1029 
 
Immunogenicity of GEN1029 
 
Evaluate the anti-tumor activity of GEN1029 
 
Anti-tumor activity measured by tumor shrinkage 
(based on computerized tomography [CT]-scan 
evaluations)  
 
Objective Response, Progression-Free Survival (PFS), 
Overall Survival (OS), Duration of Response (DoR), 
and Time to Response (TTR)  
Exploratory 
 
 
To assess biomarkers predictive of response or 
resistance to GEN1029 
 
To assess potential pharmacodynamic biomarkers of 
GEN1029   
 
DR5 expression (protein, 
 
) in tumor 
biopsies  
 
Circulating protein profiles 
 
Immune cells levels  
 
Biomarker profile 
 
To assess the metabolic response in the tumors 
 
 
 
 
Standardized uptake volume corrected for body lean 
mass (SUL) 
 
 
 
 

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Expansion Part 
Objectives 
Endpoints 
Primary 
 
 
To evaluate the Objective Response Rate (ORR) by 
indication 
 
ORR 
Secondary 
 
Evaluate the anti-tumor activity of GEN1029  
 
Anti-tumor activity measured by tumor shrinkage 
(based on computerized tomography [CT]-scan 
evaluations)  
 
Objective Response, Progression-Free Survival (PFS), 
Overall Survival (OS), Duration of Response (DoR), 
and Time to Response (TTR) 
 
To further describe the safety profile of GEN1029 
 
Adverse events (AEs) and safety laboratory parameters 
(hematology and biochemistry) 
 
Evaluate the pharmacokinetic (PK) profile as feasible, 
evaluate immunogenicity of GEN1029 after single 
and multiple infusions 
 
PK parameters  
 
Immunogenicity of GEN1029 
Exploratory 
 
 
To assess biomarkers predictive of response or 
resistance to GEN1029 
 
To assess potential pharmacodynamic biomarkers of 
GEN1029   
 
DR5 expression (protein, 
 
) in tumor 
biopsies 
 
Circulating protein profiles  
 
Immune cells levels 
 
Biomarker profile  
 
To assess the metabolic response in the tumors 
 
 
 
 
Standardized uptake volume corrected for body lean 
mass (SUL) 
 
 
 
 
 

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4 
TRIAL DESIGN 
4.1 
Description of Trial Design 
This is an open-label, multi-center phase I/IIa safety trial of GEN1029 in a mixed population of 
patients with solid tumor types. The trial consists of two parts; a dose escalation part (phase I, FIH) 
and an expansion part (phase IIa) as depicted in Figure 4-1. 
Figure 4-1 
 
 
 

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In the dose escalation part, up to 2 dose regimens may be evaluated; these are described in Section 
4.2. Those dose regimens, that are considered to be safe by the Data Monitoring Committee (DMC) 
and the sponsor safety committee, and for which a recommended phase 2 dose (RP2D) is 
established, may be further explored in the expansion part. Each expansion cohort will only include 
patients with one selected indication who are to be treated with one selected dose regimen. More 
than one dose regimen may be evaluated per indication, but in different cohorts. 
Patients in both parts of the trial will receive treatment until disease progression. Thus, the 
treatment period will last until unacceptable toxicity or disease progression is observed. Efficacy 
will be assessed every six weeks primarily based on CT-scans. The RECIST 1.1 criteria will be 
used for response evaluation (Eisenhauer et al., 2009).  
4.2 
Dose regimens 
This trial will evaluate a Biweekly Regimen (Q2W) and a Priming Regimen (Priming/Q2W), as 
described in Table 4-1. For both regimens, one cycle is 14 days. 
Table 4-1: Dosing Frequencies in the Two Dose Regimens 
Biweekly Regimen 
(Q2W) 
Priming Regimen 
(Priming/Q2W) 
Cycle 1–End of treatment 
Q2W 
Cycle 1 – Priming 
dose on Day 1 
Cycle 2– End of 
treatment 
Q2W 
4.2.1 Biweekly Regimen (Q2W) 
The trial is initiated with the Biweekly Regimen. In this dose regimen, patients are treated on day 
1 of each cycle. The escalation of this regimen is started at 0.3 mg/kg and may thereafter evaluate 
GEN1029 at the following dose levels:  
 0.3, 
 1.0, 2.0, 3.0, 
 mg/kg  
Dose escalations (and de-escalations) in the escalation part will follow the modified Bayesian 
Optimal Interval (mBOIN) design; see Section 4.3. 
4.2.2 Priming Dose Regimen 
Dose escalation based on a priming dose may be considered, applying dose levels that have been 
declared safe by the DMC and endorsed by the sponsor safety committee. The priming dose will 
be administered on Day 1 of the first cycle, and thereafter dosed with the maximum starting dose 
once every 14 days.   
Scenarios for different priming and starting dose levels are covered in Table 4-2. The priming dose 
and the starting dose in Cycle 2 will be determined based on the totality of the available data and 
selected as recommended by the DMC and confirmed by the sponsor safety committee.   

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Table 4-2: 
 
 
 
 
Dose escalation based on priming doses may potentially evaluate GEN1029 at the following dose 
levels in the second cycle (dependent on data collected during the trial):  
 0.3, 
, 1.0, 2.0, 3.0, 
 mg/kg  
Dose escalation (and de-escalations) in the escalation part will follow the mBOIN design; see 
Section 4.3. 
4.3 
Dose Escalation Part 
In the dose-escalation part, there will be a minimum of 2 nights between the first and second patient 
in each dose cohort to account for any safety signals at each new dose level. This might be modified 
according to recommendations from the DMC and as endorsed by the sponsor safety committee. 
In addition, the first cohort of the Biweekly Regimen will be a single patient cohort. Furthermore, 
no other patients within a dose cohort will receive their first treatment simultaneously, i.e. on the 
same day, during the dose escalation part of the trial, unless apparently efficacious dose levels 
which are declared safe by the DMC are further investigated. During treatment, safety assessments 
will initially be performed on a weekly basis. For the assessments of each cohort, the DLTs will 
be collected for the first two cycles i.e. DLT period of 28 days. For the priming regimen, the DLT 
period must contain 14 days evaluation of one full dose administered after the priming dose have 
been administered. A patient is defined as “evaluable” if a DLT is observed prior to completing 
the DLT period, or if the DLT period is completed without any DLTs. 
The dose escalation part will be performed as a mBOIN design (Yuan et al., 2016). This is in many 
ways similar to a traditional 3+3 design (even more similar to its 3+3+3 variant) except that the 
mBOIN design may allow re-escalation to an already investigated dose level. Re-escalation is 
allowed when the previous dose level is considered safe (based on data from additional patients). 
Re-escalation is not allowed to dose levels that have been terminated. 
Specifically for this trial a target toxicity level of 30% has been chosen leading to escalation and 
de-escalation borders of lambda1=0.24 and lambda2=0.36. 
According to the mBOIN design each time a cohort of patients has been completed, it is evaluated 
whether the next cohort should stay on the same dose, escalate to the dose level above or de-
escalate to the dose level below. This evaluation is based on the frequency of DLTs on the current 
dose level in the following way:  
 DLT frequency at current dose level <= 0.24:  
 
 
Escalate 
 DLT frequency at current dose level >0.24 and <0.36:   
Stay at same dose level 

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 DLT frequency at current dose level >= 0.36:  
 
 
De-escalate 
After completion of the DLT period for each cohort, based on the safety data and the 
recommendation from the mBOIN design algorithm (Table 4-4), the DMC will recommend the 
dose-level for the next cohort of patients, see Table 4-3. As a precaution, the DMC can also 
recommend lower dose levels than the mBOIN design algorithm recommends and even below 0.3 
mg/kg; i.e. 0.1 mg/kg.  
Table 4-3 Number of DLTs Leading to Dose Escalation, De-escalation or Remaining at the 
Same Dose Level 
Number of patients in a cohort 
3  
4 
5 
6  
7 
8 
9  
Escalate 
0  
0 
<=1 
<=1  
<=1 
<=1 
<=2  
Stay at same level 
1  
1 
- 
2  
2 
2 
3  
De-escalate 
2  
2 
2 
3 
3 
3 
4  
Terminate a dose level 
3  
>=3 
>=3 
>=4  
>=4 
>=4 
>=5  
First-in-Human Cohort: 
In order to limit patients being treated at a dose of possibly limited efficacy (i.e. 
), the 
Biweekly Regimen (the initial regimen to be explored) will begin by evaluating GEN1029 with 
the initial cohort consisting of one evaluable patient (i.e. at 0.3 mg/kg). If this patient has 
experienced a DLT or ≥ grade 3 toxicity (at least possibly drug-related), the cohort size will be 
increased to at least 3 evaluable patients. 
Dose Level Termination: 
A potential drawback of the basic BOIN design is that, theoretically, a very toxic dose level could 
be investigated in multiple cohorts, if the dose level just below it is not toxic. To avoid this 
problem, a dose level termination criterion is implemented (see Table 4-4).  
Other mBOIN specific parameters are detailed in Table 4-4. 
 
 

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Table 4-4: Design Parameters of the mBOIN Design for the Two Dose Regimens 
 
Biweekly Regimen 
(Q2W) 
Priming Regimen 
(Priming/Q2W) 
Target toxicity rate 
30% 
[lambda1; lambda2] 
[0.24; 0.36] 
DLT period 
Day 1-28 
Stopping criteria 
If the BOIN algorithm recommends that the next cohort should be 
run on a dose level that has already investigated 9 patients (to 
ensure that the trial will not keep enrolling patients on a dose level 
already adequately investigated) 
Dose level termination due 
to toxicity 
A certain dose level can no longer be investigated if an additional 
DLT-free cohort would lead to de-escalation 
Default cohort size 
3 patients 
Initial cohort size 
1 patient 
3 patients 
Possibly modified cohort 
size 
In case a cohort had less than 3 patients evaluable the next cohort 
on the same dose level may be enlarged to bring the number of 
patients on the dose level up to a multiple of 3 
Algorithm may be used if 
There are at least 3 evaluable 
patients on a dose level (except 
the initial dose level) 
There are at least 3 evaluable 
patients on a dose level 
Replacement of in-
evaluable patients 
If needed (to bring number of patients on the dose level up to 3) 
in-evaluable patients will be replaced.  
Over-recruitment on safe 
doses 
Apparently efficacious dose levels which are declared safe by the 
DMC may be further investigated, augmenting the mBOIN design, 
by adding up to a total of max. 9 patients to such dose levels 
Maximum number of 
patients to add on safe 
doses 
18 
DLT consideration in over-
recruited patients 
Do not contribute to mBOIN algorithm, but will be reported to 
DMC. (If the mBOIN algorithm later stipulates de-escalation to an 
over-recruited dose level, all patients on that dose will be counted 
as part of the mBOIN algorithm.) 
 
Determination of MTD and RP2D: 
After the mBOIN algorithm has completed (for a given regimen), the DMC and the sponsor safety 
committee will determine the MTD and the RP2D which may be the same as the algorithm 
recommends for the next cohort or it may be a lower dose. In any case the RP2D will be a dose 
with a lower observed DLT rate than the target toxicity level of 30%.  

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If there is evidence that a dose level lower than the MTD (which might not have been reached at 
this stage) has adequate efficacy (whether determined by CT scan data or by pharmacodynamic 
endpoints or predicted efficacious dose) the DMC and sponsor safety committee may decide that 
the RP2D has been determined and may decide to stop the dose escalation. 
4.4 
Expansion Part 
The aim of the expansion part is to provide further data on the safety, tolerability, PK and anti-
tumor activity of the selected dose regimen(s). 
The expansion cohorts may run in parallel. Each cohort will only contain one selected indication 
on a specific dose regimen. More than one dose regimen per indication may potentially be 
evaluated, depending on the outcome from the escalation part. Within an indication these would 
all constitute different expansion cohorts, and patients would in this case be randomized between 
the available dose regimens (see Section 6.1.2 on treatment assignment for more information). A 
total of up to seven expansion cohorts will be opened.  
In each expansion cohort, an analysis after at least 10 evaluable patients will be performed. If there 
is evidence of anti-tumor activity such as tumor shrinkage or prolonged disease stabilization, and 
without safety concerns, up to 60 patients will be allocated to an expansion cohort in a stage wise 
fashion, primarily testing pre-specified futility criteria (see Section 11.7 for further details), but 
also taking the totality of the data into account. The data will be evaluated by the sponsor safety 
committee which decides on further recruitment into the cohort. 
A DMC review of safety data will be performed when 12 patients have been recruited and have 
been followed for at least two cycles (regardless of indication and dose regimen). DMC safety 
review will be performed after 36 patients have been recruited and followed for at least two cycles 
(regardless of indication). Thereafter, DMC safety review will be performed at least quarterly. The 
DMC and the sponsor safety committee will evaluate the safety profile with particular emphasis 
on any safety signals. 
Patients in the expansion part will be treated on the dose regimen(s) from the dose escalation part 
recommended by the DMC and confirmed by the sponsor safety committee based on a positive 
benefit-risk assessment. If deemed appropriate, and based on data available, the expansion part 
may be initiated before the MTD has been reached. Furthermore, different doses and regimens 
might be explored in the expansion cohorts. 
4.5 
 Planned Number of Patients 
The dose escalation part will enroll up to approximately 100 patients shared between the Biweekly 
and Priming Regimens. Three patients were exposed in an Intensified Regimen (8xQ1W/Q2W) 
all of whom experienced DLTs and, consequently, this dosing regimen was permanently 
discontinued. 
In the expansion part, the planned number of patients depends on how many indications and 
regimens that will be evaluated. Each opened cohort (which is indication and regimen specific) 
will enroll between 10 and 60 patients. Opening all seven cohorts would allocate between 70 
(minimum 10 in each) and 420 (maximum 60 in each) patients in the expansion part. 

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4.6 
Trial Design Rationale 
Part I of this trial is a FIH, open-label, dose-escalation, safety trial studying the DR5-specific 
agonistic hexamer-forming antibody GEN1029 in patients with different types of malignant solid 
tumors in order to determine the MTD and/or RP2D the safety profile of GEN1029. 
Escalation and de-escalation in the dose escalation part will be guided by a mBOIN design, which 
is very similar to the 3+3 design but with the possibility to investigate a dose level again that would 
have been closed in a 3+3 design after de-escalation to a lower dose level and observing that level 
to not be toxic. This greatly enhances the probability of identifying the correct MTD level. 
Part II of this trial is the expansion part including up to seven indications for further investigation. 
The aim of the expansion part is to provide further data on the safety, tolerability, pharmacokinetic 
and anti-tumor activity of the selected dose. 
4.7 
First-in-Human Clinical Trial Starting Dose, dose increments and highest pre-
planned dose level 
A First-in-Human clinical trial starting dose of 0.3 mg/kg is proposed for GEN1029. This dose 
level is considered to be safe and in the lower end of the potential therapeutically active dose range, 
based on considerations from the following preclinical pharmacology, pharmacokinetic and 
toxicology studies: 
 
 
 
 
: 
 
 
 
 
 
 
 

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 
 
 
 
 
 
 
  
 
, 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
                                                 

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4.8 
End of Trial and End of Treatment Definitions 
4.8.1 End of Trial 
The trial is considered completed with the last safety follow-up visit (70 days after last dose) for 
the last patient participating in the trial. The final data from the trial site will be sent to the sponsor 
(or designee) after completion of the final patient visit within the time frame specified in the 
clinical trial agreement. The trial will run for a maximum of three years after the last patient first 
treatment. 
4.8.2 End of Treatment 
For each patient the treatment period will be until progression (cycles of 14 days) unless the patient 
fulfills one of the discontinuation of treatment criteria (see Section 8.1).  
4.8.3 Trial Termination 
The sponsor reserves the right to close the trial site or terminate the trial at any time for any reason 
at the sole discretion of the sponsor. Trial sites will be closed upon trial completion. A trial site is 
considered closed when all required documents and trial supplies have been collected and a trial-
site closure visit has been performed. 
The investigator may initiate trial-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a trial site by the sponsor or investigator may include but are not 
limited to: 
 Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or ICH-GCP guidelines 
 Inadequate recruitment of patients by the investigator 
 Discontinuation of further trial drug development 

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5 
TRIAL POPULATION(S) 
5.1 
Inclusion Criteria 
Patients are eligible to be included in the trial only if all of the following criteria apply: 
1. Patient must be ≥ 18 years of age, at the time of signing the informed consent. 
2. For the dose escalation part: 
Patients with advanced and/or metastatic CRC, NSCLC, TNBC, RCC, gastric (incl. 
esophagogastric junction), pancreas or urothelial cancer who have no available standard 
therapy likely to confer clinical benefit or who are not candidates for such available 
therapy, and for whom, in the opinion of the investigator, experimental therapy with 
GEN1029 may be beneficial. 
For the expansion part: 
Patients with advanced and/or metastatic cancer in up to seven of the following indications: 
CRC, NSCLC, TNBC, RCC, gastric, pancreas or urothelial cancer who have failed the 
following anticancer therapy for metastatic disease (if patients were eligible for the 
respective treatments): 
 
CRC: CRC patients after failure of at least 2 prior systemic regimens but not more than 
4 for advanced and/or metastatic disease (adjuvant and maintenance treatment is 
considered being part of one treatment regimen) including but not limited to 
oxaliplatin- and irinotecan-containing regimens as well as EGRF and VEGF-A 
targeting antibodies, immune checkpoint inhibitors (PD-1 or PD-L1 inhibitor), 
capecitabine, 
ziv-aflibercept, 
ramucirumab, 
regorafenib, 
vemurafenib, 
and 
trifluridine-tipiracil. 
 
NSCLC: NSCLC patients after failure of at least 1 prior systemic regimens but not 
more than 3 for advanced and/or metastatic disease (adjuvant and maintenance 
treatment is considered being part of one treatment regimen) including but not limited 
to one platinum-containing regimen (or alternative chemotherapy due to platinum 
ineligibility, e.g. a gemcitabine-containing regimen) and failure of an immune 
checkpoint inhibitor (patients must have been treated with an approved PD-1 or PD-L1 
inhibitor according to the established local label and access). Patients with epidermal 
growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) / c-
ros oncogene 1 receptor tyrosine kinase (ROS1) rearrangement, or B-Raf proto-
oncogene serine/threonine-protein kinase (BRAF) mutations should have been treated 
with appropriate targeted therapy before trial entry. 
 
