First-in-Human, Open-label, Dose-Escalation Trial With an Expansion Cohort to Evaluate the Safety of GEN1053 as Monotherapy in Subjects With Malignant Solid Tumors
Phase: PHASE1
Conditions: Solid Tumor, Adult
Sponsor: Genmab

Document Name: GCT1053-01 Protocol Amendment 1_EU-1 
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Document Number: TMF-625676 
 
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CLINICAL TRIAL PROTOCOL 
Protocol Title 
First-in-Human, Open-label, Dose-Escalation Trial with Expansion 
Cohorts to Evaluate the Safety of GEN1053 as Monotherapy and in 
Combination With an Immunomodulator in Subjects with Malignant 
Solid Tumors 
Protocol Number 
GCT1053-01 
Compound 
GEN1053 
Brief Title 
A Study to Evaluate Safety, Tolerability, and Preliminary Effect of the 
GEN1053 Antibody on Malignant Solid Tumors as Monotherapy and 
in Combination. 
Trial Phase  
Phase 1/2a  
Sponsor Name 
Genmab* 
Collaborator Name 
BioNTech 
Regulatory Agency 
Identifier Numbers 
EU CT No.  
2022-502419-12-00 
 
NCT No. 
NCT05435339 
 
IND No. 
160884 
Protocol 
Approver** 
Name 
, MD, PhD 
Title 
 
Protocol Version 
History 
Version 
Document Date 
 
Original Protocol, v1.0 
06 Apr 2022 
 
Protocol Amendment 1, v2.0 
29 Aug 2022 
 
Protocol Amendment 1_EU-1, v1.0 
07 May 2024 
* 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 Holding B.V.; 
Genmab B.V.; Genmab A/S; 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 sponsor information page. 
** This protocol was approved via electronic signature on the approval page appended to the document. 
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 that is 
indicated as privileged or confidential. 
 
 
PPD
PPD

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SPONSOR INFORMATION PAGE  
 
 
Sponsor information in the 
European Economic Area, 
United Kingdom, Switzerland, 
Georgia, Moldova and Serbia. 
Genmab A/S 
Carl Jacobsens Vej 30 
2500 Valby 
Denmark 
Sponsor information for all other 
countries 
Genmab US, Inc. 
777 Scudders Mill Rd 
Plainsboro, New Jersey 08536 
United States of America 
The sponsor contact information page will be provided separately; listing the trial responsible 
medical director, as well as the CRO(s), laboratory(ies) (names and addresses), and other 
technical/medical services used. Additional contact information may be found in the trial specific 
manuals (eg, IMP Manual, Laboratory Manual). 
 

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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 agree to comply with the International Council for Harmonisation (ICH) Tripartite Guideline 
on Good Clinical Practice (GCP), the principles in the Declaration of Helsinki, and applicable 
national or regional regulations/guidelines. 
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 treatment, the conduct of the trial, and the obligations 
of confidentiality. 
Principal (Site) Investigator: 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
Telephone Number: 
 
Signature: 
 
Date: 
 
 
 
 
(DD-Mmm-YYYY) 
NOTE: The Coordinating Investigator section below is applicable only to the country-specific 
coordinating investigators within the European Union, where applicable. 
Coordinating Investigator (where required): 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
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.  
Completed and signed forms will be filed separately from the protocol. 

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Table of Contents 
SPONSOR INFORMATION PAGE ............................................................................... 2 
INVESTIGATOR AGREEMENT................................................................................... 3 
TABLE OF CONTENTS .................................................................................................. 4 
TABLE OF TABLES ........................................................................................................ 7 
TABLE OF FIGURES ...................................................................................................... 8 
STATEMENT OF COMPLIANCE ................................................................................ 9 
1 
PROTOCOL SUMMARY ...................................................................................... 10 
1.1 
Trial Synopsis ...................................................................................................... 10 
1.2 
Schema .................................................................................................................. 16 
1.3 
Schedule of Activities .......................................................................................... 17 
1.3.1 
Dose Escalation (Monotherapy) ................................................................... 18 
1.3.2 
Dose Escalation (Combination Therapy) .................................................... 23 
1.3.3 
Expansion (Monotherapy) ............................................................................ 24 
1.3.4 
Expansion (Combination Therapy) ............................................................. 29 
2 
INTRODUCTION .................................................................................................... 30 
2.1 
Trial Rationale ..................................................................................................... 30 
2.2 
Background .......................................................................................................... 30 
2.2.1 
Overview of the Indications .......................................................................... 30 
2.2.2 
Rationale for the Development of GEN1053 ............................................... 32 
2.2.3 
Rationale for the Evaluation of GEN1053 in Combination With an IM . 34 
2.2.4 
Summary of Clinical Trials to Date and Experience With CD27-
Targeting Agents ........................................................................................... 36 
2.3 
Benefit-Risk Assessment ..................................................................................... 36 
2.3.1 
Potential Benefit ............................................................................................ 36 
2.3.2 
Potential Risks ............................................................................................... 36 
2.3.3 
Conclusion ...................................................................................................... 37 
3 
OBJECTIVES AND ENDPOINTS ........................................................................ 39 
4 
TRIAL DESIGN ....................................................................................................... 40 
4.1 
Description of Trial Design ................................................................................. 40 
4.2 
Trial Design Rationale ........................................................................................ 41 
4.2.1 
Dose Escalation (GEN1053 Monotherapy) ................................................. 41 
4.2.2 
Dose Escalation (GEN1053+IM) .................................................................. 43 
4.2.3 
Expansion ....................................................................................................... 46 
4.3 
Dose and Schedule Rationale ............................................................................. 47 
4.3.1 
IMP Dose and Schedule Rationale ............................................................... 47 
4.3.2 
AMP Dose and Schedule Rationale ............................................................. 48 
4.4 
Primary Completion Date, Estimated Trial Duration, and End of Trial 
Definition .............................................................................................................. 48 
4.4.1 
Primary Completion Date ............................................................................ 48 
4.4.2 
Estimated Trial Duration for an Individual Subject ................................. 48 
4.4.3 
End of Trial Definition and Estimated Trial Duration .............................. 48 
5 
TRIAL POPULATION ........................................................................................... 49 
5.1 
Inclusion Criteria ................................................................................................ 49 
5.2 
Exclusion Criteria ............................................................................................... 53 
5.3 
Screen Failures .................................................................................................... 56 
6 
TRIAL TREATMENT ............................................................................................ 57 

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6.1 
Investigational and Auxiliary Medicinal Products .......................................... 57 
6.1.1 
Physical Description of Trial Drug(s) .......................................................... 58 
6.1.2 
Packaging ....................................................................................................... 58 
6.1.3 
Labeling .......................................................................................................... 58 
6.2 
Product Complaint Handling ............................................................................. 58 
6.3 
Preparation/Handling/Storage/Accountability ................................................. 59 
6.3.1 
Preparation, Handling, and Storage ............................................................ 59 
6.3.2 
Drug Accountability and Destruction ......................................................... 59 
6.4 
Measures to Minimize Bias: Randomization and Blinding ............................. 59 
6.4.1 
Subject Numbering ....................................................................................... 59 
6.4.2 
Treatment Assignment .................................................................................. 60 
6.4.3 
Emergency Unblinding of Treatment Assignment ..................................... 60 
6.5 
Compliance .......................................................................................................... 60 
6.6 
Prior and Concomitant Therapies ..................................................................... 60 
6.6.1 
Prior Anticancer Therapies .......................................................................... 60 
6.6.2 
Other Prior Therapies .................................................................................. 60 
6.6.3 
Concomitant Therapies ................................................................................. 60 
6.7 
Dosing Modifications ........................................................................................... 63 
6.7.1 
Dose-Limiting Toxicity ................................................................................. 63 
6.7.2 
Dosing Modification Guidance and Stopping Criteria .............................. 65 
6.8 
Treatment of Overdose ....................................................................................... 74 
6.8.1 
Overdose of GEN1053 ................................................................................... 74 
6.8.2 
Overdose of IM .............................................................................................. 74 
6.9 
Treatment After the End of the Trial ................................................................ 74 
6.9.1 
Subject Contact and Trial Treatment After the End of the Trial ............ 74 
7 
DISCONTINUATION OF TRIAL TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL .............................................................. 75 
7.1 
Discontinuation of Trial Treatment ................................................................... 75 
7.1.1 
Safety Follow-up Evaluation ........................................................................ 76 
7.1.2 
Survival Status ............................................................................................... 76 
7.2 
Subject Withdrawal From the Trial .................................................................. 77 
7.3 
Lost to Follow-up ................................................................................................. 77 
8 
TRIAL ASSESSMENTS AND PROCEDURES ................................................... 79 
8.1 
Demography and Baseline Assessments ............................................................ 79 
8.1.1 
Demographics ................................................................................................ 79 
8.1.2 
Diagnosis and Disease Status ........................................................................ 79 
8.1.3 
Medical History ............................................................................................. 80 
8.2 
Efficacy Assessments ........................................................................................... 80 
8.2.1 
Definition of Target and Nontarget Disease ............................................... 80 
8.2.2 
Radiographic Assessments ........................................................................... 81 
8.2.3 
Assessment of Disease Response and Progressive Disease ........................ 81 
8.2.4 
iRECIST Assessment of Disease .................................................................. 82 
8.3 
Clinical Safety Assessments ................................................................................ 83 
8.3.1 
Physical Examination .................................................................................... 83 
8.3.2 
Body Measurements ...................................................................................... 84 
8.3.3 
Vital Signs ...................................................................................................... 84 
8.3.4 
Electrocardiograms ....................................................................................... 84 
8.3.5 
ECOG Performance Status .......................................................................... 85 

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8.3.6 
Clinical Laboratory Assessments ................................................................. 85 
8.4 
Adverse Events and Serious Adverse Events .................................................... 85 
8.4.1 
Definition of Adverse Events and Serious Adverse Events ....................... 86 
8.4.2 
Adverse Event Reporting.............................................................................. 86 
8.4.3 
Events Requiring Immediate Reporting ..................................................... 87 
8.4.4 
Regulatory Reporting Requirements for SUSARs ..................................... 89 
8.4.5 
Disease-Related Events/Outcomes and Other Events/Procedures Not 
Qualifying as  Adverse Events or Serious Adverse Events........................ 89 
8.4.6 
Follow-up of Adverse Events and Serious Adverse Events ....................... 90 
8.4.7 
Warnings and Precautions ........................................................................... 90 
8.5 
Pharmacokinetics ................................................................................................ 90 
8.6 
Pharmacodynamics ............................................................................................. 91 
8.7 
Biomarkers ........................................................................................................... 91 
8.7.1 
Biomarker Sample Collection ...................................................................... 91 
8.7.2 
Biomarker Assessments in Tumor Samples ................................................ 91 
8.7.3 
Biomarker Assessments in Blood Samples .................................................. 92 
8.8 
Immunogenicity ................................................................................................... 93 
9 
STATISTICAL CONSIDERATIONS ................................................................... 94 
9.1 
Statistical Hypotheses ......................................................................................... 94 
9.2 
Sample Size Determination ................................................................................ 94 
9.3 
Populations for Analyses .................................................................................... 95 
9.3.1 
Full Analysis Set ............................................................................................ 95 
9.3.2 
Safety Set ........................................................................................................ 95 
9.3.3 
Response Evaluable Set ................................................................................ 95 
9.3.4 
Dose-Determining Set ................................................................................... 95 
9.3.5 
Pharmacokinetic Analysis Set ...................................................................... 95 
9.3.6 
Immunogenicity Analysis Set ....................................................................... 95 
9.4 
Statistical Analyses .............................................................................................. 96 
9.4.1 
Subject Demographics and Baseline Characteristics ................................. 96 
9.4.2 
Efficacy ........................................................................................................... 96 
9.4.3 
Safety .............................................................................................................. 98 
9.4.4 
Pharmacokinetic Analyses ............................................................................ 99 
9.4.5 
Pharmacodynamic Analyses ....................................................................... 100 
9.4.6 
Biomarker Analyses .................................................................................... 100 
9.4.7 
Immunogenicity Analyses ........................................................................... 101 
9.4.8 
Health Economics ........................................................................................ 101 
9.4.9 
Multiplicity ................................................................................................... 101 
9.4.10 
Subgroup Analyses and Effect of Baseline Factors .................................. 101 
9.5 
Efficacy Monitoring in Expansion Cohorts .................................................... 102 
9.6 
Data Monitoring Committee ............................................................................ 103 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS – APPENDICES ................................................................ 104 
APPENDIX 1. 
REGULATORY, ETHICAL, AND TRIAL OVERSIGHT 
CONSIDERATIONS ............................................................................................. 105 
APPENDIX 2. 
CLINICAL LABORATORY TESTS ............................................ 117 
APPENDIX 3. 
ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ............. 118 

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APPENDIX 4. 
DEFINITION OF REPRODUCTIVE POTENTIAL AND 
CONTRACEPTION .............................................................................................. 121 
APPENDIX 5. 
SAMPLE STORAGE AND DESTRUCTION .............................. 123 
APPENDIX 6. 
ECOG PERFORMANCE STATUS .............................................. 124 
APPENDIX 7. 
RECIST (V1.1) CRITERIA SUMMARY ..................................... 125 
APPENDIX 8. 
STATISTICAL METHODOLOGIES – BLRM AND MBOIN .. 126 
APPENDIX 9. 
COUNTRY-SPECIFIC CONSIDERATIONS ............................. 130 
APPENDIX 10. 
ABBREVIATIONS AND DEFINITIONS .............................. 131 
11 LAY PROTOCOL SYNOPSIS ............................................................................. 135 
12 REFERENCES ....................................................................................................... 137 
PROTOCOL AMENDMENT SUMMARY OF CHANGES .................................... 140 
 
Table of Tables 
Table 1-1 
Schedule of Activities – Dose Escalation – GEN1053 Monotherapy .. 18 
Table 1-2 
PK, ADA, and ECG Sampling – Dose Escalation – GEN1053 Monotherapy
 ................................................................................................................... 20 
Table 1-3 
Biomarker Evaluation Schedule – Dose Escalation – GEN1053 Monotherapy
 ................................................................................................................... 21 
Table 1-4 
Vital Signs – Dose Escalation – GEN1053 Monotherapy .................... 22 
Table 1-5 
Schedule of Activities – Dose Escalation – GEN1053+IM Combination 
Therapy .................................................................................................... 23 
Table 1-6 
PK, ADA, and ECG Sampling – Dose Escalation – GEN1053+IM 
Combination Therapy ............................................................................. 23 
Table 1-7 
Biomarker Evaluation Schedule – Dose Escalation – GEN1053+IM 
Combination Therapy ............................................................................. 23 
Table 1-8 
Vital Signs – Dose Escalation – GEN1053+IM Combination Therapy23 
Table 1-9 
Schedule of Activities – Expansion – Subjects With HNSCC – GEN1053 
Monotherapy ............................................................................................ 24 
Table 1-10 
PK and ADA Sampling – Expansion – Subjects With HNSCC – GEN1053 
Monotherapy ............................................................................................ 26 
Table 1-11 
Biomarker Evaluation Schedule – Expansion – Subjects With HNSCC – 
GEN1053 Monotherapy .......................................................................... 27 
Table 1-12 
Vital Signs – Expansion – Subjects With HNSCC – GEN1053 Monotherapy
 ................................................................................................................... 28 
Table 1-13 
Schedule of Activities – Expansion – Crossover Subjects With HNSCC – 
GEN1053+IM Combination Therapy ................................................... 29 
Table 1-14 
Schedule of Activities – Expansion – Subjects With NSCLC – GEN1053+IM 
Combination Therapy ............................................................................. 29 
Table 1-15 
PK and ADA Sampling – Expansion – Crossover Subjects With HNSCC – 
GEN1053+IM Combination Therapy ................................................... 29 
Table 1-16 
PK and ADA Sampling – Expansion – Subjects With NSCLC – 
GEN1053+IM Combination Therapy ................................................... 29 
Table 1-17 
Biomarker Evaluation Schedule – Expansion – Crossover Subjects With 
HNSCC – GEN1053+IM Combination Therapy ................................. 29 
Table 1-18 
Biomarker Evaluation Schedule – Expansion – Subjects With NSCLC – 
GEN1053+IM Combination Therapy ................................................... 29 

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Table 1-19 
Vital Signs – Expansion – Subjects With NSCLC and Crossover Subjects 
With HNSCC – GEN1053+IM Combination Therapy ........................ 29 
Table 3-1 
Objectives and Endpoints ....................................................................... 39 
Table 4-1 
Modified BOIN Decision Guidance Rules ............................................. 44 
Table 6-1 
Investigational Medicinal Product ......................................................... 57 
Table 6-2 
Dosing Modification and Management of Treatment-Related AEs ... 65 
Table 6-3 
Dosing Modification and Management of Immune-Related Adverse Events
 ................................................................................................................... 67 
Table 6-4 
Dosing Modification and Management of Neutropenia and Febrile 
Neutropenia .............................................................................................. 71 
Table 8-1 
Reporting Period and Requirements ..................................................... 87 
Table 9-1 
Noncompartmental Pharmacokinetic Parameters ............................. 100 
Table 9-2 
The Ineffective ORR Threshold and the Response Rates That Warrant 
Further Evaluation of the Drug ........................................................... 102 
Table 9-3 
Number of Responders Required at Monitoring Time to Consider Data 
as a Likely “Success” (by Each Case) .................................................. 103 
Table 10-1 
Protocol-Required Safety Laboratory Assessments ........................... 117 
Table 10-2 
Highly Effective Methods of Contraception ....................................... 121 
Table 10-3 
Six Scenarios Defined Through the DLT Probabilities on Ten DLs (Including 
Three Intermediate DLs). ..................................................................... 127 
Table 10-4 
Operating Characteristics of BLRM Based on 6 Scenarios and 1,000 
Simulations ............................................................................................. 127 
Table 10-5 
Operating Characteristics of BOIN Based on 6 Scenarios and 10,000 
Simulations ............................................................................................. 129 
Table 10-6 
IMP/AMP EU Authorization Status .................................................... 130 
Table 10-7 
France-Specific Requirements ............................................................. 130 
Table of Figures 
Figure 1-1 
Schematic Overview of the Trial ............................................................ 16 
 
 
 

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STATEMENT OF COMPLIANCE 
GCP Compliance 
This trial will be conducted in compliance with the principles of the Declaration of Helsinki, the 
International Council for 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 that is 
indicated as privileged or confidential. 

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Trial Design and 
Duration 
This is an FIH phase 1/2a open-label, multicenter, multinational trial in subjects with non–
central nervous system (non-CNS) metastatic or advanced malignant solid tumors for 
whom there is no available standard therapy likely to confer clinical benefit, evaluating the 
safety, tolerability, preliminary antitumor activity, PK, pharmacodynamics, and 
immunogenicity of GEN1053 as monotherapy and in combination with IM. 
The trial will be conducted as follows:  
• 
The Dose Escalation part will explore the safety of escalating doses of GEN1053 as 
monotherapy (phase 1a) as well as escalating doses of GEN1053 when combined with 
a fixed dose of an IM (phase 1b) in a sequential approach in a population of subjects 
with various solid tumors.  
• 
The Expansion part is planned to provide additional safety and initial antitumor 
activity information of the RP2Ds for GEN1053 monotherapy and GEN1053+IM 
combination therapy, respectively, in selected tumor indications, as well as more 
detailed data related to the mode of action (MoA) (monotherapy), sequencing 
(crossover from monotherapy to IM combination therapy upon PD, as applicable) and 
combination with IM.  
Each part will consist of a screening period (up to 21 days prior to Cycle 1 Day 1 [C1D1]), 
a treatment period (C1D1 until discontinuation of trial treatment, and 2 safety follow-up 
visits 30 days and 60 days after the last dose of trial treatment, preceding the survival 
follow-up. Subjects will be treated in cohorts, defined as a group of subjects allocated to the 
same treatment. 
Both GEN1053 and IM will per default be administered as an IV infusion in 3-week (ie, 
21-day) cycles (Q3W) until PD, unacceptable AE, or withdrawal of consent. A trial-
independent data monitoring committee (DMC), a safety committee (SC), and a dose 
escalation committee (DEC) will be commissioned for this trial.  
During the Dose Escalation part, DLTs will be assessed in the first treatment cycle at each 
dose level (DL). The DEC will assess all available data with focus on safety and make 
recommendations for the next DL and propose the RP2D/MTD/MAD to the DMC and SC. 
The SC will make the final decisions.  
Population and 
Sample Size 
The multicenter, multinational trial population includes male and female subjects who are 
≥18 years of age, with malignant non-CNS solid tumors.  
This trial is projected to enroll approximately 170 subjects as follows: 
• 
In the Monotherapy Dose Escalation phase 1a: up to 63 (maximum 9 subjects at each 
DL) 
• 
In the Combination therapy Dose Escalation phase 1b: up to 27 subjects (maximum 9 
subjects at each DL) 
• 
In the Expansion part: approximately 80 subjects (approximately 40 subjects for each 
cohort) 
Key Inclusion 
Criteria 
For both the Dose Escalation and Expansion parts 
Subject must: 
• 
Be ≥18 years of age. 
• 
Have measurable disease according to RECIST 1.1. 
• 
Provide all prebaseline scans since failure of last prior therapy (ie, documented 
radiographic PD), if available.  
• 
Have Eastern Cooperative Oncology Group performance status ≤1. 
• 
Have organ and bone marrow function as follows: 
○ 
Bone marrow/hematological function:  
▪ 
Absolute neutrophil count (ANC) ≥1.5×109/L 
▪ 
Hemoglobin ≥9.0 g/dL 
▪ 
Platelet count ≥150×109/L 
○ 
Liver function: 
▪ 
Total bilirubin ≤ upper limit of normal (ULN) 
▪ 
Alanine aminotransferase ≤1.5×ULN 

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▪ 
Aspartate aminotransferase ≤1.5×ULN 
▪ 
Albumin ≥30 g/L 
○ 
Coagulation status: 
▪ 
Prothrombin time (PT)/International normalized ratio ≤1.5 
▪ 
Activated partial thromboplastin time (aPTT) ≤1.5×ULN 
○ 
Renal function: 
Glomerular filtration rate ≥45 mL/min/1.73 m², according to the abbreviated 
Modification of Diet in Renal Disease equation  
 
For Monotherapy Dose Escalation (phase 1a) and Combination therapy Dose 
Escalation (phase 1b) only: 
• 
Subjects with histologically or cytologically confirmed non-CNS solid tumors that are 
metastatic or advanced. 
• 
Subjects who have progressed on standard of care therapy or for whom there is no 
available standard therapy likely to provide clinical benefit, or who are not candidates 
for available therapy or who have previously refused available therapy, and for whom 
experimental therapy with GEN1053 or GEN1053+IM may be beneficial, in the 
opinion of the investigator. 
• 
Biopsies for Monotherapy Dose Escalation and Combination therapy Dose Escalation: 
○ 
All subjects must provide a fresh biopsy. A fresh biopsy is defined as being taken 
after failure/stop of last prior treatment and within 6 months prior to C1D1. 
Note: Documentation of fresh biopsy collection and shipment must be submitted to 
the sponsor as a part of the eligibility package prior to administration of the first 
dose of trial treatment. 
 
For the Expansion part Only: 
• 
Subjects with histologically or cytologically confirmed diagnosis of recurrent, 
unresectable, or metastatic HNSCC or metastatic NSCLC, who do not have any further 
available standard therapy or who are not candidates for standard therapy or who have 
previously refused standard therapy (if subjects had access), and for whom 
experimental therapy with GEN1053 (HNSCC) or GEN1053+IM (NSCLC, HNSCC 
crossover) may be beneficial, in the opinion of the investigator. 
• 
Subjects must meet the following criteria in the respective Expansion cohorts:  
 
For Expansion Cohort 1 (MoA cohort, HNSCC) GEN1053 with crossover to 
GEN1053+IM: 
○ 
Subjects with recurrent, unresectable, or metastatic HNSCC (with no surgery or 
RT options) of the oral cavity, pharynx, or larynx who have received up to 3 prior 
systemic treatment regimens for recurrent/metastatic disease with radiographic PD 
on or after last prior treatment (maintenance treatment is considered part of one 
treatment line). 
○ 
Subjects must have received prior platinum-based therapy or alternative 
chemotherapy if platinum ineligible (eg, a gemcitabine-containing regimen). 
○ 
Subjects must have received 1 prior treatment with a PD-1/PD-L1 inhibitor alone 
or in combination with other therapy and must have had radiographic PD on or 
within 6 months after treatment. 
Note: For the subjects whose most recent anticancer therapy contained a PD-
1/PD-L1 inhibitor, their recent evidence of PD must be confirmed by a second 
radiographic assessment at least 4 weeks from the date of the initial radiologically 
documented PD. 
○ 
Biopsies for Expansion Cohort 1:  

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▪ 
All subjects must provide a fresh biopsy. A fresh biopsy is defined as being 
taken after failure/stop of last prior treatment and within 6 months prior to 
C1D1. 
Note: Documentation of fresh biopsy collection and shipment must be 
submitted to the sponsor as a part of the eligibility package prior to 
administration of the first dose of trial treatment . 
 
For Expansion Cohort 2 (NSCLC) GEN1053+IM: 
○ 
Subjects with metastatic NSCLC who have received up to 4 prior systemic 
treatment regimens for advanced/metastatic disease with radiographic PD on or 
after last prior treatment (maintenance treatment is considered being part of 1 
treatment line). 
▪ 
NSCLC tumors of any histology may be enrolled. Subjects with mutations in 
KRAS, BRAF, MET genes or RET gene rearrangements or NTRK1/2/3 gene 
fusions in their tumors may only be enrolled after prior treatment with 
targeted therapy/standard of care options. Subjects with drug-sensitizing 
mutations in EGFR or ALK or ROS1 rearrangements are not eligible. 
Documentation of genomic status should be available per local assessment. 
Note: For subjects with squamous NSCLC histology, molecular testing for 
genomic alterations will not be required. 
○ 
Subjects must have received prior platinum-based therapy or alternative 
chemotherapy if platinum ineligible (eg, a gemcitabine-containing regimen). 
○ 
Subjects must have received 1 prior treatment with a PD-1/PD-L1 inhibitor alone 
or in combination with other therapy and must have had radiographic PD on or 
within 6 months after treatment.  
Note: For the subjects whose most recent anticancer therapy contained a PD-
1/PD-L1 inhibitor, their recent evidence of PD must be confirmed by a second 
radiographic assessment at least 4 weeks from the date of the initial radiologically 
documented PD. 
○ 
Biopsies for Expansion Cohort 2: 
▪ 
All subjects must provide a fresh biopsy. A fresh biopsy is defined as being 
taken after failure/stop of last prior treatment and within 6 months prior to 
C1D1. 
Note: Documentation of fresh biopsy collection and shipment must be 
submitted to the sponsor as a part of the eligibility package prior to 
administration of the first dose of trial treatment. 
Key Exclusion 
Criteria 
• 
Has uncontrolled intercurrent illness, including but not limited to:  
○ 
Ongoing or active infection requiring IV treatment with anti-infective therapy 
administered less than 2 weeks prior to first dose. 
○ 
Symptomatic congestive heart failure (Grade III or IV as classified by the New 
York Heart Association), unstable angina pectoris, or cardiac arrhythmia.  
○ 
Uncontrolled hypertension defined as systolic blood pressure ≥160 mm Hg and/or 
diastolic blood pressure ≥100 mm Hg, despite optimal medical management. 
○ 
Prolonged QTc interval at baseline of ≥470 milliseconds using Fridericia's QT 
correction formula. 
○ 
Ongoing or recent (within 1 year of screening) evidence of significant 
autoimmune disease that required treatment with systemic immunosuppressive 
treatments, which may suggest risk for irAEs.  
○ 
History of grade 3 or higher irAEs that led to treatment discontinuation of a CPI. 
A subject with irAEs below grade 3 that led to discontinuation should be discussed 
with the sponsor. Grade 3 irAEs that have fully recovered may also be discussed. 
○ 
History of chronic liver disease or evidence of hepatic cirrhosis. 
○ 
Evidence of interstitial lung disease.  
○ 
Ongoing pneumonitis or history of noninfectious pneumonitis that has required 
steroids. 
○ 
Known platelet function defects or a known history or high risk of bleeding events 
requiring transfusions or hospitalizations unless approved by sponsor.  

