Clinical trial NCT03438396
Conditions: Cervical Cancer
Sponsor: Seagen Inc.
Start date: 2018-06-12; Completion date: 2022-08-02
Enrollment: 102 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A Single arm, Multicenter, International Trial of Tisotumab Vedotin (HuMax®-TF-ADC) in Previously Treated, Recurrent or Metastatic Cervical Cancer.

Detailed description:
The purpose of the trial is to evaluate the efficacy and safety/tolerability of tisotumab vedotin in patients with previously treated, recurrent or metastatic cervical cancer. Tisotumab vedotin is an antibody-drug conjugate (ADC) targeting tissue factor (TF), a protein aberrantly expressed in a wide number of tumors including cervical cancer. Preliminary safety and efficacy data observed in a cohort of previously treated cervical cancer patients suggest a positive benefit risk profile for this population of high unmet need.

Arms: arm 1: tisotumab vedotin (IV), 2.0 mg/kg, every 3 weeks (1Q3W)
Interventions: intervention 1: tisotumab vedotin
Intervention descriptions: intervention 1: All patients will be treated with tisotumab vedotin once every three weeks until progression or toxicity

Protocol documents:
Prot_000.pdf: 
Document Name: GCT1015-04 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
Confidential 
1 
PROTOCOL AND SUMMARY OF PROTOCOL 
AMENDMENTS 
A Single arm, Multicenter, International Trial of Tisotumab 
Vedotin (HuMax®-TF-ADC) in Previously Treated, Recurrent 
or Metastatic Cervical Cancer 
Protocol no.: 
GCT1015-04 
Trial name 
innovaTV 204 
ClinicalTrials.gov Identifier 
NCT03438396 
Sponsor: 
Genmab A/S 
Collaborators: 
Seattle Genetics, Inc. 
EudraCT No.: 
2017-003413-25 
IND No.: 
135476 
IMP Name: 
Tisotumab vedotin (HuMax®-TF-ADC) 
Development Phase: 
2 
 
 
 
 
 
*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 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. 
The information in this document is confidential and is proprietary to Genmab. It is understood that information in this 
document shall not be disclosed to any third party, in any form, without prior written consent of an authorized officer of 
Genmab 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................. 2 
1 
OVERVIEW OF PROTOCOL AMENDMENTS .................................................. 3 
2 
SUMMARY OF PROTOCOL AMENDMENTS .................................................... 4 
3 
REDACTED PROTOCOL VERSION 7.0, LATEST VERSION ......................... 7 
 
 
 


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1 OVERVIEW OF PROTOCOL AMENDMENTS 
 
Protocol/Amendment No; Version  
Issue Date 
Version 1.0 (never submitted externally) 
03 November 2017 
Version 2.0 (original protocol) 
09 November 2017 
Amendment 1; Version 3.0 
22 January 2018 
Amendment 2; Version 4.0 
09 February 2018 
Amendment 3; Version 5.0 
12 February 2018 
Amendment 4; Version 6.0 
01 November 2018 
Amendment 5; Version 7.0 
17 June 2019 
 
 
 


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2 SUMMARY OF PROTOCOL AMENDMENTS 
Five protocol amendments have been made to the original protocol (dated 09-Nov-2017, protocol 
version 2. Note that version 1 was never submitted externally to investigators, health authorities, 
IRBs or IECs), of which the first 3 were issued before the first subject’s first visit. A summary of 
key changes with each amendment is provided in Table 1. 
Table 16.1.1-1 Protocol Amendments 
Amendment 
Number 
Issue Date 
Key Changes 
1 
22-Jan-2018 
(protocol 
version 3) 
The voluntary harmonisation procedure (VHP) for a coordinated European 
assessment resulted in recommendations and requests for changes to the protocol. 
• 
Justification for having no control group was added. 
• 
Based on the information on contraindications, potential risks, and identified 
risks in the current version of the investigator’s brochure, subjects with ongoing 
acute or chronic inflammatory skin disease, subjects with inflammatory lung 
disease, and subjects with inflammatory bowel disease were to be excluded from 
participation in the trial.  
• 
A subgroup analysis by region (EU/US) was added to assess regional consistency 
of treatment effects. 
• 
The term “analysis cut-off date” was defined for clarity.  
• 
In addition to the 2 already defined treatment periods (pretreatment and 
on-treatment periods) a third post-treatment observation period was defined.  
• 
The assumption of the 25% true ORR was justified. 
2 
09-Feb-2018 
(protocol 
version 4) 
After reviewing amendment 1, the VHP requested that the protocol be amended to 
clarify the statistical power for ORRs in the range 21-25%. 