TNBC: TNBC patients after failure of at least 1 prior systemic regimen for advanced 
and/or metastatic disease but not more than 4 (adjuvant and maintenance treatment is 
considered being part of  one treatment regimen) including but not limited to 
anthracycline-, antimetabolite- or microtubule inhibitor-containing regimens, or PARP 
inhibitors 
 
RCC: RCC patients after failure of at least 2 prior systemic regimens for advanced 
and/or metastatic disease but not more than 3 (adjuvant and maintenance treatment is 
considered being part of one treatment regimen) including but not limited to anti-
angiogenic agents, mTOR inhibitors and immune checkpoint inhibitors (patients must 

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have been treated with an PD-1 or PD-L1 inhibitor according to the established local 
label and access; unless contraindicated). 
 
Gastric cancer (incl. esophagogastric junction): gastric cancer patients after failure of 
at least 2 prior systemic  regimens for advanced and/or metastatic disease but not more 
than 3 (adjuvant and maintenance treatment is considered being part of one treatment 
regimen) including but not limited to one platinum-containing regimen (or alternative 
chemotherapy due to platinum ineligibility) and failure of a taxane-containing 
regimen, ramucirumab or an irinotecan-containing regimen. Patients with PD-L1 
positive tumors or HER2 overexpression should have been treated with appropriate 
targeted therapy before trial entry according to the established local label and access. 
 
Pancreas cancer: pancreas cancer patients after failure of at least 1 prior  systemic 
regimen for advanced and/or metastatic disease but not more than 2 (adjuvant and 
maintenance treatment is considered being part of one treatment regimen) including 
but not limited to taxane-, antimetabolite- or platinum-containing regimens, or 
immune check-point inhibitors according to the established local label and access. 
 
Urothelial cancer: patients after failure of at least 1 prior systemic regimen for 
advanced and/or metastatic disease but not more than 3 (adjuvant and maintenance 
treatment is considered being part of one treatment regimen) including but not limited 
to one platinum-containing regimen (or alternative chemotherapy due to platinum 
ineligibility, e.g. a gemcitabine-containing regimen) and failure of an immune 
checkpoint inhibitor (patients must have been treated with an approved PD-1 or PD-
L1 inhibitor according to the established local label and access). 
3. Patients must have measurable disease according to Response Evaluation Criteria In Solid 
Tumors (RECIST) version 1.1. 
 
A minimum of one lesion ≥ 10 mm (or twice the slice thickness if slices are not 5 mm 
thick) in the longest diameter (LD) from a non-irradiated area.  
1. Lymph nodes lesion ≥ 15 mm in the shortest diameter from a non-irradiated area. 
2. If target lesion(s) are located within previously irradiated area patients can be 
enrolled if: 
i. 
target lesions have not been irradiated within the last 3 months.  
ii. 
there has been demonstrated progression in the “in field” target lesion and after 
sponsor acceptance. 
4. In the dose escalation part all patients must provide a tumor tissue sample (Formalin Fixed 
Paraffin Embedded (FFPE) blocks/slides) from either archival tissue (preferably derived 
from advanced disease stage) or a fresh biopsy collected before Cycle 1, Day 1. 
In the expansion part a mandatory fresh biopsy (FFPE tissue blocks/slides) at screening 
(aspirates are not acceptable) is to be provided for all patients which is taken after 
failure/stop of last prior treatment, unless not clinically feasible as documented by 
investigator. In case it is not feasible to meet the required criteria for a fresh tumor biopsy, 
the sponsor medical officer’s approval of enrollment is needed. Furthermore, the latest 
available archival tumor tissue sample has to be collected if available.  
5. Have an acceptable hematological status defined as:  

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 
Hemoglobin ≥ 5.6 mmol/L (~ 9 g/dL). 
 
Absolute neutrophil count (ANC) ≥ 1500/µL (1.5109/L). 
 
Platelet count ≥ 75 109/L. 
6. Have an acceptable renal function defined as: 
 
Glomerular filtration rate (GFR) 50 mL/min/1.73 m² – e.g., according to the 
abbreviated Modification of Diet in Renal Disease (MDRD) equation: 
GFR = 186 × (SCr-1.154) × (age-0.203)  
 
(where SCr, the serum creatinine level, is expressed in mg/dL; multiply it by 0.742 if 
the patient is female; multiply it by 1.212, if the patient is African-American (Levey 
et al., 1999).  
 
Not being on dialysis. 
7. Have an acceptable liver function defined as: 
 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the 
ULN (independent of liver involvement). 
 
Bilirubin ≤ 1.5  ULN (except in patients diagnosed with Gilbert’s syndrome, who can 
have total bilirubin < 3.0 mg/dL), direct bilirubin ≤ 2  ULN. 
8. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1  
9. Body weight ≥ 40kg.  
10. Patients, both females and males, of childbearing or reproductive potential must agree to 
use adequate contraception as described below from the screening visit until six months 
after the last infusion of IMP.  
 Female trial participants of childbearing or reproductive potential must agree to use 
one of the highly effective methods of contraception described in Table 5-1 from the 
screening visit until six months after the last infusion of IMP.  
Table 5-1 Highly Effective Contraceptive Methods (from Appendix 1) 
Highly Effective Contraceptive Methods  
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation 
 Oral  
 Intravaginal  
 Transdermal  
Progestogen only hormonal contraception associated with inhibition of ovulation 
 Oral  
 Injectable  
 Implantable 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS) 
Bilateral tubal occlusion 

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Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the female trial participant and the absence of 
sperm has been confirmed. If not, an additional highly effective method of contraception 
should be used.  
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.  
 Male trial participants with female partners of childbearing or reproductive potential 
must agree to use a condom during sexual intercourse from the time of the screening 
visit until six months after the last infusion of IMP.  
11. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this protocol. 
Patient must have life expectancy of greater than three months. 
12. A female patient of childbearing potential (see Appendix 1 for definition) must have a 
negative serum (beta-hCG) pregnancy test at screening. 
13. A female patient must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction while included in the trial and for six months after the last infusion of IMP. 
Male patients must agree not to donate sperm while included in the trial and for six months 
after the last infusion of IMP. 
14. Patient must be willing and able to adhere to the prohibitions and restrictions specified in 
this protocol. 
15. Each patient must sign an informed consent form (ICF) indicating that he or she 
understands the purpose of and procedures required for the trial and are willing to 
participate in the trial. 
5.2 
Exclusion Criteria 
Patients are excluded from the trial if any of the following criteria apply: 
1. Acute deep vein thrombosis or clinically relevant pulmonary embolism, not stable for at 
least 8 weeks prior to first IMP administration. 
2. Have clinically significant cardiac disease, including: 
 
Onset of unstable angina up to six months prior to signing the ICF. 
 
Acute myocardial infarction up to six months prior to signing the ICF. 
 
Known congestive heart failure (Grade III or IV as classified by the New York Heart 
Association); and/ or a known decreased cardiac ejection fraction of < 45%. 
 
A baseline QT interval as corrected by Fridericia’s formula (QTcF) > 480 msec or a 
complete left bundle branch block (defined as a QRS interval ≥ 120 msec in left bundle 
branch block form). 
3. Uncontrolled hypertension defined as systolic blood pressure ≥160 mmHg and/or diastolic 
blood pressure ≥100 mmHg, despite optimal medical management. 

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4. Any history of intracerebral arteriovenous malformation, cerebral aneurysm, new (younger 
than 6 months) or progressive brain metastases or stroke. 
 
Transient ischemic attack > 1 month prior to screening is allowed. 
 
Patients with a history of symptomatic metastatic brain or meningeal tumors may be 
included, if the end of definitive therapy is > 6 months before the first dose of trial 
drug and the patient is having clinically or radiologically no evidence of tumor growth.  
Patients with brain metastases must not be undergoing acute corticosteroid therapy or 
steroid taper. Chronic steroid therapy is acceptable provided that the dose is stable for 
the last 14 days prior to screening. 
 
Patients with central nervous system symptoms should undergo a Computed 
Tomography (CT) scan or Magnetic Resonance Imaging of the brain to exclude new 
or progressive brain metastases. Spinal cord metastasis is acceptable. However, 
patients with spinal cord compression should be excluded. 
5. History of chronic liver disease or evidence of hepatic cirrhosis.  
6. History of organ allograft (except for corneal transplant) or autologous or allogeneic bone 
marrow transplant, or stem cell rescue within 3 months prior to the first dose of IMP. 
7. Have received granulocyte colony stimulating factor (G-CSF) or granulocyte/macrophage 
colony stimulating factor support 4 weeks prior to first IMP administration or being 
chronically transfusion dependent.  
8. Have received a cumulative dose of corticosteroid ≥ 150 mg prednisone (or equivalent 
doses of corticosteroids) within two weeks before the first IMP administration. 
9. History of ≥ grade 3 allergic reactions to monoclonal antibody therapy as well as known 
or suspected allergy or intolerance to any agent given in the course of this trial. 
10. Radiotherapy within 14 days prior to first IMP administration. (Palliative radiotherapy will 
be allowed as described in Section 6.4.2). 
11. Any anticancer therapy (including: small molecules, immunotherapy, chemotherapy 
monoclonal antibodies or any other experimental drug) given within five half-lives before 
first infusion. 
 For anti-cancer therapies with half-lives greater than 5.5 days, a washout period of 
at least four weeks is acceptable (six weeks for nitrosureas or mitomycin). 
Accepted exceptions are bisphosphonates (e.g. pamidronate, zoledronic acid, etc.) and 
denosumab. 
 
Toxic effects of prior anti-cancer therapy considered as chronic, such as 
chemotherapy-induced fatigue, alopecia, or anorexia of  grade 2, where anymore 
resolution is not expected, does not prevent the patient from participation in the trial. 
12. Any prior therapy with a compound targeting DR4 or DR5. 
13. Known past or current malignancy other than inclusion diagnosis, except for: 
 
Cervical carcinoma of Stage 1B or less. 
 
Non-invasive basal cell or squamous cell skin carcinoma. 
 
Non-invasive, superficial bladder cancer. 

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 
Prostate cancer with a current PSA level < 0.1 ng/mL. 
 
Any curable cancer with a complete response (CR) of > 2 years duration. 
14. Known human immunodeficiency virus seropositivity. 
15. Known history / positive serology for hepatitis B (unless immune due to vaccination or 
resolved natural infection or unless passive immunization due to immunoglobulin 
therapy): 
 
Positive test for antibodies to hepatitis B core antigens (anti-HBc) 
              and 
 
Negative test for antibodies to hepatitis B surface antigens (anti-HBs). 
16. Known history / positive serology for hepatitis C (unless due to immunoglobulin therapy), 
which has not been cured. 
17. Ongoing significant, uncontrolled medical condition including: 
 
Serious, non-healing wound, skin ulcer (of any grade), or bone fracture. 
18. Clinically significant active viral, bacterial or fungal infection requiring: 
 
Intravenous treatment with anti-infective therapy that has been administered less than 
two weeks prior to first dose. 
19. Substance abuse, medical, psychological or social conditions that may interfere with the 
patient’s participation in the trial or evaluation of the trial result. 
5.3 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical trial but are not 
subsequently entered in the trial. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure patients to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
serious adverse event. 
Individuals who do not meet the criteria for participation in this trial (screen failure) may be 
rescreened once only. The rescreening must be approved by the sponsor to ensure that the safety 
of the patient is not compromised. 
If rescreening is approved, complete new screening must be performed and all eligibility criteria 
must be re-assessed. If more than 4 weeks have passed since the initial screening failed the patient 
must be re-consented. Also a new ICF should be signed if updates have been made since signing 
of the first ICF. 

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6 
TREATMENT 
6.1 
Treatment Assignment 
6.1.1 Patient Numbering 
After obtaining informed consent, patients will be given a screening number before they undergo 
any screening procedure. A screening ID consists of the letter “S” followed by a three-digit 
sequence number that uniquely identifies a patient at a screening visit e.g. S004. 
When screening has been completed and the patient satisfies the eligibility criteria, the patient is 
given a patient ID. A patient ID consists of a four-digit number that uniquely identifies a patient, 
e.g., patient 0012. 
6.1.2 Treatment Assignment 
This is an open-label trial; therefore, blinding of treatment will not be performed. Allocation of 
patients will be controlled by the CRO.  
 
Escalation Part: 
When a potential patient in the dose escalation is identified at a site, the site personnel must contact 
the CRO for allocation in accordance to Section 4.3. If there is an opening in the currently enrolling 
cohort, the site will be given approval to start the screening process. If there is no opening in the 
currently enrolling cohort, the CRO will place the patient on a list of potential patients. If another 
patient fails the screening process, the CRO will alert the site that has the next patient on the 
waiting list. If the patient is still eligible, the site will be given approval to start the screening 
process.  
Expansion Part: 
In the expansion part, treatment assignment will be done through an electronic system, for 
example, the interactive response technology (IRT) system. The CRO will oversee the recruitment 
and notify the sites when cohorts are complete. If only one dose regimen is opened within an 
indication, eligible patients will be allocated to this. In the situation where more than one dose 
regimen is available to eligible patients within an indication, patients will be allocated as follows 
to available regimens: 
 If two dose regimens are available within the indication, patients will be randomized in a 1:1 
fashion, stratified by ECOG score at screening 
 Should one dose regimen within an indication be stopped during the expansion phase, the 
allocation mechanism will switch to allocation into the one regimen left. 
6.2 
Dosage and Administration 
GEN1029 should be diluted into a 0.9% NaCl (saline) 100 mL (or 250 mL dependent on total 
dose) infusion bag according to the dose assigned to the patient and administered within 24 hours 
of preparation. 
GEN1029 should be administered intravenously over a minimum of 60 minutes and the infusion 
must be completed within 90 minutes using a 0.2 μm in-line filter. The entire infusion volume 
from the prepared infusion bag needs to be administered, no dead volume is provided. The infusion 
is complete when the infusion line has been flushed with minimum 15 mL saline. 

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The dose will be calculated based on the patient’s weight rounded to the nearest kilogram, i.e., 
assigned cohort dose in mg/kg x body weight in kg. 
For patients whose body mass index (BMI) is greater than 30 kg/m2, the investigator should use a 
weight that, based on the patient’s height, corresponds to a maximum BMI of 30. 
Please refer to the IMP manual for dose calculation and additional information regarding IMP 
administration. 
6.3 
Compliance 
Trial drug will be administered by site personnel to assure compliance with trial requirements. The 
date and time of each trial drug administration will be recorded in the eCRF. 
6.4 
Concomitant Medications and Therapies 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) other than GEN1029 the patient is receiving at the time of enrollment or 
receives during the trial must be recorded along with: 
 Reason for use 
 Dates of administration including start and end dates 
 Dosage information including route, dose and frequency 
The patient must be told to notify the investigational site about any new medications he or she 
takes after the start of the trial drug. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
6.4.1 Prophylactic Concomitant Medication 
Fourteen out of 27 patients (11 out of 24 patients in the Biweekly Regimen and 3 out of 3 patients 
in the Intensified Regimen) have experienced transaminase elevations ≥ grade 2. These elevations 
seem to be primarily a first-dose effect, and  independent of dose level or presence of liver 
metastasis. Preliminary data from the ongoing dose escalation suggests that pre-medication with 
steroids may prevent elevations of transaminases.   
Therefore, mandatory pre-medication with Dexamethasone must be administered as follows: 
 4 mg/p.o. one day before dosing at Cycles 1 and 2. 
 Dose escalation part: 10 mg. i.v. at Day 1 before dosing and at Day 2 in Cycles 1 and 2. 
Expansion part: 10 mg. i.v. at Day 1 before dosing and orally at Day 2 in Cycles 1 and 2. 
If a drug-related ≥ grade 2 elevation of ALT and/or AST is observed during the second cycle or 
thereafter, dexamethasone pre-medication should be continued/re-introduced. In this case, 
Dexamethasone can be given orally on the day after the dosing day. 
Furthermore, the below guidance should be followed throughout the trial:  
 Paracetamol (Acetaminophen) and antihistamines (Diphenhydramine, 50 mg p.o. 
preferred, or Dexchlorpheniramine (5 mg i.v.), can be part of the pre-medication regimen 
as judged necessary by the investigator.  
All pre-medication must be reported on the concomitant medication page in the eCRF. 

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6.4.2 Permitted Concomitant Medications and Therapies 
Investigators may prescribe concomitant medications or treatments deemed necessary to provide 
adequate supportive care except for those medications identified as “prohibited” (Section 6.4.3). 
Administration of concomitant medications must be reported in the appropriate section of the 
eCRF.  
 Palliative radiotherapy during the trial will be allowed for local pain control provided that: 
(i) in the opinion of the investigator, the patient does not have progressive disease (PD) 
AND (ii) no more than 10% of the patient’s bone marrow is irradiated AND (iii) the 
radiation field does not encompass a target lesion. 
 G-CSF and other hematopoietic growth factors may be used in the management of acute 
toxicity, such as febrile neutropenia, when clinically indicated or at the investigator’s 
discretion. Patients are permitted to be taking chronic erythropoietin provided that no dose 
adjustment was made within two months before the first dose of IMP. 
 Blood-cell transfusion is allowed if clinically indicated.  
 Chronic steroid therapy is acceptable provided that the dose was stable for at least 2 weeks 
before the first administration of GEN1029 and remains stable thereafter. The cumulative 
dose of corticosteroid within two weeks before the first infusion should not have been ≥ 
150 mg prednisone (or equivalent doses of corticosteroids). Short-term steroid treatment is 
permitted at the discretion of the investigator. 
 Tumor lysis syndrome (TLS): For patients at risk of developing a TLS, prophylaxis 
according to standard local practice with (aggressive) hydration, allopurinol, and/or 
rasburicase is recommended. 
 Bisphosphonates (e.g. pamidronate, zoledronic acid, etc.) and denosumab. 
 Multivitamins, vitamin D and calcium. 
6.4.3 Prohibited Concomitant Therapy 
Patients must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator. 
The following medications and substances are prohibited during the trial: 
 Any other investigational therapy. 
 No dietary supplements are allowed during the trial period (except for multivitamins, 
vitamin D, calcium and supplements in prevention of weight loss). The use of traditional 
medicines is not permitted. 
If a patient receives any of these during the trial, the sponsor must be notified for evaluation of 
whether the patient can continue treatment or not. 