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• 
Any subject with history of intracerebral arteriovenous malformation (shunts), cerebral 
aneurysm, spinal cord compression (from disease), carcinomatous meningitis, or stroke 
will be excluded. 
○ 
Transient ischemic attack >1 month prior to screening is allowed. 
○ 
Subjects with newly identified or known unstable or symptomatic CNS metastases 
will be excluded. Subjects with previously treated brain metastases may 
participate provided they are radiologically stable (ie, without evidence of PD) for 
at least 28 days by repeat imaging. 
Note: The repeat imaging should be performed during trial screening).  
Subjects should be clinically stable and should not be undergoing acute 
corticosteroid therapy or steroid taper or have received stereotactic radiation or 
whole-brain radiation within 14 days prior to C1D1. Chronic steroid therapy is 
acceptable provided that the dose is stable for the last 14 days prior to C1D1 
(≤10 mg prednisone daily or equivalent). 
• 
Prior therapy:  
○ 
Radiotherapy within 14 days prior to first trial treatment administration. Palliative 
radiotherapy will be allowed. 
○ 
Treatment with an anticancer agent (within 28 days or after at least 5 half-lives of 
the drug, whichever is shorter), prior to trial treatment administration.  
○ 
Condition requiring systemic treatment with either corticosteroids (>10 mg daily 
prednisone equivalent) or other immunosuppressive medications within 14 days of 
first treatment. Inhaled or topical steroids, and adrenal or pituitary replacement 
steroid >10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease.  
○ 
Has received granulocyte or granulocyte/macrophage colony-stimulating factor 
(G-CSF/GM-CSF) support within 2 weeks prior to first trial treatment 
administration or is chronically transfusion dependent. 
• 
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 
and 
○ 
Negative test for antibodies to hepatitis B surface antigens. 
• 
Known medical history or ongoing hepatitis C infection that has not been cured.  
• 
Prior treatment with an anti-PD-1/PD-L1 targeting agent within 6 months prior to the 
initiation of trial treatment. 
Trial Treatments 
GEN1053 as monotherapy and in combination with an IM will be administered IV Q3W. 
Other Trial 
Treatment 
N/A 
Efficacy 
Assessments 
• 
Radiological/imaging assessments  
• 
Survival status 
Safety 
Assessments 
• 
Adverse events  
• 
Clinical laboratory assessments 
• 
Physical examinations 
• 
Vital signs 
• 
12-lead electrocardiograms (ECGs) 
• 
Eastern Cooperative Oncology Group performance status (ECOG-PS)  
Other 
Assessments 
• 
PK and immunogenicity samples  
• 
Biomarkers from blood and biopsy samples 
Statistics 
For the Dose Escalation part, no formal sample size calculation was performed. The Dose 
Escalation part will enroll subjects from a range of cancer types. In phase 1a, a Bayesian 
logistic regression model (BLRM) will be used to guide the choice of GEN1053 
monotherapy dose. In phase 1b, the choice of an optimal combination dose will be guided 
by Bayesian optimal interval method (BOIN), with a flat DL of IM, but could potentially 
consider different DLs of IM. For the Expansion part, no formal sample size calculation has 

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been conducted, but 40 subjects would ensure at least 90% power to detect a shift to an 
ORR of 30% from a base rate of 10% given a 1-sided binomial test at a 5% significance 
level. A futility analysis will be conducted after 10 and/or 20 subjects to estimate the 
predictive probability of success. The probability of success estimate will be updated as 
data accumulates.  
GCP 
Compliance 
This trial will be conducted in compliance with the principles of the Declaration of 
Helsinki, the International Council for Harmonisation Good Clinical Practice ICH GCP 
E6(R2), and applicable regulatory requirements. 
 

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Table 1-4 
Vital Signs – Dose Escalation – GEN1053 Monotherapy  
Preinfusion (up to 30 min before infusion) 
15 minutes after start of infusion (±5 minutes) 
At the end of infusion (±5 minutes)a 
30 minutes after end of infusion (±5 minutes) 
1 hour after end of infusion (±10 minutes) 
2 hours after end of infusion (±10 minutes) 
4 hours after end of infusion (±10 minutes)b 
Further assessment details are provided in Section 8.3.3. 
a. 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. 
b. Vital signs should only be assessed until 4 hours after end of infusion for the first 2 infusions.  
 
 

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1.3.2 
Dose Escalation (Combination Therapy) 
Schedules of assessments will be provided with selection of the IM combination therapy for each of the placeholder tables in this section 
upon amending the protocol. 
Table 1-5 
Schedule of Activities – Dose Escalation – GEN1053+IM Combination Therapy 
Table 1-6 
PK, ADA, and ECG Sampling – Dose Escalation – GEN1053+IM Combination Therapy 
Table 1-7 
Biomarker Evaluation Schedule – Dose Escalation – GEN1053+IM Combination Therapy 
Table 1-8 
Vital Signs – Dose Escalation – GEN1053+IM Combination Therapy 
 
 

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Table 1-12 
Vital Signs – Expansion – Subjects With HNSCC – GEN1053 Monotherapy 
Preinfusion (up to 30 minutes before infusion) 
At the end of infusion (±10 minutes)a 
30 minutes after end of infusion (±5 minutes) 
1 hour after end of infusion (±10 minutes) 
2 hours after end of infusion (±15 minutes) 
a. 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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1.3.4 
Expansion (Combination Therapy) 
Schedules of assessments will be provided with selection of the IM combination therapy for each of the placeholder tables in this section. 
Table 1-13 
Schedule of Activities – Expansion – Crossover Subjects With HNSCC – GEN1053+IM Combination Therapy 
Table 1-14 
Schedule of Activities – Expansion – Subjects With NSCLC – GEN1053+IM Combination Therapy 
Table 1-15 
PK and ADA Sampling – Expansion – Crossover Subjects With HNSCC – GEN1053+IM Combination Therapy 
Table 1-16 
PK and ADA Sampling – Expansion – Subjects With NSCLC – GEN1053+IM Combination Therapy 
Table 1-17 
Biomarker Evaluation Schedule – Expansion – Crossover Subjects With HNSCC – GEN1053+IM Combination 
Therapy 
Table 1-18 
Biomarker Evaluation Schedule – Expansion – Subjects With NSCLC – GEN1053+IM Combination Therapy 
Table 1-19 
Vital Signs – Expansion – Subjects With NSCLC and Crossover Subjects With HNSCC – GEN1053+IM 
Combination Therapy 
 

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diagnosed and that 14,500 deaths would occur over the same period in the US (NCCN, 2021b). 
Tobacco use, alcohol use, and HPV infection increase the risk of developing HNSCC. Patients 
with locally HPV-positive HNSCC have improved treatment outcomes compared with patients 
with HPV-negative disease. For patients with recurrent or metastatic HNSCC eligible for 
immunotherapy/combination therapy, pembrolizumab in combination with platinum (cisplatin or 
carboplatin) plus 5-FU or pembrolizumab monotherapy (for patients with PD-L1, CPS ≥1) are 
the recommended 1L regimens. 2L options include doublet cytotoxic chemotherapy regimens, 
with or without concurrent or sequential cetuximab; however, the mOS is less than 15 months 
(NCCN, 2021b). Therefore, HNSCC remains an area of high unmet medical need and further 
opportunity exists to improve outcomes with novel treatment approaches. 
2.2.1.1.1 
Rationale for HNSCC as the Selected Indication 
The MoA of GEN1053 as monotherapy will be explored in a dedicated MoA cohort in the 
Expansion phase in subjects with recurrent, unresectable, or metastatic HNSCC, allowing easy 
access to biological material and paired biopsies (at baseline and on-treatment) for biomarker 
analysis.  
A PR (59% shrinkage) has been documented with varlilumab 10 mg/kg + nivolumab 3 mg/kg 
(CD27 mAb + CPI) in a recurrent/refractory HNSCC subject who had no prior anti-CPI 
therapy and low PD-L1 (5%) tumor expression in a phase 1/2 study 
. As 
pembrolizumab is approved in 1L as monotherapy (PD-L1 CPS>1), or in combination with 
chemotherapy in PD-L1 allcomers and as single-agent for recurrent/metastatic HNSCC with PD 
on or after platin-based chemotherapy (allcomers), there is a potential to treat these CPI-resistant 
patients having limited treatment options with GEN1053 in 2L+ to reactivate their immune 
response.  
Upon PD while on GEN1053, subjects in the HNSSC Expansion cohort will have the option to 
cross over to GEN1053+IM combination therapy for potential benefit/synergy over 
monotherapy. Based on nonclinical findings, patients who do not respond to GEN1053 may 
respond to GEN1053+IM combination as a potential result of optimal agonism or activating 
diverse pathways that may overall elicit a better antitumor immune response. For instance, 
GEN1053 mediated increase of IFN-γ 
. Therefore, sequencing 
of GEN1053 followed by GEN1053+IM will be explored, as combination therapy with CPI after 
GEN1053 monotherapy is expected to provide further benefit to patients (see Section 2.2.3).  
2.2.1.2 
Non–Small-Cell Lung Cancer  
Lung cancer is the second most common malignancy with an estimated age-standardized 
incidence rate of 22.4 per 100,000 and is a leading cause of cancer death for both men and 
women (Kantar, 2021). Worldwide, approximately 2,206,771 new cases of lung cancer and 
1,796,144 deaths were estimated in 2020 (GLOBOCAN, 2020). NSCLC accounts for 85% to 
90% of all cases, with a 5-year survival rate of approximately 18% across all stages of the 
disease, and a rate of only 3.5% for metastatic disease (Jemal et al., 2011; Kantar, 2021; SEER, 
2018). In the 1L setting, treatment typically consists of platinum-based chemotherapy in 
combination with immunotherapy, or a targeted therapy, depending on molecular and biomarker 
analysis and the histology of the tumor (NCCN, 2021c). More recently, the advent of PD-1 and 
PD-L1 inhibitors have improved outcomes for patients without driver mutations (approximately 
62% of the nonsquamous population and 77% of the squamous population (Kantar, 2021)).  
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More treatment alternatives are needed for patients whose tumors do not harbor certain 
oncogenic mutations or do not express the biomarker for CPI options. Novel combinations with 
complementary approaches to enhance response may further address the unmet need in this 
population. For patients in the 2L setting, standard of care is typically limited to platinum-based 
chemotherapy, a CPI monotherapy or docetaxel, with or without ramucirumab, depending on the 
previous therapy received. For patients in the 3L setting, chemotherapy monotherapy is the 
standard. Novel therapies are needed to limit toxicity and potentially enhance efficacy in this 
population (NCCN, 2021c). 
2.2.1.2.1 
Rationale for NSCLC as Selected Indication 
CD27 and CD3D mRNA expression across 30 solid tumor indications available in the cancer 
genome atlas (TCGA) database was analyzed in silico. CD3D expression (a proxy for T-cell 
infiltration) was used to rank indications that are infiltrated with T-cells (ie, hot tumors). NSCLC 
was part of the top three of the listed indications with high CD27 expression. Moreover, more 
than 60% of the NSCLC patients in this database also showed both high CD27 and CD3D 
mRNA expression.     
Nonclinically, GEN1053 in combination with an IM showed increased T-cell proliferation, 
cytokine production and cytotoxicity in vitro and expansion of TIL, particularly CD8+ T-cells 
from NSCLC tumor biopsies ex vivo (GEN1053 IB).  
By combining GEN1053 with IM, the aim is to demonstrate an acceptable safety profile and 
improved clinical efficacy compared to single-agent therapy in subjects with metastatic NSCLC 
tumors who have progressed on prior treatment with a PD-1/-L1 inhibitor.  
2.2.2 
Rationale for the Development of GEN1053 
CD27 is an important costimulatory receptor on T cells. The activation of costimulatory 
receptors is required to unlock T-cell effector functions upon cognate antigen recognition on the 
surface of APCs in the context of MHC molecules. In an active immune response, CD27 
clustering is induced upon binding to CD70, the only known CD27 ligand, resulting in triggering 
of intracellular signaling pathways that enhance proliferation, differentiation, cytokine 
production, and survival of activated T cells (van de Ven and Borst, 2015). 
Several CD27 agonist antibodies are being or have been tested in the clinic (
; 
Burris et al., 2017; He et al., 2013). These antibodies generally show an acceptable safety profile 
but limited antitumor activity as monotherapy in solid cancers. CD27 antibodies tested in the 
clinic thus far are, at least partially, dependent on interactions with FcγR-positive cells to induce 
CD27 clustering and agonism (Starzer and Berghoff, 2020). The frequency of FcγR-positive 
cells in the TME may be variable and insufficient to drive optimal CD27 agonism. Moreover, 
CD27 antibodies with an active Fc domain may induce FcγR-mediated effector functions such as 
ADCC or ADCP leading to elimination of CD27+ effector T cells. 
GEN1053 is an agonistic CD27 antibody designed to (re)activate and increase antitumor 
immunity through potent induction of costimulatory signaling by FcγR-independent CD27 
clustering on the surface of activated T cells. GEN1053-induced CD27 agonism is facilitated by 
a hexamerization-enhancing mutation in the human IgG1 Fc domain of GEN1053 (Genmab 
proprietary HexaBody® platform) that drives clustering of membrane-bound antibodies. 
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GEN1053 has a functionally inactive Fc domain, thereby avoiding potential kill of CD27+ 
effector cells through Fc-mediated effector functions such as ADCC, ADCP, or CDC. 
2.2.2.1 
Summary of Nonclinical Studies - Monotherapy 
A nonclinical data package, consisting of nonclinical pharmacology and toxicology studies in 
vitro, in vivo, and ex vivo, is available for GEN1053: 
• GEN1053 binds human CD27 with an affinity in the nanomolar range and showed dose-
dependent binding to CD27+ human CD4+ and CD8+ T cells. 
• In vitro, GEN1053 increased proliferation of human healthy donor T cells that had been 
activated through TCR crosslinking with EC50 values in the subnanomolar range. GEN1053 
showed increased potency compared to benchmark IgG1 CD27 antibodies. CD27 agonist 
activity of GEN1053 was independent of the presence of FcγR-mediated crosslinking in 
contrast to benchmark antibodies. 
• GEN1053 increased T-cell proliferation, activation, and cytokine production in the presence 
of an enhanced PD-1/PD-L1 signaling axis. 
• GEN1053 did not induce T-cell proliferation in the absence of TCR crosslinking.  
• Ex vivo, GEN1053 increased the number of tumor-infiltrating lymphocytes in primary 
NSCLC tumor cultures. Moreover, vaccination studies in hCD27 transgenic mice 
demonstrated that GEN1053 was able to enhance the T-cell–mediated immune response in 
vivo. 
• GEN1053 increased expression of T-cell activation markers (4-1BB, CD107a, CD69, CD25) 
and the production of IFN-γ, IL-1β, IL-6, IL-13, GM-CSF, and TNF-α in activated T cells in 
vitro. 
• GEN1053 increased expression of the cytotoxicity-associated molecules GzmB and CD107a 
on T cells after exposure to tumor cells expressing their cognate antigen, with EC50 values in 
the low nanomolar range. Moreover, GEN1053 increased antigen-specific tumor-cell kill in 
vitro. 
The nonclinical pharmacology results support the premise that GEN1053 has the potential to 
increase antitumor effects in solid tumor indications that benefit from (re)activation of antitumor 
T-cell immunity.  
Nonclinical Safety Studies: 
Two repeat-dose IV toxicology studies (DRF and pivotal GLP) were conducted in cynomolgus 
monkeys with GEN1053 using dose levels of 0 (vehicle), 0.2 (DRF only), 1, 5, and 30 mg/kg 
(IV, 30 min infusion; DRF: 4 doses QW; GLP: 3 doses Q3W). 
• The main adverse effect in the monkeys was severe thrombocytopenia, which became 
apparent from 10 to 12 days after the first dose and was followed by severe anemia, 
prolonged coagulation time, widespread bleeding with hemorrhagic diathesis, and led to 

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expansion of TIL, particularly CD8+ T cells, from NSCLC tumor tissue ex vivo (GEN1053 IB, 
Section 3).  
2.2.4 
Summary of Clinical Trials to Date and Experience With CD27-Targeting 
Agents 
2.2.4.1 
GEN1053 Clinical Trials 
This is the FIH trial of GEN1053. There are no other ongoing or completed clinical trials. 
2.2.4.2 
Experience With CD27-Targeting Drugs 
To date, other CD27-targeting mAbs in clinical development, varlilumab (CDX-1127, Celldex 
Therapeutics) and MK-5890 (Merck), have shown early antitumor activity in subjects with 
advanced solid tumors in monotherapy 
 
. Importantly, they have demonstrated an acceptable safety profile in FIH trials as 
monotherapy 
.  
In clinical safety data from other CD27-agonist compounds studied in monotherapy for solid 
tumors, the most frequently observed AEs included fatigue, rash, nausea, diarrhea, pruritus, and 
IRRs. Most of these events were mild or moderate in severity. Refer to the GEN1053 IB for 
available safety information from other CD27-targeting agents.  
2.3 
Benefit-Risk Assessment 
2.3.1 
Potential Benefit 
2.3.1.1 
Potential Benefit of GEN1053 
Based on nonclinical data and published clinical data regarding other agents that target human 
CD27 mAbs in various tumor types, clinical antitumor activity can be expected for GEN1053. 
Therefore, cancer patients with limited treatment options, and for whom the investigator agrees 
that clinical trial participation is appropriate, may benefit from treatment with GEN1053.  
2.3.1.2 
Potential Benefit of GEN1053 in Combination With IM 
Based on their respective MoAs, it is hypothesized that the combination of GEN1053 with an IM 
will enhance the antitumor activity as compared with GEN1053 monotherapy (Section 2.2.3.1).  
Further details will be provided in a substantial amendment before initiating phase 1b of the trial. 
2.3.2 
Potential Risks 
2.3.2.1 
Potential Risks of GEN1053 
The nonclinical studies performed with GEN1053 demonstrated thrombocytopenia, bleeding, 
anemia, and increased plasma levels of ALT, AST, and LDH with delayed onset in monkeys. 
The exact MoA has not yet been determined. However, there was no cytokine release, 
hemocompatibility issues, or direct binding of GEN1053 to human or cynomolgus monkey 
platelets and erythrocytes detected. Possible mechanisms could be platelet aggregation caused by 
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GEN1053-induced ADAs that were rapidly cleared due to immune complex formation and thus 
not detected, or CD27-related exaggerated pharmacology affecting the lymphoid cells and bone 
marrow function at the high dose levels employed in the monkey studies. Overall, based on the 
observed toxicities in monkeys, additional safety measures will be taken when exploring 
GEN1053 in the first clinical trial.  
A mitigation plan for handling AEs, including elevated liver parameters, CRS, IRRs, and 
thrombocytopenia, related to the trial treatment has been prepared for this trial to closely monitor 
for and ensure dose delay, dose reduction, or withdrawal of subjects based on AEs that may 
occur during trial treatment (Section 6.7.2). 
Risk mitigation strategies are provided in Section 6.7.2 and summarized in Section 2.3.3.  
Targeting CD27 has not in itself led to unacceptable toxicities or safety concerns with other 
compounds in clinical development (see Section 2.2.4.2).  
Potential subjects will be fully informed of the risks and requirements of the trial, and during the 
trial, subjects 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 subjects who are fully able to understand the risks, 
benefits, and potential AEs of the trial and provide their consent voluntarily will be enrolled. 
GCT1053-01 phase 1a data showed an increased frequency of severe cytopenias and severe 
transaminase increases in subjects treated with GEN1053 with prior anti-PD-1/PD-L1 exposure 
within the last 6 months. Due to this potential risk subjects treated with anti-PD-1/PD-L1 within 
the last 6 months are excluded from participation in the trial. 
Further details are provided in the IB and its updates thereof. Currently, there are no anticipated 
events for GEN1053 described in the reference safety information. Additional safety information 
collected between IB updates will be communicated in the form of investigator notifications. 
2.3.2.2 
Potential Risks of Immunomodulators 
For combination therapy, the potential risk of overlapping toxicities depends on the MoA of the 
therapies to be combined with GEN1053. When the IM has been selected, such risk 
consideration will be made, and a substantial amendment of this protocol will be submitted and 
subject to approvals by health authorities and IRBs/ethics committee prior to initiating the 
GEN1053+IM combination Dose Escalation phase 1b of the trial.  
2.3.3 
Conclusion 
Based on the interpretation of the nonclinical data available to date, published data from other 
CD27-targeting agents, and the potential IM candidates, the conduct of this trial investigating 
GEN1053 monotherapy and GEN1053+IM sequentially is regarded as justifiable.  
A cautious approach will be applied for dose escalation from 
 in 
this FIH trial with strict DLT criteria, adequate AE management, and safety stopping rules in 
place (see Sections 6.7.1 and 6.7.2). 
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The population eligible for the current trial represents subjects with selected malignant solid 
tumors, who have failed available standard therapy or who are not candidates for standard 
therapy, and for who, in the opinion of the investigator, experimental therapy with GEN1053 or 
GEN1053+IM may be beneficial. The trial population is defined to include only subjects with a 
platelet count ≥150×109/L at baseline. Subjects with known platelet function defects or a known 
history or high risk of bleeding events requiring transfusions or hospitalizations will also be 
excluded from the trial.  
Events to be closely monitored for GEN1053 include thrombocytopenia, bleeding episodes, 
elevated liver parameters, irAEs, and IRRs. The DEC (during the escalation phases 1a and 1b) 
and the SC (throughout the trial) will closely monitor subject safety as described in Appendix 1. 
In addition, an independent DMC will further supervise that the safety of the subjects in this trial 
is properly safeguarded, acting as an external advisory body (Appendix 1). 
Subjects enrolled will have frequent visits and will be monitored closely by site staff and via 
medical monitoring throughout the trial. An elaborate risk mitigation plan for handling potential 
AEs has been prepared (and will be updated for phase 1b as deemed necessary) in order to 
manage AEs, delay the dose, or discontinue treatment based on AEs that may occur with 
GEN1053 and the selected IM(s) (Section 6, Table 6-2, Table 6-3 and Table 6-4). The 
anticipated combined safety profile will be carefully assessed prior to the start of the 
combination therapy Dose Escalation phase 1b with focus on potentially overlapping toxicities.  
All subjects enrolled in this trial will be followed and monitored by qualified health care 
professional(s) who will provide care and closely evaluate each subject’s response to GEN1053 
and GEN1053+IM both in terms of safety profile and efficacy.  
Collectively, the benefit-risk ratio is considered favorable for GEN1053.  
The sponsor is committing to sharing relevant monotherapy safety data from the monotherapy 
Dose Escalation phase 1a part with the health authorities and to submitting a substantial 
amendment before initiating the phase 1b combination Dose Escalation part of the trial.  
For further details on GEN1053, refer to the IB. 