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Amendment 
Number 
Issue Date 
Key Changes 
3 
12-Feb-2018 
(protocol 
version 5) 
• 
It was specified when the imaging assessments should start and stop. In addition, 
the frequency of survival follow-up was specified.  
• 
It was specified that chemotherapy administered in the adjuvant or neoadjuvant 
setting, or in combination with radiation therapy, should not be counted as a prior 
systemic treatment regimen. 
• 
Wording of “acceptable coagulation status” was clarified for subjects on 
anti-coagulation therapy and for subjects not on anti-coagulation therapy.  
• 
The ophthalmological exclusion criterion was revised for clarity. 
• 
The corticoid exclusion criterion was reworded and inserted as exclusion 
criterion 12.  
• 
It was clarified that if a subject intends to conceive children, she is ineligible for 
trial participation. 
• 
The time frame for prophylactic use of preservative-free lubricating eye drops 
was specified. 
• 
Guidance on permitted concomitant anti-coagulation therapy was revised for 
clarity. 
• 
The dose reduction scheme and dose delay rules were revised. 
• 
The plan for mitigating ocular AEs was revised due to 
 requirements 
including the following: 
• 
It was specified that in case of second occurrence of grade 2 conjunctivitis, 
the dosing of tisotumab vedotin was to be held and be resumed at a reduced 
dose if the event resolved to baseline within 6 weeks. If the event did not 
resolve to baseline within 6 weeks, treatment with tisotumab vedotin was to 
be permanently discontinued. 
• 
It was specified that treatment with tisotumab vedotin was to be 
permanently discontinued if a subject experiences a third occurrence of 
grade 2 conjunctivitis or any occurrence of grade ≥3 conjunctivitis. 
• 
It was specified that in case of a grade 1 keratitis, the dosing of tisotumab 
vedotin was to be held until the event was managed effectively, after which 
treatment could continue on the same dose. 
• 
A mitigation plan was added in order to include guidance on how to handle 
all other ocular AEs as well. 
• 
The mitigation plan for bleeding events was modified to specify that any event of 
pulmonary or CNS hemorrhage, irrespective of the grade, would lead to 
permanent discontinuation of treatment. 
• 
The withdrawal criterion “sponsor decision in consultation with the investigator” 
was deleted as this is an investigator decision.  
• 
It was specified that the AE reporting period ends 30 days after last dose, that no 
new AEs should be collected after this period, and that for subjects who start any 
new anti-cancer therapy during the AE reporting period, only AEs that are 
related to tisotumab vedotin should be reported. 
• 
Due to 
 requirements, it was specified that all ocular AEs, independent of 
grading, should be reported to the safety CRO within 24 hours. 


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Amendment 
Number 
Issue Date 
Key Changes 
4 
01-Nov-2018 
(protocol 
version 6) 
The main reasons for updating the protocol were: 
• 
To expand the time window for screening visit 2 by 2 days, so that this visit now 
could be performed ≤7 days prior to Cycle 1 (D1) (instead of ≤5 days prior to 
Cycle 1 [D1]).  
• 
To clarify that tisotumab vedotin was to be administered over a minimum of 
30 minutes and preferably be completed within 60 minutes. 
• 
To clarify the requirements for body weight measurement for dose calculation. 
• 
To align safety reporting requirements across the tisotumab vedotin program. 
 
5 
17-Jun-2019 
(protocol 
version 7) 
Based on health authority feedback, the timing of the primary analysis of the trial 
was changed to ensure that all responders were followed for ≥ 6 months. 
 
 
 


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3 REDACTED PROTOCOL VERSION 7.0, LATEST VERSION 




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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ............................................................................................ 6 
ABBREVIATIONS ....................................................................................................................... 7 
PROTOCOL AMENDMENTS .................................................................................................... 9 
TRIAL SYNOPSIS ...................................................................................................................... 11 
1 
VISIT ASSESSMENT SCHEDULE .................................................................. 17 
2 
INTRODUCTION ............................................................................................... 21 
2.1 
Background ............................................................................................................ 21 
2.1.1 
Overview of Disease .............................................................................................. 21 
2.1.2 
Introduction to the Investigational Medicinal Product .......................................... 21 
2.1.3 
Summary of Non-clinical Studies .......................................................................... 21 
2.1.4 
Summary of Clinical Trials ................................................................................... 22 
2.2 
Rationale ................................................................................................................ 24 
2.3 
Benefit-risk Assessment ........................................................................................ 25 
3 
OBJECTIVES AND ENDPOINTS .................................................................... 26 
4 
TRIAL DESIGN .................................................................................................. 27 
4.1 
Description of Trial Design ................................................................................... 27 
4.2 
Trial Design Rationale ........................................................................................... 27 
4.3 
Dose and Schedule Rationale ................................................................................ 28 
4.4 
End of Trial and Treatment Discontinuation Definitions ...................................... 28 
4.4.1 
End of Trial ............................................................................................................ 28 
4.4.2 
Treatment Discontinuation .................................................................................... 28 
4.4.3 
Trial Termination ................................................................................................... 28 
5 
TRIAL POPULATION ....................................................................................... 29 
5.1 
Inclusion Criteria ................................................................................................... 29 
5.2 
Exclusion Criteria .................................................................................................. 30 
5.3 
Screen Failures....................................................................................................... 32 
6 
TREATMENT ..................................................................................................... 33 
6.1 
Treatment Assignment ........................................................................................... 33 
6.1.1 
Patient Numbering ................................................................................................. 33 
6.1.2 
Treatment Assignment ........................................................................................... 33 
6.2 
Dosage and Administration ................................................................................... 33 
6.2.1 
IMP ........................................................................................................................ 33 
6.2.2 
Pre-medication ....................................................................................................... 33 
6.2.3 
Supportive Care ..................................................................................................... 34 
6.3 
Compliance ............................................................................................................ 34 
6.4 
Concomitant Medications and Therapies .............................................................. 34 
6.4.1 
Permitted Concomitant Medications and Therapies .............................................. 34 
6.4.2 
Permitted Concomitant Therapy Requiring Caution and/or Action ...................... 34 
6.4.3 
Prohibited Concomitant Therapy ........................................................................... 35 
6.5 
IMP Information .................................................................................................... 35 
6.5.1 
Physical Description of the IMP ............................................................................ 35 
6.5.2 
Packaging ............................................................................................................... 35 
6.5.3 
Labeling ................................................................................................................. 35 