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6.5 
Trial Drug Information 
6.5.1 Physical Description of Trial Drug 
GEN1029 – 20 mg/mL formulated in
 - is  a clear colorless 
solution supplied as a concentrate for solution for infusion to be diluted (at site) in 0.9% NaCl 
(saline). 
6.5.2 Packaging 
IMP will be provided in a 10R/I tubular colorless glass vial containing 7 mL or 10 mL of GEN1029 
(140 mg/vial or 200 mg/vial, respectively). 
6.5.3 Labeling 
IMP labels will contain information to meet the applicable regulatory requirements. 
6.5.4 Preparation, Handling, and Storage  
Each dose of IMP must be prepared by the site pharmacy using aseptic techniques. 
All IMP must be stored at controlled temperatures ranging from 35.6 °F to 46.4 °F (2 °C to 8 °C). 
Refer to the pharmacy manual or trial site investigational product manual for additional guidance 
on trial drug preparation, handling, and storage.  
6.5.5 Drug Accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing of 
IMP in a drug accountability log. Drug accountability will be noted by the field monitor during 
site visits and at the completion of the trial.  
At trial close-out, and as appropriate during the course of the trial, the investigator will destroy all 
used and unused IMP, packaging, drug labels, and a copy of the completed drug accountability log 
to the monitor or to the address provided in the investigator folder at each site (unless otherwise 
agreed with sponsor). 
6.6 
Technical Complaint Handling 
A technical complaint is defined as any suspicion of a product defect related to manufacturing, 
labeling, or packaging, i.e. any dissatisfaction relative to the identity, quality, durability, or 
reliability of a product, including its labeling or package integrity. A technical complaint may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of technical complaint information from trials are crucial for the protection of patients, 
investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor 
has established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of technical complaint information; all trials conducted by the sponsor or its 
affiliates will be conducted in accordance with those procedures. 
6.6.1 Procedures 
All initial technical complaints must be reported to the sponsor by the trial-site personnel within 
24 hours after being made aware of the event. 

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If the defect is combined with a serious adverse event, the trial-site personnel must report the 
technical complaint to the sponsor according to the serious adverse event reporting timelines 
(Section 10.4.4). A sample of the suspected product should be maintained for further investigation 
if requested by the sponsor. 
6.6.2 Contacting Sponsor Regarding Product Quality 
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding technical complaint issues are listed on the contact information page(s), which will be 
provided as a separate document. 

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7 
DOSE MODIFICATIONS AND SAFETY MANAGEMENT GUIDELINES 
7.1 
Dose-limiting Toxicity 
For the purpose of dose escalation, SAEs, non-serious (NS) ≥ grade 3 AEs and clinically 
significant abnormal lab values will be collected and assessed by the DMC for DLTs (in each 
cohort during the first two cycles; i.e. DLT period of 28 days). National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) v.4.03 will be used to grade the 
intensity of adverse events. 
DLT criteria are defined below: 
Hematological 
 Grade 4 neutropenia (i.e., ANC < 0.5  109 cells/L) for minimal duration of seven days.  
 Grade 3 and 4 febrile neutropenia (i.e., ANC < 1.0  109 cells/L with a single temperature 
of > 38.3°C or a sustained temperature of ≥ 38°C for more than one hour). 
 Grade 4 thrombocytopenia (≤ 25.0  109 platelets/L) for minimal duration of seven days. 
 ≥ Grade 3 thrombocytopenia associated with bleeding. 
 Grade 4 anemia. 
Note: Any grade 4 hematological AE should be checked 2x/ week for up to 4 weeks until a 
repeated value below grade 2 is reported. 
Non-hematological 
 Grade 4 infusion-related reactions. 
 Grade 4 anaphylaxis.  
 Grade 3 infusion-related reactions that do not resolve to ≤ grade 1 within 24 hours. 
 At least possibly related grade 4 AST, ALT or bilirubin elevations. 
 At least possibly related grade 3 AST, ALT or bilirubin elevations that do not resolve to 
≤ grade 1 within 7 days. 
 At least possibly related AST, ALT or bilirubin elevations by more than one grade from 
baseline (e.g. grade 0grade 2 as defined in the NCI-CTCAE Version 4.03) that do not 
resolve to ≤ grade 1 within 7 days. 
 At least possibly related ≥ grade 2 AST or ALT elevations with concomitant 
bilirubin >2.0×ULN with no signs of cholestasis, i.e. a Hy’s law case. 
 Re-occurring of at least possibly related AST, ALT or bilirubin elevations ≥ grade 3, 
observed in cycle 1 and again in cycle 2 independent of resolution. 
 At least possibly related ≥ grade 3 amylase and/or lipase elevations with significant clinical 
symptoms that do not resolve to ≤ grade 1 or baseline within 7 days. 
 Grade ≥ 3 diarrhea that does not respond to optimal antidiarrheal treatment within 2 days 
 Grade ≥ 3 vomiting that does not respond to optimal antiemetic treatment within 2 days 
 Grade 3 nausea that does not respond to optimal antiemetic treatment within 7 days 

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 Any ≥ grade 3 at least possibly related non-hematological AE, which occurs during the first 
two cycles excluding: 
o Non-hematological laboratory abnormalities that have no clinical consequences and 
resolve to ≤ grade 1 or baseline within 7 days (this also includes electrolyte 
abnormalities that respond to medical intervention). 
o Grade 3 fatigue persisting for less than 72 hours (optimal medical management must 
be applied). 
Dose-escalation part of the trial: 
 Patients experiencing a DLT (an AE fulfilling the DLT criteria within the DLT period of 
28 days) must discontinue trial drug immediately. 
 Meetings with the DMC will follow after completion of each cohort. Safety data for the 
specific cohort as well as cumulative safety data for all cohorts (SAEs, NS AEs, laboratory 
data and DLTs where applicable) will be evaluated.  
7.2 
Dose Modification Guidance and Mitigation Plans for Specific Adverse Events 
7.2.1 Dose modification Guidance 
7.2.1.1 Handling of adverse events fulfilling the DLT criteria 
Adverse events that fulfill the DLT criteria (after the DLT period has ended in the dose-escalation 
part of the trial or during the expansion part of the trial) should be handled as shown in Figure 7-1. 
Please note that specific rules apply for elevated liver parameters (see Section 7.2.2.1). 
Figure 7-1: Handling of adverse events fulfilling the DLT criteria  
 
BL=Baseline. 
*Dose delay: Next dose of IMP can maximally be delayed 14 days unless approved otherwise by the sponsor medical 
monitor. 
** If sponsor and investigator disagree, DMC should approve. 
# No delay for recovery from ≥ G2 allowed. 
## Unless grade at BL was ≥ G2 and AE has resolved to baseline grade. 

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Grade 4 AEs fulfilling DLT criteria will always lead to IMP discontinuation. 
First occurrence of AE fulfilling DLT criteria grade 3: 
 Investigator must contact sponsor for thorough discussion in order to decide whether the 
patient should be withdrawn from treatment or next dosing should be delayed. 
 Administration of GEN1029 can be delayed for up to 14 days (i.e. one cycle). If the 
intensity resolves to ≤ grade 1 or baseline within this period, re-treatment may be 
considered under the following conditions: 
o Sponsor and investigator (DMC may be consulted) will discuss any safety concerns 
in order to decide whether next dose of IMP should be administered at same dose 
level or one dose level lower (DL-1). In case investigator and sponsor disagree, the 
DMC must be consulted. 
Second occurrence of an identical AE grade 3 after re-exposure to IMP: 
 If re-treatment leads to an identical adverse event with same intensity, the next 
administration of GEN1029 can be delayed for up to 14 days. If the intensity of the AE 
resolves to ≤ grade 1 or baseline within this period, re-treatment may be considered under 
the following conditions: 
o Next dose of IMP should be administered at one dose level lower (DL-1 or DL-2) 
than the dose level causing the recurrence of the adverse event.  
Third occurrence of an identical AE ≥ grade 2 after re-exposure to IMP: 
 If re-treatment at a lower dose leads to a third identical adverse event with intensity ≥ grade 
2, the subject must permanently discontinue trial drug. No dose delay is allowed. However, 
if the adverse event is ≤ grade 1 or baseline, re-treatment may be considered under the 
following condition: 
o Next dose of IMP should be administered at same reduced dose level (DL-1 or DL-
2). 
Please note: 
 Re-escalation of treatment dose is not allowed for patients that previously have been dose-
reduced. 
 IMP must be permanently discontinued if the patient experiences an adverse event fulfilling 
the DLT criteria (after the DLT period has ended for the dose-escalation part of the trial or 
during the expansion part of the trial) that fails to resolve to  grade 1 or baseline within 14 
days after the planned dosing date. 
 IMP must be permanently discontinued if more than two dose reductions are required. 
 IMP must be permanently discontinued in case of a dose delay of more than 14 days due to 
toxicity possibly related to GEN1029 unless otherwise approved by the sponsor medical 
monitor. 
 

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7.2.1.2 Handling of adverse events not fulfilling the DLT criteria: 
Adverse events that do not fulfill the DLT criteria should be handled as following (specific rules 
apply for elevated liver parameters. Please see Section 7.2.2.1): 
 The investigators are encouraged to contact sponsor in case of any safety concern that need 
thorough discussion and evaluation. 
 
7.2.2 Mitigation Plan for Specific Adverse Events 
7.2.2.1 Elevated Liver Parameters 
All possibly IMP related events of elevated liver parameters must be managed as shown in Table 
7-1 (except for DLTs that lead to permanent discontinuation of IMP).  
Note: In case of a drug-related ≥ grade 2 elevation of ALT and/or AST, pre-medication with 
dexamethasone must be administered to the patient upon subsequent dosings (see Section 6.4.1). 
Table 7-1 Handling of Adverse Events Involving Elevated Liver Parameters 
Baseline 
Transaminases a 
 
Bilirubin a 
Action with IMP 
G0-G1 
G2: >3.0 - 5.0 x ULN  
or 
G2: >1.5 - 3.0 x ULN 
Delay dosing b, c 
G0-G1 
G3: >5.0 - 20.0 x ULN 
or 
G3: >3.0 - 10.0 x ULN 
Delay dosing  d, e  
G0-G1 
G4: >20.0 x ULN 
or 
G4: >10.0 x ULN 
Stop dosing  
G0-G1 
G2: >3.0 x ULN 
and 
>2.0 x ULN 
Stop dosingf  
Abbreviations: ALT = alanine aminotransferase, AST = aspartate aminotransferase, G = grade, ULN = upper limit of 
normal. 
a 
Any AST, ALT, and / or bilirubin ≥ grade 2 elevation needs to be checked 2x/week for up to 4 weeks.  
b 
Re-start at same dose level at 1st occurrence when resolved to ≤ grade 1 within 7 days / re-start at a reduced dose 
level at 2nd occurrence when resolved to ≤ grade 1 within 7 days. 
c 
Stop dosing at 3rd occurrence in case of unfavorable benefit-risk assessment by the DMC. 
d 
Re-start at a reduced dose level, but only when resolved to ≤ grade 1 within 7 days. 
e  
Stop dosing at 2nd occurrence. 
f 
Patients with ALT/AST>3.0 x ULN and bilirubin >2.0 x ULN with no signs of cholestasis, and for which the cause is 
at least possibly linked to study drug (i.e. a Hy’s law case), must permanently discontinue trial drug. 
 
 If a patient experiences AST, ALT or bilirubin elevations by more than one grade from 
baseline (grade 0grade 2 as defined in the NCI-CTCAE Version 4.03), next dose of 
GEN1029 must be delayed until resolution to ≤ grade 1. Upon resolution to ≤ grade 1 
within 7 days, treatment with GEN1029 may be re-started at same dose level for patients 
with 1st occurrence but at a reduced dose level (DL-1) for patients with 2nd occurrence. If 
requested by the investigator, the DMC and the sponsor may allow a patient with a 
favorable benefit-risk assessment to continue in the trial on a reduced dose even if the 
resolution to grade 1 occurs within 4 weeks. In case of 3rd occurrence a benefit-risk 
assessment should be conducted by the DMC. In case of an unfavorable benefit-risk 
assessment GEN1029 therapy should be permanently discontinued. 
 If a patient experiences grade 3 AST, ALT or bilirubin elevations, GEN1029 therapy must 
be delayed until resolution to ≤ grade 1. Upon resolution to ≤ grade 1 within 7 days 
treatment with GEN1029 may be re-started at reduced dose level (DL-1). If requested by 
the investigator, the DMC and the sponsor may allow a patient with a favorable benefit-
risk assessment to continue in the trial on a reduced dose even if the resolution to grade 1 

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occurs within 4 weeks. In case of 2nd occurrence GEN1029 therapy should be permanently 
discontinued. 
 Patients with grade 4 AST (>20.0 x ULN), grade 4 ALT (>20.0 x ULN) and / or grade 4 
bilirubin (>10.0 x ULN) elevations, or other grade 4 liver toxicity must permanently 
discontinue trial drug. 
 Patients with ALT/AST >3.0 x ULN and bilirubin >2.0 x ULN with no signs of cholestasis, 
and for which the cause is at least possibly linked to study drug (i.e. a Hy’s law case), must 
permanently discontinue trial drug. 
Please note: 
 In case of elevated liver parameters ≥ grade 2, AST, ALT, and bilirubin laboratory values 
must be checked (unscheduled visits) twice a week for up to 4 weeks until a repeated value 
below grade 2 is reported. 
Table 7-2 Guidance for Supportive Care in Case of Elevated Liver Parameters 
On-treatment levels 
Supportive Care 
Transaminases > 3 – 5 x ULN or 
bilirubin > 1.5 – 3 x ULN 
Consider administering corticosteroids (initial dose of 0.5-1 mg/kg 
prednisone or equivalent) followed by taper. 
Transaminases >5.0 x ULN or 
bilirubin >3.0 x ULN 
Consider administering corticosteroids (initial dose of 1-2 mg/kg 
prednisone or equivalent) followed by taper. 
 
7.2.2.2 Infusion-Related Reactions 
 Pre-medication to prevent infusion-related reactions may be administered at the 
investigator's 
discretion 
according 
to 
local 
guidelines 
(e.g., 
antihistamine, 
acetaminophen/paracetamol and corticosteroids). The use of paracetamol (acetaminophen) 
as pre-medication should be considered to be omitted to prevent transaminase elevations, 
and used with caution during all treatment cycles. 
 Grade 1: If an infusion-related reaction grade 1 occurs, the infusion does not need to be 
interrupted and can be continued at the investigator’s discretion at half the infusion rate 
under close medical supervision. 
 Grade 2-3: If an infusion-related reaction grade 2 or 3 occurs, the infusion should be 
interrupted and appropriate medical management instituted. The infusion may be re-started 
at the investigator’s discretion at half the infusion rate under close medical supervision if 
symptoms have resolved to ≤ grade 1 within an hour. 
o Patients who have experienced prior infusion related grade 2 or 3 reactions in the 
trial should be pre-medicated (antihistamine, acetaminophen and corticosteroids 
are recommended). 
o If the patient has a second Grade 3 infusion-related reaction despite pre-medication, 
the infusion should be stopped and the patient should be withdrawn from treatment. 
 Grade 4: If anaphylaxis or grade 4 infusion-related reactions occur, administration of IMP 
should be discontinued immediately and permanently and appropriate medical therapy 
should be administered. 

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Please note: 
 As a routine precaution, patients enrolled in this trial must be observed for 2 hours after 
each infusion, in an area with resuscitation equipment and emergency agents. 
 At all times during GEN1029 infusion, immediate emergency treatment of an anaphylactic 
reaction according to institutional standards must be assured. In order to treat possible 
anaphylactic reactions, for instance, dexamethasone 10 mg and epinephrine in a 1:1000 
dilution or equivalents should always be available along with equipment for assisted 
ventilation. 
 All pre-medication must be reported on the concomitant medication page in the eCRF 
7.2.2.3 Diarrhea 
Due to the observation that diarrhea may be associated with GEN1029 treatment in a dose 
independent manner and can be severe, the following guidance is introduced to manage diarrhea 
events as they occur (Table 7-3).  

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Table 7-3 Guidance for Managing Diarrhea 
Toxicity 
Grade 
(CTCAE) 
Dose 
Modification 
Investigations 
Management 
Grade 1 
Continue 
treatment 
No specific diagnostic work-up 
recommended.  
The investigations described below 
may be considered if the event is 
prolonged or progressive. 
 
Close monitoring and consider the 
following treatments if needed: 
 
Loperamide or 
diphenoxylate/atropine 
 
Fluid and electrolyte 
supplementation  
Grade 2 
Hold treatment 
until event 
improves to ≤ G1 
Blood work-up (including complete 
blood count, electrolytes, urea, 
creatinine and C-reactive protein) 
Stool evaluation to rule out infectious 
etiology (e.g. stool culture and tests for 
Clostridium difficile toxin, parasite, 
CMV or other viral etiology, ova and 
parasite) 
Stool calprotectin and lactoferrin to 
assess intestinal inflammation 
Consider CT scan of abdomen/pelvis  
GI consultation for further evaluation 
(i.e. capsule endoscopy, colonoscopy 
or flexible sigmoidoscopy ± 
esophagogastroduodenoscopy with 
biopsy from stomach, duodenum, 
terminal ileum, colon) 
 
NB - Treatment for the event can be 
initiated while awaiting test results 
Close monitoring and 
administration of corticosteroids.  
 
For G2, unless diarrhoea is 
transient, treat with 3 mg oral 
budesonide once daily. 
Budesonide may be increased to 6 
mg once daily if there is no 
response in 2-3 days. 
 
Consider if in-patient care is 
required for G3/G4 diarrhoea. 
  
For G3, treat with 3-6 mg oral 
budesonide once daily. May 
administer IV methylprednisolone 
(2mg/kg/day) if symptoms persist 
for ≥ 3-5 days*. 
 
For G4, administer IV 
methylprednisolone 
(2mg/kg/day)*. 
 