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4 TRIAL DESIGN 
4.1 
Description of Trial Design 
This is a FIH phase 1/2a open-label, multicenter, multinational trial in subjects with non-CNS 
metastatic or advanced solid tumors for whom there is no available standard therapy likely to 
confer clinical benefit, evaluating the safety, tolerability, preliminary antitumor activity, PK, 
pharmacodynamics, and immunogenicity of GEN1053 as monotherapy as well as in combination 
with IM. 
The trial will be conducted with a Dose Escalation part (phase 1a and 1b) and an Expansion part 
(phase 2a) as follows:  
• Phase 1a – Monotherapy Dose Escalation 
• Phase 1b – Combination therapy Dose Escalation  
• Phase 2a – Expansion 
The Dose Escalation part will explore the safety of escalating doses of GEN1053 as 
monotherapy (phase 1a) as well as escalating doses of GEN1053 when combined with a fixed 
dose of an IM (phase 1b) in a sequential approach in a population of subjects with various solid 
tumors.  
The sponsor will share relevant monotherapy safety data from phase 1a with the health 
authorities and submit a substantial amendment before initiating the combination Dose 
Escalation phase 1b.   
The Expansion part is planned to provide additional safety and initial antitumor activity 
information of the RP2Ds for GEN1053 monotherapy and GEN1053+IM combination therapy, 
respectively, in selected tumor indications. In the first Expansion cohort (HNSCC), more 
detailed data related to the MoA of GEN1053 monotherapy will be generated. Upon PD while on 
GEN1053, and provided that the RP2D for the combination has been determined in phase 1b, 
subjects will have the option to cross over to GEN1053+IM to explore the effect of sequencing 
the trial treatments. In the second Expansion cohort, GEN1053+IM will be evaluated in subjects 
with NSCLC.  
Each part will consist of a screening period (up to 21 days prior to C1D1), a treatment period 
(C1D1 until discontinuation of trial treatment), and 2 safety follow-up visits 30 days and 60 days 
after each subject receives the last dose of trial treatment, preceding the survival follow-up. 
Subjects will be treated in cohorts, defined as a group of subjects allocated to the same treatment.  
Both GEN1053 and IM will per default be administered as an IV infusion in 3-week (ie, 21-day) 
cycles (Q3W) (refer to Section 6, Trial Treatment) until PD, unacceptable AE, or withdrawal of 
consent (refer to Section 7.1).  
The protocol may be amended to explore additional doses/schedules and combination 
compounds both during Dose Escalation and/or in separate Expansion cohorts based on 
emerging data. Randomization between relevant doses/schedules will be considered in the 

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and may be required for additional subjects. Furthermore, no subjects within a cohort will 
receive their first treatment simultaneously, ie, on the same day during dose escalation except for 
DLs declared safe by the SC which are further investigated by backfilling.  
Identification of MTD/MAD (Monotherapy): 
To address the trial objectives in this FIH trial, the Monotherapy Dose Escalation phase 1a will 
be initiated in single-subject cohorts for the first 2 DLs followed by 3-subject cohorts for 
subsequent DLs. However, a 1-subject cohort will be converted to a 3-subject cohort if any of 
the following events are observed:  
• Any grade ≥2 AE within the first 21 days of Cycle 1, unless clearly related to underlying 
disease or extraneous causes.  
• A DLT (see Section 6.7.1) within the first 21 days of Cycle 1. 
If cohort conversion occurs at the first DL, the subsequent DLs will be explored in 3-subject 
cohorts with the option to expand as described below. 
To aid in determining the DL for the next cohort, the relationship between the probability of 
DLT and DL will be described by a 2-parameter BLRM with overdose control (EWOC) (Babb et 
al., 1998; Neuenschwander et al., 2008). After each cohort, the model parameters will be updated 
based on the available DLT information and a DL for the next cohort suggested based on the 
posterior distributions of probabilities of DLTs at each DL. Compared to the standard 3+3 and 
accelerated titration designs, the BLRM provides both more flexibility and better accuracy of the 
estimated MTD while ensuring subject safety. 
All escalations are constrained (ie, a new DL can only be 1 step higher than the previous DL 
[intermediate DLs will count as half a step]). De-escalations can skip DLs. The dose escalation is 
limited to only main DLs until the first DLT is observed; thereafter the intermediate DLs become 
available. Backfilling of intermediate DLs may also be considered. 
The following provides a description for subject accrual and provisions for dose escalation/de-
escalation decision guidance. 
1. After completion of Cycle 1 of each cohort, based on the cumulative safety data and the 
BLRM, the SC will endorse the DL for the next cohort of subjects.  
2. The initial 2 DLs will be single-subject cohorts. In case of a treatment-related Grade ≥2 AE 
during the first cycle or a DLT (Section 6.7.1), the cohort(s) will be expanded to 3 subjects 
and the BLRM method will be applied after first DLT. 
3. A subject will be considered as evaluable for dose determination if they fulfil the criteria of the 
DDS (refer to Section 9.3.4). 
4. Once the first DL has been cleared, the BLRM method will be used to support 
recommendations for the DL for the next cohort, with the following 3 exceptions: 
o If no DLTs have been observed, escalation may be considered. 
o For cohorts requiring ≥3 evaluable subjects, if only 2 evaluable subjects are available for 
assessment (all others drop out) and neither subject has experienced a DLT, 2 subjects will 

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be considered sufficient for decision making. 
o If 2 subjects in a cohort experience DLTs, the BLRM model will be updated and 
reevaluated before the enrollment of any additional subject. 
o If a decision has been made to escalate to a higher DL, but 1 or more additional subject(s) 
treated at preceding DLs (see provision 6) experience(s) a DLT in Cycle 1, then the 
BLRM will be updated before any additional subject is enrolled to the current (higher) 
DL. 
5. Following the principle of EWOC, the BLRM model only allows escalation to DLs that are 
likely to be safe.  
6. For further understanding of the safety, tolerability, and PK of GEN1053, additional cohorts 
of up to 9 subjects may be enrolled at preceding DLs, or at intermediate DLs before or while 
proceeding with further dose escalation or even thereafter (backfill subjects). Backfill 
subjects within a DL can receive their first treatment simultaneously. 
7. A cohort may be expanded to enroll additional subjects. This is in order to ensure availability 
of sufficient data due to the potential for subjects to discontinue therapy during Cycle 1 
without DLT (eg, because of early PD) and allow flexibility. 
8. After repeating the above steps, the MTD is declared when at least 9 subjects have been 
evaluated at a DL and the BLRM recommends allocating an additional cohort to the same 
DL. This DL is the MTD identified by the BLRM. MTD may be declared based on at least 6 
subjects if the recommendation is to escalate and the next DL is not available. 
9. The dose escalation stops when either the MTD has been declared or no doses are considered 
safe.  
More details on the BLRM can be found in Appendix 8. 
The SC (after consultation with the DEC and DMC) will determine the MTD and the RP2D 
based on the BLRM estimate and the totality of data. The MTD and RP2D may be the same as 
the algorithm recommends for the next cohort or it may be a lower dose. 
If there is evidence that a DL lower than the MTD has adequate efficacy (whether determined by 
scan data, by pharmacodynamic endpoints, or predicted efficacious dose), the DMC may 
recommend, and the SC may decide, that an RP2D has been determined and may decide to stop 
the dose escalation. 
The overall decision process for the next DL and/or to propose the RP2D/MTD/MAD based on 
the above guidance is summarized in Section 4.1. 
4.2.2 
Dose Escalation (GEN1053+IM) 
Identification of first GEN1053 dose to be combined with IM: After the MTD/MAD of 
GEN1053 as monotherapy has been determined, the first GEN1053 DL to be combined with an 
IM (at a fixed dose) is targeted to be the MTD/MAD minus at least 2 DLs (MTD-2). The 
selection of the starting DL for GEN1053 for combination with IM will follow the decision 
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Upon selection of the GEN1053 start dose and IM for combination therapy, a substantial 
amendment will be issued. This amendment will be subject to approvals by health authorities and 
IRBs/ethics committees, before initiating phase 1b and the Expansion cohort 2 of this trial. 
Dose Escalation Principles for GEN1053+IM 
In Combination therapy Dose Escalation (GEN1053+IM) phase 1b, escalating doses of 
GEN1053 (starting from MTD-2) will be evaluated in subjects with non-CNS metastatic or 
advanced malignant solid tumors in combination with a fixed dose of an IM using a mBOIN 
design (Liu and Yuan, 2015). DLTs will be assessed at each DL in the first treatment cycle, ie, a 
DLT evaluation period of 21 days from C1D1. 
The minimum number of subjects treated at each DL is 3. Apart from that, the precautions for 
subject enrollment within a DL in phase 1a of the trial (Section 4.2.1) also apply for phase 1b of 
the trial.  
A limited number of subjects will be enrolled into phase 1b of the trial. This causes operational 
challenges on applying a BLRM design, which also tends to be conservative in its choice of 
MTD. Therefore, escalation and de-escalation in the combination Dose Escalation part will be 
guided by a mBOIN design. Although similar to the 3+3 design, it adds the ability to 1) 
investigate a DL multiple times that would have been closed in a 3+3 design; 2) repeatedly 
escalate and de-escalate; and 3) treat more than 6 subjects at a DL. The mBOIN selects the true 
MTD at a higher rate and treats a higher percentage of the subjects at the MTD. 
The DLT rate for a given DL is estimated as total number of DLTs/total number of subjects 
treated and qualifying for DDS (at that DL). Based on the accrued data (at each DL), the mBOIN 
decision guidance rules are supplied in Table 4-1. For further details on the mBOIN 
methodology, please see Appendix 8. 
Table 4-1 
Modified BOIN Decision Guidance Rules 
 
Total Number of Subjects 
Treated at a DL 
3 
4 
5 
6 
7 
8 
9 
Decision Based 
on Total Number 
of DLTs at the 
DL 
Escalate 
0 
0 
≤1 
≤1 
≤1 
≤1 
≤2 
Remain 
1 
1 
- 
2 
2 
2 
3 
De-escalate 
2 
2 
2 
3 
3 
3 
4 
Terminate a DL 
3 
≥3 
≥3 
≥4 
≥4 
≥4 
≥5 
DL=dose level; DLT=dose-limiting toxicity. 
If de-escalation is mandated, GEN1053 will be decreased to the preceding lower main DL while 
the IM DL per default will be kept fixed during the combination escalation part of the trial. A 
dose modification of the IM may be proposed by the DEC, the SC, or the DMC in case of 
emerging safety concerns for the combination treatment. The SC must endorse any such proposal 
before implementation. A dose modification of IM will be considered a new escalation 
combination cohort with a similar number of subjects as in other Combination therapy Dose 
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The SC (after consultation with the DEC and DMC) will determine the MTD and the RP2D 
based on the mBOIN estimate and the totality of data. The MTD and RP2D may be the same as 
the algorithm recommends for the next cohort or it may be a lower dose. 
If there is evidence that a DL lower than the MTD has adequate efficacy (whether determined by 
scan data, pharmacodynamic endpoints, or predicted efficacious dose), the DMC may 
recommend, and SC may decide, that the RP2D has been determined and may stop the 
combination therapy dose escalation. 
The overall decision process for the next DL and/or to propose the RP2D/MTD/MAD is 
summarized in Section 4.1 and will also be based on the above guidance and the principles in 
Sections 4.2.2.2 to 4.2.2.6. 
4.2.2.1 
Modifications to BOIN 
The escalation stops if there are 9 subjects already dosed on next proposed DL. 
4.2.2.2 
Dose Level Termination 
A potential drawback of the basic BOIN design is that, theoretically, a very toxic DL could be 
investigated in multiple cohorts if a neighboring DL is not toxic. To avoid this problem, a DL 
termination criterion will be implemented: A certain DL can no longer be investigated if an 
additional DLT-free cohort would lead to de-escalation. For example, if there are no DLTs at the 
current DL, but 3 out of 4 subjects had DLTs at the next higher DL, any outcome would lead to 
de-escalation (regardless of 0, 1, 2, or 3 DLTs, there would be least 3 DLTs for 7 subjects). All 
DLs with a higher dose than that of the terminated DL should also be terminated. 
4.2.2.3 
Cohort Size 
In the Combination therapy Dose Escalation phase 1b, the mBOIN may be executed if 1 subject 
is non-DLT evaluable and the remaining 2 subjects are DLT-evaluable, provided that neither of 
the 2 subjects experience any DLT during the 21-day DLT period. If a DL has a total of 2 
subjects who are DLT-evaluable and no DLTs are observed, the mBOIN rule is to escalate. 
Additionally, over-recruitment by 1 subject will be allowed, so that each 3-subject cohort may 
consist of 2 to 4 subjects who are evaluable for DLTs. 
In the event a cohort has less than 3 DLT evaluable subjects, the next cohort at the same DL may 
be expanded to bring the number of subjects at the DL up to a multiple of 3. 
4.2.2.4 
Stopping Rules 
• If the DEC suggests revisiting a DL where 9 subjects have been dosed, the SC may decide to 
stop further dose escalation. 
• If it is known a priori before revisiting a DL that the guidance would be to “decrease,” that 
regimen can be terminated (see Table 4-1).  
The MTD may be declared based on 6 subjects if the recommendation is to escalate and the next 
level is not available. 

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4.2.2.5 
Backfill Cohorts 
Backfill subjects are those that are added after a DL has been declared as safe, and escalation has 
proceeded to next higher DL. More than one backfill subject within a DL can therefore receive 
treatment simultaneously. Additional subjects may be enrolled to backfill DLs that have been 
cleared for safety to better understand the safety, tolerability, PK, pharmacodynamics, or 
antitumor activity. Additional subjects per DL may be enrolled in this fashion bringing the 
number of subjects at a DL up to a maximum of 9 subjects. Any DLTs observed in such subjects 
will not directly contribute to the mBOIN design evaluation. 
If the mBOIN algorithm later stipulates de-escalation to an over-recruited DL, all subjects on 
that dose will be included in the mBOIN algorithm. 
4.2.2.6 
Other Dose Escalation/De-escalation Procedures  
The following provides a description of the procedures not directly associated with the mBOIN 
as such, but that will impact subject accrual and provisions for dose escalation/de-escalation 
decisions. 
1. 1. After completion of Cycle 1 of each DL, based on the safety data and the mBOIN, the SC 
will endorse the DL for the next cohort of subjects after consideration of the 
recommendations of the DEC. Escalation to the next DL will not occur until all subjects 
needed for a specific cohort have passed the Cycle 1/DLT evaluation period. 
2. 2. A subject will be considered as evaluable for dose determination if they fulfil the criteria of 
the DDS (refer to Section 9.3.4). 
 
4.2.3 
Expansion  
The aim of the Expansion part is to provide further data on the safety, tolerability, MoA, PK, and 
antitumor activity of the selected RP2Ds and schedules in subjects with recurrent, unresectable, 
or metastatic HNSCC (GEN1053) and in subjects with metastatic NSCLC (GEN1053+IM), 
respectively.  
In Expansion cohort 1, subjects with recurrent, unresectable, or metastatic HNSCC who have 
been previously treated with a PD-1/PD-L1 inhibitor and platinum will be treated with the 
GEN1053 RP2D Q3W until one of the predefined criteria for treatment discontinuation are met. 
In case of PD (Section 7.1) on GEN1053 monotherapy, subjects in the HNSCC Expansion 
cohort will have the option to cross over to combination therapy with GEN1053+IM for the 
potential benefits as summarized in Section 2.2.3, once the GEN1053 RP2D for the combination 
has been determined.  
In Expansion cohort 2, subjects with metastatic NSCLC that have been previously treated with a 
PD-1/PD-L1 inhibitor will be treated with the RP2D for GEN1053 in combination with IM (both 
Q3W) until one of the predefined criteria for treatment discontinuation are met.  
The Expansion part will enroll approximately 40 subjects within each Expansion cohort. 

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5 TRIAL POPULATION 
The inclusion and exclusion criteria for enrolling subjects in this trial are described below. For 
questions regarding these criteria, the investigator must consult with the appropriate sponsor 
representative and resolve any issues before enrolling a subject in the trial. Waivers are not 
allowed. 
Note: Investigators, in coordination with the sponsor’s medical officer, or delegate, should 
ensure enrollment criteria are met and the eligibility review is completed. If a subject’s status 
changes (including laboratory results or receipt of additional medical records) after screening 
but before the first dose of trial treatment is given, such that the subject no longer meets all 
eligibility criteria, then the subject should be excluded from participation in the trial. 
5.1 
Inclusion Criteria  
Each subject must fulfill all the following criteria to be enrolled in the trial. 
For both the Dose Escalation and Expansion parts 
1. Subject (or their legally acceptable representative [not applicable in EU/EEA]) must sign an 
ICF indicating that the purpose of the trial and the procedures required for the trial are 
understood and indicating that the subject is willing to participate in the trial prior to 
initiating any other trial related assessments or procedures. Where required by local or 
country specific regulations, each subject must sign a separate ICF indicating agreement to 
provide samples for genomic biomarker analysis (DNA and RNA). 
Subject must: 
2. Be ≥18 years of age. 
3. Have measurable disease according to RECIST 1.1. 
4. Provide all prebaseline scans since failure of last prior therapy (eg, documented radiographic 
PD), if available. 
5. Have Eastern Cooperative Oncology Group performance status ≤1. 
6. Be willing and able to adhere to the prohibitions and restrictions specified in this protocol. 
7. Have organ and bone marrow function as follows: 
a. 
Bone marrow/hematological function:  
i. ANC ≥1.5×109/L 
ii. Hemoglobin ≥9.0 g/dL 
iii. Platelet count ≥150×109/L 
b. Liver function: 
i. Total bilirubin ≤ ULN 
ii. ALT ≤1.5×ULN 
iii. AST ≤1.5×ULN 
iv. Albumin ≥30 g/L 

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c. 
Coagulation status: 
i. PT/INR ≤1.5 
ii. aPTT ≤1.5×ULN 
Note: Subjects receiving anticoagulant therapies should have PT and aPTT within the 
therapeutic range of intended use of anticoagulants. 
d. Renal function: 
GFR ≥45 mL/min/1.73 m², according to the abbreviated MDRD equation:  
    GFR = 186 × (SCr - 1.154) × (age - 0.203) × (0.742 if female),  
where SCr is expressed in mg/dL and the result is multiplied by 1.212 if the subject is 
Black. 
8. A female subject with reproductive potential (postmenopausal or permanently sterilized is 
considered as not having reproductive potential) must agree to use adequate contraception 
during the trial and for 6 months after the last administration of GEN1053. Adequate 
contraception is defined as highly effective methods of contraception (refer to Appendix 4 for 
more information). In countries where 2 forms of highly effective methods of contraception 
are required, this will be an inclusion criterion. 
9. A female subject with reproductive potential must have a negative serum beta-human 
chorionic gonadotropin test at screening.  
10. A female must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the trial and for 6 months after the last dose of trial treatment. 
11. A man who is sexually active with a woman of childbearing potential and has not had a 
vasectomy must agree to use a barrier method of birth control, eg, either condom with 
spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, during and for 6 
months after the last GEN1053 treatment administration; all men must also refrain from 
donating sperm during the trial and for 6 months after receiving the last dose of GEN1053. 
For Monotherapy Dose Escalation (phase 1a) and Combination therapy Dose Escalation 
(phase 1b) only:  
12. Subjects with histologically or cytologically confirmed non-CNS solid tumors that are 
metastatic or advanced. 
13. Subjects who have progressed on standard of care therapy or for whom there is no available 
standard therapy likely to provide clinical benefit, or who are not candidates for available 
therapy or who have previously refused available therapy, and for whom experimental 
therapy with GEN1053 or GEN1053+IM may be beneficial, in the opinion of the 
investigator. 
14. Biopsies for Monotherapy Dose Escalation and Combination therapy Dose Escalation 
(Table 1-3 and Table 1-7): 
a. All subjects must provide a fresh biopsy. A fresh biopsy is defined as being taken after 
failure/stop of last prior treatment and within 6 months prior to C1D1. 
Note: Documentation of fresh biopsy collection and shipment must be submitted to the 
sponsor as a part of the eligibility package prior to administration of the first dose of 
trial treatment.  

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b. All subjects should provide an FFPE archival tissue sample from the latest available 
archival tumor tissue, if available. 
c. Local results from the most recent PD-L1 test should be provided prior to enrollment, if 
available.  
 
For the Expansion part only:  
15. Subjects with histologically or cytologically confirmed diagnosis of recurrent, unresectable, 
or metastatic HNSCC or metastatic NSCLC, who do not have any further available standard 
therapy or who are not candidates for standard therapy or who have previously refused 
standard therapy (if subjects had access), and for whom experimental therapy with GEN1053 
(HNSCC) or GEN1053+IM (NSCLC, HNSCC crossover) may be beneficial, in the opinion 
of the investigator. 
16. Subjects must meet the following criteria in the respective Expansion cohorts:  
 
For Expansion Cohort 1 (MoA cohort, HNSCC) GEN1053 with crossover to 
GEN1053+IM: 
a. Subjects with recurrent, unresectable, or metastatic HNSCC (with no surgery or RT 
options) of the oral cavity, pharynx, or larynx who have received up to 3 prior systemic 
treatment regimens for recurrent, unresectable, or metastatic disease with radiographic 
PD on or after last prior treatment (maintenance treatment is considered part of one 
treatment line). 
b. Subjects must have received prior platinum-based therapy or alternative chemotherapy if 
platinum ineligible (eg, a gemcitabine-containing regimen). 
c. Subjects must have received 1 prior treatment with a PD-1/PD-L1 inhibitor alone or in 
combination with other therapy and must have had radiographic PD on or within 6 
months after treatment.  
Note: Subject must have received at least 2 doses of a PD-1/PD-L1 inhibitor.  
Note: For the subjects whose most recent anticancer therapy contained a PD-1/PD-L1 
inhibitor, their recent evidence of PD must be confirmed by a second radiographic 
assessment at least 4 weeks from the date of the initial radiologically documented PD.  
d. HPV p16 test results available per local standard of care for subjects with oropharyngeal 
disease, if available.   
Note: Oral cavity, hypopharynx, and larynx cancer are not required to undergo HPV 
testing by p16 IHC as by convention these tumor locations are assumed to be HPV 
negative. 

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e. Biopsies for Expansion Cohort 1 (Table 1-11):  
i. All subjects must provide a fresh biopsy. A fresh biopsy is defined as being taken 
after failure/stop of last prior treatment and within 6 months prior to C1D1. 
Note: Documentation of fresh biopsy collection and shipment must be submitted to 
the sponsor as a part of the eligibility package prior to administration of the first 
dose of trial treatment.  
ii. All subjects should provide an FFPE archival tissue sample from the latest available 
archival tumor tissue, if available. 
f. Local results from the most recent PD-L1 test should be provided prior to enrollment, if 
available.  
 
For Expansion Cohort 2 (NSCLC) GEN1053+IM: 
g. Subjects with metastatic NSCLC who have received up to 3 prior systemic treatment 
regimens for metastatic disease with radiographic PD on or after last prior treatment 
(maintenance treatment is considered being part of 1 treatment line). 
i. 
NSCLC tumors of any histology may be enrolled. Subjects with mutations in KRAS, 
BRAF, MET genes or RET gene rearrangements or NTRK1/2/3 gene fusions in their 
tumors may only be enrolled after prior treatment with targeted therapy/standard of 
care options. Subjects with drug-sensitizing mutations in EGFR or ALK or ROS1 
rearrangements are not eligible. Documentation of genomic status should be available 
per local assessment.  
Note: For subjects with squamous NSCLC histology, molecular testing for genomic 
alterations will not be required. 
h. Subjects must have received prior platinum-based therapy or alternative chemotherapy if 
platinum ineligible (eg, a gemcitabine-containing regimen). 
i. Subjects must have received 1 prior treatment with a PD-1/PD-L1 inhibitor alone or in 
combination with other therapy and must have had radiographic PD on or within 6 
months after treatment.  
Note: Subject must have received at least 2 doses of a PD-1/PD-L1 inhibitor.  
Note: For the subjects whose most recent anticancer therapy contained a PD-1/PD-L1 
inhibitor, their recent evidence of PD must be confirmed by a second radiographic 
assessment at least 4 weeks from the date of the initial radiologically documented PD. 
j. Biopsies for Expansion Cohort 2 (Table 1-18) 
i. All subjects must provide a fresh biopsy. A fresh biopsy is defined as being taken 
after failure/stop of last prior treatment and within 6 months prior to C1D1. 
Note: Documentation of fresh biopsy collection and shipment must be submitted to 
the sponsor as a part of the eligibility package prior to administration of the first 
dose of trial treatment. 
ii. All subjects should provide an FFPE archival tissue sample from the latest available 
archival tumor tissue, if available. 
k. Local results from the most recent PD-L1 test should be provided prior to enrollment, if 
available.  

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5.2 
Exclusion Criteria 
Any potential subject who meets any of the following criteria will be excluded from participating 
in the trial. 
1. Has uncontrolled intercurrent illness, including but not limited to:  
a. Ongoing or active infection requiring IV treatment with anti-infective therapy 
administered less than 2 weeks prior to first dose. 
b. Symptomatic congestive heart failure (Grade III or IV as classified by the New York 
Heart Association), unstable angina pectoris, or cardiac arrhythmia.  
c. Uncontrolled hypertension defined as systolic blood pressure ≥160 mm Hg and/or 
diastolic blood pressure ≥100 mm Hg, despite optimal medical management. 
d. Prolonged QTc interval at baseline of ≥470 milliseconds using Fridericia's QT 
correction formula. 
e. Ongoing or recent (within 1 year of screening) evidence of significant autoimmune 
disease that required treatment with systemic immunosuppressive treatments, which 
may suggest risk for irAEs.  
Note: The following condition is not exclusionary: Residual hypothyroidism that 
required only hormone replacement. 
f. History of grade 3 or higher irAEs that led to treatment discontinuation of a CPI. A 
subject with irAEs below grade 3 that led to discontinuation should be discussed with 
the sponsor. Grade 3 irAEs that have fully recovered may also be discussed. 
g. Prior history of myositis, Guillain-Barré syndrome, or myasthenia gravis of any 
grade. 
h. History of chronic liver disease or evidence of hepatic cirrhosis. 
i. Evidence of interstitial lung disease.  
j. Ongoing pneumonitis or history of non-infectious pneumonitis that has required 
steroids. 
k. 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 
trial treatment. 
l. Serious, non-healing wound, skin ulcer (of any grade), or bone fracture. 
m. Known platelet function defects or a known history or high risk of bleeding events 
requiring transfusions or hospitalizations unless approved by sponsor.  
2. All subjects should undergo a CT scan or MRI of the brain to document new or existing CNS 
lesions. Any subject with history of intracerebral arteriovenous malformation (shunts), 
cerebral aneurysm, spinal cord compression (from disease), carcinomatous meningitis, or 
stroke will be excluded. 
a. Transient ischemic attack >1 month prior to screening is allowed. 
b. Subjects with newly identified or known unstable or symptomatic CNS metastases 
will be excluded. Subjects with previously treated brain metastases may participate 

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provided they are radiologically stable (ie, without evidence of PD) for at least 28 
days by repeat imaging. 
Note: The repeat imaging should be performed during trial screening. 
Subjects should be clinically stable and should not be undergoing acute corticosteroid 
therapy or steroid taper or have received stereotactic radiation or whole-brain 
radiation within 14 days prior to C1D1. Chronic steroid therapy is acceptable 
provided that the dose is stable for the last 14 days prior to C1D1 (≤10 mg prednisone 
daily or equivalent). 
3. Prior therapy:  
a. Radiotherapy within 14 days prior to first trial treatment administration. Palliative 
radiotherapy will be allowed. 
b. Treatment with an anticancer agent (within 28 days or after at least 5 half-lives of the 
drug, whichever is shorter), prior to trial treatment administration.  
c. Condition requiring systemic treatment with either corticosteroids (>10 mg daily 
prednisone equivalent) or other immunosuppressive medications within 14 days of 
first treatment. Inhaled or topical steroids, and adrenal or pituitary replacement 
steroid >10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease.  
d. Treatment with bisphosphonates (eg, pamidronate, zoledronic acid, etc) and RANK-L 
inhibitors initiated within 28 days before the first planned dose of trial treatment 
administration. The initiation of bisphosphonates is also not allowed during the first 
4 weeks of trial treatment, unless approved by sponsor. 
e. Has received any investigational agent (including investigational vaccines) or used an 
invasive investigational medical device within 28 days before the planned first dose 
of trial treatment or is currently enrolled in an interventional trial.  
Note: A subject who is in the follow-up phase of an interventional trial may 
participate if the subject has not received the investigational agent within 28 days of 
the first dose of trial treatment.  
f. Prophylaxis with live, attenuated vaccines within 28 days prior to first dose of trial 
treatment; or prophylaxis with the first and/or subsequent injection(s) of SARS-CoV-
2 nucleic acid vaccine within 28 days prior to first dose of trial treatment.  
Note: SARS-CoV-2 vaccine is generally permitted, including mRNA-based, protein-
based, or nonreplicating viral vector-based vaccines. Please consider choosing an 
appropriate type of SARS-CoV-2 vaccine and consult with an infectious disease 
expert if desired.  
Note: SARS-CoV-2 vaccine should not be administered during the DLT observation 
period. 
g. Has received G-CSF or GM-CSF support within 2 weeks prior to first trial treatment 
administration or is chronically transfusion dependent. 
h. History of ≥ grade 3 allergic reactions to monoclonal antibody therapy or known or 
suspected allergy or intolerance to any agent to be given during the course of this 
trial. 
i. Prior treatment with a CD27-targeting agent 

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j. Only for Expansion part: Discontinued treatment due to PD within the first 6 weeks 
of a CPI-containing treatment. 
k. Prior treatment with a T-cell agonist or a CTLA-4–targeting agent within 12 weeks 
prior to the initiation of trial treatment.  
l. Prior treatment with an anti-PD-1/PD-L1 targeting agent within 6 months prior to the 
initiation of trial treatment.  
4. Toxicities from previous anticancer therapies that have not resolved to baseline levels or to 
grade 1 or less with the exception of alopecia, anorexia, vitiligo, fatigue, hyperthyroidism, 
hypothyroidism, and peripheral neuropathy. Anorexia, hyperthyroidism, hypothyroidism, and 
peripheral neuropathy must have recovered to ≤ grade 2. 
5. Known past or current malignancies other than inclusion diagnosis, except for: 
a. Cervical carcinoma of Stage 1B or less. 
b. Noninvasive basal cell or squamous cell skin carcinoma. 
c. Noninvasive, superficial bladder cancer. 
d. Prostate cancer with a current prostate-specific antigen level <0.1 ng/mL. 
e. Any curable cancer with a complete response of >2 years duration. 
6. Known allergies, hypersensitivity, or intolerance to trial treatments (including its excipients). 
7. Any condition for which, in the opinion of the investigator, participation would not be in the 
best interest of the subject or that could prevent, limit, or confound the protocol-specified 
assessments. 
7FR.  France: See Appendix 9 for requirements per local health authorities. 
8. Has had major surgery (eg, requiring general anesthesia) within 4 weeks before screening, or 
will not have fully recovered from surgery, or has surgery planned during the time the 
subject is expected to participate in the trial.  
Note: A subject with a planned surgical procedure to be conducted under local anesthesia 
may participate. 
9. Known history of seropositivity for human immunodeficiency virus.  
Note: HIV testing is required at screening only if required per local health authorities or 
institutional standards. 
10. Known history/positive serology for hepatitis B (unless immune due to vaccination or 
resolved natural infection or unless passive immunization due to immunoglobulin therapy): 
a.  Positive test for antibodies to hepatitis B core antigens 
and 
b. Negative test for antibodies to hepatitis B surface antigens. 
11. Known medical history or ongoing hepatitis C infection that has not been cured. 
Note: Hepatitis C testing is required at screening only if required per local health authorities 
or institutional standards. 