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6.5.4 
Preparation, Handling and Storage ........................................................................ 35 
6.5.5 
Drug Accountability .............................................................................................. 36 
6.5.6 
Handling of Other Trial Treatment ........................................................................ 36 
6.6 
Technical Complaint Handling .............................................................................. 36 
6.6.1 
Procedures ............................................................................................................. 36 
6.6.2 
Contacting Sponsor Regarding Product Quality ................................................... 36 
7 
DOSE MODIFICATIONS AND SAFETY MANAGEMENT 
GUIDELINES ...................................................................................................... 37 
7.1 
Dose Modification Guidance ................................................................................. 37 
7.1.1 
Dose Reduction ...................................................................................................... 37 
7.1.2 
Dose delay ............................................................................................................. 37 
7.2 
Mitigation Plans for Specific Adverse Events ....................................................... 38 
7.2.1 
Ocular Adverse Events .......................................................................................... 38 
7.2.2 
Other Adverse Events ............................................................................................ 41 
7.3 
Summary of Safety Stopping Rules ....................................................................... 43 
8 
DISCONTINUATION, FOLLOW-UP AND COMPLETION ....................... 45 
8.1 
Discontinuation of Treatment ................................................................................ 45 
8.2 
Withdrawal from the Trial ..................................................................................... 45 
8.3 
Withdrawal from the Optional Research Samples................................................. 46 
8.4 
Withdrawal from the Use of Samples in Future Research .................................... 46 
8.5 
Follow-up for Safety Evaluations .......................................................................... 46 
8.6 
Lost to Follow-up .................................................................................................. 46 
9 
TRIAL ASSESSMENTS ..................................................................................... 47 
9.1 
Demography and Baseline Assessments ............................................................... 47 
9.1.1 
Demographics ........................................................................................................ 47 
9.1.2 
Medical History ..................................................................................................... 47 
9.1.3 
Concomitant Medication ....................................................................................... 47 
9.1.4 
Prior Cancer Therapy and Surgery ........................................................................ 47 
9.2 
Efficacy assessments ............................................................................................. 47 
9.2.1 
Tumor imaging: ..................................................................................................... 47 
9.2.2 
Survival Status ....................................................................................................... 50 
9.3 
Clinical Safety Assessments .................................................................................. 50 
9.3.1 
Physical Examination ............................................................................................ 50 
9.3.2 
Body Measurements .............................................................................................. 50 
9.3.3 
Vital Signs ............................................................................................................. 50 
9.3.4 
Electrocardiograms ................................................................................................ 51 
9.3.5 
ECOG .................................................................................................................... 51 
9.3.6 
Eye Examination and Ophthalmological Evaluation ............................................. 51 
9.4 
Pharmacokinetics ................................................................................................... 52 
9.4.1 
Evaluations ............................................................................................................ 52 
9.4.2 
Analytical Procedures ............................................................................................ 52 
9.5 
Clinical Laboratory Assessments .......................................................................... 52 
9.6 
Immunogenicity ..................................................................................................... 54 
9.6.1 
Evaluations ............................................................................................................ 54 
9.6.2 
Immunogenicity Assessments ............................................................................... 54 
9.7 
Biomarker Investigations ....................................................................................... 54 
9.7.1 
Biomarker Assessments in Tumor Samples .......................................................... 54 