Corticosteroids should be 
continued until the event improves 
to ≤ G1 and then tapered. 
Grade 3 
Hold treatment 
until event 
improves to ≤ G1 
Grade 4 
Permanently 
discontinue 
treatment 
*Patients who respond to IV methylprednisolone can be switched to oral budesonide for continued treatment and 
taper. 
Patients should be made aware of the potential for diarrhoea to occur and to inform the investigator immediately if 
they experience changes in bowel habits, nausea, vomiting, abdominal pain, cramping, fever and blood or mucus in 
the stool. 
7.3 
Safety Stopping Rules 
Treatment with IMP should be discontinued due to safety concerns under the following conditions: 
 Patients experiencing a DLT (an adverse event fulfilling DLT criteria within the DLT 
period during the dose-escalation part of the trial).  

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 If the patient experiences an adverse event fulfilling the DLT criteria after the DLT period 
has ended in the dose-escalation part of the trial or during the expansion part of the trial, 
that fails to resolve to  grade 1 or baseline within 14 days after the planned dosing date. 
N.B. Grade 4 AEs fulfilling DLT criteria will always lead to IMP discontinuation. 
 If more than two dose reductions are required. 
 Dose delay of more than 14 days due to toxicity possibly related to GEN1029.  
 Possibly related event of elevated liver parameters 
 
Patients with grade 4 AST (>20.0 x ULN), grade 4 ALT (>20.0 x ULN) and / or 
grade 4 bilirubin (>10.0 x ULN) elevations, or other grade 4 liver toxicity. 
 
2nd occurrence of a grade 3 AST, ALT or bilirubin elevation (if first occurrence 
resolved to ≤ grade 1 within 7 days). 
 
Patients with ALT/AST>3.0 x ULN bilirubin >2.0 x ULN with no signs of 
cholestasis, and for which the cause is at least possibly linked to study drug (i.e. a 
Hy’s law case). 
 
In case of a negative benefit-risk assessment performed by DMC due to 3rd 
occurrence of AST, ALT or bilirubin elevations by more than one grade from 
baseline (grade 0grade 2; if it resolved to grade 0 at prior occurrences). 
 2nd occurrence of a grade 3 infusion-related reaction despite pre-medication prior to 
infusion. 
 1st occurrence of anaphylaxis or  grade 4 infusion-related reactions. 
 
Please note: 
 Observation procedures and assessments are to be continued for the rest of the cycle. 
Patients should, whenever possible, irrespective of the reason for discontinuation, be 
examined as soon as possible (specified as the end of treatment visit). 

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8 
DISCONTINUATION, FOLLOW UP AND COMPLETION 
8.1 
Discontinuation of Treatment 
Patients will be withdrawn from treatment for the following reasons: 
 Safety Stopping Rules (as defined in Section 7.3) 
 Pregnancy 
 Patient choice 
 Investigator or sponsor decision due to individual patient safety issues not covered by other 
withdrawal criteria 
 Disease progression 
 Initiation of other anti-cancer treatment (the expansion part only) 
 Intercurrent illness that precludes further participation or requires a prohibited concomitant 
treatment 
Patients should, whenever possible, irrespective of the reason for discontinuation, be examined as 
soon as possible at the end of treatment visit. 
8.2 
Withdrawal from the Trial 
Patients will be withdrawn from the trial (dose escalation or expansion parts), including safety 
follow-up evaluations and follow-up contact, for the following reasons: 
 A patient may withdraw from the trial at any time at his or her own request 
 At the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons 
 Lost to Follow-Up (see Section 8.4) 
 Patient died 
 Trial closure 
 Initiation of other anti-cancer treatment (the dose-escalation part only) 
If the patient withdraws consent for disclosure of future information, the sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a patient withdraws from the trial, he or she may request destruction of any samples taken and 
not tested, and the investigator must document this in the site trial records. 
The sponsor will make any effort to ensure patients are followed up for completion of safety 
assessment in the trial. See Table 1-1 and Table 1-6 for data to be collected at the time of trial 
discontinuation and follow-up and for any further evaluations that need to be completed. 
When a patient withdraws before completing the trial, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Trial drug assigned to the withdrawn patient 
may not be assigned to another patient. 
Patients who withdraw will not necessarily be replaced. 

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Withdrawal From the Use of Samples in Future Research 
The patient may withdraw consent for use of samples for research (refer to Section 13.2.5). In this 
case, samples will be destroyed after they are no longer needed for the clinical trial. Details of the 
sample retention for research are presented in the ICF. 
8.3 
Safety Follow up Evaluations 
Patients discontinuing from treatment for any reason will have safety follow-up visits 30 and 70 
days after last treatment and will also be contacted every 13 weeks after last dose until end of trial.  
Data collected should be added to the adverse events eCRF and the concomitant medications 
eCRF. 
8.4 
Lost to Follow-up 
For patients whose status is unclear because they fail to appear for trial visits without stating an 
intention to withdraw consent, the investigator should show "due diligence" by contacting the 
patient, family or family physician as agreed in the informed consent form and by documenting in 
the source documents steps taken to contact the patient, e.g. dates of telephone calls, registered 
letters, etc. A patient should not be considered lost to follow-up until due diligence has been 
completed (where possible, 3 telephone calls and, if necessary, a certified letter to the patient’s last 
known mailing address or local equivalent methods). Patients lost to follow-up should be recorded 
as such on the appropriate disposition eCRF. 

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9 
ASSESSMENTS 
9.1 
Demography and Baseline Characteristics 
9.1.1 Demographics 
Date of birth and/or age, race, ethnic origin, gender and smoking and drinking habits will be 
recorded at screening in the eCRF. 
9.1.2 Disease Status 
Primary site of cancer and initial and current disease stage [Tumor Nodes Metastasis (TNM) 
staging system] will be recorded at screening in the eCRF. 
For patients with: 
 NSCLC, the patients’ tumor status with respect to EGFR mutations and ALK / ROS1 
rearrangement. 
 CRC, the patients’ tumor status with respect to BRAF and RAS mutations, and gastric 
cancer, the patients’ tumor status with respect to HER2-neu expression mutations will be 
also recorded (incl. date of the assessment). 
9.1.3 Medical History 
Relevant past and all current disease data will be recorded in the eCRF. Any past surgery not 
related to cancer should be recorded in the medical history.  
9.1.4 Concomitant Medication 
Any medication or therapy other than GEN1029 is considered concomitant medication and should 
be recorded in the eCRF with the following information: 
 Start date 
 Route of administration 
 Stop date of administration or ongoing at trial termination 
 Indication/reason for use 
 The total daily dose should be filled in whenever possible. 
Relevant prior concomitant medication given within 4 weeks prior to screening and all medication 
given from visit 0 (Screening) until the 70-day safety follow-up must be recorded. 
During the patient follow-up period only new anti-cancer treatment will be collected. 
9.1.5 Prior Cancer Therapy and Surgery 
Administration of prior anti-cancer therapies and surgeries must be reported in the appropriate 
section of the eCRF. Number of cycles, best response and stop reason along with dates of 
administration and progression should be reported. 
Radiotherapy should be recorded if the indication is cancer. 

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9.1.6 Liver Ultrasound 
All patients will need to have an ultrasound of the liver at screening to investigate potential 
underlying factors related to potential  liver toxicity of GEN1029. This will cover the assessment 
of liver morphology, i.e. size, capsular contour (smooth, coarse, lobulated), parenchymal 
echogenicity, vascularity, biliary tree, and masses or collections. 
Ideally, fast the patient for 6 hours to reduce bowel gas and prevent gall bladder contraction. A 
patient may take small amounts of still water by mouth prior to scan, particularly for taking any 
medications. 
Equipment selection: 
 Depending on the size of the patient a curved linear array 2-6Mhz. 
 If there is nodularity of the liver border then a linear array with a 7-12MHZ frequency will 
better appreciate this.  
 Good colour / power / Doppler capabilities when assessing vessels or vascularity of a structure. 
The normal anatomy and any pathology found, including measurements and vascularity should be 
documented.  
Doppler evaluation should be used to document blood flow characteristics and blood flow 
direction, which is crucial in the diagnosis of portal hypertension. 
Common pathology to be assessed at minimal should contain: 
 Hepatic steatosis 
 Fatty liver 
 Fibrosis 
 Cirrhosis 
 Liver cysts 
 Haemangioma 
 Portal hypertension 
 Portal vein thrombosis 
 Hepatic vein thrombosis 
 Liver abscess/collection 
 Trauma 
 Tumor / metastases 
 Abscess 
The basic hard copy imaging should cover the following: 
 Longitudinal  
 Left lobe 
 Caudate lobe 
 IVC 
 Porta hepatis 
 Comparison to Rt Kidney 
 Transverse  
 Left lobe 
 Left hepatic vein 
 Left portal vein 
 Right portal vein 

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 Middle and Right hepatic vein 
 Demonstrate hepatopetal flow in portal vein 
 Demonstrate hepatic vein flow 
 Document the normal anatomy. Any pathology found in 2 planes, including measurements and 
any vascularity 
9.2 
Efficacy Assessment 
The RECIST 1.1 criteria will be used for response evaluation (Eisenhauer et al., 2009). 
The same imaging modality and ideally the same scanner should be used throughout the trial to 
optimize the reproducibility of the assessment and preserve the accuracy of the assessment of 
response or progression.  
As an exploratory analysis the metabolic response in the tumors will be assessed by PET scan in 
selected patients as described below. The metabolic response will not be used for efficacy 
assessments, and hence the patient’s ability to stay on treatment will be based on the RECIST 1.1 
response only  
Chest x-rays and ultrasound should not be used to measure tumor lesions. 
9.2.1 Dose Escalation Part 
In the dose escalation part, PET-CT scans must be taken at screening and, if avid at screening, also 
at Cycle 2 Day 2, and week 12 (±7 days). If a patient, who has been exposed to GEN1029, did not 
have any PET-CT scans while on treatment and the PET-CT scan at screening displayed avidity, 
a PET-CT scan should be taken at the end of trial visit (please refer to Section 9.2.3 for additional 
details on PET-CT scans). 
The PET-CT scan at screening is with contrast of thorax, abdomen and pelvis. If there is suspicion 
of brain metastases or tumors, a scan of the head will be performed before inclusion.  
Up to five target lesions (maximum two per organ) will be defined at screening and these must be 
followed throughout the trial. Non-target lesions will also be assessed throughout the trial. 
A CT scan must be performed at Cycle 3, Day 8-14 after first dose. If PET-CT at screening showed 
no avidity, a CT scan has to be done instead of a PET-CT scan in week 12 (±7 days). From week 
18 (±7 days) until week 50 after first dosing, CT scans must be performed every 6 weeks (±7 days), 
and every 12 weeks (±7 days) thereafter. Imaging assessments should follow calendar days and 
should not be adjusted for delays in cycle starts. 
Additional CT-scans may be performed at the investigators discretion to confirm response or new 
symptoms. The intervals should not be shorter than four weeks.  In this case the investigator must 
choose the imaging technology based on the clinical indication. Information from additional scans 
should be added to an unscheduled visit in the eCRF  
9.2.2 Expansion Part 
In the expansion part, all patients will have a CT-scan with contrast of thorax, abdomen and pelvis 
performed during screening. If there is suspicion of brain metastases or tumors, a CT-scan of the 
head will be performed before inclusion.  
Up to five target lesions (maximum two per organ) will be defined at screening and these must be 
followed throughout the trial. Non-target lesions will also be assessed throughout the trial. 

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Scans will be performed at week 6 (-7 days), every 6 weeks (±7 days) for 50 weeks, and every 12 
weeks (±7 days) thereafter from the date of first dose until disease progression is assessed by the 
investigator, the start of new anti-cancer therapy, withdrawal of consent, or death, whichever 
occurs first. Imaging assessments should follow calendar days and should not be adjusted for 
delays in cycle starts. 
Additional CT-scans may be performed at the investigators discretion to confirm response or new 
symptoms. The intervals should not be shorter than four weeks.  In this case the investigator must 
choose the imaging technology based on the clinical indication. Information from additional scans 
should be added to an unscheduled visit in the eCRF.  
Magnetic resonance imaging can consistently be performed instead of CT scan if the patient is 
allergic to iodine contrast or at the discretion of the investigator, after approval of the sponsor. 
At the discretion of the investigators and after approval of the sponsor, combined PET-CT may be 
performed for tumor assessments in the expansion part, but only if the CT portion is of similar 
diagnostic quality to CT alone. Please refer to Section 9.2.3 for additional details on PET-CT. 
9.2.3 PET-CT 
FDG (18F-Fluoro-Deoxy-Glucose) imaging (or dual-phase fluorodeoxyglucose positron emission 
tomography [dual-phase 18F-FDG-PET]) will be performed according to Table 1-1. The PET 
shall be combined with CT and the CT portion must be of similar diagnostic quality to CT 
alone. 
The patient needs to fast for 4 to 6 hours prior to the FDG-PET scan. The patient can drink water 
freely during the fast and should be encouraged to do so. He/she may also take regular medications 
as scheduled during the fast. Blood glucose level will be checked on the day of the FDG-PET scan 
and results assessed prior to the administration of FDG. The patient should have a blood glucose 
level ≤ 180 mg/dL (≤ 10 mmol/L) in order to have the FDG-PET scan. If the level is higher, the 
scan should be rescheduled if possible. Regular diet can be resumed after the scan. The interval 
between FDG administration and scanning must be 60 minutes +/- 10 minutes and it is particularly 
important that the time interval between injection and start of the scan is the same at on treatment 
as compared to baseline. 
All patients should be encouraged to increase fluid intake for a few hours after the scan to promote 
excretion of the FDG. A diuretic (furosemide, typically 20-40 mg IV) may be administered at the 
discretion of the Investigator before or during the FDG-PET scan in order to accelerate elimination 
of the [18F] FDG from the renal collecting system.  
Diazepam may be used to promote muscle relaxation and reduce muscular uptake if tumor deposits 
are in the neck or shoulder girdle area. Diazepam administration and diuretic administration must 
be recorded in the Concomitant Medications eCRF page. 
Note that the PET must be performed before any tumor biopsy to avoid potential false positive 
findings. The baseline FDG-PET assessment during screening should be performed at the closest 
date as possible from start of study treatment, at least one week before tumor biopsy.  
9.2.3.1 Ad PET Scan Acquisition: 
Attenuation corrected FDG-PET scans (from skull base to mid-thigh) will be performed. The 
patient will be administered 370–740MBq (10-20mCi) 2-[F-18]-fluoro-2-deoxy-D glucose (FDG) 
intravenously (dose is dependent on local practice and scanner type). The administered activity 
and time of FDG administration must be recorded ).  

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Approximately one hour following the administration of FDG, a whole body PET scan (base of 
skull to thighs) is performed and the time of the commencement of the scanning is recorded. The 
sequence of the scan must be the same for the baseline scan and all on treatment scans, and the 
interval between FDG administration and scanning should be as similar as practical. 
Preferably for a given patient the same scanner should be used at all time-points. The FDG-PET 
images will be analyzed by the site. 
9.2.3.2 Local Scan Interpretation  
The PET-CT scans will be analyzed by an experienced reader (the same reader should interpret all 
scans for each subject).  
Of note, if tumor lesions showed no avidity at baseline, no further PET scans should be performed.   
9.2.4 Reading of the Scans 
In the dose escalation and expansion parts, the reading of the scans will be done by a local 
radiologist. Sites should attempt to maintain the same radiologist throughout the trial. Results from 
the radiology evaluations shall be recorded in the eCRF and a copy of the evaluation reports should 
be kept in the patient’s file.  
9.3 
Pharmacokinetics 
9.3.1 Evaluations 
Venous blood samples of approximately 2 mL will be collected for measurement of plasma 
concentrations of Hx-DR5-01 plus Hx-DR5-05 as specified in Table 1-3 and Table 1-8. The actual 
date and time (24-hour clock time) of each sample will be recorded. 
Samples will be used to evaluate the pharmacokinetics of GEN1029. Venous blood samples will 
be collected and each plasma sample will be divided into aliquots. Samples collected for analyses 
of plasma concentration may additionally be used to evaluate safety or efficacy aspects that address 
concerns arising during or after the trial period. 
 
 Patient confidentiality will be maintained. At visits where plasma concentration 
will be evaluated, one blood draw of sufficient volume can be used. 
9.3.2 Analytical Procedures 
Plasma samples will be analyzed to determine concentrations of Hx-DR5-01 and Hx-DR5-05 
using validated methods. Samples may also be used to determine anti-drug antibodies or 
neutralizing antibodies. 
9.4 
Clinical Safety Assessments 
9.4.1 Physical Examination 
A complete physical examination will at a minimum include general appearance of the following 
body systems: lymph node regions, mouth and throat, respiratory, cardiovascular system, 
abdomen, extremities, muscular-skeletal system, neurological system, and skin. 
Height (without shoes) must be measured at visit 0 (Screening) and rounded to nearest centimeter. 

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Body weight (without overcoat and shoes) will be measured at visit 0 (Screening), at day 1 of each 
cycle, as part of the dose calculation, and at end of treatment visit, and will be recorded in the 
eCRF. 
If body weight is assessed seven days or less (using the site scale) before the day of the planned 
dosing, this weight can be used for dose calculation and is to be is recorded in the eCRF. 
9.4.2 Vital Signs 
Vital signs, including temperature, blood pressure and heart rate, should be measured with the 
patient in a supine or reclined position and recorded in the eCRF. Within each visit, preferably the 
same equipment shall be used for vital sign measurements. On infusion days, vital signs should be 
assessed just before and no longer than 30 minutes before infusion start, during and after the 
infusions until 4 hours after end of infusion of the three first infusions (dose escalation part only) 
and until 2 hours after the remaining infusions, as indicated in Table 1-5 and Table 1-9 for the dose 
escalation and expansion parts, respectively. 
9.4.3 Electrocardiograms 
The electrocardiograms (ECGs) will be recorded digitally at the sites by using the standard 12-
leads as outlined in Table 1-2 and Table 1-7 for the dose escalation and expansion parts, 
respectively. ECGs will be performed in accordance with the ECG manual issued by the vendor. 
The digital ECGs will be transmitted from the sites electronically to a central laboratory for a 
treatment-blinded measurement of the cardiac intervals and morphologic assessment by a central 
cardiologist. 
An overall interpretation of the ECGs will be performed by the investigator, or the investigator 
may delegate this task to a cardiologist, if applicable. The investigator ECG interpretation must be 
done using the paper ECG reading from the ECG machine by signing and dating the print out. In 
case of discrepancy between central and the investigator ECG readings, the central reading will be 
used for trial analysis purposes. 
For the ECG recordings, the patients must be resting and in a supine or reclined position for at 
least 10 minutes. Any irregularity observed or occurring during the ECGs (e.g., vomiting, cough) 
should either induce a repeat of the ECG or be annotated on the eCRF with the description and 
time of the occurrence. 
9.4.4 ECOG Performance Status 
The eastern cooperative oncology group (ECOG) performance status will be assessed by the 
investigator at screening, on Day 1 of each cycle, and at the end of treatment visit. Performance 
status will be scored using the ECOG performance status scale index 
Table 9-1 ECOG performance status 
Score  
Description  
0 
Fully active, able to carry out all normal activity without restriction. 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light housework, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair. 
5 
Dead. 