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12. Substance abuse or medical, psychological, or social conditions that may interfere with the 
subject’s participation in the trial or evaluation of the trial result. 
13. Has been dosed before in this trial. 
14. Is pregnant or breastfeeding and cannot discontinue breastfeeding for the duration of the trial 
or at least 6 months after the last trial treatment administration or intends to conceive 
children within 6 months of ending trial treatment. 
5.3 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but do not 
meet the protocol-defined eligibility criteria (refer to Sections 5.1 and 5.2) as assessed during 
screening. A minimal set of screen failure information is required to ensure transparent reporting 
of screen failure subjects to follow ICH guidelines, meet the CONSORT publishing 
requirements, and to respond to queries from regulatory authorities. Minimal information to be 
documented includes demography, reason for screening failure (eg, eligibility criteria not met, 
subject withdrew consent, or other reasons), and any AEs related to a protocol-mandated 
procedure (eg, tumor biopsy, CT scan), including washout or discontinuation of prior 
medications. 
Individuals who do not meet the criteria for participation in this trial (screen failures) may be 
rescreened once. The rescreening must be approved by the sponsor to ensure that the safety of 
the subject is not compromised. All eligibility criteria must be reassessed at the rescreening visit. 
Results from assessments performed during the previous screening period are acceptable for 
rescreening purposes if performed within the specified time frame and the inclusion/exclusion 
criteria are met.  
A new unique subject identifier will not be allocated to the subject at rescreening. Rescreened 
subjects will be required to sign a new ICF if updates have been made since signing the most 
recent ICF. 

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6 TRIAL TREATMENT 
6.1 
Investigational and Auxiliary Medicinal Products 
Trial treatment is defined as any IMP, AMP, or medical device(s) intended to be administered to 
a trial subject according to the trial protocol. IMP(s) specifically are referred to as trial drug(s). 
GEN1053 will be administered by qualified site personnel as IV infusion over a minimum of 60 
minutes on Day 1 of each treatment cycle of 21 days (Q3W) after all procedures and assessments 
have been completed.  
In the Dose Escalation phases 1a or 1b, subjects will be administered GEN1053 according to 
DLs outlined in Section 4.2.1. In the Expansion part, subjects will be administered the RP2D(s) 
from Dose Escalation phase 1a or 1b for either GEN1053 monotherapy or combination therapy, 
respectively.  
Infusion times and recommendations may be adjusted by the sponsor in consultation with 
investigators, based on emerging safety information from the Dose Escalation phases. Such 
changes will be documented in the SC meeting minutes. Infusion durations that exceed the 
planned length of time due to IV bag overfill, minor equipment calibration factors, and/or subject 
factors not under the control of administering personnel will not be considered protocol 
deviations. The actual infusion time should be accurately documented. 
As a routine precaution, all subjects must be observed for at least 4 hours after ending infusion of 
trial treatment on Day 1 during Cycle 1 and Cycle 2. For all subsequent cycles, subjects must be 
observed for at least 2 hours after end of infusion of trial treatment, unless they have experienced 
an IRR in any previous cycle. In the latter case, the clinical observation should continue to be 4 
hours.  
Trial treatment should be administered as described in Table 6-1 for IMPs. Further details on any 
AMPs will be provided in a substantial amendment before initiating phase 1b or phase 2a of the 
trial. Detailed dosing modification guidance is provided in Section 6.7. Information regarding 
prior and concomitant therapy is provided in Section 6.6.  
Table 6-1 
Investigational Medicinal Product 
 
GEN1053a,b 
IMa,b 
Schedule 
Day 1 of each cycle (Q3W) 
TBD 
Cycle length 
3 weeks 
TBD 
Strength 
20 mg/mL 
TBD 
Dosage formulation 
concentrate for solution for infusion 
TBD 
Route of 
administration 
IV 
TBD 
Dosing instructions 
Refer to IMP Manual 
TBD 
IM=immunomodulator; IMP=investigational medicinal product; IV=intravenous(ly); Q3W=every 3 weeks; TBD=to 
be determined (once the IM has been selected). 
a. 
Refer to the IMP Manual for further details. 
b. Refer to Appendix 9 for EU authorization status.  

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6.1.1 
Physical Description of Trial Drug(s) 
6.1.1.1 
GEN1053 
GEN1053 is a clear to opalescent, colorless to slightly yellow solution supplied as concentrate 
for solution for infusion to be diluted (at site). 
GEN1053 is supplied in a vial containing 5 mL (100 mg/vial). 
GEN1053 will be manufactured and provided under the responsibility of the sponsor. 
Refer to the individual IBs for a list of excipients. 
6.1.1.2 
Immunomodulator 
Details will be provided with an amendment before initiating phase 1b. 
6.1.2 
Packaging 
GEN1053 and IM will be packed to meet the applicable regulatory requirements. For further 
information see IMP Manual. 
6.1.3 
Labeling 
GEN1053 and IM labels will contain information to meet the applicable regulatory requirements. 
For further details see the GEN1053 and IM IMP Manuals.  
6.2 
Product Complaint Handling 
A product complaint is defined as any suspicion of a product defect related to manufacturing, 
labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, durability, or 
reliability of a product, including its labeling or package integrity. A complaint may have an 
impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of complaint information from trials are crucial for the protection of subjects, 
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 complaint information; all trials conducted by the sponsor, or its 
affiliates will be conducted in accordance with those procedures.  
Product complaints must be reported to the sponsor’s QA department by the trial-site personnel 
within 24 hours of awareness the event. The IMP Manual contains contact information (email 
and telephone) for Genmab QA and instructions for reporting complaints. 
In addition to reporting the complaint, if the product defect is combined with an AE or SAE, the 
trial-site personnel must report the AE or SAE to the sponsor according to the AE and SAE 
reporting process and timelines (refer to Section 8.4.2). A sample of the suspected product 
should be maintained for further investigation if requested by the sponsor. 

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6.3 
Preparation/Handling/Storage/Accountability 
6.3.1 
Preparation, Handling, and Storage  
Guidance for the preparation, handling, and storage of trial treatment is described in the IMP 
Manual. 
6.3.2 
Drug Accountability and Destruction 
The investigator or designee must maintain an accurate record of received, returned, and/or 
destroyed trial treatment supplied by the sponsor and administration of trial treatment to trial 
subjects in a drug accountability log/record. Drug accountability will be verified on a continuous 
basis by the site monitor during site monitoring visits and at the completion of the trial. For trials 
using IRT, drug accountability will be documented within the system. 
When drug accountability has been verified by the site monitor, all expired/unused trial 
treatment (vials, capsules, prefilled syringes) can be destroyed or returned to the sponsor in 
accordance with the guidance in the trial specific IMP Manual.  
Final drug accountability will be assessed at the end of the trial (or at site closure if applicable) 
in accordance with local regulations and guidelines. 
6.4 
Measures to Minimize Bias: Randomization and Blinding 
6.4.1 
Subject Numbering 
After signing the ICF, subjects will be assigned a unique subject identifier before undergoing any 
screening procedure(s). Subjects that meet all of the eligibility criteria may be treated. 

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6.4.2 
Treatment Assignment  
This is an open-label trial; therefore, blinding of treatment will not be performed. Randomization 
will not be used in the Dose Escalation part of this trial.  
6.4.3 
Emergency Unblinding of Treatment Assignment 
Not applicable 
6.5 
Compliance 
Trial treatment will be administered by site personnel to assure compliance with trial 
requirements. The date and time of each trial treatment administration will be documented. 
Intervention start and stop dates, including dates for trial treatment delays and/or dose reductions 
(if applicable) will also be documented. 
6.6 
Prior and Concomitant Therapies 
The sponsor’s medical monitor or delegate should be contacted if there are any questions 
regarding prior or concomitant medication or therapies. 
6.6.1 
Prior Anticancer Therapies 
Prior anticancer therapies received from the time of initial diagnosis until the first dose of trial 
treatment for the treatment of malignant solid tumors in the Dose Escalation phases 1a and 1b 
and HNSCC and NSCLC in the Expansion (including surgery, RT, chemo-radiotherapy, 
systemic treatment regimens, etc) must be documented. 
The best response, reason for discontinuation, dates of administration, and date of PD should be 
reported for prior anticancer therapies. 
Refer to Section 6.6.3.2 for details regarding prohibited prior anticancer therapies or wash-out 
periods for prior anticancer therapies. 
6.6.2 
Other Prior Therapies 
Any other medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) received within 28 days before administration of the first 
dose of trial treatment must be documented. 
Refer to Section 6.6.3.2 for details regarding prohibited prior therapies or wash-out periods for 
prior therapies. 
6.6.3 
Concomitant Therapies 
All concomitant medications received within 28 days prior to the first dose of trial treatment and 
up to 60 days after the last dose of trial treatment should be recorded. All concomitant 
medications administered during SAEs are to be recorded. All the concomitant medication will 
be recorded on the eCRF including all prescription, over-the-counter products, herbal 

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supplements, and IV medications and fluids. If changes occur during the trial period, 
documentation of drug dosage, frequency, route, and date should also be included on the eCRF. 
The subject must be told to notify the trial site about any new medications (including over-the-
counter or prescription medicines, vitamins, and vaccines) they take after the start of the trial 
treatment. All medications (other than trial treatment) and significant nondrug therapies 
(including physical therapy, herbal/natural medications, and blood transfusions) administered 
during the trial (ie, beginning with administration of the first dose of trial treatment until 60 days 
after the last dose of trial treatment) must be documented. 
Investigators may prescribe concomitant medications or treatments deemed necessary to provide 
adequate supportive care except for those medications identified as “prohibited” 
(Section 6.6.3.2). 
Concomitant therapies should also be documented beyond the safety follow-up period only in 
conjunction with worsening of AEs or new SAEs related to trial treatment. 
6.6.3.1 
Permitted Concomitant Medications and Therapies 
The following concomitant medication and therapies are permitted during the trial: 
• Palliative RT during the trial will be allowed for local pain control provided that: 
(i) in the opinion of the investigator, the subject does not have PD, AND 
(ii) no more than 10% of the subject’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 and ≥ grade 3 neutropenia, when clinically indicated or 
at the investigator’s discretion. In case of recurring ≥ grade 3 neutropenia, use of growth 
factors is mandated. 
• Red blood cell and platelet transfusions, if clinically indicated. 
• Steroid treatment is permitted to modulate symptoms of an irAE at the discretion of the 
investigator (refer to Section 6.7.2). Replacement therapy (eg, thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is also 
allowed.  
• Multivitamins, vitamin D, calcium, and supplements, for prevention of weight loss. 
• Prescribed medicinal cannabinoids as palliative therapy. 
• SARS-CoV-2 vaccine is generally permitted, including mRNA-based, protein-based, or non-
replicating viral vector-based vaccines. Consider choosing an appropriate type of SARS-
CoV-2 vaccine and consult with an infectious disease expert if desired. 
Note: SARS-CoV-2 vaccine should not be administered during the DLT observation period. 
The trial site will supply supportive medication, eg, premedication, and antiviral medication. 

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6.6.3.2 
Prohibited Concomitant Therapy 
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered. 
Subjects 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 trial treatment: 
• Any other investigational therapy. 
• Antineoplastic systemic chemotherapy or biological therapy not specified in this protocol. 
• Immunotherapy not specified in the protocol. 
• Immunosuppressive doses of systemic corticosteroids (ie, prednisone >10 mg daily) for any 
purpose other than to modulate AEs of suspected immunologic etiology are prohibited with 
the following exception: subjects are permitted the use of topical, ocular, intraarticular, 
intranasal, and inhalational corticosteroids (with minimal systemic absorption). Short-term 
oral or IV use in doses >10 mg/day prednisone equivalent for chronic obstructive pulmonary 
disease exacerbations OR adrenal replacement steroid doses >10 mg daily prednisone are 
permitted. A brief (less than 3 weeks) course of corticosteroids for prophylaxis (eg, contrast 
dye allergy) or for treatment of nonautoimmune conditions (eg, delayed-type hypersensitivity 
reaction caused by a contact allergen) up to a cumulative dose of 200 mg prednisone is 
permitted.  
• Live or live attenuated vaccines within 28 days prior to the first dose of trial treatment, while 
participating in the trial, and for 3 months following the last dose of trial treatment. 
Note: Seasonal influenza vaccines are generally killed virus vaccines and are permitted; 
however, intranasal influenza vaccines are live attenuated and are not allowed. 
Treatment with bisphosphonates (eg, pamidronate, zoledronic acid, etc) and RANK-L inhibitors 
initiated within 28 days before the first planned trial treatment dose administration or planned to 
be initiated during the first 4 weeks of trial treatment, unless approved by sponsor.  
Information on potential drug-drug interactions is unknown for GEN1053. Caution should be 
used regarding the use of herbal medications as there may be unknown interactions with trial 
treatment. Discontinuation of the use of herbal medications prior to trial enrollment is 
encouraged. 
If a subject receives any of the aforementioned prohibited treatments for any reason, the sponsor 
must be notified for evaluation of whether the subject can continue treatment in the trial. 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  

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6.7 
Dosing Modifications 
6.7.1 
Dose-Limiting Toxicity 
The occurrence of any of the toxicities outlined in this section will be considered a DLT if 
occurring within the DLT evaluation period, unless clearly related to underlying disease or 
extraneous causes. The DLT evaluation period is defined as 21 days from the first dose of trial 
drug, ie, Cycle 1 in the Dose Escalation phase 1a (monotherapy) or phase 1b (combination 
therapy) of the trial. During the DLT evaluation period, the occurrence of any of the toxicities 
listed below, which are assessed as related to trial treatment, will be considered DLTs.. 
Toxicities will be graded for severity according to the NCI-CTCAE, version 5.0. CRS will be 
evaluated according to the ASTCT criteria (Lee et al., 2019). 
 
General 
• All grade 5 events 
• Grade 4 anaphylaxis 
• Grade 4 IRRs 
 
Hematological events  
• Grade 4 neutropenia (ie, ANC <0.5×109 cells/L [<500/µL]) for minimal duration of 7 days  
• Grade 3 and grade 4 febrile neutropenia (ie, ANC <1.0×109 cells/L with a single temperature 
of >38.3 °C [100.9 °F] or with a sustained temperature of ≥38 °C [≥100.4 °F] for more than 1 
hour)  
• Grade 4 thrombocytopenia (≤25.0×109 platelets/L [<25,000/µL]) 
• Grade 3 thrombocytopenia with clinically significant bleeding 
• Grade 4 anemia 
 
Non-hematological events: 
• Grade 4 AST, ALT, or bilirubin elevation. 
• Grade 3 AST, ALT, or bilirubin elevation that does not recover to ≤ grade 1 within 14 days.  
• AST or ALT elevations ≥ grade 2 with concomitant bilirubin >2.0×ULN with no signs of 
cholestasis, ie, a Hy’s law case. 
• Any grade 4 irAE. 

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• Grade 3 irAEs that do not improve to ≤ grade 1 within 7 days by appropriate care or with 
corticosteroids except for: 
o Grade 3 pneumonitis, which always qualifies as a DLT. 
o Grade 3 nephritis (defined as inflammation of the kidney affecting the structure 
associated with grade 3 creatinine increase), which always qualifies as a DLT. 
• Grade 4 CRS 
• Grade 3 CRS which has not resolved to ≤ grade 2 within 48 hours following adequate 
intervention (including repeated anticytokine therapy) 
• Any other ≥ grade 3 nonhematological AE (including liver toxicities other than increases of 
transaminases and bilirubin), which occurs during the first GEN1053 treatment cycle 
excluding: 
o Grade 3 fever (>40.0 °C) for ≤ 24 hours. 
o Grade 3 hypotension (resolving to baseline or ≤ grade 1 within 24 hours). 
o Grade 3 IRRs that resolve to ≤ grade 1 within 24 hours. 
o Grade 3 anorexia when grade 2 anorexia was present at baseline or that lasts for <14 days 
after the last trial treatment administration.  
o Grade 3 nausea/vomiting or diarrhea for less than 72 hours with adequate antiemetic and 
other supportive care 
o Grade 3 fatigue for less than 7 days 
o Grade 3 or higher electrolyte abnormality that lasts up to 72 hours, is not clinically 
complicated, and resolves spontaneously or responds to conventional medical 
interventions  
The investigator must notify the medical monitor immediately of a DLT. Frequent laboratory 
monitoring of CBC including differential count should be initiated to document start and 
resolution of hematological AEs. All AEs occurring during the defined DLT evaluation period 
will be assessed according to the criteria above. All GEN1053 or GEN1053+IM related AEs will 
be monitored and included in the evaluation of the toxicity profile of GEN1053 or GEN1053+IM 
unless the event is clearly determined to be unrelated to trial treatment (eg, PD). 
Subjects experiencing a DLT within the DLT evaluation period should discontinue trial drug 
immediately. If requested by the investigator, the sponsor may allow a subject with a DLT to 
continue in the trial. For this decision, a thorough benefit-risk assessment of the individual 
subject is required, and consultation of the DMC may be considered. 
If a subject experiences a toxicity that would have qualified as a DLT, but occurs after the DLT 
evaluation period, the subject’s benefit-risk must be thoroughly assessed. Continued treatment 
with GEN1053 and/or IM must be agreed between the sponsor and the investigator. 

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6.7.2 
Dosing Modification Guidance and Stopping Criteria 
6.7.2.1 
Dose Delays and Interruptions for GEN1053 or GEN1053+IM 
The methodology for dose escalation is provided in Sections 4.2.1 and 4.2.2. 
No intrasubject dose de-escalation will be allowed. The doses of GEN1053 or IM cannot be 
reduced but may be delayed. 
• Administration of trial treatment can be delayed for up to 21 days (ie, 1 cycle) unless 
otherwise approved by the sponsor medical monitor. If the severity resolves to ≤ grade 1 or 
baseline within this period, retreatment may be considered under the following conditions: 
o In case of safety concerns, and for subjects who experience a recurrence of the same AEs 
of < grade 3 severity with rechallenge of GEN1053 or GEN1053+IM, a consultation 
between the sponsor and investigator will occur to determine whether the subject should 
continue trial treatment at the same schedule or whether the dosing interval in subsequent 
cycles should be increased. The sponsor may also consult the DMC as specified in 
Appendix 1. 
o A subject who experiences the same AE of ≥ grade 3 with rechallenge of GEN1053 or 
GEN1053+IM must discontinue trial treatment immediately. 
• For subjects receiving GEN1053+IM combination therapy, both GEN1053 and IM should be 
withheld or discontinued. Subjects may only continue GEN1053 or IM monotherapy if 
approved by the sponsor.  
Decisions regarding dosing modification of trial treatment should be made using clinical 
judgment, considering relatedness of the AE to the trial treatment and the subject’s underlying 
condition. For guidance, please see Table 6-2. The investigators are encouraged to contact 
sponsor in case of any safety concern that needs thorough discussion and evaluation.  
Note that specific rules apply for irAEs, thrombocytopenia, neutropenia, CRS, and IRRs (see 
Sections 6.7.2.2 and 6.7.2.3). 
Table 6-2 
Dosing Modification and Management of Treatment-Related AEs 
CTCAE Grade/Severity 
Hold Treatment (Y/N) 
Dosing Modification 
Grade 1 or Grade 2 
(Mild or moderate) 
N 
Continue treatment at the discretion of the investigator. If 
thrombocytopenia ≥ grade 2 is identified, with or without bleeding, 
further treatment should be interrupted (see Section 6.7.2.3).  
 
Grade 3 (Severe) 
Y 
Withhold treatment until resolution to ≤ grade 1 or baseline 
 
Grade 4 
(Life-Threatening) 
Y 
Permanent discontinuation except if approved by medical monitor. If 
continuing on treatment, toxicity must resolve to grade 1 or baseline. 
 
AE=adverse event; N=no; Y=yes.  
For recurrent treatment-related AEs upon rechallenge, please see guidance in text. 

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Table 6-3 
Dosing Modification and Management of Immune-Related Adverse Events 
Immune-Related AEs 
Toxicity Grade  
(CTCAE v5.0) 
Dose Modification 
Guidance for Management of irAEs 
Pneumonitis  
Grade 1 
 
 
Withhold treatment or proceed with close monitoring. 
Monitor for signs and symptoms of pneumonitis. 
Evaluate for pneumonitis with radiographic imaging. 
For ≥ grade 2: 
Administer corticosteroids (initial dose of 1 to 2 mg/kg prednisone or 
equivalent) followed by taper. Consider bronchoscopy with 
BAL±transbronchial biopsy. Add prophylactic antibiotics for 
opportunistic infections. 
 
For ≥ grade 3: Administer methylprednisolone IV 1-2 mg/kg. 
 
Grade 2 
Withhold treatment until resolution to ≤ grade 1 and 
corticosteroid has been tapereda 
 
 
 
Grade 3 or Grade 4 
Permanently discontinue 
Colitis  
Grade 2 
Withhold treatment until resolution to ≤ grade 1 and 
corticosteroid has been tapereda 
Monitor for signs and symptoms of colitis. Consider gastroenterology 
consultation and confirm diagnosis of colitis. Endoscopic evaluation 
for cases grade 2 or higher. 
Administer corticosteroids (initial dose of 1 to 2 mg/kg prednisone or 
equivalent) followed by taper. Consider adding infliximab or 
vedolizumab if inadequate response.  
Grade 4: Administer 1-2 mg/kg methylprednisolone IV or equivalent 
followed by taper. 
Grade 3  
Withhold treatment until resolution to ≤ grade 1 and 
corticosteroid has been tapereda 
Grade 4 
Permanently discontinue 
Hepatitis (ALT, AST, 
or bilirubin increased) 
 
Grade 2 
(asymptomatic) 
Withhold treatment until resolution to ≤ grade 1 and 
corticosteroid has been tapereda 
Initiate work-up for other causes of elevated liver enzymes such as 
viral hepatitis, alcohol history, iron study, thromboembolic event, liver 
ultrasound, and cross-sectional imaging for potential liver metastasis. 
Liver function tests must be monitored closely, the first time within 48 
hours, and at least twice per week (unscheduled visits) for up to 
4 weeks until resolution to ≤ grade 1. 
Consider immediate administration of corticosteroids (initial dose of 
0.5-1 mg/kg prednisone or equivalent) or at the latest within 3 days if 
no improvement, followed by taper.  
For AST or ALT elevations ≥ grade 2 with concomitant bilirubin 
>2.0×ULN with no signs of cholestasis, ie, a Hy’s law case, 
permanently discontinue. 
Grade 3 or 
symptomatic  
Permanently discontinue if symptomatic  
Withhold treatment until resolution to ≤ grade 1 and 
corticosteroid has been tapered 
-  If the grade 3 AST, ALT, or bilirubin increase resolves 
to ≤ grade 1 within 14 days, trial treatment may be 
continued after sponsor medical monitor approval 
Initiate work-up for other causes of elevated liver enzymes such as 
viral hepatitis, alcohol history, iron study, thromboembolic event, liver 
ultrasound, and cross-sectional imaging for potential liver metastasis. 
Monitor liver function tests (unscheduled visits) twice per week for up 
to 4 weeks until resolution to ≤ grade 1. 

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Immune-Related AEs 
Toxicity Grade  
(CTCAE v5.0) 
Dose Modification 
Guidance for Management of irAEs 
-  If the grade 3 AST, ALT, or bilirubin increase does 
NOT resolve to ≤ grade 1 within 14 days, permanently 
discontinue trial treatment 
Immediately administer corticosteroids (grade 3: initial dose of 1-2 
mg/kg methylprednisolone IV or equivalent; Grade 4: 2 mg/kg 
methylprednisolone IV or equivalent) followed by taper. 
Consider adding prophylactic antibiotics for opportunistic infections. 
If no improvement within 3-5 days despite methylprednisolone IV or 
equivalent is observed, consider prompt treatment with 
immunosuppressive therapy (eg, mycophenolate mofetil at 500 mg 
every 12 hours; discuss with medical monitor).  
 
Infliximab should not be used. 
 