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9.7.2 
Biomarker Assessments in Blood Samples ........................................................... 55 
9.7.3 
Sample collections ................................................................................................. 56 
9.7.4 
Additional Analyses .............................................................................................. 56 
9.8 
Pharmacogenomic (DNA) Evaluations ................................................................. 56 
9.9 
Patient Reported Outcomes ................................................................................... 57 
10 
SAFETY MONITORING AND ADVERSE EVENT REPORTING ............. 58 
10.1 
Adverse Event Definitions ..................................................................................... 58 
10.1.1 
Definition of Adverse Events ................................................................................ 58 
10.1.2 
Definition of Serious Adverse Events ................................................................... 58 
10.1.3 
Definition of Adverse Events of Special Interest .................................................. 58 
10.1.4 
Definition of Overdose of Tisotumab Vedotin ...................................................... 59 
10.1.5 
Definition of Reproductive Potential and Contraception ...................................... 59 
10.1.6 
Definition of Infusion Related Reactions .............................................................. 60 
10.2 
Reporting ............................................................................................................... 60 
10.2.1 
Pre-existing Conditions ......................................................................................... 62 
10.2.2 
Diagnosis ............................................................................................................... 62 
10.2.3 
Disease Progression or Death ................................................................................ 62 
10.2.4 
Unrelated Procedures ............................................................................................. 62 
10.2.5 
Laboratory test abnormalities ................................................................................ 62 
10.2.6 
Start Date and Time ............................................................................................... 63 
10.2.7 
Infusion-Related Reactions (IRRs) ........................................................................ 63 
10.2.8 
Seriousness Criteria ............................................................................................... 63 
10.2.9 
Intensity ................................................................................................................. 63 
10.2.10 
Relationship to the Investigational Medicinal Product .......................................... 63 
10.2.11 
Action Taken with the Investigational Medicinal Product .................................... 63 
10.2.12 
Outcome ................................................................................................................. 64 
10.2.13 
End Date and Time ................................................................................................ 64 
10.3 
Events Requiring Immediate Reporting ................................................................ 64 
10.3.1 
Serious Adverse Events and Ocular Adverse Events ............................................ 64 
10.3.2 
Overdose and Medication Errors ........................................................................... 64 
10.3.3 
Pregnancy .............................................................................................................. 65 
10.4 
Suspected Unexpected Serious Adverse Reactions (SUSARs) ............................. 65 
10.5 
Follow-Up on Adverse Events............................................................................... 65 
10.6 
Warnings and Precautions ..................................................................................... 66 
10.7 
Data Monitoring Committee .................................................................................. 66 
11 
STATISTICS ........................................................................................................ 67 
11.1 
Analysis Sets .......................................................................................................... 67 
11.1.1 
Full Analysis Set .................................................................................................... 67 
11.1.2 
Safety Set ............................................................................................................... 67 
11.2 
Patient Demographics and Baseline Characteristics.............................................. 67 
11.3 
Treatments ............................................................................................................. 67 
11.4 
Primary Objective .................................................................................................. 67 
11.4.1 
Endpoint ................................................................................................................. 68 
11.4.2 
Statistical Hypothesis, Model and Method of Analysis ........................................ 68 
11.4.3 
Handling of Missing Values/Censoring/Discontinuations .................................... 68 
11.4.4 
Supportive and Sensitivity Analyses ..................................................................... 68 
11.5 
Secondary Objectives ............................................................................................ 68 


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11.5.1 
Secondary Efficacy Objectives .............................................................................. 68 
11.5.2 
Safety Objectives ................................................................................................... 70 
11.5.3 
Pharmacokinetics ................................................................................................... 72 
11.5.4 
Biomarkers ............................................................................................................. 72 
11.5.5 
Resource Utilization .............................................................................................. 73 
11.5.6 
Patient-reported Outcomes .................................................................................... 73 
11.6 
Exploratory Objectives .......................................................................................... 73 
11.7 
Interim Analyses .................................................................................................... 73 
11.8 
Sample Size Calculation ........................................................................................ 73 
12 
DATA HANDLING AND RECORD KEEPING ............................................. 74 
12.1 
Data Flow............................................................................................................... 74 
12.2 
Source Documentation........................................................................................... 74 
12.3 
Case Report Form Completion .............................................................................. 75 
12.4 
Data Quality Management ..................................................................................... 75 
12.5 
Record Retention ................................................................................................... 76 
13 
ETHICS ................................................................................................................ 77 
13.1 
Trial-Specific Design Considerations .................................................................... 77 
13.2 
Regulatory Ethics Compliance .............................................................................. 77 
13.2.1 
Investigator Responsibilities .................................................................................. 77 
13.2.2 
Independent Ethics Committee or Institutional Review Board ............................. 77 
13.2.3 
Informed Consent .................................................................................................. 77 
13.2.4 
Privacy of Personal Data ....................................................................................... 78 
13.2.5 
Long-term Retention of Samples ........................................................................... 79 
14 
ADMINISTRATIVE PROCEDURES ............................................................... 80 
14.1 
Protocol Amendments ........................................................................................... 80 
14.2 
Regulatory Documentation .................................................................................... 80 
14.2.1 
Regulatory Approval/Notification ......................................................................... 80 
14.3 
Patient Identification, Enrollment, and Screening Logs ........................................ 80 
14.4 
Monitoring ............................................................................................................. 80 
14.5 
On-Site Audits ....................................................................................................... 81 
14.6 
Publication ............................................................................................................. 81 
15 
REFERENCES .................................................................................................... 83 
 
Appendix 1 Recommendations Related to Contraception and Pregnancy Testing in Clinical 
Trials 
Appendix 2 
Investigator’s Agreement 
Appendix 3 
Signature from sponsor's responsible Medical Officer 
       


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


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ABBREVIATIONS 
 
1L 
First line 
2L 
Second line 
1Q3W 
Once every 3 weeks 
3Q4W 
Once weekly for 3 weeks followed by one week with no treatment 
ADA 
Anti-drug antibody 
ADC 
Antibody-drug conjugate 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase  
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
ASA 
Acetylsalicylic acid 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
AUC0-t 
Area-under-the-concentration-time curve 
CI 
Confidence interval 
Cmax 
Maximum observed concentration 
CONSORT 
Consolidated standards of reporting trials 
CR 
Complete response 
CXR 
Chest X-ray 
eCRF 
Electronic case report form 
CRO 
Contract research organization  
CTCAE 
Common terminology criteria for adverse events 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern cooperative oncology group 
EORTC-QLQ-C30 
European organization for research and treatment of cancer quality of 
life version 3.0 of the core questionnaire 
EORTC-QLQ-CX24 
European organization for research and treatment of cancer quality of 
life questionnaire, cervical cancer module 
FAS 
Full analysis set 
GCP 
Good clinical practice 
GFR 
Glomerular filtration rate 
HIV 
Human immunodeficiency virus 
HRQL 
Health related quality of life 