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9.5 
Clinical Laboratory Assessments 
The tests detailed in Table 9-2 will be drawn and shipped for centralized testing, except urinalysis 
which will be analyzed locally, and results will be reported to the investigators by the central 
laboratory as described in the laboratory manual. The investigator must review the laboratory 
report, document this review, and record any clinically relevant changes occurring during the trial 
in the AE section of the CRF. 
Local laboratory values for biochemistry and hematology must be obtained within 24 hours prior 
to each IMP administration and reviewed by the investigator prior to each IMP administration to 
ensure the patient can be dosed in line with the dosing instructions as defined in the protocol. In 
the first 3 cycles, all biochemistry safety samples must be assessed locally as well to monitor liver 
function. Furthermore, local laboratory values may be obtained at the discretion of the investigator 
and used for other clinical treatment decisions of the patient with the exception of evaluation of 
patient eligibility, which must be evaluated based on central laboratory data. However, if the 
central laboratory values obtained during screening are unexpectedly unavailable when the patient 
is scheduled for the first administration of GEN1029, local laboratory values may be used 
following agreement with the sponsor’s Medical Monitor. 
For clinical treatment decisions, e.g. IMP administration or safety reasons, for an individual 
patient, local laboratory values take precedence over central laboratory values. Local laboratory 
values must be recorded in the eCRF if they are of clinical importance, e.g. if they result in a 
clinical laboratory AE, used as supportive information on an AE or lead to dose 
modifications/delays of the IMP. Furthermore local laboratory values of clinical significance will 
be assessed for the evaluation of DLT. If a central laboratory value indicates dose 
modification/delay, but the local laboratory value does not, the medical officer should be contacted 
and the site will be asked to retrospectively record the corresponding local laboratory value in the 
eCRF. Any local or central laboratory values leading to a dose modification/delay should be 
recorded as an AE (Section 10.2.6).  
For the analyses and reporting of the trial results, the central laboratory values will be used. All 
recorded local laboratory values will be listed. 
A manual with detailed description of the procedures for sampling, handling, storage, and 
shipment of the laboratory samples and all material such as test tubes and labels for central analysis 
will be provided by the central laboratory. The manual and the result reports will include all 
reference ranges. 
Laboratory equipment may provide standard analyses not requested in the protocol but produced 
automatically in connection with the requested analyses. Such data will not be included in the 
database, but must be reported to the investigator. 

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Table 9-2 Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC Count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
mean corpuscular volume 
mean corpuscular 
hemoglobin 
mean corpuscular 
hemoglobin concentration 
coagulation factors 
prothrombin time, 
(international normalized 
ratio and activated partial 
thromboplastin time) 
Biochemistry 
BUN (Blood Urea 
Nitrogen) 
Potassium 
Aspartate 
Aminotransferase 
(AST) 
Total and direct 
bilirubin 
 
Creatinine (GFR 
calculation) 
Sodium 
Alanine 
Aminotransferase 
 (ALT) 
 albumin 
 
Glucose  
Calcium 
Alkaline 
phosphatase 
Magnesium  
lactate dehydrogenase 
uric acid 
C-reactive 
Protein 
Lipase 
Amylase 
gamma-glutamyl 
transferase 
glycosylated 
hemoglobin 
Chloride 
Cholesterol 
Triglycerides 
High density 
lipoprotein 
low density 
lipoprotein 
Urinalysis* 
protein, leukocyte pregnancy test (as needed in women of childbearing potential only) by 
dipstick 
Other Screening 
Tests 
Follicle-stimulating hormone and estradiol (as needed in women of childbearing potential 
only) 
Hepatitis B and C 
CMV 
 
 
NOTES : 
*Urinalysis will be analyzed at the local laboratory. 
For the Cytomegalovirus (CMV), anti-IgG and IgM will be assessed. In case of positive IgM, it will be confirmed 
with CMV PCR; for HCV, anti-IgG will be assessed and, if positive, it will be confirmed with HCV PCR. 
 
In case of discrepancies leading to protocol deviations, this will be reported, reviewed and 
discussed with the sponsor medical team and documented. 
9.6 
Immunogenicity 
9.6.1 Evaluations 
Venous blood samples of approximately 2 mL will be collected for measurement of plasma 
concentrations of anti-drug antibodies as specified in Table 1-1 and Table 1-6. 

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Samples will be used to evaluate the presence of antibodies to GEN1029. Venous blood samples 
will be collected and each plasma sample will be divided into 2 aliquots (one for ADA and a back-
up). Samples collected for ADA to GEN1029 may additionally be used to evaluate safety or 
efficacy aspects that address concerns arising during or after the trial period for further 
characterization of immunogenicity. Genetic analyses will not be performed on these serum 
samples. Patient confidentiality will be maintained. At visits where antibodies to GEN1029 will 
be evaluated, one blood draw of sufficient volume can be used. 
9.6.2 Analytical Procedures 
The detection and characterization of antibodies to GEN1029 will be performed using a validated 
assay methods under the supervision of the sponsor. All samples collected for detection of 
antibodies to GEN1029.  
9.6.3 Immunogenicity Assessments  
Antibodies to GEN1029 will be evaluated in plasma samples collected from all patients according 
to the visit schedule. These samples will be tested by the sponsor or sponsor's designee. 
Plasma samples will be screened for antibodies binding to GEN1029 and the titer of confirmed 
positive samples will be reported. Two titer methods will be used; one method will determine the 
response against Hx-DR5-01 and the other against Hx-DR5-05. Other analyses may be performed 
to verify the stability of antibodies to GEN1029 and/or further characterize the immunogenicity of 
GEN1029. 
9.7 
Biomarkers 
Biomarker investigations in this study will include both candidate stratification biomarkers, that 
may predict drug response to the treatment, and pharmacodynamic biomarkers, to further 
understand the mechanism of action, potential mechanisms of resistance,  dynamic changes over 
time and the understanding of DR5 biology in cancer and the pathomechnism of disease. 
9.7.1 Biomarker assessments in tumor samples 
Tumor biopsies will be collected at screening from each patient according to inclusion criteria and 
must be in accordance with the collection and processing guidance provided in the laboratory 
manual: 
 To ensure sufficient tumor tissue, it is mandatory to collect core needle biopsies, which should 
be CT-guided for internal solid tumor lesions and performed by experienced interventionalists. 
It should be noted that it is not allowed to take biopsies from target lesions at baseline and 
during treatment. Archival biopsies should be FFPE. Fresh biopsies should be collected as both 
mandatory FFPE tissue (blocks/slides) and optional fresh frozen tissue. 
Biomarker analyses in tumor samples at baseline, during and at end of treatment visit may help to 
confirm GEN1029’s mechanism of action, enable the identification of biomarkers predictive of 
response or resistance to GEN1029, study dynamic changes over time, gain insight in the evolution 
of disease and tumor immune microenvironment.  
 
 
 

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Protein expression analyses 
DR5 expression and expression of other proteins related to GEN1029’s mechanism of action (for 
example; caspases as a measure of apoptotic activity) may be evaluated in tumor biopsies by 
immunohistochemistry on an automated staining platform. Tumor sections will be scored by a 
certified pathologist, and digital images will be made from stained tumor sections in order to be 
used for exploratory digital pathology analyses. 
9.7.2 Biomarker assessments in blood samples 
Biomarker assessments will also be performed using whole blood samples to investigate potential 
pharmacodynamic markers and explore the relationship to efficacy and/or mechanism of action of 
GEN1029. Assessments will be performed at baseline (before infusion at C1D1) and at later cycles 
during treatment including visits in close proximity with a planned CT scan, and at the end of 
treatment in order to enable correlation analyses with response to treatment or disease progression.  
Protein expression analyses 
Levels of proteins related to GEN1029’s mechanism of action, including levels and activation 
status of complement components and cytokines, may be measured so changes associated with the 
mechanism of action of GEN1029 can be monitored. 
Immunophenotyping analyses 
Immunophenotyping, including single cell sorting/sequencing, may be performed (for example; 
measurement of 
) at baseline and 
during treatment so changes associated with the mechanism of action of GEN1029 can be 
monitored.  
 
 
 
 
 
  
9.7.3 Additional analyses 
In addition to the biomarker analyses listed above, other biomarkers deemed relevant to gain 
further knowledge about the pathomechanism of the disease or about GEN1029 (i.e. mode of 
action related effect or safety of the drug) may be measured, based on newly emerging data from 
other ongoing trials and/or literature data. Biomarker samples may further be used to help address 
emerging issues and to enable the development of safer, more effective, and, ultimately, 
individualized therapy. 

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Moreover, biomarker analyses are dependent upon the availability of appropriate biomarker assays 
and clinical response rates. Biomarker analysis may be deferred or not performed, if during or at 
the end of the trial, it becomes clear that the analysis will not have sufficient scientific value for 
biomarker evaluation, or if there are not enough samples or responders to allow for adequate 
biomarker evaluation. In the event the trial is terminated early or shows poor clinical efficacy, 
completion of biomarker assessments is based on justification and intended utility of the data. 

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10 SAFETY MONITORING AND ADVERSE EVENT REPORTING 
10.1 Adverse Event Definitions 
10.1.1 Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical trial patient, 
temporally associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated 
with the use of a medicinal product. 
AEs (including laboratory abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. When a clear diagnosis 
cannot be identified, each sign or symptom should be reported as a separate AE. 
10.1.2 Definition of Serious Adverse Event 
A serious adverse event (SAE) is defined as an adverse event that meets one of the following 
criteria: 
 Is fatal or life-threatening1 
 Results in persistent or significant disability/incapacity 
 Constitutes a congenital anomaly/birth defect 
 Is medically significant, i.e., defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above. Medical and 
scientific judgment must be exercised in deciding whether an AE is “medically important” 
 Requires inpatient hospitalization or prolongation of existing hospitalization2  
 
1 The term "life-threatening" in the definition of "serious" refers to an event in which the patient 
was at risk of death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it was more severe. 
2 Hospitalizations for the following reasons should not be reported as SAEs: 
 Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
 Elective or pre-planned treatment for a pre-existing condition during trial that has not 
worsened since signing the informed consent 
 Social reasons and respite care in the absence of any deterioration in the patient’s general 
condition 
 Treatment on an emergency outpatient basis that does not result in hospital admission and 
involves an event not fulfilling any of the definitions of a SAE given above  
10.1.3 Definition of Adverse Events of Special Interest (AESI) 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which are 
of scientific and medical concern specific to the sponsor’s product or program, for which ongoing 
monitoring and rapid communication by the investigator to the sponsor may be appropriate. Such 
events may require further investigation in order to characterize and understand them.  

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Adverse events of special interest are defined on the basis of an ongoing review of the safety data. 
AESIs are discussed further in Section 10.3 and in the investigator’s brochure. 
10.1.4 Definition of Infusion-Related Reactions 
Infusion-related AEs are defined as any AEs occurring during infusion or where the onset of the 
event occurs within 24 hours after the end of infusion and is coded by Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term as: 
“Arthralgia”, “Asthenia”, “Bronchospasm”, “Chills”, “Cough”, “Hyperhidrosis”, “Dizziness”, 
“Pyrexia”, “Fatigue”, “Flushing”, “Headache”, “Hypertension”, “Hypotension”, “Infusion related 
reaction”, “Lethargy”, “Malaise”, “Myalgia”, “Nausea”, “Pruritus”, “Tachycardia”, “Tumor 
pain”, or by MedDRA High Level term as “Exfoliative conditions” or “Dyspneas”, “Dyspnoeas”, 
“Breathing abnormalities” or by MedDRA High Level Group Term as “Allergic conditions”. 
Investigators should consider the clinical picture and isolated events, such as “Fatigue”, occurring 
within 24 hours after the end of infusion, might be considered not to constitute an infusion-related 
reaction, if judged not to be infusion-related by the investigator. 
For infusion-related reactions the causality of the event (Section 10.2.11) should be judged as “at 
least possibly related” by the investigator. 
10.2 Adverse Event Reporting 
Non-serious Adverse Events: 
Non-serious AEs should be reported from the time the patient signs the ICF until the safety follow 
up visit (at 70 days after the last IMP dose) or the end of trial (EOT)/withdrawal visit), whichever 
comes first.  
Serious Adverse Events 
SAEs should be reported from the time the patient signs the ICF until the safety follow up visit (at 
70 days after the last IMP dose) or the end of trial (EOT)/withdrawal visit, whichever comes first. 
Please note: 
 Final assessment of AEs must be performed by a medically qualified person, i.e., a medical 
doctor. 
 All AEs that occur in patients during the AE reporting period must be reported, whether or 
not the event is treatment-related. 
 All AEs should be entered in the eCRF and assessment should be made at each visit (or 
more frequently, if necessary) of changes in severity, the suspected relationship to the trial 
treatment, action taken to trial drug, and the outcome. Instructions for reporting changes in 
an ongoing AE during a patient's participation in the trial are provided in the eCRF 
completion guideline. 
 If an AE becomes grade 3 or results in an SAE it should be reported both in the eCRF and 
on the relevant paper form (SAE paper form or non-serious grade 3 form). 
 All AEs should be followed until they are resolved or until end of trial, whichever comes 
first. At least possibly related non-serious ≥ grade 3 AEs and SAEs still ongoing after end 
of trial 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 
and all queries have been resolved. 

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10.2.1 Pre-existing Condition 
In this trial, a pre-existing condition (i.e. a disorder present before the AE reporting period started 
and noted on the medical history/physical examination form) is not to be reported as an AE. If a 
pre-existing condition worsens during the IMP treatment period, the event should be reported as 
an AE. 
10.2.2 Diagnosis 
The diagnosis/cause of an AE should be recorded rather than the symptoms of the AE. If no 
diagnosis is available each sign and symptom should be recorded as individual AEs. 
10.2.3 Study Disease 
Signs and symptoms, which according to the investigator are expected and well known 
consequences of the indication, both in intensity and frequency, should not be reported as AEs or 
SAEs. Any unexpected change in the intensity or frequency should be reported as an AE (or SAE 
if applicable). 
10.2.4 Disease Progression or Death 
Progression of malignancy, if documented by use of an appropriate method (as per RECIST 
criteria), should not be reported as an SAE. However all deaths (including death caused by disease 
progression) should be reported as SAEs. 
10.2.5 Unrelated Procedures 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
reported as AEs. A medical condition for which an unscheduled procedure was performed, should 
however be reported if it meets the definition of an AE. For example, an acute appendicitis should 
be reported as the AE and not the appendectomy. 
10.2.6 Laboratory test abnormalities 
Laboratory abnormalities that are considered clinically significant, i.e. induce clinical signs or 
symptoms, require concomitant therapy or require changes in trial treatment should be recorded 
as an AE in the eCRF. Whenever possible, a diagnosis, rather than a symptom should be provided 
(e.g. anemia instead of low hemoglobin). Laboratory abnormalities that meet the criteria for AEs 
should be followed until they have returned to normal or an adequate explanation of the 
abnormality is found. When an abnormal laboratory or test result corresponds to a sign/symptom 
of an already reported AE, it is not necessary to separately record the laboratory/test result as an 
additional event. 
NOTE: A CTCAE grade 3 or 4 event (severe) does not automatically indicate an SAE. 
10.2.7 Start Date and Time 
Start date for an (S)AE is the date of occurrence of the first symptom of the disease, e.g. if chest 
pain occurs on 01 April 2016 and the patient is hospitalized with myocardial infarction on 04 April 
2016, then the onset date of the SAE myocardial infarction is 01 April 2016. 
The time should be filled in if the event starts on a dosing day or if the duration of the event is less 
than 24 hours. 