Hepatology consult, abdominal workup, and imaging as appropriate. 
Grade 4 
Permanently discontinue 
T1DM 
or 
Hyperglycemia 
Newly diagnosed 
T1DM 
or 
Grade 3-Grade 4 
hyperglycemia 
Withhold until glucose control is obtainedb,c 
Monitor for hyperglycemia or other signs and symptoms of diabetes. 
Consider endocrine consultation. 
Consider administration of insulin for type 1 diabetes. 
Consider administration of antihyperglycemic agents in subjects with 
hyperglycemia. 
Hypophysitis 
Grade 2 
Continue treatment at the discretion of the investigator 
Monitor for signs and symptoms of hypophysitis. Consider endocrine 
consultation. 
Consider administration of corticosteroids and initiate hormonal 
replacements as clinically indicated. Corticosteroid taper should be 
initiated upon irAE improving to grade 1 or less. 
Grade 3 or Grade 4 
Withhold until subject is stabilized on replacement 
therapy or permanently discontinueb 
Hypothyroidism 
Grade 2 
Continue treatment at the discretion of the investigator  
Consider endocrine consultation  
Prescribe thyroid hormone supplementation in symptomatic subjects 
with any degree of TSH elevation or in asymptomatic subjects with 
TSH levels that persist.>10 mIU/L (measured 4 weeks apart) 
Grade 3-Grade 4 
Withhold until symptoms resolve to baseline with 
appropriate supplementation 
Hyperthyroidism  
Grade 2 
Continue treatment at the discretion of the investigator 
Monitor for signs and symptoms of thyroid disorders. 
Consider management with thionamides and beta-blockers as 
appropriate. 
Grade 3-Grade 4  
Withhold until symptoms resolve to baseline with 
appropriate therapy consultation or permanently 
discontinueb,c 
Nephritis and renal 
dysfunction 
Grade 1 
Consider temporary hold pending consideration of 
baseline renal function and to confirm etiologya 
Monitor subjects for elevated or changes in serum creatinine before 
every dose.  
For ≥ grade 2: If worsening or no improvement, consider 
administration of corticosteroids (prednisone 0.5 to 2 mg/kg or 
equivalent) followed by taper. Corticosteroid taper should be initiated 
upon irAE improving to grade 1 or less. Consider nephrology 
consultation. 
Grade 2 
Withhold treatment until resolved to baselinea 
Grade 3-Grade 4  
Permanently discontinue 
Cutaneous toxicities 
Grade 1 or Grade 2 
Continue treatment at the discretion of the investigator 
Based on the severity of the skin toxicity, consider administration of 
corticosteroids. Corticosteroid taper should be initiated upon irAE 
improving to grade 1 or less. 
Grade 3 
Withhold treatment until resolved to ≤ grade 1a 
Grade 4 
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Immune-Related AEs 
Toxicity Grade  
(CTCAE v5.0) 
Dose Modification 
Guidance for Management of irAEs 
For signs or symptoms of SJS or TEN, withhold and refer the subjects 
for specialized care. Monitor closely for improvement regardless of 
grade. If SJS or TEN is confirmed, permanently discontinue. 
For other d 
Grade 2 
Continue treatment at the discretion of the investigator 
Based on type and severity of AE, consider administration of 
corticosteroids. Permanently discontinue for any grade 3 irAE that 
recurs and for any life-threatening irAEs. 
Grade 3 
Withhold or permanently discontinueb 
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BAL=bronchoalveolar lavage; CTCAE=Common Terminology Criteria for Adverse Events; 
irAE=immune-related adverse event; SJS=Stevens-Johnson syndrome; T1DM=type 1 diabetes mellitus; TEN=toxic epidermal necrolysis; TSH: thyroid-stimulating hormone. 
a. The next dose of trial treatment can maximally be delayed 21 days unless approved otherwise by the sponsor medical monitor. If irAE resolves within 21 days to baseline, restart 
treatment at the same dose level after consulting the sponsor medical monitor. 
b. Investigator must contact the sponsor to discuss whether the subject should be withdrawn from trial treatment or if the next dose should be delayed. Subjects may be treated with the 
same dose and schedule. The sponsor may also consult the DEC as specified in Appendix 1. 
c. For subjects with grade 3 or 4 immune-related endocrinopathy leading to withholding of trial treatment dosing, treatment may be resumed when the AE recovers to ≤ grade 2 and is 
controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM). 
d. Refer to 
 reference for guidance on immune-related musculoskeletal, nervous system, hematologic, cardiovascular, ocular and specific cutaneous toxicities. 
CCI

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Attribution of Toxicity 
When GEN1053 is administered in combination with IM (GEN1053+IM), attribution of an AE 
to a single component is likely to be difficult. Therefore, while the investigator may attribute a 
toxicity event to GEN1053, IM or both for AEs listed in Table 6-3, both treatment with 
GEN1053 and IM must be withheld according to the recommended dosing modifications in 
Section 6.7.2.1. 
If the toxicities do resolve and conditions are aligned with what is defined in Table 6-3, 
GEN1053+IM combination therapy may be restarted at the discretion of the investigator. 
Reinitiation of either GEN1053 or IM as monotherapy may only be considered after 
communication with and approval by the sponsor. 
6.7.2.3 
Dosing Modification for Specific Adverse Events With GEN1053 or IM 
Thrombocytopenia Related to GEN1053 
The following guidelines should be followed for GEN1053-related thrombocytopenia: 
• If thrombocytopenia ≥ grade 2 is identified, with or without bleeding, further treatment must 
be interrupted.  
• If grade ≥ 2 thrombocytopenia fails to resolve to grade ≤1 within 21 days after the planned 
dosing date, the subject is to discontinue trial treatment unless approved otherwise by the 
sponsor. Per protocol, observation procedures and assessments will continue until the subject 
withdraws from the trial or starts another course of systemic anticancer therapy. 
• Retreatment may be considered if thrombocytopenia resolves to grade ≤1 within 21 days 
after the planned dosing date. The sponsor and investigator will discuss any safety concerns 
in order to decide whether the next cycle should be administered at the same schedule or 
whether the dosing interval in subsequent cycles should be increased.  
• If the retreatment results in grade ≥2 thrombocytopenia, the next administration of trial 
treatment should be delayed for up to 21 days until the toxicity has resolved to grade ≤1. The 
sponsor and investigator will discuss any safety concerns in order to decide whether next 
cycle should be administered at the same schedule or whether the dosing interval in 
subsequent cycles should be increased. 
• If more than 2 dose interruptions occur due to grade ≥2 thrombocytopenia, trial treatment 
will be discontinued. Per protocol, observation procedures and assessments will continue 
until the subject withdraws from the trial or starts another course of systemic anticancer 
therapy. 
• Trial treatment must be prematurely discontinued if the subject experiences grade 4 
thrombocytopenia or grade 3 thrombocytopenia with bleeding. For subjects with platelet 
count <50×109/L, aspirin or other concomitant medications with effect on platelet function or 
coagulation should be paused. For subjects with severe, persistent thrombocytopenia 
potentially related to GEN1053, it is recommended to perform a bone marrow biopsy.  

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Bleeding: 
Subjects with any bleeding symptoms, even mild, (eg, unjustified bruising, purpura, petechiae, 
epistaxis or gingival bleeding) will be instructed to contact the site immediately. Lab tests must 
be drawn to assess hematological parameters including platelets in case of signs of bleeding. 
Importantly, ≥ grade 3 thrombocytopenia and ≥ grade 2 bleeding events need to be reported 
within 24 hours irrespective of event seriousness (see Section 8.4.3).  
• For any clinically significant bleeding event, supportive care may be provided following 
local guidelines. For significant bleeding associated with thrombocytopenia of ≥ grade 2, 
platelet transfusions, high-dose corticosteroids or immunoglobulin therapy should be 
considered according to local standards. 
Neutropenia and Febrile Neutropenia Associated With GEN1053 or IM Administration 
Table 6-4 
Dosing Modification and Management of Neutropenia and Febrile 
Neutropenia 
CTCAE Term 
Toxicity Grade  
(CTCAE v5.0) 
Dose Modification 
Guidance for Management of AE 
Neutropenia 
or 
Febrile 
neutropenia 
Grade 3 or Grade 4  Withhold treatment until 
resolution to ≤ grade 1 
 
Administer colony-stimulating factors including 
G-CSF, pegylated G-CSF, or GM-CSF according to 
Institutional standards. 
For grade 3 or 4 neutropenia occurring in Cycle 1, 
grade 3 or 4 neutrophil count must be observed in 
2 consecutive assessments at least 12 hours apart 
without improvement prior to administration of growth 
factors. 
AE=adverse event; CTCAE=Common Terminology Criteria for Adverse Events; G-CSF=granulocyte colony-stimulating factor; 
GM-CSF=granulocyte/macrophage colony-stimulating factor. 
Cytokine Release Syndrome Related to GEN1053 or IM 
In the unexpected case an event of CRS occurs, grading of the CRS should be made according to 
the ASTCT criteria (Lee et al., 2019). 
Trial treatment should be permanently discontinued in case of a grade 4 CRS event or a cytokine 
blockade-refractory grade 3 CRS lasting >72 hours. However, per protocol, observation 
procedures and assessments are to continue until the subject withdraws from the trial or starts 
another course of systemic anticancer therapy. 
Rescue medication, in terms of antidotes to reverse the action of GEN1053, are not available and 
potential events of CRS must be treated symptomatically. Subjects with CRS should receive 
supportive care following an international guideline (Lee et al., 2014) or local SoC, with 
supportive treatment controlling fever, hypotension, and hypoxia and in more severe cases with 
IL-6 mAb (tocilizumab), systemic steroids and vasopressors. 
Infusion-Related Reactions Associated With GEN1053 Administration 
The following treatment guidelines are provided below for subjects who experience an IRR 
associated with administration of trial treatment:  

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• Grade 1: If an IRR 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. 
• Grades 2 to 3: If an IRR grade 2 or 3 occurs, the infusion should be interrupted, and 
appropriate medical management instituted. The infusion may be restarted 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 Subjects who have experienced prior infusion-related grade 2 or 3 reactions in the trial 
should be premedicated. Premedication to prevent IRR in subsequent infusions may be 
administered at the investigator's discretion according to local guidelines but preferably 
includes an antihistamine (eg, diphenhydramine 50 mg or equivalent antihistamine), 
acetaminophen/paracetamol (eg, acetaminophen 500-1000 mg or equivalent), and if 
considered necessary, subjects should receive corticosteroids at a suggested maximum 
dose of 100 mg prednisone or equivalent. 
o If the subject has a second grade 3 IRR despite premedication, the infusion should be 
stopped, and the subject should discontinue trial treatment.  
• Grade 4: If anaphylaxis or grade 4 IRR occurs, trial treatment should be discontinued 
immediately and permanently, and appropriate medical therapy should be administered. 
Note: 
• As a routine precaution, all subjects must be observed during Cycle 1 and Cycle 2 on Day 1 
for at least 4 hours after ending infusion of GEN1053. For all subsequent cycles, subjects 
must be observed for at least 2 hours after ending infusion of GEN1053, unless they have 
experienced an IRR in any previous cycle. In the latter case, the clinical observation should 
continue to be 4 hours. Subjects must always be observed for at least 2 hours after ending 
infusion of IM. 
• During dose escalation, an overnight stay will be required for the first subject in each DL and 
may be required for additional subjects if recommended by the sponsor.  
• Subjects must be observed in an area with resuscitation equipment and emergency agents. 
• At all times during infusion of trial treatment, 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 premedications must be reported on the concomitant medication page in the eCRF. 
6.7.2.4 
Safety Stopping Rules for Trial Treatment 
Treatment with trial treatment should be discontinued due to safety concerns under the following 
conditions: 

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• Subjects experiencing a DLT (refer to Section 6.7.1) should discontinue trial drug 
immediately. If requested by the investigator, the sponsor may allow a subject with a DLT to 
continue in the trial. For this decision, a thorough benefit-risk assessment of the individual 
subject is required, and consultation of the DMC may be considered. 
• If a subject experiences a toxicity that would have qualified as a DLT, but that occurs after 
the DLT evaluation period, the subject’s benefit-risk must be thoroughly assessed. Continued 
treatment with GEN1053 and/or IM must be agreed between the sponsor and the 
investigator. 
• If the subject experiences a TRAE that meets the criteria for treatment discontinuation as 
specified in Sections 6.7.2.2 and 6.7.2.3 and Table 6-3 and Table 6-4. 
• An AE that fails to resolve to ≤ grade 1 within 21 days due to a toxicity possibly related to 
trial drug, unless otherwise approved by the sponsor medical monitor. 
• Treatment-related grade 4 or life-threatening AE, except with approval from the medical 
monitor. 
• Second occurrence of an IRR of ≥ grade 3 despite premedication prior to the second infusion. 
• First occurrence of anaphylaxis or a grade 4 IRR. 
• Subjects with grade 4 transaminase or bilirubin elevation. 
• Subjects with abnormal liver function parameters that meet Hy’s law criteria as defined in 
Section 6.7.1. 
• In case of thrombocytopenia not resolving to ≤ grade 1 within 21 days after the planned 
dosing date, unless approved otherwise by the sponsor. 
• If the subject experiences grade 4 thrombocytopenia or grade 3 thrombocytopenia with 
clinically significant bleeding. 
• First episode of CRS grade 4. 
• First episode of cytokine blockade-refractory grade 3 CRS lasting >72 hours. 
Note: 
• Subjects should, whenever possible, irrespective of the reason for discontinuation, be 
examined as soon as possible for details regarding discontinuation of treatment (refer to 
Section 7.1). 
6.7.2.5 
Safety Stopping Rules for the Trial 
The trial can be stopped for unacceptable toxicity based on a risk-benefit assessment after 
consultation with the DMC. Deaths considered related to GEN1053 will always be assessed by 
the DMC.  

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In addition, trial stopping rules for unacceptable toxicity will be introduced in the Expansion part 
based on data collected during the Dose Escalation part of this trial.  
6.8 
Treatment of Overdose 
6.8.1 
Overdose of GEN1053 
For this trial, an overdose of GEN1053 is defined as a subject receiving a dose in excess of 10% 
of that specified in this protocol.  
In case of overdose, medication errors, misuse, and/or abuse of GEN1053, subjects should 
receive supportive care according to local guidelines and potential side effects of GEN1053 
should be treated symptomatically. 
In the event of an overdose, the investigator should: 
• Closely monitor the subject for any AEs/SAEs and laboratory abnormalities. 
• Obtain a plasma/serum sample for PK analysis if requested by the sponsor’s medical monitor 
(determined on a case-by-case basis). 
• Document the quantity of the excess dose as well as the duration of the overdose. 
• Contact the sponsor's medical monitor immediately (see Section 8.4.3). 
6.8.2 
Overdose of IM 
Further details on the IM will be provided in a substantial amendment before initiating phase 1b 
of the trial. 
6.9 
Treatment After the End of the Trial 
6.9.1 
Subject Contact and Trial Treatment After the End of the Trial 
Investigators should attempt to recontact the subject to obtain long-term follow-up information 
regarding the subject’s safety or survival status as noted in the ICF (refer to Appendix 1, 
Informed Consent Process). 
For subjects with a potential treatment benefit, subjects may be eligible for continued treatment 
with Genmab IMP(s) by an extension protocol or as provided for by the local country’s 
regulatory mechanism. However, Genmab reserves the unilateral right, at its sole discretion, to 
determine whether to supply Genmab IMP(s) and by what mechanism, after termination of the 
trial and before the product(s) is/are available commercially. 

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7 DISCONTINUATION OF TRIAL TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Trial Treatment 
Subjects can decline to continue receiving trial treatment and/or other protocol-required therapies 
or procedures at any time during the trial but continue participation in the trial. Subjects who 
have discontinued trial treatment and/or other protocol-required therapies or procedures should 
not be automatically removed from the trial. Whenever safe and feasible and unless the subject 
withdraws consent, it is imperative that subjects remain on-trial to ensure safety surveillance 
and/or collection of outcome data (ie, continue efficacy evaluations according to the trial 
protocol). 
The subject may discontinue both trial treatment and further participation in trial activities; 
however, they may continue to be followed for survival (see Section 7.1.2) and are not 
considered discontinued from the trial (see Section 7.2), provided that consent for trial 
participation has not been withdrawn. 
A subject’s trial treatment must be discontinued for any of the following reasons: 
• Unacceptable AE requiring treatment discontinuation (refer to Section 6.7.1 and 6.7.2.4) 
• Pregnancy 
• Clinical progression 
• Radiographic PD or confirmed radiographic PD by iRECIST (if applicable) 
Note: If the investigator considers radiographic changes secondary to drug-induced 
inflammation and not to tumor progression, the investigator may postpone a diagnosis of PD 
until the next radiographic evaluation in the trial (see Section 8.2.4 for treatment beyond 
PD). 
• Death 
• Investigator believes that it is in the best interest of the subject to stop GEN1053 or 
GEN1053+IM treatment 
• Subject non-compliance 
• Sponsor decision 
• Subject request to discontinue trial treatment 
• Lost to follow-up (see Section 7.3) 
• Termination of the trial by the sponsor 

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For subjects receiving GEN1053+IM combination therapy, both GEN1053 and IM should be 
discontinued. Subjects may only continue GEN1053 or IM monotherapy if approved by the 
sponsor.  
Subjects should, whenever possible, irrespective of the reason for discontinuation, be examined 
as soon as possible and the treatment discontinuation visit should be performed. If the treatment 
discontinuation visit coincides with a regularly scheduled cycle visit, the treatment 
discontinuation evaluations will supersede those of the regularly scheduled cycle visit. If the 
timing of the treatment discontinuation visit and first safety follow-up visit are the same, the 
treatment discontinuation visit may represent the first safety follow-up visit. For subjects 
crossing over from GEN1053 to GEN1053+IM, re-baseline visit details are provided in 
Table 1-13. 
When a subject discontinues treatment with trial treatment, the subject remains in the trial and is 
followed until meeting one of the reasons listed in Section 7.2.  
In addition, the subject will still be followed for safety (see Section 7.1.1) and survival status 
(see Section 7.1.2) through the end of the trial. 
Subjects should always be followed for safety as detailed in Section 8.4 and Appendix 3. 
After trial treatment discontinuation, the subject should receive suitable treatment as decided by 
the investigator (see Section 6.9). 
7.1.1 
Safety Follow-up Evaluation 
Subjects discontinuing from treatment for any reason will have 2 safety follow-up visits, at 
30 days (+5 days) and 60 days (±7 days) after the last trial treatment administration, respectively. 
If the subject initiates new anticancer treatment within 30 days of the last trial treatment 
administration, the safety follow-up visit should be performed prior to starting new anticancer 
treatment. Once new anticancer treatment is initiated, the subject will move into survival status 
follow-up (see Section 7.1.2). 
7.1.2 Survival Status 
Survival status will be assessed every 12 weeks (±14 days), beginning from the day the subject 
receives the last trial treatment administration and continuing until the subject dies, withdraws 
consent for survival status follow-up, or the trial ends. Subjects may be contacted by telephone, 
email, or visit. Subjects who are not available, or whose designated family members are not 
available, for this assessment should be entered as “lost to follow-up” (see Section 7.3 and 
Section 6.8). In the monotherapy dose escalation part, there will be no survival follow-up for the 
last subject discontinuing treatment. 
Site personnel, or an independent third party, will attempt to collect the survival status of the 
subject within legal and ethical boundaries for all subjects enrolled. Survival status may be 
collected through medical records, national registries, or publicly available information as 
allowed per local regulation. If survival status is determined as deceased, this will be 
documented. 

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7.2 
Subject Withdrawal From the Trial 
A subject will be withdrawn from the trial for any of the following reasons: 
• Death 
• Lost to follow-up 
• Sponsor decision 
• Subject withdraws consent 
• Maximum trial duration met 
When a subject withdraws before completing the trial, the reason for withdrawal is to be 
documented. 
During both the monotherapy Dose Escalation phase 1a and the combination therapy Dose 
Escalation phase 1b, subjects who withdraw before the end of the DLT period may be replaced. 
These replacement subjects will be assigned to the same treatment cohort as the subjects they are 
replacing. 
If a subject discontinues trial treatment and withdraws from the trial before PD, the treatment 
discontinuation visit assessments should be obtained whenever possible. If the reason for 
withdrawal from the trial is withdrawal of consent, then no additional assessments are allowed, 
but the sponsor may retain and continue to use any data collected before such a withdrawal of the 
consent. 
When a subject withdraws before completing the trial, the reason for withdrawal is to be 
documented. 
If a subject withdraws from the trial, he/she may request destruction of any samples taken and 
not tested, and the investigator must notify the sponsor accordingly (see Appendix 5 for further 
details). 
7.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if the subject repeatedly fails to return for 
scheduled visits and is unable to be contacted by the trial site. The following actions must be 
taken if a subject fails to return to the clinic for a required trial visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible, counsel the subject on the importance of maintaining the assigned visit schedule 
and ascertain whether the subject wishes to and/or should continue in the trial. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the subject (where possible, 3 telephone calls, and if necessary, a 
certified letter to the subject’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the subject’s medical record. 

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• Should the subject continue to be unreachable, the subject will be considered to have 
discontinued from the trial. 
 

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8 TRIAL ASSESSMENTS AND PROCEDURES 
Overview 
The Schedule of Activities (Section 1.3) summarizes the frequency and timing of efficacy, PK, 
immunogenicity, pharmacodynamic/biomarker, safety, and other measurements applicable to 
this trial. 
All assessments should be performed prior to trial treatment administration, unless otherwise 
indicated in the Schedule of Activities. 
Blood collections for PK and pharmacodynamic assessments should be kept as close to the 
specified time as possible. Other measurements may be done earlier than specified timepoints if 
needed. 
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulations, to establish the absence of pregnancy at any time 
during the participation in the trial. 
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples 
must be as specified, and where applicable, under controlled temperature conditions as indicated 
in the laboratory manual. 
8.1 
Demography and Baseline Assessments 
8.1.1 
Demographics 
Demographic details will be assessed at screening. 
8.1.2 
Diagnosis and Disease Status 
A subject’s history relating to the underlying disease including primary diagnosis, date of 
diagnosis, as well as disease status at trial entry, staging, and risk category will be recorded. The 
following should be recorded at screening: 
The primary site of cancer, and initial and current disease stage (TNM staging system), will be 
recorded at screening. 
For all subjects, record the PD-L1 status as per local assessment, if available. 
For all subjects, record the dMMR or MSI status as per local assessment, if available. 
The following should be recorded if available for subjects with the following types of cancer: 
• Breast cancer: HER2, ER, and PgR status as per local assessment 
• Ovarian: BRCA status as per local assessment 
• HNSCC: HPV status in subjects with oropharyngeal disease as per local assessment 

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• NSCLC: the tumor mutational status including EGFR, ALK, KRAS, BRAF, MET, ROS1 
genes or RET gene rearrangements or NTRK1/2/3 gene fusions as per local assessment 
• Cervical cancer: HPV status as per local assessment 
Additionally, if known, locally assessed cancer-associated mutations, gene signatures, and 
immune therapy prognostic targets may also be recorded. 
8.1.3 
Medical History 
Any medical condition (signs, symptoms, and diagnosis) occurring prior to first dose of trial 
treatment should be documented in the source documents as medical history. Medical conditions 
that occur after the ICF is signed and prior to first dose of trial treatment should only be reported 
as AEs if they were assessed by the investigator to be caused by a protocol-mandated procedure 
(ie, tumor biopsy and/or CT scan), including wash-out or discontinuation of prior medications. 
Any medical history/current medical condition that worsens after the first dose of trial treatment 
will be documented as an AE. See additional reporting details in Section 8.4 and Appendix 3. 
Recording of prior therapies are detailed in Section 6.6, selected prior laboratory data in 
Section 8.3.6 and for prebaseline scans in Section 8.2.3. 
8.2 
Efficacy Assessments 
Disease burden must be documented at screening and reassessed at each subsequent tumor 
evaluation. Response will be assessed by the investigator on the basis of physical examinations, 
CT scans and other modalities (eg, MRI, brain scans), using RECIST v1.1 (Eisenhauer et al., 
2009), Appendix 7).  
Importantly, in subjects who discontinue trial treatment without evidence of radiographic PD, 
tumor imaging must be performed until evidence of radiographic PD. 
If the subject withdraws or is lost to follow-up, the data already collected and the data from the 
end of the trial visit will be kept. 
8.2.1 
Definition of Target and Nontarget Disease 
Up to 5 target lesions (maximum 2 per organ) will be defined at screening and these must be 
followed throughout the trial. Biopsied tumor lesions or tumor lesions situated in a previously 
irradiated area, or in an area subjected to other loco-regional therapy, are not considered 
evaluable. For subjects with a single target lesion, it is mandatory to perform the imaging before 
taking the biopsy (both must be performed during the screening period). Biopsies cannot be 
taken from this single target lesion on-treatment unless approved by the sponsor medical 
monitor. Nontarget lesions will also be assessed throughout the trial.  
Each lesion that is measured at baseline must be measured by the same method (either same 
imaging method or by photography, including a metric ruler) and when possible, the same local 
radiologist/physician throughout the trial so that the comparison is consistent.  

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Initial tumor imaging at screening must be performed within 21 days prior to the date of first 
dose. If a CT scan or MRI has been performed within 21 days prior to visit C1D1 as part of 
standard procedure, it is acceptable as a screening scan for the trial. Scans that exceed the 21-day 
window may be used for trial enrollment with sponsor approval. The site must review screening 
images to confirm the subject has measurable disease per RECIST 1.1. 
8.2.2 
Radiographic Assessments 
Efficacy will be assessed based on imaging at screening and on treatment as described in 
Section 8.2.3.  
Guidelines for on-trial imaging and process: 
• All subjects will have imaging of the brain, thorax, abdomen, and pelvis performed during 
screening. Head and neck imaging is always required for subjects with HNSCC. Imaging of 
the pelvis is not required for subjects with HNSCC but is strongly recommended. 
• Tumor imaging is strongly preferred to be acquired by CT with contrast. For the abdomen 
and pelvis, contrast-enhanced MRI may be used when CT with iodinated contrast is 
contraindicated, or when mandated by local practice. MRI is the strongly preferred modality 
for imaging the brain. Localized CT with contrast or MRI (with or without contrast; for 
sarcomas with contrast) must be acquired for assessment of lesions of the 
skeleton/extremities and head and neck if not visible on other images. At the discretion of the 
investigators and after approval of the sponsor, combined PET/CT (eg, FDG-PET) may be 
performed for tumor assessments as per RECIST 1.1, but only if the CT portion is of similar 
diagnostic quality to CT alone. 
• 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 PD. Chest X-rays and ultrasound should not be used to measure tumor lesions. 
8.2.3 
Assessment of Disease Response and Progressive Disease 
• 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 PD is 
assessed by the investigator (unless the investigator elects to continue treatment and follow 
iRECIST beyond RECIST PD), the start of new anticancer 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. If imaging shows PD, then a subsequent 
imaging assessment, in clinically stable subjects only, should be performed within 4 to 7 
weeks to confirm PD if following iRECIST. Imaging is not required when subject is in 
survival follow-up. 
• Imaging assessments should be scheduled using the date of first dose as the reference date 
(not the date of the previous tumor assessment) and should be respected regardless of 
whether trial treatment is temporarily withheld, or unscheduled assessments performed. 
• The reading of the scans will be done by a local radiologist. To the greatest extent possible, 
sites should maintain the same radiologist throughout the trial. Results from the radiology 

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evaluations are to be recorded, and a copy of the evaluation reports should be kept in the 
subject’s file. RECIST 1.1 criteria will be used for secondary endpoint response evaluation 
(Eisenhauer et al., 2009) and Appendix 7; iRECIST will be used for exploratory endpoint 
response evaluation (Seymour et al., 2017).  
• Additional CT or MRI scans may be performed at the investigator’s discretion to confirm 
response or new symptoms. Tumor imaging to confirm PR or CR should be performed at 
least 4 weeks after the first indication of a response is observed. In this case, the investigator 
must choose the imaging technology based on the clinical indication.  
o If an off-schedule imaging assessment is performed because progression is suspected, 
subsequent imaging assessments should be performed in accordance with the original 
imaging schedule. 
o Additional imaging assessments may be performed at any time during the trial at the 
investigator’s discretion to support the efficacy evaluations for a subject, as necessary. 
Clinical suspicion of PD at any time requires a physical examination and imaging 
assessments to be performed promptly rather than waiting for the next scheduled imaging 
assessment. 
• Sites will be required to submit electronic copies of prebaseline scans (since failure of last 
prior therapy, as available) and all subsequent scans on an ongoing basis to a centralized 
imaging CRO for exploring the tumor growth and possible independent review of disease 
assessments for subjects enrolled. Images obtained at an unscheduled timepoint should be 
captured in the eCRF and submitted to the central imaging vendor for subjects enrolled in the 
Expansion part. 
o Imaging data will be centrally collected and checked for quality by an imaging CRO 
designated by the sponsor. The local investigator’s assessment will be used as primary 
for the endpoint analyses and for treatment decision making. Central review of the 
imaging data may be performed if deemed necessary. 
 