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ICF 
Informed consent form 
ICH 
International conference on harmonization 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional review board 
IRC 
Independent review committee 
ITT 
Intention to treat 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMAE 
Monomethyl auristatin E 
ORR 
Objective response rate 
OS 
Overall survival 
PFS 
Progression free survival 
PK 
Pharmacokinetics 
PR 
Partial response 
PT 
Prothrombin time 
RECIST 
Response evaluation criteria in solid tumors 
Q6W 
Every 6 weeks 
Q12W 
Every 12 weeks 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SUSAR 
Suspected unexpected serious adverse reactions 
TF 
Tissue factor 
TTR 
Time to response 
ULN 
Upper limit of normal 
 
 










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- 
Paclitaxel+cisplatin or carboplatin  
       OR 
- 
Paclitaxel+topotecan, 
in combination with bevacizumab unless patients are ineligible for 
bevacizumab treatment according to local standards. 
o Have received no more than 2 prior systemic treatment 
regimens for recurrent or metastatic cervical cancer. 
Chemotherapy administered in the adjuvant or neoadjuvant 
setting, or in combination with radiation therapy should not be 
counted as a prior systemic treatment regimen.  
o Are not candidates for curative therapy, including but not 
limited to, radiotherapy or exenterative surgery. 
 Measurable disease according to RECIST v1.1 as assessed by 
IRC.  
 Age ≥ 18 years. 
 Acceptable 
renal 
function: 
Calculated 
(Cockcroft-Gault) 
Glomerular Filtration Rate (GFR) > 50 mL/min. 
 Acceptable liver function: Alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST) ≤ 3 times the upper limit of 
normal (ULN) (if liver tumor/metastases are present, then ≤ 5  
ULN is allowed); bilirubin ≤ 1.5  ULN, except in patients 
diagnosed with Gilbert’s syndrome, direct bilirubin ≤ 2  ULN. 
 Acceptable hematological status: Hemoglobin ≥ 5.6 mmol/L 
(9.0 g/dL), absolute neutrophil count (ANC) ≥ 1500/µL 
(1.5109/L); platelet count ≥ 100109/L assessed at least 2 weeks 
after transfusion with blood products and/or growth factor 
support. 
 Acceptable coagulation status: 
o For patients not on anti-coagulation therapy: 
- Activated partial thromboplastin time (aPTT) ≤ 1.25 ULN. 
- International normalized ratio (INR) ≤ 1.2. 
o For patients on anti-coagulation therapy: 
- aPTT ≤ 1.25 ULN. 
- INR: Patients on anti-coagulants that require laboratory 
assessments for dose titration (warfarin or other Vitamin K 
dependent anti-coagulant agents) must be on a steady dose 
(no active titration) for ≥ 4 weeks prior to first planned 
administration of tisotumab vedotin and must have an INR 
≤ 2.5 for eligibility. 
- Patients on anti-coagulants that do not require laboratory 
assessments for dose titration do not need to be on a steady 


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dose for ≥ 4 weeks prior to first planned administration of 
tisotumab vedotin.  
- Concurrent chronic use of prophylactic AcetylSalicylic 
Acid (ASA, e.g., aspirin) is prohibited for patients on any 
type of anti-coagulation therapy. 
 Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 or 1 prior to the first planned administration of IMP.  
 Life expectancy of at least three months. 
 A negative serum pregnancy test for patients of reproductive 
potential. Patients that are postmenopausal or permanently 
sterilized (please refer to Section 10.1.5 for definitions), can be 
considered as not having reproductive potential. 
 Patients of reproductive potential must agree to use adequate 
contraception during and for 6 months after the last IMP 
administration. Adequate contraception is defined as highly 
effective methods of contraception (please refer to Section 10.1.5 
for more information). In countries where two highly effective 
methods of contraception are required this will be an inclusion 
criterion. 
 All patients 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 IMP. 
 All patients must provide a fresh or archival biopsy prior to the 
first planned administration of IMP, unless determined it is 
unfeasible after sponsor medical review. For specific tissue 
requirements, please refer to Section 9.7.3.  
 Following receipt of verbal and written information about the trial, 
patients must provide signed informed consent before any trial-
related activity is carried out. 
Exclusion Criteria 
 Patients with primary neuroendocrine or sarcomatoid histologies. 
 Hematological: Known past or current coagulation defects leading 
to an increased risk of bleeding; diffuse alveolar hemorrhage from 
vasculitis; known bleeding diathesis; ongoing major bleeding; 
trauma with increased risk of life-threatening bleeding or history 
of severe head trauma or intracranial surgery within 8 weeks of 
trial entry. 
 Cardiovascular: Clinically significant cardiac disease including 
unstable angina, acute myocardial infarction 6 months prior to 
screening; any medical history of congestive heart failure (Grade 
III or IV as classified by the New York Heart Association), any 
medical history of decreased cardiac ejection fraction of < 45%; a 
marked baseline prolongation of QT/QTc interval (e.g., repeated 
demonstration of a QTc interval >450 msec); a complete left 