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10.2.8 Information about infusion-related reactions 
If the start date of an AE is the same as an infusion date, the investigator is to assess whether the 
AE is related to the infusion. 
10.2.9 Seriousness Criteria 
Indicate whether or not the AE is determined to be “serious” based on the criteria defined in 
Section 10.1.2. 
10.2.10 Intensity 
The investigator will use the NCI’s CTCAE version 4.03 to describe the severity of AEs. 
10.2.11 Relationship to Investigational Medicinal Product 
A suspected adverse reaction is one in which there is a reasonable possibility that the IMP caused 
the adverse event, this means there is evidence to suggest a causal relationship between the IMP 
and the adverse event. 
The investigator must assess whether or not the event is related to the IMP. The relationship is to 
be judged using the following terms: 
 At least possibly related 
 Not related 
If the relationship changes over time, the last judgment by the investigator should be reported. 
Relatedness has to be assessed and reported from the first time the AE is being reported. 
10.2.12 Action Taken with Investigational Medicinal Product 
The action taken with the IMP should be noted as: 
 Dose not changed 
 Dose reduced 
 Drug interrupted 
 Drug withdrawn 
 Not applicable 
 Unknown 
 
Drug interrupted should be use if the infusion is interrupted or if a treatment is postponed due to 
mitigation of AEs. 
Not applicable should only be used if the AE occurs before first treatment or in the follow-up 
period. 
10.2.13 Outcome 
The outcome of the AE must be judged by investigator using the following terms: 
 Fatal 
 Not recovered/not resolved 
 Recovered/resolved 

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 Recovered/resolved with sequelae 
 Unknown 
10.2.14 End Date and Time 
The end date should be filled in if the outcome of an event is fatal, recovered/resolved or 
recovered/resolved with sequelae. The time should be filled in if the event starts on a dosing day 
or if the duration of the event is less than 24 hours. 
10.3 Adverse Events of Special Interest 
10.3.1 Elevation of Transaminases 
Alanine aminotransferase (ALT) increased and aspartate aminotransferase (AST) increased have 
been reported in more than 50% of the patients. The majority of these were considered to be related 
to the IMP and appeared to be independent of the dose level. Guidance for managing elevated 
transaminases has been included in Section 7.2.2.1. 
10.3.2 Diarrhea 
Diarrhea has been reported in more than 40% of the patients and was the most frequently reported 
SAE. The majority of these were considered to be related to the IMP. Guidance for managing 
diarrhea has been included in Section 7.2.2.3. 
10.4 Events Requiring Immediate Reporting 
10.4.1 Serious Adverse Events and Non-Serious   Grade 3 Adverse Events 
SAEs and non-serious  grade 3 AEs must be reported from the investigational site to the sponsor 
no later than 24 hours following a) the patient visit at which such AE was reported, noted or 
recognized; or b) the principal investigator’s or any investigator personnel’s receipt of the test 
results or other information at, or from which, such development was reported, noted or 
recognized. 
Grade 3 and 4 abnormal laboratory test results must be reported as AEs when these are assessed 
as clinically significant by the reporting investigator. 
All events fulfilling the definition of Hy’s Law (i.e. ALT/AST ˃ 3×ULN and Bilirubin ˃ 2×ULN) 
must be reported as SAEs. 
10.4.2 Overdose and Medication Errors 
For this trial, an overdose is defined as a patient receiving a dose of the IMP 10% in excess of the  
intended dose specified in this protocol.  
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the patient. 
Medication errors include infusion rate errors and uses outside what is foreseen in the protocol, 
including misuse and abuse of the product.  
All events of overdose and/or medication errors with IMP must be reported from the 
investigational site to the sponsor within 24 hours of awareness whether associated with an adverse 
event or not. 

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In addition, overdose and/or medication errors with IMP must also be recorded in the AE page of 
the eCRF whether associated with an AE or not. 
Overdose, medication errors, misuse and abuse do not automatically make an AE serious, but if 
the consequences are serious, for example death or hospitalizations, the event is serious and must 
be reported as an SAE. 
Rescue medication to reverse the action of GEN1029 is not available. In case of overdose, 
medication errors, misuse and/or abuse of trial drug patients should receive supportive care 
according to local guidelines and potential side effects of GEN1029 should be treated 
symptomatically. 
In the event of an overdose, the investigator should: 
i. 
Contact the Medical Monitor immediately. 
ii. 
Closely monitor the patient for any AE/SAE and laboratory abnormalities until GEN1029 
can no longer be detected systemically. 
iii. 
Obtain a plasma sample for PK analysis if requested by the Medical Monitor (determined 
on a case-by-case basis). 
iv. 
Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF. 
10.4.3 Pregnancy 
Any pregnancy that occurs during trial participation must be reported. Pregnant trial patients must 
be withdrawn from treatment immediately, whereas male patients may continue in the trial should 
pregnancy of female partners occur. In this case, a separate informed consent will be obtained from 
the female partner for collection of information regarding the pregnancy. 
Each pregnancy must be reported to sponsor or designee within 24 hours of learning of its 
occurrence. The pregnancy must be followed-up to determine outcome (including premature 
termination) and status of mother and child. The child must be followed at least to the age of one 
month. Pregnancy complications and elective terminations for medical reasons must be reported 
as an AE or SAE. Spontaneous abortions 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, must be promptly 
reported to sponsor or designee. 
10.4.4 Timelines for Immediate Reporting 
The required timeframes and reporting forms for reporting of serious adverse events (SAEs), 
non-serious  grade 3 adverse events (NS  grade 3 AEs), overdose, medication errors and 
pregnancies are presented in Table 10-1. 

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Table 10-1 Timeframes for Reporting SAEs, NS  Grade 3 AEs, Overdose, Medication errors 
and Pregnancies 
Initial Reports 
Follow-up Information on a 
Previous Report 
Type of Event 
Time 
Frame 
Documents 
Time 
Frame 
Documents 
All SAEs and NS  
grade 3 AEs*** 
24 hours* 
Safety Reporting Form 
24 hours* 
Site DCF 
3 days ** 
CDS DCF 
All events of Overdose 
and/or Medication 
errors with IMP 
24 hours* 
Safety Reporting Form 
24 hours* 
Site DCF 
3 days ** 
CDS DCF 
Pregnancy 
24 hours* 
Pregnancy Form 
3 days 
Updated Pregnancy Form 
DCF=Data Clarification Form; CDS=Corporate Drug Safety  
*  All new information regarding SAEs (initial and follow-up) must be reported from sites to sponsor within 24 hours. 
** Sites should make every effort to respond to follow-up queries from sponsor within 3 business days if information 
is available. 
*** AESIs that are serious or NS grade 3 AEs should follow these reporting timelines. 
 
Completed Safety Reporting Forms, Pregnancy Forms, DCFs or any IMP related SAE occurring 
any time after the patient has terminated trial participation, must immediately be forwarded to the 
Safety CRO: 
 
If you have access to a secured email you may forward completed forms to  
Email to: 
 
If you do not have access to a secured email, please forward completed forms to  
 
Fax:  Europe: 
, US: 
 
10.5 Suspected Unexpected Serious Adverse Reactions (SUSARs) 
The sponsor has a legal responsibility to notify, as appropriate and according to local regulations, 
both the local regulatory authority and other regulatory agencies about the safety of the product 
under clinical investigation. Prompt notification of SAEs by the investigator to the sponsor is 
essential so that legal obligations and ethical responsibilities towards the safety of patients are met. 
The sponsor will ensure that all relevant information about Suspected Unexpected Serious Adverse 
Reactions (SUSARs) is recorded and reported as soon as possible, but within a maximum of 15 
calendar days (fatal or life-threatening SUSARs within a maximum of seven days) of first 
knowledge by the sponsor or designee, to the competent regulatory authorities and/or to the ethics 
committee according to the applicable local regulatory requirements. Relevant follow–up 
information of fatal or life-threatening SUSARs will be communicated subsequently within an 
additional eight days. 

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The investigator should be aware of local reporting regulations to the IEC/IRB. The safety CRO 
will either supply the investigator with the reports which should be passed on to the IEC/IRB or 
report directly to the IEC/IRB, depending on local regulations. 
10.6 Follow-Up on Adverse Events 
All AEs should be followed until they are resolved or until the safety follow-up visit, whichever 
comes first. At least possibly related non-serious ≥ grade 3 AEs and SAEs still ongoing after  end 
of trial 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 and all queries have 
been resolved. 
10.7 Warnings and Precautions 
No evidence available at the time of the approval of this trial protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided investigator’s 
brochure (IB). Additional safety information collected between IB updates will be communicated 
in the form of investigator notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the trial as needed. 
10.8 Data Monitoring Committee 
This trial will institute a data monitoring committee (DMC) which will function independently of 
all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the trial. The DMC will consist at a minimum of two physicians with 
appropriate disease area qualifications and, where applicable, a statistician.  The functions and 
responsibilities of the DMC will be described in the DMC Charter, which will be approved by the 
DMC. 
During the dose escalation phase, the DMC will be responsible for reviewing safety and 
pharmacokinetic data after completion of the cohort on each dose-level. A DMC meeting including 
both an open and closed session will be held in order to discuss data. During the open session, 
sponsor employees and  investigators will participate together with the DMC. During the closed 
session, only DMC members will participate. After the closed session, the sponsor will be 
informed of the DMC’s recommendations. The sponsor safety committee will hereafter meet to 
evaluate the recommendations provided by the DMC and decide whether the dose of IMP should 
be escalated, de-escalated or held at same dose-level.  
During the expansion phase of the trial, the DMC may meet at regular intervals, as defined in the 
DMC charter. 
The DMC will also review the safety, pharmacokinetic and efficacy data at the end of the trial in 
order to provide an overall Risk Benefit assessment, as defined in the DMC charter. 

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11 STATISTICS 
All statistical analyses will be performed by a Contract Research Organization (CRO), under the 
direction of sponsor personnel.  
The Statistical Analysis Plan (SAP) will be developed and finalized before database lock and will 
describe the patient populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical analyses 
of the primary and secondary endpoints. 
All presentations will be done separately for the dose escalation part and the expansion part. 
In the reporting of the dose escalation part tables will report by cohort while in the expansion part 
tables will report by indication. 
All data will be listed. Baseline is defined as the latest available measurement made before the 
first treatment with IMP. 
A patient will be considered as having completed the trial when all planned trial visits have been 
performed. 
11.1 Analysis Sets 
11.1.1 Full Analysis Set 
The full analysis set (FAS) and safety set are defined in the same way and comprise all subjects 
who received at least 1 dose of trial treatment. Subjects will be analyzed according to the actual 
trial treatment received. 
11.1.2 Safety Set 
See the definition of the FAS. 
11.1.3 Per-Protocol Set 
Not applicable. 
11.1.4 Dose-Determining Analysis Set 
The Dose-Determining Set (DDS) consists of all patients from the safety set who either have 
received between 80% and 125% of the planned dose and have completed the DLT observation 
period, or have experienced a DLT during cycle 1. This constitutes an evaluable patient for the 
determination of MTD Statistical Analyses. 
11.2 Patient Demographics and Baseline Characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively for the FAS.  
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. 
Relevant medical histories and current medical history at baseline will be summarized by system 
organ class and preferred term. 

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11.3 Treatments 
The Safety Set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 75th 
percentiles, minimum, and maximum will be presented. 
The duration of exposure in months to GEN1029 as well as the dose intensity (computed as the 
ratio of actual cumulative dose received and actual duration of exposure) will be summarized by 
means of descriptive statistics using the safety set. 
Concomitant medications and significant non-drug therapies prior to and after the start of the IMP 
will be listed and summarized according to the anatomical therapeutic chemical (ATC) 
classification system, by dose cohort. 
11.4 Analysis of Dose Escalation Part 
11.4.1 Primary Objectives 
The primary objectives are to: 
 Determine the MTD and the recommended Phase 2 dose (RP2D) 
 Establish the safety profile of GEN1029. 
11.4.1.1 Primary Endpoints 
 Number of DLTs during the DLT period (initial 28 days of treatment). See Section 4.3 for 
how the MTD will be determined.  
 Summary tables for adverse events (AEs) will include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs.  
The incidence of treatment-emergent adverse events (new or worsening from baseline) will 
be summarized by System Organ Class (SOC) and or Preferred Term (PT), severity 
(CTCAE grade), type of adverse event, and relationship to IMP. 
SAEs, non-serious AEs and AEs of special interest (AESI) during the on-treatment period 
will be tabulated. 
All deaths (on-treatment and post-treatment) will be summarized. 
All AEs, deaths and SAEs (including those from the pre and post-treatment periods) will 
be listed and those collected during the pre-treatment and post-treatment period will be 
flagged. 
Further summaries of AEs will be specified in the statistical analysis plan. 
11.4.2 Secondary Safety Objectives 
11.4.2.1 Clinical Safety Data 
Liver toxicity will be described separately as a priori this is the most relevant potential safety 
concern. 

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11.4.2.2 Laboratory Safety Data 
Grading of laboratory values will be assigned programmatically as per the National Cancer 
Institute’s CTCAE version 4.03. The calculation of CTCAE grades will be based on the observed 
laboratory values only, clinical assessments will not be taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
For laboratory tests where grades are not defined by the CTCAE, results will be categorized as 
low/normal/high based on laboratory normal ranges. 
The following summaries will be generated separately for hematology, and biochemistry tests: 
 Listing of all laboratory data with values flagged to show the corresponding CTCAE grades, if 
applicable, and the classifications relative to the laboratory normal ranges. 
For laboratory tests where grades are defined by the CTCAE: 
 Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline. 
 Shift tables using CTCAE grades to compare baseline to the worst on-treatment value. 
For laboratory tests where grades are not defined by the CTCAE: 
 Shift tables using the low/normal/high/ (low and high) (or other project-specific) classification 
to compare baseline to the worst on-treatment value. 
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might be 
specified in the analysis plan. 
11.4.2.3 Other Safety Data 
ECG 
12-lead ECGs including PR, QRS, QT, QTcF, and RR intervals will be obtained for each patient 
during the trial in accordance with Table 1-2 (dose escalation part) and Table 1-7 (expansion part). 
ECG data will be read and interpreted centrally. 
Categorical analysis of QT/QTc interval data based on the number of patients meeting or 
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from baseline will 
be presented. In addition, a listing of these patients will be produced. 
Vital signs 
Data on vital signs will be tabulated and listed; notable values will be flagged. 
11.4.3 Pharmacokinetics 
Individual curves of plasma/serum concentration of each component of GEN1029 including 
information on actual dose, will be presented for all patients. All available data will be shown in 
these figures. Concentrations below the limit of quantitation will be set to LLOQ/2. 
PK parameters (Table 11-1) will be calculated based on non-compartmental methods and will be 
calculated separately for Cycle 1, Cycle 2 and Cycle 3. 

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The relation between derived PK parameters and covariates such as actual dose, weight and dose, 
and selected laboratory parameters will be evaluated graphically. 
If deemed applicable compartmental modeling approaches to parameter estimation will be applied. 
Further exploratory analyses of PK data may be performed. 
Table 11-1 Non-compartmental Pharmacokinetic Parameters 
AUC0-14days 
The AUC from time zero to day 14 (mass x time x volume-1) 
AUCinf 
The AUC from time zero to infinity (mass x time x volume-1) 
AUClast 
The AUC from time zero to last quantifiable measurement 
Cmax 
The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration 
after single dose administration  
Tmax 
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration  
T1/2 
The elimination half-life associated with the terminal slope (z) of a semi logarithmic 
concentration-time curve  
CL 
The total body clearance of drug from the plasma 
 
11.4.4 Immunogenicity of GEN1029 
As a result of Immunogenicity analysis samples will be scored ADA positive or ADA negative 
and subsequently reported. From positive ADA samples titer values and neutralizing antibody 
scores (postivie or negative) will be determined and reported. ADA negative samples with drug 
on board above the drug tolerance limits of the ADA method will be scored inconclusive due to 
possible drug intereference. The association between positive/non-positive ADA and PK (pre-
dose, AUC, Cmax), major safety signals (CTCAE ≥ grade 3) and efficacy information (change in 
tumor size by CT scan) will be explored.  
11.4.5 Secondary Efficacy Objective 
The secondary efficacy objective is to further evaluate the anti-tumor activity of GEN1029.  
11.4.5.1 Secondary Efficacy Endpoints 
11.4.5.1.1 Definition of Response 
RECIST criteria (v1.1) will be used to define response. Based on the definition of response (Table 
11-2) and the combined evaluation (see Table 1 in Eisenhauer et al., 2009), each patient will be 
assigned 1 of the following categories at each CT scan visit and as Best Overall Response (BOR): 
1) CR 
2) PR 
3) SD 
4) PD or 
5) Not Evaluable 
BOR is the best response recorded from the start of the treatment until disease 
progression/recurrence (the smallest measurements recorded since the treatment started will be 
used as the reference for PD). 

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Table 11-2 Definition of Response (RECIST Criteria v1.1) 
 
Category 
Criteria 
Based on 
target lesions 
Complete 
Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes  must 
have reduction in short axis to < 10 mm. 
Partial Response 
(PR) 
≥ 30% decrease in the sum of the LD of target lesions, taking as reference 
the baseline sum of LDs. 
Stable Disease 
(SD)  
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of LDs while in trial. 
Progressive 
Disease (PD) 
≥ 20% (and ≥ 5 mm) increase in the sum of the LDs of target lesions, taking 
as reference the smallest sum of the target LDs recorded while in trial or the 
appearance of 1 or more new lesions. 
NE 
Not evaluable 
Based on non-
target lesions 
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). 
SD 
Persistence of 1 or more non-target lesion(s) or/and maintenance of tumor 
marker level above the normal limits. 
PD 
Appearance of 1 or more new lesions and/or unequivocal progression of 
existing non-target lesions. 
NE 
Not evaluable 
LD =Longest Diameter; SD for non-target lesions defined as “Non-CR/Non-PD” by Eisenhauer et al., 2009.  
 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of PD at that time should be classified as having “symptomatic deterioration”. 
Every effort should be made to document the objective progression even after discontinuation of 
treatment. 
 