8.2.4 
iRECIST Assessment of Disease 
For subjects who continue trial treatment beyond initial RECIST-defined PD, efficacy 
assessments must continue. 
iRECIST is based on RECIST 1.1 but has been modified to account for the unique response 
patterns observed with immunotherapy. In this trial, iRECIST will be evaluated as an exploratory 
endpoint (Seymour et al., 2017). 
iRECIST PD should be confirmed within 4 to 7 weeks after the first radiologic evidence of PD in 
clinically stable subjects. Subjects who have unconfirmed PD may continue on-trial treatment 
until PD is confirmed as long as the subject is clinically stable and has provided written informed 
consent prior to receiving additional treatment. Subjects who are clinically stable must meet the 
following criteria: 

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• Subject must have clinical benefit from continuation of trial treatment (as assessed by the 
investigator) and must not have rapid PD 
• Subject is tolerating trial treatment  
• Subject must have a stable ECOG status 
• Treatment beyond PD will not delay an imminent intervention to prevent serious 
complications for PD (eg, CNS metastases requiring immediate treatment).  
Any clinically unstable subjects should be discontinued from trial treatment at the first 
occurrence of radiographic PD. Subjects that are clinically unstable are not required to have 
repeated imaging to confirm PD by iRECIST; however, a confirmation of progression scan may 
be obtained at the investigator’s discretion after consultation with the sponsor.  
If repeat imaging shows iRECIST iCPD, subjects will discontinue trial treatment. However, if 
the subject is deriving benefit after iCPD is observed, an exception to continue trial treatment 
must be approved by the sponsor medical monitor. If repeat imaging shows iRECIST iSD, 
iRECIST iPR, or iRECIST iCR, imaging should be continued every 6 weeks (±7 days) and the 
subject should continue on trial treatment. Subjects who have repeat imaging to confirm PD do 
not need to undergo the next scheduled tumor imaging if it is less than 4 weeks later. 
8.3 
Clinical Safety Assessments 
Details regarding the DMC, DEC, and SC are provided in Appendix 1. 
AEs will be reported and followed by the investigator as specified in Section 8.4 and Appendix 
3. 
Any clinically relevant changes occurring during the trial must be documented. Any clinically 
significant abnormalities persisting at the end of the trial/early withdrawal will be followed up by 
the investigator until resolution or until a clinically stable condition is reached depending on if 
they correspond to an AE, AESI or an SAE as per Section 8.4.6. 
The trial will include the following evaluations of safety and tolerability according to the time 
points provided in the Schedule of Activities, Section 1.3. 
8.3.1 
Physical Examination 
A complete (full) physical exam should be performed during screening period. At subsequent 
visits, a symptom-directed/clinically indicated (brief) physical examination may be performed. 
Full Physical Examination: 
The investigator or qualified designee will perform a full physical examination according to 
standard of care at the time points specified in the Schedule of Activities, Section 1.3. After the 
first dose of trial treatment, new or worsening findings that are considered clinically significant 
should be reported as AEs. 

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Brief Physical Examination: 
For cycles that do not require a full physical examination (as specified in the Schedule of 
Activities, Section 1.3), the investigator or qualified designee will perform a symptom-directed 
physical examination as clinically indicated prior to trial treatment administration. After the first 
dose of trial treatment, new or worsening findings since the last assessment that are considered 
clinically significant should be documented as AEs. 
8.3.2 
Body Measurements 
8.3.2.1 
Height 
Height (without shoes) must be measured at screening and rounded to the nearest centimeter or 
inch. 
8.3.2.2 
Weight 
Body weight (without overcoat and shoes) will be measured as indicated in the Schedule of 
Activities (Section 1.3) and rounded to the nearest kilogram or pound. 
8.3.3 
Vital Signs 
Vital signs, including temperature (°C or °F), blood pressure (mm Hg), and heart rate (beats/min) 
should be measured with the subject in a supine or reclined position and recorded. Subjects 
should be resting and in a horizontal or half laid position for at least 10 minutes before vital signs 
are measured. Temperature should be measured as an oral, axillary, rectal, or ear temperature. 
The temperature should be documented as a value corrected according to local standards. 
Within each visit, preferably the same equipment shall be used for vital sign measurements. 
Vital signs will be measured as indicated in the Schedule of Activities (Section 1.3) according to 
Table 1-4, Table 1-8, Table 1-12, and Table 1-19. 
On infusion days, vital signs should be assessed as described in Table 1-4 and Table 1-12 for 
GEN1053 monotherapy and in Table 1-8 and Table 1-19 for GEN1053+IM combination therapy, 
respectively. 
8.3.4 
Electrocardiograms 
The ECGs will be recorded digitally at the sites by using the standard 12-leads as indicated in the 
Schedule of Activities (Section 1.3). 
For the ECG recordings, the subject must be resting and in a supine or reclined position for at 
least 10 minutes. Any irregularity observed or occurring during the ECGs (eg, vomiting, cough) 
should either induce a repeat of the ECG or be annotated with the description and time of the 
occurrence. 
ECGs will be performed in accordance with the ECG manual issued by the vendor. 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. 

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Information in this section should be used in conjunction with the additional details provided in 
Appendix 3. 
8.4.1 
Definition of Adverse Events and Serious Adverse Events 
The definitions of AEs, SAEs, AESIs as well as attribution definitions; severity criteria; special 
reporting situations; and procedures are provided in Appendix 3. 
8.4.1.1 
Adverse Events of Special Interest 
For GEN1053, the following events have been defined as AESIs, irrespective of relatedness to 
trial treatment: 
• AEs of thrombocytopenia (ie, low PLT counts that are considered clinically significant, 
induce clinical signs or symptoms, require concomitant therapy, or require changes in trial 
treatment) 
• AEs of bleedings 
AESIs can be serious or nonserious, as per standard seriousness criteria (Appendix 3). For AESIs 
requiring expedited reporting, please see Section 8.4.3.5. AESIs defined for treatment with IM 
will be determined and amended before starting phase 1b. 
8.4.1.2 
Other Events of Interest  
Infusion-Related Reactions 
IRRs are defined as any AE occurring during infusion or where the onset of the event occurs 
within 24 hours after ended infusion. For IRRs, the causality of the event should be judged as 
“related” by the investigator. 
Investigators should consider the clinical picture and isolated events, such as “fatigue,” occurring 
within 24 hours after the end of infusion and assess whether they do or do not constitute an IRR 
(refer to Section 6.7.2.3 for further IRR treatment guidance). 
8.4.2 
Adverse Event Reporting 
As noted in Section 8.1.3, medical conditions (signs, symptoms, and diagnosis) that occur after 
the ICF is signed and prior to the first dose should only be reported as AEs if they were assessed 
by the investigator to be caused by a protocol-mandated procedure (ie, tumor biopsy and/or CT 
scan), including wash-out or discontinuation of prior medications. 
All other AEs, whether serious or nonserious (see definitions in Appendix 3), will be 
documented from the first dose of trial treatment until the last safety follow-up visit, subject 
withdrew consent, subject started new anticancer treatment, or the subject dies, whichever comes 
first. The safety reporting periods are defined in Table 8-1. 

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Medication errors (including infusion rate errors) and uses outside what is foreseen in the 
protocol, including misuse and abuse of trial treatment, whether associated with an AE or not, 
should be reported to the sponsor within 24 hours of knowledge of the event. Medication errors 
related to concomitant medication should only be reported if associated with AEs whether 
serious or not.  
8.4.3.4 
Pregnancy 
Pregnancy is not allowed in this trial. However, if any pregnancy occurs during trial 
participation, the pregnancy must be reported using the pregnancy reporting paper form available 
in the investigator site file. 
All reports of pregnancy in female subjects or partners of male subjects must be reported to the 
sponsor within 24 hours of knowledge of the event, using the pregnancy reporting paper form 
available in the investigator site file. In the case of pregnancy in the partner of a male subject, a 
separate ICF will be obtained from the female partner for collection of information regarding the 
pregnancy. 
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 1 month. Pregnancy 
complications and elective terminations 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 subject has completed the trial and considered by 
the investigator as possibly related to the IMPs and AMPs must be promptly reported to the 
sponsor or designee. 
Pregnant trial subjects must be withdrawn from treatment immediately, whereas male subjects 
may continue in the trial should pregnancy of female partners occur. 
8.4.3.5 
Adverse Events of Special Interest or Other Events of Interest 
AESIs in this protocol are defined in Section 8.4.1.1.  
The following AESIs need to be reported to the sponsor within 24 hours of awareness 
irrespective of event seriousness: 
• Grade 3+ thrombocytopenia (ie, AEs of thrombocytopenia with PLT count less than 
50×109/L) 
• Grade 2+ bleedings (ie, bleeding that requires medical intervention/hematocrit monitoring, as 
per CTCAE criteria per type of bleeding) 
Note: AEs of grade 1 bleedings and of ≤ grade 2 thrombocytopenia must be reported as per 
regular AE timelines, depending on whether they fulfill or not any seriousness criterion 
based on the investigator’s assessment. 
All AESIs will be closely monitored to timely identify, quantify and qualify any relevance of the 
nonclinical findings to humans and the adequacy of the mitigation strategies described in 
Sections 2.3.2, 2.2.2.1, 2.2.3.1 and 6.7.2. All AESIs will be taken into consideration during DEC 
reviews and SC decisions, regardless of their occurrence (within or outside the DLT period). 

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8.4.4 
Regulatory Reporting Requirements for 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(s) 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 
subjects are met (see Section 8.4.3.2). 
The sponsor will ensure that all relevant information about SUSARs is documented and reported 
as soon as possible, but within a maximum of 15 calendar days (fatal or life-threatening SUSARs 
within a maximum of 7 calendar days) of first knowledge by the sponsor or designee, to the 
competent regulatory authorities and/or to the ethics committee/IRBs according to the applicable 
local regulatory requirements. Relevant follow–up information of fatal or life-threatening 
SUSARs will be communicated subsequently within the required reporting timelines. The 
sponsor will also communicate relevant information on SUSARs with the investigators in 
predefined periods and according to local regulations. 
The investigator should be aware of local reporting regulations to the IEC/IRB. The 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. SUSARs aggregated line listings 
will be distributed quarterly, or every 6 months, or in periods as warranted for regulatory 
compliance; the investigator must review such safety information in a timely manner and signoff 
for the review as instructed by the sponsor, to document the awareness about the latest safety 
updates that may impact on the investigator’s responsibilities for subject care. 
8.4.4.1 
Regulatory Reporting Requirements for AMPs 
Where an AE is suspected to be related only to an AMP, and does not result from a possible 
interaction with the IMP, safety reporting will be done by the sponsor in accordance with 
Chapter 3 of TITLE IX of Directive 2001/83/EC. 
8.4.5 
Disease-Related Events/Outcomes and Other Events/Procedures Not Qualifying as 
 
Adverse Events or Serious Adverse Events 
The following should not be reported as an AE or SAE: 
• Events that are clearly consistent with the expected pattern of the underlying disease or its 
progression should not be recorded as AEs or SAEs. 
o That is, the terms “Disease Progression”; “Progression of Disease”; or “Malignant 
Disease Progression” and other similar terms should not be used to describe an AE or 
SAE. These data are captured as efficacy assessment data only. 
 In most cases, the expected pattern of progression will be based on the response 
criteria. In rare cases, the determination of clinical progression will be based on 
symptomatic deterioration. However, every effort should be made to document 
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 Clinical symptoms may be reported as AEs or SAEs if the symptom cannot be 
determined as reasonably due to progression of the underlying malignancy or does 
not fit the expected pattern of progression for the disease under study. 
• Hospitalization due solely to progression of the underlying cancer should not be reported as 
an SAE. See Appendix 3, under the definition of SAE, for additional reasons when 
hospitalizations should not be reported as SAEs. 
8.4.5.1 
Unrelated Procedures 
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not be 
reported as AEs. However, a medical condition for which an unscheduled procedure was 
performed should be reported if it meets the definition of an AE (eg, an acute appendicitis should 
be reported as the AE and not the appendectomy). 
8.4.6 
Follow-up of Adverse Events and Serious Adverse Events 
All AEs must be followed until they are resolved or until the last safety follow-up visit or the 
start of new anticancer treatment, whichever comes first. 
All SAEs and events qualifying for immediate reporting (see Section 8.4.3) that are ongoing at 
the safety follow-up visit(s) should continue to be followed on a regular basis until the event has 
been resolved or until the investigator assesses it as chronic and all queries have been resolved. 
8.4.7 
Warnings and Precautions 
Refer to the IB for detailed information for precautions and warnings for GEN1053.  
Additional relevant safety information collected between IB updates will be communicated in 
the form of investigator notifications. Significant information will be included in the ICF and 
should be discussed with the subject during the trial as needed. 
8.5 
Pharmacokinetics 
Venous blood samples will be collected for analyzing matrix concentrations of GEN1053 as 
specified in the Schedule of Activities (Section 1.3). Date and 24-hour clock time of each sample 
will also be recorded.  
Samples collected for GEN1053 PK will be divided into aliquots prior to analysis and may 
additionally be used to evaluate safety or efficacy aspects to address any concerns that may arise 
during or after the trial period. Genetic analysis will not be performed on these samples. Subject 
confidentiality will be maintained.  
Samples will be analyzed to determine concentrations of GEN1053 using a validated, specific, 
and sensitive method by or under the supervision of the sponsor. 
Additional information about the collection, handling, and shipment of samples is included in the 
laboratory manual. 

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8.6 
Pharmacodynamics 
Refer to Section 8.7 for pharmacodynamic biomarkers.  
8.7 
Biomarkers 
8.7.1 
Biomarker Sample Collection 
Samples for biomarker analyses will be collected as specified in the Schedule of Activities. 
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. 
Details on the collection, processing, storage, and shipment of biomarker samples will be 
provided in separate documents (eg, sample handling sheets, laboratory manual). 
All biopsies performed in this trial will be done by trained medical staff including specialized 
radiologists or surgeons depending on the location of the lesion and according to the local 
standard of care. Lesions will be selected by the investigator or the radiologist with the best 
interest of the subject in mind. Biopsies will only be done if there is a low risk of complications 
for the subject. 
8.7.2 
Biomarker Assessments in Tumor Samples 
A fresh biopsy collected before treatment with trial treatment (ie, during the screening period) is 
required for all subjects for enrollment. This fresh biopsy must not be older than 6 months and 
taken after failure/stop of last prior treatment, but before treatment with trial treatment. 
Documentation of fresh biopsy collection and shipment must be submitted to the sponsor as a 
part of the eligibility package prior to administration of the first dose of trial treatment. The fresh 
biopsy should be a core biopsy or resected tissue. A fine needle aspirate will not be sufficient. 
The following specimen types are not acceptable biopsy samples: cytological specimens, 
aspirates, bone, or bone marrow. All tumor biopsies should be FFPE. A subject must also 
provide an archival tumor sample, if available. Refer to Section 8.2.1 for additional information 
on biopsy procedures related to defining target lesions. 
During the trial, an on-treatment biopsy is also required, between Cycle 2 Day 8 and Cycle 2 
Day 21 (inclusive) of trial treatment; and if any additional tumor biopsies are collected that are 
part of normal clinical practice, these will also be examined as described below.  
Biomarker analyses in tumor samples at baseline and during treatment may help to confirm the 
GEN1053 or GEN1053+IM MoAs and enable the identification of biomarkers predictive of 
response to GEN1053 or GEN1053+IM. Tumor biopsies will be evaluated for target expression 
(protein or RNA), as well as molecular profiling to identify potential mechanisms of tumor 
response and/or treatment-induced changes in the immune microenvironment. 

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8.7.2.1 
Protein Expression Analyses 
Expression of proteins related to malignant solid tumor biology or GEN1053 and GEN1053+IM 
MoAs may be evaluated in tumor biopsies by IHC 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. 
8.7.2.2 
RNA Expression Analyses 
RNA sequencing may be performed on tumor biopsies to determine CD27, 
 
 RNA expression levels, as well as to evaluate other potential genes associated with 
CD27, 
 biology, with immune effector cell activation, or with cancer 
biology in general. 
8.7.2.3 
DNA Analyses 
Tumor biopsies may also be analyzed using NGS for analyses of DNA mutations, copy number 
variations, microsatellite instability, indels, and/or rearrangements or polymorphisms in genes 
associated with CD27, 
 expression or function, GEN1053 and 
GEN1053+IM proposed MoAs, or cancer biology in general.  
8.7.3 
Biomarker Assessments in Blood Samples 
Biomarker assessments may also be performed using whole blood samples to investigate 
potential pharmacodynamic markers and explore the relationship to the efficacy and/or MoA of 
GEN1053 and GEN1053+IM. Assessments will be performed at baseline (before infusion at 
Cycle 1 Day 1) and during treatment in order to enable correlation analyses with response to 
treatment or disease biology. 
8.7.3.1 
Immunophenotyping Analyses 
Immunophenotyping (eg, measurement of T cells, B cells, NK cells, monocytes, DCs) may be 
performed at baseline and during treatment at planned visits to evaluate changes associated with 
the MoA of GEN1053 and GEN1053+IM, subject response to GEN1053 and GEN1053+IM, and 
disease biology. Target engagement may be determined at baseline and during treatment at 
planned visits to evaluate changes associated with the MoA of trial treatment, DL, and subject 
response to trial treatment. 
8.7.3.2 
Cytokine or Soluble Factors Analyses 
Cytokine and complement factors (C3a and Bb) analysis may be performed at baseline and 
during treatment at planned visits to investigate safety and potential pharmacodynamic markers 
of GEN1053 and GEN1053+IM. sCD27 analysis may be performed at baseline as an exploratory 
biomarker. 
8.7.3.3 
Cell-Free DNA/RNA (cfDNA/RNA) and Tumor-Derived DNA (ctDNA) Analyses 
cfDNA/RNA, including ctDNA and/or exoRNA, may be measured, and analyses such as RNA 
expression levels, DNA mutations, copy number variations, microsatellite instability, indels, 
CCI
CCI
CCI

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and/or rearrangements in genes may be performed to evaluate the association of such biomarkers 
with GEN1053 and GEN1053+IM MoAs, subject response, or disease biology. 
A whole blood sample may also be evaluated to confirm the tumor specificity of any genomic 
alterations that are identified. Where required by local or country specific regulations, each 
subject must sign a separate ICF indicating agreement to provide samples for genomic biomarker 
analysis (DNA/RNA). 
If DNA/RNA research evaluations are performed, the results may be reported in a separate 
report. 
8.8 
Immunogenicity 
Venous blood samples will be drawn for analysis of ADAs in serum samples as per the time 
points specified in the Schedule of Activities (Section 1.3). 
Samples will be screened for ADAs binding to GEN1053 and the titer of confirmed positive 
samples will be reported. Neutralization characterization of ADAs may also be performed using 
appropriate methods. 
Further details are included in the laboratory manual. 
Samples will be collected to evaluate the presence of ADAs against GEN1053 in monotherapy 
as well as in the combination cohorts. Samples collected for ADAs to GEN1053 in monotherapy 
as well as in combination therapy, may additionally be used to evaluate safety or efficacy aspects 
that address any concerns arising during or after the trial period for further characterization of 
immunogenicity. Genetic analyses will not be performed on these serum samples. Subject 
confidentiality will be maintained.  

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9 STATISTICAL CONSIDERATIONS 
The statistical analysis of the data collected in this trial is the responsibility of the sponsor. A 
description of the statistical methods to be used to analyze the data is outlined below. The 
analyses will be detailed further in the SAP. 
The SAP will be developed and finalized before database lock and will describe the subject 
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. 
Subjects in the Dose Escalation part will typically be analyzed according to the DL received. 
Subjects in the Expansion part will be analyzed according to their assigned Expansion cohort. 
Exploratory analyses may be considered for HNSSC subjects crossing over from GEN1053 to 
GEN1053+IM due to PD. 
The main analyses will be timed as follows:  
• Interim analysis, Monotherapy Dose Escalation phase 1a and Combination therapy 
Dose Escalation phase 1b: Main safety and pharmacodynamic analyses will be conducted 
on all subject data at the end of the escalation (upon completion of DLT evaluation of the last 
subject in the Escalation phase). 
• Primary analysis, Expansion phase 2a: The Expansion part consists of parallel cohorts, 
wherein each Expansion cohort may report its individual main analysis. Main safety, 
pharmacodynamic and efficacy analyses will be conducted at the time all subjects who are 
still receiving trial treatment have at least 2 postbaseline scans performed (such that the 
exploratory efficacy endpoints can be assessed) or have completed the safety follow-up 
period or have ended the trial.  
9.1 
Statistical Hypotheses 
Due to the early stage of this trial, no formal hypothesis testing for confirmative purposes will 
occur.  
9.2 
Sample Size Determination 
No formal sample size calculation was performed.  
In the Dose Escalation and Expansion parts: 
• In the Monotherapy Dose Escalation phase 1a: up to 63 (maximum 9 subjects at each DL) 
subjects who are ≥18 years of age and have malignant solid tumors will be treated. 
• In the Combination therapy Dose Escalation phase 1b: up to 27 subjects (maximum 9 
subjects in each cohort) 
• In the Expansion phase 2a: approximately 80 subjects (approximately 40 for each cohort). 

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For the Expansion part, a sample of 40 per cohort is deemed enough to provide a preliminary 
assessment of efficacy. A sample size of 40 subjects would ensure at least 90% power to detect a 
shift to an ORR of 30% from a base rate of 10% given a 1-sided binomial test at a 5% 
significance level. In addition, efficacy monitoring will be applied as described in Section 9.5. 
9.3 
Populations for Analyses 
9.3.1 
Full Analysis Set 
The FAS and safety set are defined in the same way and will comprise all subjects who receive 
at least 1 dose of trial drug. Subjects will be analyzed according to the actual trial treatment 
received. 
9.3.2 
Safety Set 
The safety set is equal to the FAS. 
9.3.3 
Response Evaluable Set  
The response evaluable set consists of all subjects who have baseline evaluable disease 
according to RECIST 1.1 and at least 1 postbaseline disease assessment. It also includes subjects 
who die or are withdrawn from treatment due to clinical progression before the first response 
assessment; these subjects are treated as nonresponders. 
9.3.4 
Dose-Determining Set 
The DDS will include all FAS subjects in the escalation part who meet the minimum exposure 
criterion and have sufficient safety evaluations or experience a DLT during the first 21 days of 
dosing (ie, in Cycle 1).  
A subject will meet the minimum exposure criterion if the subject receives at least 80% of the 
preplanned dose of each trial treatment during the DLT period. 
Subjects who do not experience a DLT during Cycle 1 (the first 21 days of dosing) will be 
considered to have sufficient safety evaluations if they have been observed for ≥21 days 
following the first dose and are considered by both the sponsor and investigators to have enough 
safety data to conclude that a DLT did not occur. Subjects will be analyzed according to the trial 
treatment received, as defined for the FAS. 
9.3.5 
Pharmacokinetic Analysis Set 
The PAS will include all subjects who receive at least 1 dose of trial drug and who provide at 
least 1 evaluable PK sample for GEN1053 in monotherapy and combination therapy. Refer to 
Table 1-3, Table 1-6, Table 1-10, Table 1-15 and Table 1-16 for further detail on sampling times.  
9.3.6 
Immunogenicity Analysis Set 
The IAS will include all subjects who receive at least 1 dose of GEN1053 as monotherapy or 
combination therapy and have a baseline and at least 1 evaluable on-treatment (predose) ADA 
sample for GEN1053 as monotherapy or combination therapy. 

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9.4 
Statistical Analyses 
This section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. The SAP will be finalized prior to database 
lock, and it will include a more technical and detailed description of the statistical analyses 
described in this section. 
Baseline is the last available measurement prior to first dosing of trial treatment, if not otherwise 
specified. 
9.4.1 
Subject Demographics and Baseline Characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively for all subjects, by dose cohort and by indication in Expansion for the 
FAS. 
Relevant medical histories and current medical histories at baseline will be summarized 
separately by system organ class and/or preferred term, (for all subjects, by dose cohort, and by 
indication in Expansion). 
9.4.2 
Efficacy 
9.4.2.1 
Antitumor Activity Based on RECIST 1.1 
RECIST criteria (v1.1) will be used to define response (Eisenhauer et al., 2009). Additional 
details of RECIST can be found in Appendix 7. 
The BOR is the best response recorded from the start of the treatment until PD/recurrence (the 
smallest measurements recorded will be used as the reference for PD). Subjects with CR or PR 
are considered to be objective responders. Subjects with CR, PR, or SD are considered to be in 
disease control. Subjects for whom data are NE are counted as nonresponders.  
The best change (maximal reduction in the sum of the diameters in the target lesions) in target 
lesions at any time on trial will be reported using waterfall plots. 
Individual subject data listings and summaries of objective response, best overall tumor 
response, and disease control will be presented by dose cohort/indication and total.  
9.4.2.1.1 
Objective Response Rate 
The confirmed ORR is defined as the proportion of subjects with BOR of confirmed CR or 
confirmed PR (ie, “responders”), as per local review and according to RECIST v1.1. Repeat 
imaging may be performed no less than 4 weeks after the criteria for CR or PR are met to 
confirm the initial response. 
An assessment of SD requires at least 5 weeks from C1D1 to scan date. 