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bundle branch block (defined as a QRS interval ≥ 120 msec in left 
bundle branch block form) or an incomplete left bundle branch 
block. 
 Central 
nervous 
system: 
Any 
history 
of 
intracerebral 
arteriovenous malformation, cerebral aneurysm, or stroke 
(transient ischemic attack > 1 month prior to screening is 
allowed). 
 Ophthalmological: Active ocular surface disease at baseline. 
Patients with any prior episode of cicatricial conjunctivitis or 
Steven Johnson syndrome are ineligible. 
 Other cancer: Known past or current malignancy other than 
inclusion diagnosis, except for: Non-invasive basal cell or 
squamous cell skin carcinoma; noninvasive, superficial bladder 
cancer; any curable cancer with a complete response (CR) of 
 5 years duration. 
o Brain metastases are allowed if the following criteria are met: 
Definitive therapy (for example: surgery or stereotactic brain 
radiotherapy) has been completed > 8 weeks before the first 
dose of IMP; no evidence of clinical or radiologic progression 
of the brain metastases; patients have completed perioperative 
corticosteroid therapy or steroid taper. NOTE: Chronic steroid 
therapy is acceptable provided that the dose is stable for 1 
month prior to screening. 
 Surgery/procedures: Major surgery within 4 weeks or minor 
surgery within 7 days prior to the first IMP administration. 
Patients who have planned major surgery during the treatment 
period must be excluded from the trial. 
 Peripheral neuropathy grade > 2. 
 Prior therapy: 
o Any prior treatment with MMAE-derived drugs. 
o Radiotherapy within 21 days prior to the first administration 
of IMP. Patients must have recovered from all clinically 
significant radiation-related toxicities. At least 42 days must 
have elapsed from the last administration of chemo-
radiotherapy. 
o Small molecules, chemotherapy, immunotherapy, monoclonal 
antibodies, or any experimental agents (not specified in this 
protocol) within 28 days prior to the first administration of 
IMP. 
 Other: Ongoing significant, uncontrolled medical condition; 
clinically significant active viral, bacterial or fungal infection 
requiring IV or oral treatment with antimicrobial therapy ending 
less than 7 days prior to first IMP administration; clinically 
relevant bilateral hydronephrosis which cannot be alleviated by 
ureteral stents or percutaneous drainage; patients with clinical 


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symptoms or signs of gastrointestinal obstruction and who require 
parental hydration and/or nutrition; inflammatory bowel disease 
including Crohn's disease and colitis ulcerosa; ongoing acute or 
chronic inflammatory skin disease; inflammatory lung disease 
including moderate and severe asthma and chronic obstructive 
pulmonary disease (COPD) requiring chronic medical therapy. 
 Known seropositivity of human immunodeficiency virus; known 
medical history or ongoing hepatitis B or C infection. 
 Has a diagnosis of immunodeficiency or is receiving systemic 
steroid therapy (dosing exceeding 10 mg daily of prednisone or 
equivalent) or any other form of immunosuppressive therapy 
within 7 days prior to the first dose of tisotumab vedotin. 
 Patient is pregnant, breast feeding or intends to conceive children 
starting from date of signed ICF and continuing until  6 months 
after the last dose of trial treatment. 
 Patient has any condition for which, in the opinion of the 
investigator, participation would not be in the best interest of the 
patient (e.g. compromise the well-being) or that could prevent, 
limit, or confound the protocol-specified assessments. 
 Patient has known allergies, hypersensitivity, or intolerance to 
tisotumab vedotin or its excipients (please refer to the 
Investigator's Brochure). 
Efficacy Assessments 
To investigate the confirmed ORR of tisotumab vedotin per RECIST 
v1.1 assessed by IRC in patients with previously treated, recurrent or 
metastatic cervical cancer. 
Safety Assessments 
To assess the safety and tolerability of tisotumab vedotin. 
Other Assessments 
Not applicable 
Statistics 
The primary analysis of confirmed ORR and a 2-sided 95% exact 
confidence interval will be calculated based on a data cutoff 
approximately 6 months after all responders have experienced their 
first response as assessed by the investigator per RECIST v1.1. 
Assuming a true confirmed ORR of 21% - 25% for tisotumab vedotin, 
100 patients provides 80% power to exclude an ORR of 11% or less. 
GCP Compliance 
This trial will be conducted in compliance with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP 
[R2]), and applicable regulatory requirements. 


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1 
VISIT ASSESSMENT SCHEDULE 
Table 1-1 lists all of the assessments and indicates with an “X” the visits when they are performed. 
All data obtained from these assessments must be supported in the patient’s source documentation. 
Table 1-2 shows the timing of the PK sampling. 