Confirmation 
SD: follow-up measurements occurring at least 6 weeks (± 7 days) after first treatment must have 
met the SD criteria at least once. 
PR and CR: no formal confirmation response is required. However, a repeat CT-scan may be 
performed no less than 4 weeks after the criteria for response is met to substantiate/confirm CT 
response. If the response is still present this will be called confirmed response/confirmed complete 
response. 
Reporting of Objective Response Rate (ORR) results: 
Patients in response categories 1 and 2 are considered responders and patients in response 
categories 4 and 5 are considered as failing to respond to treatment. Patients in response categories 
1, 2 and 3 are considered to be in disease control. 
Individual patient data listings and summaries of objective response, best overall tumor response 
and disease control will be presented by dose cohort/indication and total.  
The maximal response (maximal reduction in the sum of the LD in the target lesions) in target 
lesions at any time on trial will be reported using waterfall plots. 
11.4.5.1.2 Progression-free Survival 
PFS is defined as the time from the date of C1D1 to the date of the first documented progression 
or death due to any cause. PFS will be assessed via local review according to RECIST 1.1 

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(Eisenhauer et al., 2009). PFS will be censored in accordance with Table C1 in Appendix C in the 
FDA Guidance for Industry: Clinical Trial Endpoints for the Approval of Non-small Cell Lung 
Cancer Drugs and Biologics (FDA 2015).  
Progression-free survival will be derived for all patients and presented graphically as well as 
summarized using survival analysis methods.  
The quartile estimates of PFS from the Kaplan Meier product limit algorithm will be presented. 
The 2-sided 95% confidence interval will be presented as well. The number of events may be 
small, and thereby limit use of the Kaplan Meier method to provide reliable information. In this 
case, descriptive statistics (e.g., n, mean, standard deviation, median, minimum and maximum) for 
PFS will be presented. 
11.4.5.1.3 Overall Survival 
Overall survival is defined as the number of days from Day 1 in Cycle 1 to death due to any cause. 
If a patient is not known to have died, then OS will be censored at the latest date the patient was 
known to be alive (on or before the cut-off date). 
Overall survival will only be analyzed for the expansion part using the same techniques and 
presented in the same manner as PFS. 
11.4.5.1.4 Duration of Response 
Duration of response (DoR) only applies to patients whose best overall response is complete 
response (CR) or partial response (PR) and is defined as the number of days from the first 
documentation of objective tumor response (CR or PR) to the date of first PD or death due to 
underlying cancer. Subjects continuing without progression or death due to underlying cancer will 
be censored at the date of their last adequate tumor assessment. 
DoR will be summarized in the same way as PFS. 
11.4.5.1.5 Time to Response 
Time to response (TTR) is defined as the number of days from Day 1 in Cycle 1 to the first 
documented response of either CR or PR, which must be subsequently confirmed (although date 
of initial response is used, not date of confirmation). CR and PR are based on tumor response data 
as per local review and according to RECIST 1.1. 
The TTR calculations is restricted to those subjects in the FAS with a confirmed PR or CR. TTR 
will be listed and summarized by treatment group. 
11.4.5.1.6 Tumor Shrinkage 
Tumor shrinkage (based on CT-scan evaluations) will be listed and summarized. 
11.5 Analysis of Expansion Part 
In general, the analysis methodology for the endpoints of the dose expansion part will be the same 
as the one used for the corresponding endpoints in the dose escalation part, only summarizing by 
cohort (which is regimen and indication specific). 
11.5.1 Primary Objective 
The primary objective of the expansion part is to evaluate the ORR by cohort.  

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11.5.1.1 Primary Endpoint  
The primary endpoint for the dose expansion part is the ORR as defined in Section 11.4.5.1. The 
primary analysis will be based on the confirmed responses. Supportive to this, an analysis using 
both confirmed and unconfirmed response will be carried out. 
11.5.1.2 Statistical Hypothesis, Model and Method of Analysis 
If only one regimen is evaluated for an indication there is no formal hypothesis to be tested in the 
dose expansion part. The ORR will be estimated with exact 2-sided 95% confidence intervals (CIs) 
for each arm using the Clopper-Pearson method. Other response rates such as BOR and rate of 
disease control will be reported similarly. 
Should there be more than one regimen evaluated for an indication the endpoints will be reported 
per regimen (and indication) as described above. In addition for each indication tested in multiple 
regimens, a logistic regression model, adjusted for screening ECOG score and regimen (with two 
possible levels) will be used to report the comparative efficacy of the evaluated regimens.  
The odds ratio in response rates between two initiated regmeins within one indication will be tested 
at the two-sided 5% Type-I error rate level.  
The totality of the data together with the planned comparison will guide the selection of a regimen 
for further development.  
11.5.1.3 Handling of Missing Values/Censoring/Discontinuations 
Any patients with missing information regarding response to treatment will be counted as non-
responders. 
11.5.2 Secondary Efficacy Objective 
The secondary efficacy objectives and endpoints in the dose expansion part are (besides the ORR 
that is primary endpoint) those that are described in Section 11.4.4.  
11.5.3 Secondary Safety Objective  
The safety objective with the expansion part is to further describe the safety profile of GEN1029.  
AEs and laboratory parameters will be reported as described in 11.4.1 and 11.4.2. All listings and 
tables will be presented by cohort in the expansion part. 
11.5.4 Pharmacokinetics 
PK parameters will be calculated as feasible, depending on the availability of the data. 
11.5.5 Immunogenicity of GEN1029 
Immunogenicity of GEN1029 in the expansion part will be reported as described in Section 11.4.4. 
The association between positive/non-positive ADA and PK (pre-dose, AUC, Cmax), major safety 
signals (CTCAE ≥ grade 3) and efficacy information (change in tumor size by CT scan) will be 
explored and reported as feasible. 

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11.6 Explorative Analysis 
11.6.1 Biomarkers 
Biomarker analyses in this study are exploratory and focused on identifying potential 
pharmacodynamic (PD) or predictive markers that may be further validated in prospective trials 
with GEN1029 (HexaBody-DR5/DR5), as well as to further understand the biological impact of 
GEN1029 on downstream pathway activities and tumor cell processes. 
Biomarkers, such as DR5 expression (protein or 
) and immune cell populations, will be 
tabulated for all patients who had samples collected and testing performed. Biomarker assessments 
will be summarized by time point using descriptive statistics. Changes in biomarker parameters, 
as compared to baseline, will be calculated and analyzed for association with relevant clinical 
endpoints such as objectives response, PFS, OS. Subgroup analysis may be performed to evaluate 
differences between biomarker parameters in groups of responders and non-responders or other 
clinically relevant subgroups, and to evaluate the associations between biomarker parameters and 
specific clinical endpoints. Univariate and multivariate analyses, as well as pathway analyses may 
also be performed if applicable. Any pharmacodynamic measures will be listed, tabulated, and 
plotted as appropriate. Patients may be grouped by cohort, regimen, or clinical response. 
Results of biomarker analyses may be presented in a separate report. Planned analyses are based 
on the availability of clinically valid assays and may be deferred if emerging study data show no 
likelihood of providing useful scientific information. 
11.6.2 Metabolic Response in the Tumors 
As an exploratory analysis the metabolic response in the tumors will be evaluated following the 
Positron Emission Tomography Response Criteria In Solid Tumors (PERCIST 1.0), see (Wahl et 
al., 2009). The metabolic endpoint is the standardized uptake volume corrected for body lean mass 
(SUL). Percentage change from screening in SUL will be summarized by scan visit for the hottest 
lesion. The metabolic response will also be classified and summarized (according to PERCIST 
1.0) as a) complete metabolic response (CMR); b) partial metabolic response (PMR); c) stable 
metabolic disease (SMD); and d) progressive metabolic disease (PMD). 
11.6.3 
 
 
 
 
11.7 Interim Analyses 
In the expansion part each cohort will contain of up to 4 stages, targeting a maximum sample size 
of 60 patients. For each stage, the success of the stage is predicted. If the predictive probability of 
success is less than 10% the stage is not further explored in order not to expose patients to in-
efficacious doses based on an interim futility analysis, as detailed in Table 11-3 and Table 11-7. 
The interim analysis divides each cohort into a maximum of 4 stages in total. The analysis will be 
based on both the uncomfirmed and confirmed CR or PR observed when the interim-sample size 
is accomplished.  

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Table 11-3: Cohort stages and Sample Sizes 
Stage 
Sample size at interim 
(n) 
Sample size at end of stage  
(N) 
1 
Not applicable 
10 
2 
10 
20 
3 
20 
40 
4 
40 
60 
 
At the interim, a Bayesian predictive probability approach will be used to evaluate the futility 
criteria (Lee and Liu, 2008). By using predictive probabilities, it is possible to directly assess the 
outcome of a trial (in this case stage), if continued to its end (Saville et al., 2014). Given the interim 
data, the predicted probability is a weighted average of posterior probabilities, as if calculated 
given the outcome at the end of the stage. The weights correspond to how likely each outcome is. 
The predictive probabilities may in fact be calculated at any time point during Stage 2, 3 and 4.  
As originally suggested by Lee and Liu (Lee and Liu, 2008) the predictive probability approach is 
operated with respect to a historical response rate (p0) only. However, as applied here, also a target 
response rate (p1) that warrants further evaluation of the drug, is being used to evaluate futility. In 
general, this decreases the Type I error rate and increases the Type II error rate as more studies 
would be stopped. For more details, please see Section 11.8.2. 
For Stage 2, the success criteria for each cohort is a posterior density (given completion of stage) 
of the responder rate that exceeds p0 by 
 and p1 by 
. Stage 2 is further explored if the 
predictive probability of success, as calculated at end of Stage 1, is greater than 
. Similar 
considerations yield for Stage 3 and 4, but the success criteria are a posterior density of the 
responder rate that exceeds p0 by 
and p1 by 
. The success criteria based on the posterior 
probabilities are illustrated in Figure 11-1, where the more conservative expansion strategy being 
used for Stage 3 and 4 as compared to Stage 2 becomes clear. 

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Figure 11-1: Success criteria based on posterior probabilities 
In addition to the interim analysis for futility, interim data from the trial may be presented at 
scientific meetings. 
The Statistical Analysis Plan will describe the planned interim analyses in greater detail. 
11.8 Sample Size Calculation 
11.8.1  Dose Escalation Part 
The actual number of patients depends on the true relationship between dose and DLT probability 
and could range between 10 to 25 patients for a given scenario, as presented below. Similarly, the 
number of dose levels explored depends on the toxicity profile. Up to 18 additional patients may 
be recruited to dose levels below MTD where it is found relevant to further explore the efficacy.  
In total up to approximately 100 patients are planned to be recruited during the escalation part. 
The patients are shared between the Biweekly and Priming Regimens.  
Table 11-4 below shows 6 different scenarios for the probability of a patient having a DLT at 6 
dose levels, which in our case could be the 6 lowest dose levels. For each scenario the total 
expected number of patients, when following the mBOIN design, is shown in the rightmost 
column. For each of the dose levels and scenarios, first the probability of a DLT and then the 
expected number of patients at the dose level is shown. The mBOIN design algorithm behaves as 
intended with most patients exposed to the dose levels with DLT probability close to the target 
DLT rate and fewer patients exposed in total if the toxicity is high at the lowest dose levels.   

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Table 11-4 
Modified BOIN Design Characteristics for 6 Dose Levels 
 
Probability(DLT) and expected number of patients at dose level 
Total 
Scenario 
Dose = 1 
Dose = 2 
Dose = 3 
Dose = 4 
Dose = 5 
Dose = 6 
No. Pat. 
1 
 
Pr(DLT) 
0% 
1% 
2% 
4% 
8% 
16% 
 
No. Pat. 
1.0 
3.1 
3.2 
3.5 
4.2 
8.7 
23.8 
2 Pr(DLT) 
1% 
2% 
4% 
8% 
16% 
32% 
 
No. Pat. 
1.1 
3.2 
3.5 
4.2 
6.2 
7.2 
25.3 
3 Pr(DLT) 
5% 
15% 
25% 
40% 
50% 
60% 
 
No. Pat. 
1.8 
5.6 
6.5 
4.6 
1.5 
0.2 
20.2 
4 Pr(DLT) 
20% 
35% 
50% 
60% 
65% 
70% 
 
No. Pat. 
4.9 
6.8 
2.7 
0.4 
0.0 
0.0 
14.9 
5 Pr(DLT) 
30% 
40% 
50% 
60% 
70% 
75% 
 
No. Pat. 
5.4 
5.5 
1.8 
0.3 
0.0 
0.0 
13.0 
6 Pr(DLT) 
1% 
1% 
1% 
60% 
65% 
70% 
 
No. Pat. 
1.0 
3.1 
8.3 
6.7 
0.4 
0.0 
19.6 
 
If 4 dose levels are explored the pattern identified repeats, but the total number of patients is lower, 
see Table 11-5.  
Table 11-5: Modified BOIN Design Characteristics for 4 Dose Levels 
 
Probability (DLT) and expected number of patients* at dose level 
Total 
Scenario 
Dose = 1 
Dose = 2 
Dose = 3 
Dose = 4 
No. Pat. 
1 
 
Pr(DLT) 
2% 
4% 
8% 
16% 
 
No. Pat. 
3.2 
3.5 
4.2 
8.6 
19.5 
2 Pr(DLT) 
4% 
8% 
16% 
32% 
 
No. Pat. 
3.4 
4.2 
6.1 
6.9 
20.6 
3 Pr(DLT) 
15% 
25% 
40% 
50% 
 
No. Pat. 
5.2 
6.4 
4.3 
1.3 
17.3 
4 Pr(DLT) 
35% 
50% 
60% 
65% 
 
No. Pat. 
6.4 
2.9 
0.5 
0.0 
9.9 
5 Pr(DLT) 
40% 
50% 
60% 
70% 
 
No. Pat. 
6.0 
2.3 
0.4 
0.0 
8.7 
6 Pr(DLT) 
1% 
60% 
65% 
70% 
 
No. Pat. 
8.3 
6.6 
0.4 
0.0 
15.4 
* Based on 50,000 simulations 
11.8.2  Expansion Cohorts 
The maximum sample size for each expansion cohort is 60 patients, divided over up to 4 stages as 
described in Section 11.7. The historical (p0) and target (p1) response rates being used to evaluate 
the operating characteristics are presented in Table 11-6.  

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Table 11-6: Response Rate Characteristics by Indication 
 
Colorectal Cancer 
(CRC) 
Triple Negative 
Breast Cancer 
(TNBC) 
Other indications* 
Historical response rate (p0) 
2% 
7.5% 
10% 
Target response rate that 
warrants further evaluation of 
the drug (p1) 
15% 
20% 
25% 
*NSCLC, RCC, gastric, pancreas or urothelial cancer 
Given p0 and p1 it is possible to prospectively calculate the required number of responders to 
further explore each stage as presented in Table 11-7. A priori it is assumed that the response rate 
is distributed as Beta(0.2, 0.8). 
Table 11-7: Continuation Criteria in Terms of Number of Responders 
Indication 
Stage 2 
(n=10; N=20) 
Stage 3 
(n=20; N=40) 
Stage 4 
(n=40; N=60) 
CRC 
≥1/10 
≥2/20 
≥4/40 
TNBC 
≥1/10 
≥2/20 
≥6/40 
Other 
≥1/10 
≥3/20 
≥7/40 
Numbers of responses serve as a guideline; however, the totality of efficacy data will be considered when making decisions to terminate or 
continue an arm. 
The operating characteristics in terms of the probability for not exploring a stage, and the 
probability that the estimated response rate is greater than p1 (if the stage is completed) are 
presented in Table 11-8. The operating characteristics are based on 50,000 simulations of each 
assumption of true response rate. For the colorectal cohort there is a high probability to stop under 
p0 early on, which partly is due to the requirement to beat p1 (15%) with some confidence as well. 
This requirement has less impact on the TNBC cohort and the other indications (NSCLC, RCC, 
gastric, pancreatic and urothelial cancer) for which the stopping rate is lower.  
Table 11-8: Operating Characteristics in Terms of a) Probability for not Exploring each 
Stage; and b) the Probability that the Estimated Response Rate is Greater than p1 (if the 
Stage is Completed) 
Indication 
True ORR 
Stage 2 
(n=10; N=20) 
Stage 3 
(n=20; N=40) 
Stage 4 
(n=40; N=60) 
a) 
b) 
a) 
b) 
a) 
b) 
CRC 
(p0=2%; p1=15%) 
2% 
81% 
1% 
94% 
0% 
99% 
0% 
15% 
20% 
56% 
18% 
54% 
13% 
55% 
TNBC 
(p0=7.5%; 
p1=20%) 
7.5% 
46% 
6% 
55% 
1% 
92% 
0% 
20% 
11% 
58% 
7% 
56% 
16% 
54% 
Other* 
(p0=10%; p1=25%) 
10% 
35% 
4% 
68% 
1% 
90% 
0% 
25% 
6% 
58% 
9% 
55% 
10% 
54% 
*NSCLC, RCC, gastric, pancreas or urothelial cancer 

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11.8.3 Statistical Power for Comparing Two Regimens within one Indication 
If more than one regimen is evaluated for the same indication in two different cohorts in the 
expansion part, the response rates in the two cohorts will be compared as described in Section 
11.5.1.2). The power (probability of being able to detect a statistically significant difference 
between two regimens A and B with underlying true response rates 𝜃𝐴, and 𝜃𝐵, respectively) for 
different stages of sample sizes, is presented in Table 11-9. It is noted that the sample sizes at the 
final analysis may not be equal. 
For each scenario, 50,000 trials were simulated, and the logistic regression model (see Section 
11.5.1.2) was estimated using SAS PROC GENMOD to test the significance (at the one-sided 
Type I error rate of 5%) of Regimen B being better than Regimen A. The power is the percentage 
of trials were the p-value of the regimen effect was <5% (one-sided). The simulations are 
constrained on having at least two responders in each cohort at N=20, and at least four responders 
in each cohort at N=40 and N=60. This reflects the expansion strategy within each cohort and 
implies that there is some similarity imposed on the realized trials that impacts the following power 
assessment.  
Table 11-9: Power (Probability to Detect a Significant Difference Between two Regimens) 
𝜃𝐴 
𝜃𝐵 
Power 
@NA=NB=20 
Power 
@NA=NB=40 
Power 
@NA=NB=60 
10% 
15% 
0% 
0% 
6% 
10% 
20% 
2% 
5% 
24% 
10% 
25% 
6% 
18% 
52% 
15% 
20% 
1% 
3% 
9% 
15% 
25% 
4% 
11% 
26% 
15% 
30% 
10% 
27% 
49% 
20% 
25% 
2% 
5% 
9% 
20% 
30% 
6% 
15% 
23% 
20% 
35% 
13% 
30% 
45% 
25% 
30% 
4% 
7% 
8% 
25% 
35% 
8% 
15% 
22% 
 
Due to foreseen scenarios and the constraint imposed on the simulations, the probability to 
conclude that there is a significant improvement with Regimen B over Regimen A is low to 
moderate. The power ranges from 0% up to 52%, depending on the underlying assumed response 
rates and the sample sizes. This can also be expressed as that the probability of not being able to 
detect a difference based on the statistical model lies between 48 and 100%.  
 

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12 DATA HANDLING AND RECORD KEEPING 
12.1 Data Flow 
Figure 12-1 Outline of Data Flow 
electronic
CRF
Investigators
External
Database(1)
External
Database(2)
Clinical study Database
Coding
Sponsor
Queries
Generation
Edit checks
Queries
       Data
reconciliation
Database
    lock
Listings
Progress
reports
 
 
12.2 Source Documentation 
At a minimum, source documentation must be available for the following to confirm data collected 
in the eCRF: patient identification, eligibility, and trial identification; trial discussion and date of 
signed informed consent; dates of visits; results of safety and efficacy parameters as required by 
the protocol; record of all adverse events and follow-up of adverse events; concomitant 
medication; drug receipt/dispensing/return records; trial drug administration information; and date 
of trial completion and reason for early discontinuation of trial drug or withdrawal from the trial, 
if applicable.  
In addition, the author of an entry in the source documents should be identifiable. 
Specific details required as source data for the trial will be reviewed with the investigator before 
the trial and will be described in the monitoring guidelines (or other equivalent document). 
 