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9.4.2.1.2 
Duration of Response 
DoR only applies to subjects whose confirmed BOR is CR or PR and is defined as the time from 
the first documentation of objective tumor response (CR or PR) to the date of first PD or death 
due to any cause.  
DoR will be censored and summarized in the same way as PFS, see below. 
9.4.2.2 
Exploratory Objectives 
9.4.2.2.1 
Biomarkers 
Biomarker analyses in this trial are exploratory and focused on confirming the MoA of 
GEN1053, identifying potential PD markers to help identify the appropriate dose and schedule of 
GEN1053, and identifying potential predictive markers that may be further validated in 
prospective trials with GEN1053.  
Expression of biomarkers, such as CD27, 
 on peripheral immune cell 
populations, as well as cytokine measurements, will be tabulated for all subjects who have 
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 objective 
response, PFS, and OS. Subgroup analyses may be performed to evaluate differences between 
biomarker parameters in groups of responders and nonresponders 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. Subjects may be grouped by cohort, dose schedule, or clinical response. Further 
details will be provided in the SAP. 
Results of biomarker analyses may also be presented in a separate report. 
9.4.2.2.2 
Antitumor Activity Based on iRECIST 
Responses assigned using iRECIST (NCCN, 2021a; Seymour et al., 2017) have a prefix of “i” 
(eg, iCR or iPR, and iUPD or iCPD) to differentiate them from responses assigned using 
RECIST 1.1. Similar nomenclature is used for iSD, iPFS, iDoR, iDCR, and iORR. 
The exploratory analysis methodology is similar to that described in Section 9.4.2.1. 
9.4.2.2.3 
Progression-Free Survival 
PFS is defined as the time from the date of C1D1 to the date of the first documented PD or death 
due to any cause. PFS will be assessed via local review according to RECIST v1.1 (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).  
CCI

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PFS will be analyzed in the FAS population. The PFS distribution will be estimated using the 
Kaplan-Meier method, and the Kaplan-Meier curves, medians, and 95% CIs of the medians will 
be presented for each Expansion cohort.  
9.4.2.2.4 
Overall Survival 
OS is defined as the time from date of C1D1 to date of death due to any cause. If a subject is not 
known to have died, then OS will be censored at the latest date the subject was known to be alive 
(on or before the cutoff date). 
The OS distribution will be estimated using the Kaplan-Meier method, and the Kaplan-Meier 
curves, medians, first and third quartiles, and 95% CIs of the medians will be presented for each 
Expansion cohort. 
9.4.2.2.5 
Tumor Growth 
Prebaseline scans will be collected to explore tumor growth and selected, concomitant 
prebaseline laboratory data (neutrophils, lymphocytes, platelets, hemoglobin, albumin, and 
LDH) will be collected to explore their association with tumor growth prior to treatment, and to 
evaluate drug effect on tumor growth. For this analysis, scans will be centrally read to ensure a 
consistent reading of prebaseline and on-treatment scans. These central readings will only be 
used to evaluate the prebaseline and on-treatment change in tumor size based on target lesions. 
The response to treatment described in Section 9.4.2.1 will be based on investigator readings. 
The results of this exploratory analysis will be reported in a separate report. 
9.4.3 
Safety 
9.4.3.1 
Adverse Events 
For all safety analyses, the FAS (which is identical to the safety set) will be used. 
The overall observation period will be divided into 3 mutually exclusive segments: 
1. Pretreatment period: from day of subject’s informed consent to the day before first dose of 
trial medication 
2. On-treatment period: from day of first dose of trial medication to 30 days after last dose of 
trial medication 
3. Posttreatment period: starts when the on-treatment period ends 
Summary tables for AEs will include only AEs that started or preexisting AEs that worsened 
during the on-treatment period (ie, TEAEs).  
The incidence of TEAEs (new or worsening from baseline) will be summarized by system organ 
class and/or preferred term; intensity (based on grades of NCI-CTCAE version 5.0) (see Section 
8.4.1); type of AE; relationship to each trial treatment. 
SAEs, nonserious AEs, and AESIs during the on-treatment period will be tabulated.  

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All deaths (on-treatment and posttreatment) will be summarized.  
All AEs, fatal AEs, AESIs, and SAEs (including those from the pre- and posttreatment periods) 
will be listed and those collected during the pretreatment and posttreatment period will be 
flagged. 
Further summaries of AEs will be specified in the SAP. 
9.4.3.2 
Clinical Laboratory Tests 
Grading of laboratory values will be assigned programmatically as per NCI-CTCAE version 5.0. 
The calculation of CTCAE grades will be based on the observed laboratory values only, clinical 
assessments will not be considered. 
CTCAE grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
9.4.3.3 
Other Safety Data (eg, Vital Signs, ECG Parameters) 
The following will be provided, as necessary. 
• ECOG-PS will be summarized. 
• Abnormal findings in physical examinations will be summarized. 
• 12-lead ECGs including PR, QRS, QT, heart-rate-corrected QTcF, and RR intervals will be 
obtained for each subject during the trial. ECG data will be read and interpreted centrally in 
the Dose Escalation phase only. Any relationship between QTcF and PK concentrations 
across DLs and time points will be investigated.  
• Vital signs data will be tabulated and listed; notable values may be flagged. 
9.4.3.4 
Patient-Reported Outcomes 
Not applicable 
9.4.4 
Pharmacokinetic Analyses 
Individual curves of concentration of GEN1053, including information on actual dose, will be 
presented for all subjects. All available data will be shown in these figures. PK parameters will 
be calculated based on noncompartmental methods as specified in Table 9-1. These PK 
parameters will be calculated separately for the Cycle 1 and Cycle 3 administrations. Cmax, tmax, 
and predose values will be summarized and presented graphically for all trial days where 
measured. 
The relationship between derived PK parameters and covariates such as actual dose, weight, and 
selected laboratory parameters will be evaluated graphically. 
Descriptive statistics of PK endpoints will include arithmetic and geometric means, standard 
deviation, %CV, median, minimum, and maximum. 

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Missing concentration values will be reported as is in data listings. Concentration values below 
LLOQ will be handled as LLOQ/2 in summary statistics and reported as is in data listings. Any 
missing PK parameter data will not be imputed. 
Further exploratory analyses of PK data may be performed. 
Table 9-1 
Noncompartmental Pharmacokinetic Parameters 
CL 
The total body clearance of drug from the plasma 
V 
Volume of distribution 
t1/2 
The elimination half-life associated with the terminal slope (λz) of a semi-
logarithmic concentration-time curve 
Cmax 
The maximum (peak) observed plasma, blood, serum, or other body fluid 
drug concentration after single dose administration 
Ctrough 
The minimum observed plasma, blood, serum, or other body fluid drug 
concentration prior to the subsequent dose.  
tmax 
The time to reach maximum (peak) plasma, blood, serum, or other body fluid 
drug concentration after single dose administration 
AUCtau 
The AUC from time zero to day 21 (mass × time × volume ˗1) 
AUClast 
The AUC from time zero to last quantifiable measurement 
 
9.4.5 
Pharmacodynamic Analyses 
Please see Section 9.4.6. 
9.4.6 
Biomarker Analyses 
The exploratory biomarker assessments are intended to evaluate potential pharmacodynamic and 
safety biomarkers, and to identify markers predictive of response or resistance to GEN1053 as 
monotherapy or in combination with IM. Since this clinical trial is not designed to test specific 
biomarker-related statistical hypotheses, the analysis of these data should be viewed as 
exploratory and hypotheses-generating. Analyses may include how the peripheral T-cell 
activation and proliferation and cytokine release distribute between the type of responder groups. 
Descriptive analysis will be performed, and further details for additional analyses will be defined 
in the SAP. Results from exploratory biomarker assessments may be documented in separate 
reports. 
Biomarkers, including pharmacodynamic markers, may be listed, tabulated, and plotted when 
deemed appropriate. Analyses may be stratified by clinical covariates or molecular subgroups 
using the appropriate statistical methods (eg, ANCOVA), proportional hazards regression, or 
Kaplan-Meier methods) depending on the endpoint and the hypotheses. Baseline biomarker 
levels or changes in biomarker levels may be assessed for correlation with tumor response and 
other clinical endpoints to identify responsive or resistant subgroups, as well as biomarkers or 
pathways attenuated following treatment. 
Additional analyses that may be performed after the completion of the end-of-trial CSR will be 
documented in separate reports. These analyses may include but are not limited to the meta-
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generated from samples collected during the trial but analyzed after the database lock and 
completion of the CSR. These analyses will be described in an addendum of the SAP, or in a 
standalone analysis plan document, as appropriate. 
Planned analyses are based on the availability of clinically valid assays and may be deferred if 
emerging trial data show no likelihood of providing useful scientific information. 
9.4.7 
Immunogenicity Analyses 
ADA titers to GEN1053 in monotherapy or in combination therapy will be separately listed and 
positive/negative host immune response to GEN1053 and presence of neutralizing antibodies 
may be summarized (positive/negative). The presence of PK concentrations above a certain 
threshold, which depend on the drug tolerance of the ADA assay at the same time as the ADA 
sample, may make the ADA undetectable and hence render nonconclusive. The association 
between positive/non-positive ADA, PK (predose, AUC, Cmax) and safety findings will be 
explored. 
9.4.8 
Health Economics 
Not applicable 
9.4.9 
Multiplicity 
There will be no correction for multiple tests. 
9.4.10 
Subgroup Analyses and Effect of Baseline Factors 
To determine whether the treatment effect is consistent across various subgroups, the estimate of 
the between-group treatment effect (with a nominal 95% CI) for the ORR will be estimated and 
plotted within each category of the following classification variables (where applicable): 
• Age category (eg, <65, ≥65 years) 
• Sex (female, male) 
• Race category (where permitted) 
• ECOG status 
• Geographic region of enrolling site  
• Histology (eg, squamous, nonsquamous) 
• Smoking status  
• Prior therapy 
The consistency of the treatment effect will be assessed descriptively via summary statistics by 
category for the classification variables listed above. 

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10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS – APPENDICES  

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Appendix 1. Regulatory, Ethical, and Trial Oversight Considerations 
The principles of the Declaration of Helsinki, the consolidated ICH-GCP, and applicable 
regulations and national law(s) (eg, 21 CFR and European regulation 536/2014 for clinical trials) 
in the country(ies) where the trial takes place shall constitute the main reference guidelines for 
ethical and regulatory conduct. 
ICH GCP E6(R2) 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 subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the trial data are credible. 
The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, advertisements) 
must be submitted to an IRB/IEC by the investigator and reviewed and approved by the IRB/IEC 
before the trial is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate hazard 
to trial subjects. 
Investigator Responsibilities 
The investigator is responsible for ensuring that the trial is performed in accordance with the 
protocol, ICH GCP E6(R2), and applicable regulatory and country-specific requirements. This 
includes supervision of the trial and staff. Delegation of responsibilities should be to only 
qualified staff and should be documented. In case the investigator is unavailable (eg, on 
vacation), the investigator should ensure that a qualified, trained deputy physician is available for 
medical care of the subjects. The investigator shall notify the sponsor immediately of any serious 
breach of ICH GCP E6(R2), the protocol, or any regulation where required. 
Independent Ethics Committee or Institutional Review Board 
This trial will be undertaken only after the IEC/IRB has given written approval of the final 
protocol, amendments to the protocol (if applicable), the ICF, applicable recruiting materials, 
and subject compensation programs, and the sponsor has received a copy of this written 
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved. 
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data, or trial conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and written approval before 
implementation of the change(s). 
The IB and updates to the IB, unexpected SAEs where a causal relationship cannot be ruled out, 
serious breaches, serious non-compliance, annual written summaries of the trial status, and 
deviations to the protocol implemented to eliminate immediate hazards to the subjects must be 
submitted to the IEC/IRB. 

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Interim reports on the trial and/or review(s) of trial progress will be submitted by the 
investigator, where applicable, to the IEC/IRB at intervals stipulated in its guidelines. 
At the end of the trial, the investigator (or sponsor where required) will notify the IEC/IRB about 
the trial completion, within the required timelines. 
Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the trial and for 
1 year after completion of the trial. 
Administrative Procedures 
Protocol Amendments 
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. Approval must be obtained from the IRB/EC and regulatory authorities (as 
locally required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to subjects or changes that involve logistical or administrative 
aspects only (eg, change in the sponsor’s medical monitor or contact information). 
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 deviation from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the sponsor (see the separate 
sponsor Contact Information page, which will be provided separately from the protocol). Except 
in emergency situations, this contact should be made before implementing any deviations 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 documented in the eCRF and 
source documents will reflect any deviation from the protocol, and the source documents will 
describe this departure and the circumstances requiring it. 
Regulatory Documentation 
This protocol and any amendments must be submitted to the appropriate regulatory authorities in 
each respective country, in accordance with local regulations. A trial may not be initiated until 
all local regulatory requirements are met. 
Subject Identification, Enrollment, and Screening Logs 
The investigator agrees to complete a subject identification log to permit easy identification of 
each subject during and after the trial. This document will be reviewed by the sponsor trial-site 
contact for completeness. 
The subject identification log will be treated as confidential and will be filed by the investigator 
in the Investigator Site file and will never be transferred to the sponsor or any third parties. To 

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ensure subject confidentiality, no copy will be made. All reports and communications relating to 
the trial will identify subjects by their unique subject identifier. 
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the trial. 
Informed Consent Process 
The ICF(s) that is/are used must be approved by the reviewing IEC/IRB and be in a language 
that the subject can read and understand. The ICF should be in accordance with principles that 
originated in the Declaration of Helsinki, ICH GCP E6(R2), applicable regulatory requirements, 
and sponsor policy. 
It is the personal responsibility of the investigator or an authorized member of the trial-site 
personnel to explain to potential subjects (or their legally acceptable representatives [not 
applicable in EU/EEA]) the aims, methods, reasonably anticipated benefits, and potential 
hazards of the trial, and any discomfort participation in the trial may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time without justifying the reason. They will be informed that 
choosing not to participate will not affect the care the subject will receive for the treatment of 
their disease. Subjects will be told that alternative treatments are available if they refuse to take 
part and that such refusal will not prejudice future treatment. Finally, they will be told that the 
investigator will maintain a subject identification register for the purposes of long-term follow up 
if needed and that their records may be accessed by IRB/IEC and health authorities and 
authorized sponsor personnel without violating the confidentiality of the subject, to the extent 
permitted by the applicable law(s) or regulations. 
By signing the ICF the subject (or legally acceptable representative [not applicable in EU/EEA]) 
is authorizing such access, including permission to obtain information about survival status, and 
agrees to allow their trial physician to recontact the subject for the purpose of obtaining consent 
for additional safety evaluations, if needed, and subsequent disease-related treatments, or to 
obtain information about survival status. 
The subject (or his/her legally acceptable representatives [not applicable in EU/EEA]) will be 
given sufficient time to read the ICF and the opportunity to enquire about details of the trial prior 
to deciding whether to participate in the trial. After this explanation and before any trial-specific 
procedure is performed, consent should be appropriately documented by means of either the 
subject’s or their legally acceptable representative’s (not applicable in EU/EEA) personally dated 
signature. 
Subjects (or his/her legally acceptable representative [not applicable in EU/EEA]) will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
European regulation 536/2014 for clinical studies, local regulations, ICH guidelines, HIPAA and 
EU GDPR requirements, where applicable, and the IRB/IEC or trial center. The investigator or 
authorized person obtaining the informed consent must also sign and date the ICF. After having 
obtained the consent, a copy of the ICF must be given to the subject. 

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If the subject (or legally acceptable representative [not applicable in EU/EEA]) is unable to read 
or write, an impartial witness should be present for the entire informed consent process (which 
includes reading and explaining all written information) and should personally date and sign the 
ICF after the oral consent of the subject (or legally acceptable representative [not applicable in 
EU/EEA]) is obtained. 
The sponsor will, on an ongoing basis, assess whether reconsent of subjects is needed. A subject 
who is rescreened is not required to sign another ICF unless the subject’s rights, risks regarding 
trial participation, or well-being has changed since the first ICF was obtained. 
A separate ICF will be used for the required DNA/RNA research component of the trial if 
required by local regulations. 
Data Protection 
The investigator will ensure that the confidentiality of all subjects’ data will be preserved. In the 
eCRF or any other documents submitted to the sponsor/sponsor’s representative, the subjects 
will not be identified by their names, but by an identification code, which consists of an assigned 
number in the trial. The confidential subject identification code and the signed ICF will be 
maintained by the investigator in strict confidence. 
In relation to the collection and handling of data, including any personal data, potential risks to 
the subjects have been assessed and adequate technical and organizational measures are 
implemented to ensure a level of security appropriate to the risk. The security measures 
implemented entail among other things that: 
• Access to data has been restricted so that access is only granted to authorized individuals. 
• Data are only stored on IT systems and networks that are protected against virus, malware, 
and unauthorized access. 
• Data are backed-up at regular intervals. In case of a data breach, a clear allocation of roles 
and responsibilities for managing the data breach, including notifying affected subjects and 
authorities, has been established in order to mitigate any adverse impact on the subjects. 
Additional technical security measures implemented include that: 
• All data are encrypted when at rest. 
• Data has been pseudonymized to the effect that only authorized individuals can link data to 
identified individuals. 
• A data breach response plan has been established. 
The collection and processing of personal data from subjects enrolled in this trial will be limited 
to those data that are necessary to fulfill the objectives and purposes of the trial and as 
specifically defined in the protocol. 
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 

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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, as detailed above. Sponsor personnel whose responsibilities require access to 
personal data agree to keep the identity of subjects confidential. 
The informed consent obtained from the subject (or their legally acceptable representative [not 
applicable in EU/EEA]) includes explicit consent or description of other legal basis for the 
processing of personal data for the purpose of the trial and for the investigator/institution to 
allow direct access to 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, as specified in the ICF. 
The subject has the right to request access to their personal data and the right to request 
rectification of any data that are not correct or complete by contacting the investigator. 
Reasonable steps will be taken by the investigator to respond to such a request, taking into 
consideration the nature of the request, the conditions of the trial, the clinical trial agreement 
including any other relevant agreement, and applicable laws and regulations. The investigator 
will inform and work together with the sponsor when handling such requests. 
In case of a potential data breach of the personal data, the investigator will inform the sponsor 
immediately and will contain the breach from spreading, where possible. Investigator and 
sponsor will work together to assess the risk to the individuals concerned, based on the 
circumstances of the case, including which data was involved, what security measures were in 
place (for instance, if the data was encrypted or pseudonymized), who might have accessed the 
data, etc. 
Based on this assessment, the data breach might be reported to the relevant authorities and/or the 
individuals concerned. Mitigating actions will be taken to avoid this event from reoccurring. 
Committees Structure 
Dose Escalation Committee: 
The DEC will be chaired by the sponsor’s medical monitor (or delegate) and membership will 
include investigator(s), a sponsor clinical scientist, a safety physician, a statistician, a clinical 
pharmacologist, and other sponsor staff, as appropriate. The DEC will meet at regular frequency 
throughout the Dose Escalation part. 
The schedule of DEC meetings will depend on the completion of DLT(s) evaluation period. 
All available data, including but not limited to safety, PK, and pharmacodynamic data, covering 
the DLT evaluation period will be reviewed by the DEC. Cumulative data from prior DLs and 
treatment doses after the DLT period may also be presented. Recommendations on dose 
escalation (or de-escalation) will be made by the DEC to the Safety Committee. 
Safety Committee: 
The sponsor’s SC is a cross-functional committee that evaluates the evolving safety profile of the 
product, supports assessment of the product's benefit-risk profile and recommends risk 
management strategies to ensure safety of subjects who participate in Genmab sponsored clinical 

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trials or subjects treated with marketed Genmab drugs. For the GCT1053-01 Dose Escalation 
phase, the SC will consider the recommendation made by the DEC and make the final decision 
regarding dose escalation (or de-escalation). Additionally, the SC will consider the DMC’s 
recommendations regarding proceeding of the trial to the next trial design phase including 
recommendations for the RP2D for both GEN1053 monotherapy and combination therapy. 
During the Expansion phase, the SC will meet at regular intervals and as needed as per the SC 
charter. 
The SC can stop further enrollment if treatment-emergent toxicity is determined to result in an 
unfavorable change in subject benefit-risk. Enrollment may be temporarily held, if needed, for 
the SC to evaluate the emerging data. In case of emerging safety issues with potential impact on 
the trial conduct, the SC will consult the DMC on an ad hoc basis. 
Decisions will be communicated to investigators. Decisions with potential to affect subject safety 
(eg, due to unfavorable change in benefit-risk assessment) will be promptly communicated to 
investigators and regulatory authorities, as required. 
Data Monitoring Committee: 
A DMC will be established to ensure the continuing safety of the subjects enrolled in this trial as 
an external advisory body. The DMC will assess the totality of safety information of the trial to 
propose whether the trial can proceed to the subsequent design phase. This committee will 
consist of at least 3 members with a minimum of 1 medical expert in the relevant therapeutic 
area; the committee membership responsibilities, authorities, and procedures will be documented 
in its charter.  
During the trial, the DMC will review data with emphasis on safety results at the decision points, 
when the trial is to proceed to the subsequent trial design phase. The DMC is to recommend 
whether the risks to trial subjects remain acceptable and that adequate risk mitigation plans are in 
place to safeguard subjects’ safety as the trial progresses. The relevant decision points are: 
1. The opening of the combination arm in the Dose Escalation phase 1b 
2. The declaration of the RP2D for GEN1053 monotherapy based on the dose escalation in the 
Monotherapy Dose Escalation phase 1a and the opening of the monotherapy cohort in the 
Expansion phase  
3. The declaration of the RP2D for the GEN1053+IM combination based on the combination 
therapy dose escalation in the Combination therapy Dose Escalation phase 1b and the 
opening of the combination cohort in the Expansion phase 
The DMC will also be presented with the trial analyses upon trial completion. 
All available data, including safety, PK, and pharmacodynamic data, will be reviewed by the 
DMC. After review, the DMC will make recommendations to the SC regarding the continuation 
of the trial. The DMC can recommend that the trial should be stopped for unacceptable toxicity 
based on a risk-benefit assessment. Deaths considered related to GEN1053 will always be 
assessed by the DMC. 

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The DMC will also be available on an ad hoc basis, ie, to advise and recommend actions in 
relation to urgent safety signals, mitigation plans, etc, if requested by the SC. Additionally, if 
other compounds are to be tested in combination with GEN1053 or/and if alternative 
doses/schedules are to be tested in the escalation period, the DMC may be consulted for their 
recommendation. The SC will conclude on any such decision. 
Dissemination of Clinical Trial Data 
The protocol information will be registered in a publicly accessible database (eg, 
clinicaltrials.gov, CTIS, and/or other national registries/Health Authority websites). In addition, 
after trial completion (defined as last subject last visit globally) and finalization of the study 
report, the results of this trial will be submitted for disclosure and posted in a publicly accessible 
database of clinical trial results as required by local regulations (eg, clinicaltrials.gov, CTIS).  
Data Quality Assurance, Record Retention, Monitoring, and On-Site Audits 
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 (or sponsor’s 
delegate), and direct transmission of clinical laboratory data from a central laboratory, ECG data 
from the ECG vendor, and review of radiographic scans, pathology reports (as applicable) from 
the central imaging vendor into the sponsor’s database. Written instructions will be provided for 
collection, handling, storage, and shipment of samples. 
Guidelines for eCRF completion will be provided. The sponsor/CRO will review eCRFs for 
accuracy and completeness during on-site or remote 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, the data will be reviewed for accuracy and 
consistency with the data sources. 
Record Retention 
In compliance with ICH GCP E6(R2), 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 subject, 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 
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. Medical Records (subjects’ hospital record) is retained/archived 
according to applicable local regulation. 
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 qualified and trained 

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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. 
Monitoring 
The sponsor will use a combination of remote and on-site monitoring to monitor this trial. The 
sponsor or delegate 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 (ie, the first subject has 
signed the ICF) has begun. At these visits, the monitor will verify 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. Where allowed in 
accordance with local regulations, or in the event of a national emergency, and in agreement with 
the investigator, remote source data verification or source data review may be performed. 
The investigator must permit the monitor access to all source data, including electronic medical 
records, and/or documents with 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 contact 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. 
On-Site Audits and Inspections 
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. Subject privacy 
must, however, be respected. The principal 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 designee(s). 
Similar procedures for inspections 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 

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support of a regulatory submission. The investigator should immediately notify the sponsor if 
they have been contacted by a regulatory agency concerning an upcoming inspection. Regulatory 
inspectors must be allowed direct access to original medical records (source data/documents). 
Source Documents and Case Report Form Completion 
Source Documentation 
Source documents provide evidence for the existence of the subject and substantiate the integrity 
of the data collected. Source documents are filed at the investigator’s site. At a minimum, the 
type and level of detail of source data available for a subject should be consistent with that 
commonly documented at the trial site as a basis for standard medical care. Specific details 
required as source data for the trial will be reviewed with the investigator before the trial, 
described in the monitoring guidelines (or equivalent), and captured in a source data verification 
log at site. 
For each subject, the investigator must indicate in the hospital/medical source records that the 
subject participates in this trial and the date of obtaining the ICF. The records should document 
data on the condition of the subject at the time the subject is enrolled in the trial, to enable 
verification of eligibility. Limited redacted source documents can be shared with the sponsor 
during screening for eligibility determination, where permitted by local regulations. Signed and 
dated ICFs will be stored and archived according to local requirements. In addition, the 
following information, at the minimum, will also be recorded in the hospital/medical source 
records for each subject: 
• Subject’s name and date of birth. 
• Screening/subject/randomization number 
• Trial identification. 
• Confirmation of eligibility for participation in the trial, including diagnosis. 
• Medical history. 
• Date of each visit. 
• Any assessment performed eg, results of safety and efficacy evaluations. 
• Concomitant medications. 
• Occurrence of any AEs/SAEs (including description and duration). 
• Status of the subject at the end of trial. 
• Reason for treatment discontinuation/trial withdrawal, if applicable. 
Any worksheets used to capture data to facilitate completion of the eCRF will become part of the 
subject's source documentation. In some cases, eg, demographic data (race, ethnicity, sex at 
birth), the eCRF may be considered the subject’s source documentation. 

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In addition to the source data in medical records, data may be recorded directly electronically 
(eg, ECGs, PROs). Such data are considered source data and are accessible by both the 
investigator and sponsor. 
The author of an entry in the source should be identifiable. 
Information included in the subject’s hospital records may be subject to local regulations. If there 
is a discrepancy between local requirements and the protocol, local regulations should be 
followed. 
Case Report Form Completion 
CRF data will be transcribed into an EDC system by trial-site personnel from the source 
documents. Both EDC and other electronically captured trial data will be transmitted in a secure 
manner to the sponsor within agreed upon time frames. 
Data relating to the trial must be documented and reported in English. Trial site personnel must 
complete the CRF as soon as possible after the data are available and preferably within 5 days. 
Source data and the CRFs should be available for review at the next scheduled monitoring visit. 
All eCRF entries, response to queries, corrections, and alterations must be made by the 
investigator or other authorized trial-site personnel. The completed eCRF must be verified and 
approved by the investigator or qualified physician who is a subinvestigator and who is 
delegated this task on the Delegation of Authority Form. 
Corrections to the eCRF after data entry can be done as follows (corrections must be verified and 
approved by the investigator or qualified physician who is a subinvestigator and who is 
delegated this task on the Delegation of Authority Form): 
• 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 sponsor or designee can generate a query for resolution by the trial-site personnel. 
Trial and Site Start and Closure 
The trial start date will be the first act of recruitment (ie, the first subject signs the informed 
consent form). 
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. 
In addition, the investigator may initiate trial-site closure at any time, provided there is 
reasonable cause and sufficient notice is given to the sponsor in advance of the intended 
termination. 