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Footnotes to Trial Flowchart 
1 
Day 1 of cycle 1 is to be performed no more than 28 days after screening visit 1. Each cycle is 21 days. Day 1 of cycle 2 is to be performed 21 days ± 3 days after day 1 of cycle 1, day 1 of cycle 
3 is to be performed 21 days ± 3 days after day 1 of cycle 2 etc. 
2 
Survival follow-up is to be performed every 60 days (±7days), beginning from the day of last IMP dose, and include collection of survival status and information of any new anti-cancer treatment. 
3 
The day 4 and day 8 visits are only to be performed for cycle 1. The day 8 visit should be performed at least 72 hours after the day 4 visit. 
4 
Informed consent can be obtained outside the screening visit window (but should be obtained within a reasonable window prior to the screening date).  
5 
An unscheduled visit can be setup if deemed necessary.  Relevant assessments should be made depending on the reason for the unscheduled visit. 
6 
All patients will have a chest X-ray (CXR), and CT or MRI scan of the abdomen and pelvis performed during screening. Please refer to 9.2.1.1. 
7 
CT or MRI scans must be performed every 6 weeks (±7 days) for the first 30 weeks and every 12 weeks (±7 days) thereafter, calculated from the date of first IMP dosing. Imaging should continue 
until the patient experiences IRC verified disease progression, begins a new anti-cancer therapy, withdraws from the trial or dies, whichever comes first. Time points for radiographic evaluation 
should be calendar based and does not depend on cycle visits i.e. radiological evaluation should be performed regardless of IMP administration delays. 
8 
ECOG assessment and local laboratory values for biochemistry, hematology and coagulation factors must be obtained and reviewed by the investigator within 24 hours prior to IMP administration 
from cycle 2 and onwards. ECOG assessment and local laboratory values do not need to be obtained prior to first dosing of IMP (cycle 1, day 1). If ECOG is assessed and/or local laboratory values 
are obtained, after patient enrolment has been granted and prior to first administration of IMP, these parameters must meet eligibility criteria. If they do not, investigator must hold IMP dosing and 
contact the sponsor Medical Officer. 
9 
Health related quality of life questionnaires should be completed by the patient as first thing upon arrival for a visit (i.e. before any disease or treatment-related dialog with the study nurse/treating 
physician or initiation of other preparations for the trial/IMP infusion). Health related quality of life questionnaires must be completed at the screening visit, on day 1 of cycle 2 and 4 and at the 
treatment discontinuation visit. 
10 
Please specifically ask if the patient has experienced any bleeding events, peripheral neuropathy and/or ocular adverse events. 
11 
To be performed by the treating physician: Patients should be questioned about any changes in sight/ocular symptoms. A visual inspection of the eye orbit and conjunctiva and control of normal 
eye movement should be performed. All patients should be informed to contact their treating physician immediately in case of any ocular symptoms appearing between IMP administration days. 
12 
The patient should be referred to an ophthalmologist for prompt review (preferably within 72 hours and no later than within one week) in case of ocular symptoms any time during trial and/or any 
abnormal findings during the eye examination performed by the treating physician.  
13 
To be performed by an ophthalmologist: All patients must have their eyes evaluated by an ophthalmologist during screening. 
14 
Preventive eye therapy must be administered prior to each IMP administration. Refer to Section 6.2.2. 
15 
Any change in the patient´s trial status should be recorded on the relevant forms in the eCRF.  
16 
All laboratory parameters will be analyzed centrally, except coagulation parameters which must be measured locally. 
17 
INR, aPTT and PT must be measured locally (i.e., no central measurements should be performed for these values). Please refer to Table 9-3. 
18 
Only for patients of reproductive potential (please refer to Section 10.1.5 for definition). Serum (beta-hCG) laboratory test must be taken at screening (analyzed centrally). A urine pregnancy test 
(performed locally) must be taken every second cycle, i.e., on day 1 of cycles 1, 3, 5, etc., at the treatment discontinuation visit and at the safety follow-up visit. 
19 
Sample to be taken before IMP administration. 
20 
The most recent available archived sample should be used. If no biopsies are available, a new biopsy must be obtained before IMP administration, unless reviewed by sponsor’s Medical Officer 
and deemed unfeasible. 
21 
Optional tumor sample at time of IRC verified progressive disease. 
22 
Sample to be taken before IMP administration, at cycles 1, 2, 3, 4 and 5 
23 
Only at cycle 1. 
24 
Sample to be taken before IMP administration, at cycles 1, 2, 4 and 8. 
25 
Sample to be taken before IMP administration at cycle 1 
 
 




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2 
INTRODUCTION 
2.1 
Background 
2.1.1 Overview of Disease 
Cervical cancer poses a significant medical problem worldwide with an estimated incidence of more 
than 500,000 new cases. The disease accounts for approximately 8% of female cancer deaths (Ferlay 
et al., 2012) and up to 85% of deaths in some developing countries. In the US, approximately 12,800 
new cases and 4,210 deaths are estimated to occur this year (American Cancer Society, 2017). 
2.1.2 Introduction to the Investigational Medicinal Product 
The investigational medicinal product (IMP), tisotumab vedotin, is an antibody-drug conjugate (ADC) 
composed of a human monoclonal immunoglobulin G1 (subtype κ) targeting tissue factor (TF) 
conjugated via a protease cleavable valine citrulline linker to the drug monomethyl auristatin E 
(MMAE), a dolastatin 10 analog (Doronina et al., 2003; Hamblett et al., 2004; Sun et al., 2005). 
Dolastatins and auristatins belong to a class of chemotherapies that act as microtubule disrupting 
agents.  
Tisotumab vedotin efficiently binds to TF. TF has a central physiological role in initiation of the 
coagulation cascade but is during oncological transformation upregulated and expressed on the 
membrane of neoplastic cells as well as on tumor-associated endothelial cells. Upon binding to TF, 
tisotumab vedotin is rapidly internalized into tumor cells where it undergoes lysosomal degradation 
resulting in release of the cytotoxic payload. Tumor cell death occurs due to MMAE-mediated 
disruption of microtubules and bystander “cytotoxicity” effect of neighboring tumor cells. Please refer 
to Section 2.2 for more details. 
2.1.3 Summary of Non-clinical Studies 
Tisotumab vedotin treatment resulted in potent and long-lasting tumor regression in TF-expressing 
xenograft models derived from a variety of solid cancers, including patient-derived xenograft models 
with heterogeneous TF expression. Moreover, potent tumor regression was observed in xenograft 
models of bladder, lung, cervical and ovarian cancer that had received prior treatment with paclitaxel.  
Given the contribution of TF in hemostasis, assessment of tisotumab vedotin in coagulation was 
performed. Tisotumab vedotin showed only modest impact (19% inhibition) on coagulation in an FXa 
generation assay and in thromboelastography studies. The effect of high dose treatment with the naked 
antibody, tisotumab, on coagulation parameters in vivo was studied in cynomolgus monkeys. 
Tisotumab had no impact on coagulation parameters or functional bleeding time at a dose of 
100 mg/kg. Furthermore, tisotumab vedotin had no impact on coagulation parameters at 5 mg/kg 
repeated dosing in cynomolgus monkeys. 
The safety profile of tisotumab vedotin in cynomolgus monkey studies was as expected for 
MMAE/tubulin-disrupting agents.  
Further details on non-clinical studies can be found in the Investigator’s Brochure. 