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12.3 Case Report Form Completion 
Case report forms are provided for each patient in electronic format. 
Electronic data capture (EDC) will be used for this trial. The trial data will be transcribed by trial-
site personnel from the source documents onto an electronic CRF, and transmitted in a secure 
manner to the sponsor within the timeframe agreed upon between the sponsor and the trial site. 
The electronic file will be considered to be the CRF. 
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the patient's source documentation. All data relating to the 
trial must be recorded in eCRFs prepared by the sponsor. Data must be entered into eCRFs in 
English. Trial site personnel must complete the eCRF as soon as possible after a patient visit, and 
the forms should be available for review at the next scheduled monitoring visit. 
All subjective measurements, such as ECOG will be completed by the same individual who made 
the initial baseline determinations whenever possible. 
All eCRF entries, corrections, and alterations must be made by the investigator or other authorized 
trial-site personnel. The investigator must verify that all data entries in the eCRFs are accurate and 
correct. If necessary, queries will be generated in the EDC tool. 
If corrections to an eCRF are needed after the initial entry into the eCRF, this can be done in three 
different ways: 
 Trial-site personnel can make corrections in the EDC tool at their own initiative or as a response 
to an auto query (generated by the EDC tool). 
 The monitor can generate a query for resolution by the trial-site personnel. 
 The clinical data manager can generate a query for resolution by the trial-site personnel. 
 The sponsor can generate a query for resolution by the trial-site personnel. 
12.4 Data Quality Management 
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate trial sites, review of protocol procedures with the investigator and 
trial-site personnel before the trial, periodic monitoring visits by the sponsor and direct 
transmission of clinical laboratory data from a central laboratory, ECG data from ECG vendor and 
CT-scans and reads from the scan vendor (expansion part only) into the sponsor's data base. 
Written instructions will be provided for collection, handling, storage, and shipment of samples. 
Guidelines for eCRF completion will be provided and reviewed by the trial-site personnel before 
the start of the trial. The sponsor will review eCRFs for accuracy and completeness during on-site 
monitoring visits and after transmission to the sponsor; any discrepancies will be resolved with 
the investigator or designee, as appropriate. After upload of the data into the trial database they 
will be verified for accuracy and consistency with the data sources. 
12.5 Record Retention 
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
and all source documents, as well as a source document location list, that support the data collected 
from each patient, as well as all trial documents as specified in ICH/GCP guideline Section 8, 
Essential Documents for the Conduct of a Clinical Trial, and all trial documents as specified by 

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the applicable regulatory requirement(s). The investigator/institution will take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents must be retained for 25 years after end of trial. These documents will be 
retained for a longer period if required by the applicable regulatory requirements. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the trial records, custody must be transferred to a person who will accept 
the responsibility. The sponsor must be notified in writing of the name and address of the new 
custodian. Under no circumstance shall the investigator relocate or dispose of any trial documents 
before having obtained written approval from the sponsor. 
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this trial, the investigator/institution must permit access to such reports. 

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13 ETHICS 
13.1 Trial-Specific Design Considerations 
Thorough scientific evaluation of any promising treatment before market authorization is an 
ethical requirement. In the continuing search for medications with improved efficacy and safety 
profiles, it is necessary to fully investigate and understand new products before public exposure. 
This trial is being conducted to evaluate the multiple-dose pharmacokinetics of GEN1029 in 
patients with malignant solid tumors. The results of this trial will provide useful information on 
the pharmacokinetics of GEN1029. These data are also needed to assist in developing dosage 
adjustment guidance for future trials. 
As with all clinical and pharmacokinetic trials, there are risks associated with venipuncture and 
multiple blood sample collection. To avoid multiple venipunctures, which cause additional 
discomfort and other potentially toxic effects, the use of intravenous indwelling catheters is 
permitted in this trial. The blood sample collection scheme was designed to collect the minimum 
number of blood samples that accurately and completely describe the pharmacokinetics of 
GEN1029. This minimizes the total volume of blood (approximately 1300 mL for the first 24 
cycles) collected from each patient during the trial.  
Potential patients will be fully informed of the risks and requirements of the trial and, during the 
trial, patients will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the trial is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only patients who are fully able to understand the risks, benefits, and 
potential adverse events of the trial, and provide their consent voluntarily will be enrolled. 
13.2 Regulatory Ethics Compliance 
13.2.1 Investigator Responsibilities 
The investigator is responsible for ensuring that the trial is performed in accordance with the 
protocol, current ICH guidelines on GCP, and applicable regulatory and country-specific 
requirements. 
GCP is an international ethical and scientific quality standard for designing, conducting, recording, 
and reporting trials that involve the participation of human subjects. Compliance with this standard 
provides public assurance that the rights, safety, and well-being of trial patients are protected, 
consistent with the principles that originated in the Declaration of Helsinki 2013, and that the trial 
data are credible. 
13.2.2 Independent Ethics Committee or Institutional Review Board 
This trial will be undertaken only after the IEC/IRB has given full approval of the final protocol, 
amendments (if any, excluding the ones that are purely administrative, with no consequences for 
patients, data or trial conduct), the ICF, applicable recruiting materials, and patient compensation 
programs, and the sponsor has received a copy of this approval. This approval letter must be dated 
and must clearly identify the IEC/IRB and the documents being approved. 
Approval for the collection of optional samples for research and for the corresponding ICF must 
be obtained from the IEC/IRB. Approval for the protocol can be obtained independent of this 
optional research component. 

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For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for patients, data or trial conduct), the amendment and applicable ICF revisions must 
be submitted promptly to the IEC/IRB for review and approval before implementation of the 
change(s). 
Where applicable, interim reports on the trial and/or reviews of trial progress will be submitted by 
the investigator to the IEC/IRB at intervals stipulated in the IEC/IRB guidelines. 
At the end of the trial, the investigator (or sponsor where required) will notify the IEC/IRB about 
the trial completion. 
13.2.3 Informed Consent 
Each patient must give written consent according to local requirements after the nature of the trial 
has been fully explained. The ICF(s) must be signed before performance of any trial-related 
activity. The ICF(s) that is/are used must be approved by both the sponsor and by the reviewing 
IEC/IRB and be in a language that the patient can read and understand. The informed consent 
should be in accordance with principles that originated in the Declaration of Helsinki 2013, current 
ICH guidelines including ICH-GCP E6(R2), applicable regulatory requirements, and sponsor 
policy. 
Before enrollment in the trial, the investigator or an authorized member of the trial-site personnel 
must explain to potential patients the aims, methods, reasonably anticipated benefits, and potential 
hazards of the trial, and any discomfort participation in the trial may entail. Patients will be 
informed that their participation is voluntary and that they may withdraw consent to participate at 
any time. They will be informed that choosing not to participate will not affect the care will receive 
for the treatment of their disease. Finally, they will be told that the investigator will maintain a 
patient identification register for the purposes of long-term follow up if needed and that their 
records may be accessed by health authorities and authorized sponsor personnel without violating 
the confidentiality of the patient, to the extent permitted by the applicable law(s) or regulations. 
By signing the ICF the patient is authorizing such access, and agrees to allow his or her trial 
physician to re-contact the patient for the purpose of obtaining consent for additional safety 
evaluations, if needed. 
The patient will be given sufficient time to read the ICF and the opportunity to ask questions. After 
this explanation and before entry into the trial, consent should be appropriately recorded by means 
of the patient's personally dated signature. After having obtained the consent, a copy of the ICF 
must be given to the patient. 
Patients will be asked for consent to provide optional samples for research (where local regulations 
permit). After informed consent for the trial is appropriately obtained, the patient will be asked to 
sign and personally date a separate ICF indicating agreement to participate in the optional research 
component. Refusal to participate in the optional research will not result in ineligibility for the 
trial. A copy of this signed ICF will be given to the patient. 
Where local regulations require, a separate ICF may be used for the required DNA component of 
the trial. 
13.2.4 Privacy of Personal Data 
The collection and processing of personal data from patients enrolled in this trial will be limited 
to those data that are necessary to fulfill the purpose and the objectives of the trial. 

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These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized disclosures 
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place. 
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity 
of patients confidential. 
The informed consent obtained from the patient includes explicit consent for the processing of 
personal data for the purpose of the trial and for the investigator/institution to allow direct access 
to his or her original medical records (source data/documents) for trial-related monitoring, audit, 
IEC/IRB review, and regulatory inspection. This consent also addresses the transfer of the data to 
other entities and to other countries. 
The patient has a number of rights. Among these the right to request through the investigator access 
to his or her personal data and the right to request rectification of any data that are not correct or 
complete. Further, the patient has the right to withdraw its consent to process his or her personal 
data. Personal data collected prior to the patients withdrawal will still be used and will not be 
withdrawn or deleted but no new personal data will be collected or processed for trial purposes 
unless it relates to an already reported side effect. Reasonable steps will be taken by the 
Investigator to respond to such requests, taking into consideration the nature of the request, the 
conditions of the trial, the applicable laws and regulations and the investigators obligations stated 
in the clinical trial agreement (including the data processor agreement).  
Exploratory biomarker research is not conducted under standards appropriate for the return of data 
to patients. In addition, the sponsor cannot make decisions as to the significance of any findings 
resulting from exploratory research. Therefore, exploratory research data will not be returned to 
patients or investigators, unless required by law or local regulations. Privacy and confidentiality 
of data generated in the future on stored samples will be protected by the same standards applicable 
to all other clinical data. 
13.2.5 Long-Term Retention of Samples for Additional Future Analyses 
If it is determined at any time before trial completion that additional material is needed from a 
FFPE tumor sample for the successful completion of the protocol-specified analyses, the Sponsor 
may request that additional material be retrieved from existing samples. 
 
 
 
 
In this case, such analyses would be specific to research related to the trial drug or diseases being 
investigated in the clinical trial. 

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14 ADMINISTRATIVE PROCEDURES 
14.1 Protocol Amendments 
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by 
the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the 
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or 
when the relevant competent authority has raised any grounds for non-acceptance, except when 
necessary to eliminate immediate hazards to the patients, in which case the amendment must be 
promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the 
change(s) involves only logistic or administrative aspects of the trial, the IRB (and IEC where 
required) only needs to be notified. 
During the course of the trial, in situations where a departure from the protocol is unavoidable, the 
investigator or other physician in attendance will contact the appropriate sponsor representative 
(see contact information page(s) provided separately). Except in emergency situations, this contact 
should be made before implementing any departure from the protocol. In all cases, contact with 
the sponsor must be made as soon as possible to discuss the situation and agree on an appropriate 
course of action. The data recorded in the eCRF and source documents will reflect any departure 
from the protocol, and the source documents will describe this departure and the circumstances 
requiring it. 
14.2 Regulatory Documentation 
14.2.1 Regulatory Approval/Notification 
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A trial may not be initiated until all local regulatory 
requirements are met. 
14.3 Patient Identification, Enrollment, and Screening Logs 
The investigator agrees to complete a patient identification and enrollment log to permit easy 
identification of each patient during and after the trial. This document will be reviewed by the 
sponsor trial-site contact for completeness. 
The patient identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the trial file. To ensure patient confidentiality, no copy will be made. All reports 
and communications relating to the trial will identify patients by patient identification and date of 
birth. In cases where the patient is not randomized into the trial, the date seen and date of birth will 
be used. 
The investigator must also complete a patient screening log, which reports on all patients who 
were seen to determine eligibility for inclusion in the trial. 
14.4 Monitoring 
The sponsor will use a combination of remote and on-site monitoring to monitor this trial. 
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a trial site visit log that will be kept at the trial site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 

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monitor will compare the data entered into the eCRFs with the hospital or clinic records (source 
documents). The nature and location of all source documents will be identified to ensure that all 
sources of original data required to complete the eCRF are known to the sponsor and trial-site 
personnel and are accessible for verification by the sponsor trial-site contact. If electronic records 
are maintained at the trial site, the method of verification must be discussed with the trial-site 
personnel. 
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the eCRF are consistent with the original source data. Findings 
from this review of eCRFs and source documents will be discussed with the trial-site personnel. 
The sponsor expects that, during monitoring visits, the relevant trial-site personnel will be 
available, the source documentation will be accessible, and a suitable environment will be 
provided for review of trial-related documents. The monitor will meet/talk with the investigator 
on a regular basis during the trial to provide feedback on the trial conduct. 
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these 
remote contacts, trial-site personnel will be available to provide an update on the progress of the 
trial at the site. 
14.5 On-Site Audits 
Representatives of the sponsor's clinical quality assurance department may visit the trial site at any 
time during or after completion of the trial to conduct an audit of the trial in compliance with 
regulatory guidelines and company policy. These audits will require access to all trial records, 
including source documents, for inspection and comparison with the eCRFs. Patient privacy must, 
however, be respected. The investigator and trial-site personnel are responsible for being present 
and available for consultation during routinely scheduled trial-site audit visits conducted by the 
sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part 
of a national GCP compliance program or to review the results of this trial in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection. 
14.6 Publication 
All information, including but not limited to information regarding GEN1029 or the sponsor's 
operations (e.g. patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including pharmacogenomic or exploratory biomarker 
research data, generated as a result of this trial, are considered confidential and remain the sole 
property of the sponsor. The investigator agrees to maintain this information in confidence and use 
this information only to accomplish this trial, and will not use it for other purposes without the 
sponsor's prior written consent. 
The investigator understands that the information developed in the trial will be used by the sponsor 
in connection with the continued development of GEN1029, and thus may be disclosed as required 
to other clinical investigators or regulatory agencies. To permit the information derived from the 
clinical trials to be used, the investigator is obligated to provide the sponsor with all data obtained 
in the trial. 

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The results of the trial will be reported in a CTR generated by the sponsor and will contain eCRF 
data from all trial sites that participated in the trial and direct transmission of clinical laboratory 
data from a central laboratory into the sponsor's database. Recruitment performance or specific 
expertise related to the nature and the key assessment parameters of the trial will be used to 
determine a coordinating investigator. Results of exploratory biomarker analyses performed after 
the CTR has been issued will be reported in a separate report and will not require a revision of the 
CTR. Trial patient identifiers will not be used in publication of results. Any work created in 
connection with performance of the trial and contained in the data that can benefit from copyright 
protection (except any publication by the investigator as provided for below) shall be the property 
of the sponsor as author and owner of copyright in such work. 
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines  (Battisti et al., 2015; ICMJE, 2016), the sponsor shall have the right to publish 
such primary (multicenter) data and information without approval from the investigator. The 
investigator has the right to publish trial site-specific data after the primary data are published. If 
an investigator wishes to publish information from the trial, a copy of the manuscript must be 
provided to the sponsor for review at least 60 days before submission for publication or 
presentation. Expedited reviews will be arranged for abstracts, poster presentations, or other 
materials. If requested by the sponsor in writing, the investigator will withhold such publication 
for up to an additional 60 days to allow for filing of a patent application. In the event that issues 
arise regarding scientific integrity or regulatory compliance, the sponsor will review these issues 
with the investigator. The sponsor will not mandate modifications to scientific content and does 
not have the right to suppress information. For multicenter trial designs and sub-study approaches, 
secondary results generally should not be published before the primary endpoints of a trial have 
been published. Similarly, investigators will recognize the integrity of a multicenter trial by not 
submitting for publication data derived from the individual trial site until the combined results 
from the completed trial have been submitted for publication, within 12 months of the availability 
of the final data (tables, listings, graphs), or the sponsor confirms there will be no multicenter trial 
publication. Authorship of publications resulting from this trial will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant contribution 
to the design of the trial or analysis and interpretation of the data, provided critical review of the 
paper, given final approval of the final version, and agreed to be accountable for all aspects of the 
work  (ICMJE, 2010). 
14.7 Registration of Clinical Trials and Disclosure of Results 
The sponsor will register and/or disclose the existence of and the results of clinical trials as 
required by law. 

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Appendix 1 Recommendations Related to Contraception and Pregnancy Testing in 
Clinical Trials 
 
 
 
 
 

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Appendix 2 INVESTIGATOR AGREEMENT 
I have read this protocol and agree that it contains all necessary details for carrying out this trial. I will 
conduct the trial as outlined herein and will complete the trial within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this trial. I will discuss this material with them to ensure that they are fully informed 
regarding the trial drug, the conduct of the trial, and the obligations of confidentiality. 
NOTE: The Coordinating Investigator section below is applicable only to the country-specific coordinating 
investigators within the EU. 
Coordinating Investigator (where required): 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Signature: 
 
Date: 
 
 
 
 
(DD-Mmm-YYYY) 
 
Principal (Site) Investigator: 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Telephone Number: 
 
Signature: 
 
Date: 
 
 
 
 
(DD-Mmm-YYYY) 
 
 
Note: If the address or telephone number of the investigator changes during the course of the trial, 
written notification will be provided by the investigator to the sponsor, and a protocol amendment will 
not be required. 

Signature Page for 
Signature Page for 
Reason for signing: Approved
Name:
Role: Clinical Operations - Biostatistics
Date of signature: 24-Oct-2019 09:27:44
GMT+0000
Reason for signing: Approved
Name: 
Role: Clinical Operations - Trial Management
Date of signature: 24-Oct-2019 10:54:59
GMT+0000
Reason for signing: Approved
Name:
Role: Medical
Date of signature: 24-Oct-2019 15:46:29
GMT+0000
Reason for signing: Approved
Name:
Role: Drug Safety
Date of signature: 25-Oct-2019 19:25:07
GMT+0000
Reason for signing: Approved
Name: 
Role: Clinical Operations
Date of signature: 28-Oct-2019 09:19:10
GMT+0000
Reason for signing: Approved
Name:
Role: Medical
Date of signature: 28-Oct-2019 14:32:06
GMT+0000