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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 guidance documents/trial plans, ICH GCP E6(R2), and 
applicable regulatory requirements. 
• Inadequate recruitment of subjects by the investigator 
• Discontinuation of further GEN1053 and/or IM development. The sponsor may, based on 
available data, discontinue further development of GEN1053 and/or IM. Following trial 
termination, the sponsor will make their best effort to provision posttrial access to GEN1053 
and/or IM for those ongoing trial subjects with a potential treatment benefit, in accordance 
with local laws and requirements.  
If the trial is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the trial of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the subject(s) and should ensure appropriate subject therapy 
and/or follow-up. 
Liabilities and Insurance 
The sponsor is responsible for taking out relevant clinical trial insurance in accordance with local 
law and regulations. 
Publication Policy 
All information, including but not limited to information regarding GEN1053 monotherapy or 
GEN1053+IM combination therapy or the sponsor’s operations (eg, 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 
exploratory 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. CROs involved in the trial are not 
permitted to publish without the sponsor’s prior written approval. 
The investigator understands that the information developed in the trial will be used by the 
sponsor in connection with the continued development of GEN1053 or GEN1053+IM, and thus 
may be shared as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical trial to be used, the investigator is obligated to provide the 
sponsor with all data obtained in the trial. 
Trial subject 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. 

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Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines (Battisti et al., 2015; ICMJE, 2010; ICMJE, 2019), the sponsor in conjunction 
with any collaborative group(s), shall have the right to publish such primary (multicenter) data 
and information as per the prespecified and approved publication plan. 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-trial 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 current version of ‘Recommendations for the 
Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals’ (ICMJE 
Recommendations), 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. 

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Appendix 3. Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting 
Definitions 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical trial subject, 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. 
Definition of Serious Adverse Events 
An SAE is defined as an AE that meets 1 of the following criteria: 
• Is fatal or life-threatening: 
o The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject 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 were more severe. 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, ie, defined as an event that jeopardizes the subject or may require 
medical or surgical intervention to prevent 1 of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Hospitalizations for the following reasons should not be reported as SAEs: 
o Routine treatment or monitoring of the underlying disease, not associated with any 
deterioration in the condition 
o Solely due to progression of the underlying cancer 
o Elective or preplanned treatment for a preexisting condition that is unrelated to the 
underlying disease and has not worsened since signing the ICF 
• Social reasons and respite care in the absence of any deterioration in the subject’s general 
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• Treatment on an emergency outpatient basis that does not result in hospital admission and 
involves an event not fulfilling any of the definitions of an SAE given above. 
Definition of Adverse Events of Special Interest 
• AESIs are defined as events (serious or nonserious) 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. AESIs are defined 
on the basis of an ongoing review of the safety data. AESIs are defined for this protocol in 
Section 8.4.1.1 and discussed further in the IB. 
Definition of Infusion-Related Reactions 
IRRs are defined as any AE occurring during infusion or where the onset of the event occurs 
within 24 hours after ended infusion. For IRRs, the causality of the event should be judged as 
“related” by the investigator. 
Investigators should consider the clinical picture and isolated events, such as “fatigue,” occurring 
within 24 hours after the end of infusion and assess whether they do or do not constitute an IRR. 
Reporting Period 
This is trial specific and defined in Section 8.4.2, Adverse Event Reporting. Events requiring 
immediate reporting are listed in Section 8.4.3. 
Procedures for Recording and Reporting 
All AEs, serious or nonserious, must be documented. 
• The diagnosis/cause of an AE should be documented rather than the symptoms of the AE. 
• If no diagnosis is available, then each sign and symptom should be documented as an 
individual AE. 
• All AEs that occur during the AE reporting period must be documented, whether or not the 
event is considered treatment-related. 
• All AEs should be documented and reassessment made at each visit (or more frequently, if 
necessary). 
• Final assessment of AEs must be performed by a medically qualified person. 
Laboratory abnormalities that are considered clinically significant, induce clinical signs or 
symptoms, require concomitant therapy, or require changes in trial treatment should be 
documented as an AE. 
• Whenever possible, a diagnosis should be provided (eg, 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 for the abnormality is found. 

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Note: A CTCAE grade 3 or 4 laboratory abnormality does not automatically indicate an 
SAE. 
Disease-related events and outcomes not qualifying as AEs or SAEs are trial specific and 
provided in Section 8.4.5. 
Evaluation of Adverse Events 
Severity 
Toxicities will be graded for severity according to the NCI-CTCAE, version 5.0. Exception are 
CRS events, which are to be graded by ASTCT criteria (Lee et al., 2019). 
Relationship to Trial Treatment 
The investigator must assess whether or not the event is related to the individual trial treatment. 
If a subject is on combination treatment, this assessment should be done separately for each trial 
treatment. The relationship is to be judged using the following terms: 
• 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 event is being reported. 
A suspected adverse reaction is one in which there is a reasonable possibility that the trial 
treatment caused the AE, this means there is evidence to suggest a causal relationship between 
the trial treatment and the AE (ie, considered related). Refer to the IB. 
Annual Safety Reporting by Sponsor 
Within the EU, the sponsor will submit an Annual Safety Report for GEN1053, including data 
on multi-drug therapy. 
 

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Appendix 4. Definition of Reproductive Potential and Contraception 
A man who is sexually active with a woman of childbearing potential and has not had a 
vasectomy must agree to use a barrier method of birth control, eg, either condom with 
spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, during the trial and for 
6 months after the last GEN1053 administration; all men must also refrain from donating sperm 
during the trial and for 6 months after receiving the last dose of GEN1053. When the IM is 
selected, the duration since last dose will be defined. 
Female subjects of reproductive potential must agree to use adequate contraception during and 
for 6 months after receiving the last dose of GEN1053. When the IM is selected, the duration 
since last dose will be defined. Adequate contraception is defined as highly effective methods of 
contraception (see Table 10-2). Birth control methods are considered highly effective if they 
have a failure rate of less than 1% per year when used consistently and correctly. 
In this trial, subjects are considered to have reproductive potential unless they are 
postmenopausal or permanently sterile. 
• A postmenopausal state is defined as no menses in subjects >45 years of age for 12 months 
without an alternative medical cause. A high FSH level in the postmenopausal range may be 
used to confirm a postmenopausal state in subjects not using hormonal contraception or 
hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a 
single FSH measurement is insufficient. 
• Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy. 
All female subjects must agree not to donate eggs (ova, oocytes) for the purpose of assisted 
reproduction during the trial and for 6 months after receiving the last dose of GEN1053 or IM.  
Table 10-2 
Highly Effective Methods of Contraception 
• 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulationa: 
○ 
Oral 
○ 
Intravaginal  
○ 
Transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulationa: 
○ 
Oral 
○ 
Injectable 
○ 
Implantableb 
• 
Intrauterine deviceb 
• 
Intrauterine hormone-releasing systemb 
• 
Bilateral tubal occlusionb 
• 
Vasectomized partnerb, c 
• 
Sexual abstinenced 
a. Hormonal contraception may be susceptible to interaction with GEN1053 or IM, which may reduce the efficacy 
of the contraception method, and therefore must be supplemented with a barrier method for non-vasectomized 
male partner (preferably a condom with spermicidal foam/gel/film/cream/suppository). 
b. Contraception methods that, in the context of this guidance, are considered to have low user dependency. 

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c. Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner 
of the female subject of reproductive potential (ie, the trial subject) and that the vasectomized partner has 
received medical assessment of the surgical success. 
d. In the context of this guidance, 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 trial treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject. 
Table adapted from “Recommendations related to contraception and pregnancy testing in clinical trials, version 
1.1.” (CTFG, 2020). 

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Appendix 5. Sample Storage and Destruction 
Any sample collected according to the Schedule of Activities (Section 1.3) can be analyzed for 
any of the tests outlined in the protocol and for any tests necessary to minimize risks to trial 
subjects. This includes testing to ensure analytical methods produce reliable and valid data 
throughout the course of the trial. This can also include, but is not limited to, investigation of 
unexpected results, incurred sample reanalysis, and analyses for method transfer and 
comparability.  
All samples and associated results will be coded before being shipped from the site for analysis 
or storage. Samples will be tracked using a unique identifier that is assigned to the samples for 
the trial. Results are stored in a secure database to ensure confidentiality.  
Exploratory biomarker research may also be performed to investigate and better understand 
NSCLC, HNSCC, and other malignant solid tumors; the dose response and/or prediction of 
response to GEN1053; and characterize aspects of the molecule (eg, MoA/target, metabolites). 
Results from this analysis are to be documented and maintained; but are not necessarily reported 
as part of this trial. Samples can be retained for up to 5 years after the last subject receives the 
first dose of trial treatment. Samples will be destroyed after the 5-year retention . 
Since the evaluations are not expected to benefit the subject directly or to alter the treatment 
course, the results of any exploratory biomarker research are not placed in the subject’s medical 
record and are not to be made available to the subject, members of the family, the personal 
physician, or other third parties, except as specified in the informed consent.  
The subject retains the right to request that the sample material be destroyed by contacting the 
investigator. Following the request from the subject, the investigator is to provide the sponsor 
with the required trial and subject number so that any remaining samples and any other 
components from the cells can be located and destroyed. However, information collected from 
samples before the request for destruction will be retained by Genmab.  
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from the 
sample materials and is responsible for the destruction of the sample(s) at the request of the 
subject through the investigator, at the end of the storage period, or as appropriate (eg, the 
scientific rationale for experimentation with a certain sample type no longer justifies keeping the 
sample). If a commercial product is developed from this research project, the sponsor owns the 
commercial product. The subject has no commercial rights to such product and has no 
commercial rights to the data, information, discoveries, or derivative materials gained or 
produced from the sample. See Appendix 1 for subject confidentiality. 

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Appendix 6. ECOG Performance Status 
 
Eastern Cooperative Oncology Group (ECOG) performance status 
Score 
Performance Status 
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, eg, 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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Appendix 7. RECIST (v1.1) Criteria Summary 
 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
Term 
Definition 
Complete response (CR) 
All of the following: 
• 
Disappearance of all target and non-target tumor lesions 
AND 
• 
Reduction in short axis to <10 mm in all pathological target and non-
target lymph nodes* 
AND 
• 
Normalization of tumor marker level (if applicable) 
Partial response (PR) 
≥30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. 
Stable disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters (nadir) while on study. 
Progressive disease (PD) 
At least one of the following: 
• 
≥20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (nadir; this includes the baseline 
sum if that is the smallest on study) AND an absolute increase of 
≥5 mm in the sum of diameters 
OR 
• 
Unequivocal† appearance of 1 or more new lesion(s) 
OR 
• 
Unequivocal progression of non-target lesions‡ 
  
Note: A measurable lesion must be accurately measured in at least 1 dimension (longest diameter in the plane of measurement is 
to be recorded) with a minimum size of 10 mm by CT scan (CT slice thickness no greater than 5 mm). 
*  When lymph nodes are included as target lesions, the sum of lesions may not reach 0 mm even if CR criteria are met, since a 
normal lymph node is defined as having a short axis <10 mm. 
†  Not attributable to differences in scanning technique, change in imaging modality, or findings thought to represent something 
other than tumor (healing or flare of preexisting lesions). 
‡  Modest increases in the size of one or more non-target lesions are not considered unequivocal progression. 
From RECIST v1.1 (Eisenhauer et al., 2009). 
 

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Appendix 8. Statistical Methodologies – BLRM and mBOIN 
BLRM 
A 2-parameter BLRM guided by the EWOC principle will be used to make dose 
recommendations and estimate the MTD during the escalation phase of the trial. The DLT target 
interval is taken to be (0.16, 0.33). 
For each available DL, including intermediate doses (d=1,…,nmax DL), the log odds of the DLT 
rate (πd) is modeled as a linear function of logarithmic standardized dose d (computed by 
dividing by the reference dose d*): 
𝑙𝑙𝑙𝑙𝑙𝑙(𝜋𝜋𝑑𝑑/(1 −𝜋𝜋𝑑𝑑)) = 𝛼𝛼0 + 𝛼𝛼1𝑙𝑙𝑙𝑙𝑙𝑙(𝑑𝑑/𝑑𝑑∗) 
For this trial a bivariate normal prior is placed on (α0, log(α1)), with α0 marginally N(m1, s1), 
log(α1) marginally N(m2, s2), and a correlation of r. The prior was selected to be minimal 
informative in the sense of Neuenschwander et al (2008). In order to determine a reasonable 
prior distribution, let us make assumptions that seem reasonable: 
1. Any toxicity probability above 0.1 would be very unlikely at the minimum dose 
2. Any toxicity probability below 0.2 would be very unlikely at the maximum dose 
So, assuming the prior probability of DLT rate exceeds 0.1 at the lowest dose is at most 5%, and, 
that the probability of the rate falls below 0.2 at the highest dose is at most 5%, a minimal 
informative prior distribution is derived as starting point for the calculations. Further, the prior 
medians of πd for all DLs are assumed to fall on a straight line in log dose on logit scale. These 
conditions determine the parameters of a minimal informative prior beta distribution specific for 
each DL. A final step identifies a bivariate normal distribution that minimizes the distance 
between quantiles (0.05, 0.5, 0.95) of the beta distributions. 
EWOC: a DL is considered to be safe to escalate to if there is less than 25% probability that the 
DLT rate on the corresponding DL during the DLT evaluation period is 33% or more. At any 
time during the trial, the method will not assign a subject to a dose that is not safe by this 
definition. If all DLs are considered unsafe, the trial will stop early, with the MTD estimated to 
be below the experimental dose range. 
The scenarios outlined in below Table 10-3 were evaluated by simulations using the R package 
crmPack (Sabanés Bové et al., 2019). The results are summarized in Table 10-4. 

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Table 10-5 
Operating Characteristics of BOIN Based on 6 Scenarios and 10,000 
Simulations 
Simulation Scenario 
DL1 
DL2 
DL3 
Total 
Mean 
%Early 
Stopping 
1 
Prob(DLT) 
1% 
2% 
3% 
- 
- 
Selection(%) 
0% 
 0.1% 
99.9% 
- 
0% 
% Pts treated 
9.7% 
10.6% 
79.7% 
11.3 
- 
2 
Prob(DLT) 
3% 
4.5% 
10% 
- 
- 
Selection (%) 
0.1% 
0.1% 
99.8% 
- 
0% 
% Pts treated 
10.8% 
13.9% 
75.3% 
12 
- 
3 
Prob(DLT) 
17% 
20% 
30% 
- 
- 
Selection (%) 
11.8% 
26.1% 
60.2% 
- 
1.9% 
% Pts treated 
22.4% 
33.3% 
44.3% 
15.6 
 
4 
Prob(DLT) 
20% 
30% 
40% 
- 
- 
Selection (%) 
27.4% 
40.6%% 
28.8% 
- 
3.2% 
% Pts treated 
31.9% 
39.2% 
29% 
16.9 
 
5 
Prob(DLT) 
30% 
40% 
50% 
- 
- 
Selection (%) 
52.9% 
25.3% 
9.6% 
- 
12.2% 
% Pts treated 
47.3% 
34.8% 
17.9% 
14.7 
- 
6 
Prob(DLT) 
40% 
50% 
60% 
- 
- 
Selection (%) 
53.6% 
12.2% 
1.7% 
- 
32.5% 
% Pts treated 
60.7% 
28.5% 
10.8% 
12 
- 
BOIN=Bayesian optimal interval; DLT=dose-limiting toxicity; N95=95% quantile of number subjects dosed across 10,000 
simulations; Prob=probability; Pts=patients.  
Based on output from BOIN application provided by https://trialdesign.org/ 
 

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Appendix 10. Abbreviations and Definitions 
 
Abbreviation 
Definition 
1L 
first line 
2L 
second line. If followed by “+”: second line or higher. 
5-FU 
fluorouracil  
ADA 
antidrug antibody 
ADCC 
antibody-dependent cellular cytotoxicity 
ADCP 
antibody-dependent cellular phagocytosis 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AMP 
auxiliary medicinal product 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
anti-HBc 
antibody to the hepatitis B core antigen 
anti-HBs 
antibody to the hepatitis B surface antigen 
APC 
antigen-presenting cell 
APTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ASTCT 
American Society for Transplantation and Cellular Therapy 
AUC 
area under the concentration-time curve 
β-hCG 
beta-human chorionic gonadotropin 
BAL 
bronchoalveolar lavage 
Baseline 
Baseline is the last available measurement prior to first dosing of trial treatment, if not 
otherwise specified. 
BLRM 
Bayesian logistic regression model 
BOIN 
Bayesian optimal interval method 
BOR 
best overall response 
BRAF 
B-Raf proto-oncogene, serine/threonine kinase 
BRCA 
breast cancer 
%CV 
percent coefficient of variation 
C 
cycle 
CBC 
complete blood count 
CD 
cluster of differentiation  
CDC 
complement-dependent cytotoxicity 
cfDNA 
cell-free deoxyribonucleic acid 
CFR 
Code of Federal Regulations 
Cmax 
maximum (peak) concentration 
CNS 
central nervous system 
CONSORT 
Consolidated Standards of Reporting Trials 
CPI 
checkpoint inhibitor 
CPS 
combined positive score 
CR 
complete response 
CRF 
case report form 
CRO 
contract research organization 
CRP 
C-reactive protein 
CRS 
cytokine release syndrome 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTFG 
clinical trials facilitation group 
Ctrough 
predose trough concentration 
CTLA-4 
cytotoxic T-lymphocyte-associated-protein 4 
ctDNA 
circulating tumor-derived deoxyribonucleic acid 

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Abbreviation 
Definition 
CXCL9/10 
CXC motif chemokine ligand 9/10 
D/d 
day(s) 
DC 
dendritic cell 
DCR 
disease control rate 
DDS 
dose determining set 
DEC 
dose escalation committee 
DL 
dose level 
DLT 
dose-limiting toxicity 
DMC 
data monitoring committee 
dMMR 
deficient mismatch repair 
DNA 
deoxyribonucleic acid 
DoR 
duration of response 
DRF 
dose range finding 
EC 
effective concentration 
ECG 
electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group performance status 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EEA 
European Economic Area 
EGFR 
epidermal growth factor receptor 
ER 
estrogen receptor 
EU 
European Union 
EWOC 
escalation with overdose control 
FAS 
full analysis set 
Fc 
fragment, crystallizable 
FcγR 
Fc gamma receptor 
FDG 
fluorodeoxyglucose 
FDG-PET 
fluorodeoxyglucose-positron emission tomography 
FIH 
first-in-human 
FSH 
follicle-stimulating hormone 
FFPE 
formalin-fixed, paraffin-embedded 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GDPR 
General Data Protection Regulation  
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyltransferase 
GLP 
Good Laboratory Practice 
GM-CSF 
granulocyte/macrophage colony-stimulating factor 
GzmB 
granzyme B 
Hb 
hemoglobin 
HBsAg 
hepatitis B surface antigen 
HER2 
human epidermal growth factor receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act  
HIV 
human immunodeficiency virus 
HNSCC 
head and neck squamous cell carcinoma 
HNSTD 
highest nonseverely toxic dose 
HPV 
human papillomavirus 
hr 
hour(s) 
IAS 
immunogenicity analysis set 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
iCPD 
immune confirmed progressive disease 
iCR 
immune complete response 

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Abbreviation 
Definition 
iDCR 
immune disease control rate 
iDoR 
immune duration of response 
IEC 
independent ethics committee 
IFN-γ 
interferon gamma 
Ig 
immunoglobulin 
IgG 
immunoglobulin G 
IHC 
immunohistochemistry 
IL 
interleukin  
IM 
immunomodulator 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
iORR 
immune overall response rate 
iPFS 
immune progression-free survival 
iPR 
immune partial response 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
iRECIST 
immune Response Evaluation Criteria in Solid Tumors 
IRR 
infusion-related reaction 
IRT 
interactive response technology 
iSD 
immune stable disease 
iUPD 
immune unconfirmed progressive disease 
IV 
intravenous(ly) 
KRAS 
KRAS proto-oncogene, GTPase 
LDH 
lactate dehydrogenase 
LLOQ 
lower limit of quantification 
LLOQ/2 
half the lower limit of quantification 
MET 
MET proto-oncogene, receptor tyrosine kinase 
mAb 
monoclonal antibody 
 
 
MAD 
maximum administered dose 
mBOIN 
modified Bayesian Optimal Interval 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MDRD 
Modification of Diet in Renal Disease 
MHC 
major histocompatibility complex 
MoA 
mechanism of action 
mOS 
median overall survival 
MPV 
mean platelet volume 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NGS 
next-generation sequencing 
NK 
natural killer 
NOAEL 
no-observed-adverse-effect level 
NSCLC 
non–small cell lung cancer 
NTRK1/2/3 
neurotrophic receptor tyrosine kinase 1/2/3 
ORR 
objective response rate 
OS 
overall survival 
PAD 
pharmacologically active dose 
PAS 
pharmacokinetic analysis set 
PBMC 
peripheral blood mononuclear cell 
PBPK 
physiologically based pharmacokinetic 
CCI
CCI

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Abbreviation 
Definition 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed death-ligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PgR 
progesterone receptor 
PK 
pharmacokinetic(s) 
PLT 
platelet 
PPoS 
predictive probability of success approach 
PR 
partial response 
PRO 
patient-reported outcome(s) 
PT 
prothrombin time  
RET 
ret proto-oncogene 
Q3W 
every 3 weeks 
QA 
quality assurance 
QW 
weekly 
QTc 
corrected QT interval 
QTcF 
QT intervals using Fridericia’s correction 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
ROS1 
c-ros oncogene 1 
RP2D 
recommended phase 2a dose 
RT 
radio therapy 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SC 
safety committee 
sCD27 
soluble CD27 
SCr 
serum creatinine 
SD 
stable disease 
SJS 
Stevens-Johnson syndrome 
SoC 
standard of care 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
elimination half-life 
T4 
free thyroxine 
T3 
total triiodothyronine 
T1DM 
type 1 diabetes mellitus 
TCGA 
the Cancer Genome Atlas Program 
TCR 
T-cell antigen receptor 
TEAE 
treatment-emergent adverse event 
TEN 
toxic epidermal necrolysis 
TRAE 
treatment-related adverse event 
TME 
tumor microenvironment 
tmax 
time to maximum (peak) concentration 
TNF 
tumor necrosis factor 
TNM 
tumor nodes metastasis 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
UNS 
unscheduled 
US 
United States 
WBC 
white blood cell 

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11 LAY PROTOCOL SYNOPSIS 
Protocol Title 
First-in-human, open-label, dose-escalation trial with expansion cohorts to evaluate the 
safety of GEN1053 as monotherapy and in combination with an immunomodulator in 
subjects with malignant solid tumors 
Brief Title 
A study to evaluate safety, tolerability, and preliminary effect of the GEN1053 antibody 
on malignant solid tumors as monotherapy and in combination. 
Protocol Number 
GCT1053-01 
Regulatory Agency 
Identifier Number(s) 
EU CT No. 
2022-502419-12-00 
NCT No. 
NCT05435339 
Rationale 
GEN1053 is an antibody that binds to a molecule on cells involved in killing cancer 
cells. Studies in cells and animals have indicated that GEN1053 can stimulate the 
fighting of cancer by binding to these cells. GEN1053 may not only work alone but also 
together with other cancer drugs.  
The purpose of the first part of this trial is to identify doses of GEN1053 that can either 
work alone or together with other cancer drugs in fighting cancer and determine the 
severity of possible side effects.  
The purpose of the second part of this trial is to determine the severity of the possible 
side effects and the potential benefit of GEN1053 or potential added benefits of 
combining GEN1053 with other cancer drugs in patients with various cancers in the 
head and neck or lung. 
Objectives/Endpoints 
Primary Objective(s) 
Primary Endpoint(s) 
• 
Determine the optimal dose or 
highest tolerable dose of 
GEN1053 when given alone or 
when given together with other 
cancer drugs 
• 
Measure and assess the types 
and frequencies of side effects 
and tolerability of GEN1053 
when given alone or in 
combination with other cancer 
drugs  
• 
How often side effects occur and how 
serious they are 
• 
How often laboratory values are outside 
the normal range and by how much 
Secondary Objective(s) 
Secondary Endpoints(s) 
• 
Evaluate how the body handles 
GEN1053  
• 
Concentration levels of GEN1053 in the 
blood and how they change over time  
 
• 
Evaluate if the body reacts to 
GEN1053 
• 
Concentration levels of compounds in 
blood called an “anti-drug antibody” that 
the body may produce to counteract 
GEN1053 
 
• 
Evaluate how the tumor is 
affected by GEN1053 or 
GEN1053 in combination with 
other cancer drugs 
• 
Measures of how the tumor has reacted 
(shrinkage or growth) to treatment 
 
Brief Summary 
Participants will receive either GEN1053 alone or in combination with other cancer 
drugs into the vein once every 3 weeks. All participants will receive active drug; no one 
will receive placebo.  

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All participants will receive study treatment for an estimated period of 6 months, or 
until: 
• 
the cancer progresses 
• 
there are side effects requiring that treatment be stopped 
• 
the patient decides to withdraw 
• 
the doctor believes it is in the patient’s best interest to stop treatment. 
 
Participation in the study will require visits to the site. For the first 12 weeks there will 
be weekly visits and after that, visits will be every 3 weeks. At site visits, there will be 
various tests (such as blood draws) and procedures (such as recording of heart activity, 
computerized X-rays) to monitor whether the treatment is safe and effective. 
The study duration (including screening, treatment, and follow-up) for each participant 
is estimated to be about 20 months. 
Trial Population 
In the first part: Patients with various incurable cancers, 18 years of age or older, with 
acceptable kidney and liver function.  
In the second part: Patients with cancers in the head and neck or certain types of lung 
cancer, 18 years of age or older, with acceptable kidney and liver function.  
Ethical 
Considerations 
Research in cells and animals suggests that GEN1053 may be effective in treating 
cancer in humans and may also work together with other cancer drugs. 
Being treated with GEN1053 alone or in combination with other cancer drugs in this 
trial may or may not make the health better for an individual patient. Although the 
health of one patient may not get better, other patients may benefit from the knowledge 
gained from this trial in the future. Patients’ health will be observed and monitored 
during the trial and all tests and procedures performed throughout the trial are done to 
ensure that GEN1053 or GEN1053 in combination with other cancer drugs is both safe 
and effective (that is, the drugs can fight cancer).  
Overall, the possible benefits of this trial outweigh the risks.