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2.1.4  Summary of Clinical Trials 
Tisotumab vedotin is being investigated in two clinical trials; GEN701 and GEN702. Each trial 
consists of two parts; I) a dose escalation part and II) a cohort expansion part. As of 16-May-2018, 
238 patients have been enrolled across both trials. 
GEN701: A first in human trial investigating treatment with tisotumab vedotin once every 3 weeks 
(1Q3W). The indications included ovary, cervix, endometrium, bladder, castration-resistant prostate 
cancer, esophagus, non-small cell lung cancer, and squamous cell carcinoma of the head and neck. 
Part I) The dose escalation part has been finalized. The recommended phase 2 dose was 
identified as tisotumab vedotin 2.0 mg/kg 1Q3W. 
Part II) The expansion part of GEN701 is ongoing. Patients enrolled in the GEN701 expansion 
cohorts are administered tisotumab vedotin 2.0 mg/kg 1Q3W.  
GEN702: Investigating treatment with tisotumab vedotin once weekly for 3 weeks followed by one 
week with no treatment (3Q4W). The indications included ovary, cervix, endometrium, bladder, 
castration-resistant prostate cancer, esophagus and non-small cell lung cancer. 
Part I) The dose escalation part has been finalized. The recommended phase 2 dose was 
identified as tisotumab vedotin 1.2 mg/kg 3Q4W. 
Part II). Patients enrolled in the GEN702 expansion cohort were initially treated with the 
frequent dosing regimen of tisotumab vedotin 1.2 mg/kg 3Q4W. However, this dosing regimen 
was later discontinued due to severe ocular adverse events (AEs) and patients enrolled in 
GEN702 were instead offered tisotumab vedotin 2.0 mg/kg 1Q3W, that in GEN701 had been 
found to be potentially efficacious and tolerable. GEN702 expansion part has been completed 
and CSR is pending. 
2.1.4.1 Summary of Clinical Safety across Indications  
As of 16-May-2018, 199 patients have received tisotumab vedotin 1Q3W in doses ranging from 0.3 to 
2.2 mg/kg. The number of patients by dose level was: 0.3 mg/kg (n=3); 0.6 mg/kg (n=3); 0.9 mg/kg 
(n=3); 1.2 mg/kg (n=3); 1.5 mg/kg (n=3); 1.8 mg/kg (n=3); 2.0 mg/kg (n=175); 2.2 mg/kg (n=6). 
Across all indications enrolled on the 1Q3W dosing regimen, the most commonly reported treatment-
emergent AEs (hereafter referred to as AEs) observed in > 20% of the patients were epistaxis (64%), 
fatigue (53%), nausea (47%), alopecia (40%), conjunctivitis (36%), constipation (34%), decreased 
appetite (33%), diarrhea (28%), vomiting (26%) and neuropathy peripheral (26%). 
Grade ≥ 3 AEs were reported in 57% of patients. The most frequently reported AEs ≥ grade 3 were 
fatigue (9.5%), anemia (7.0%), abdominal pain (4.5%), hypokalemia (4.0%), hyponatremia (3.5%), 
vomiting (3.0%), dyspnea and conjunctivitis (2.5% each).  
Serious adverse events (SAEs) were reported in 47% of patients. Abdominal pain was the most 
frequently reported SAE (4.5%), followed by vomiting (3.0%), constipation, hyponatremia, and 
anemia (2.5% each).  
AEs leading to discontinuation were reported in 30% of patients; across all indications the most 
frequently AEs leading to discontinuation were neuropathy peripheral (5.5%), conjunctivitis (3.5%), 
and peripheral sensory neuropathy (2.5%). 


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Across all trials, eleven of 228 patients (4.8%) experienced an AE with a fatal outcome. Two patients 
died due to AEs considered by the investigator to be related to tisotumab vedotin (pharyngeal tumor 
hemorrhage [0.6 mg/kg 1Q3W] and pneumonia [2.0 mg/kg 1Q3W]). The other fatal adverse events 
were not considered related to trial drug by the investigator and included disease progression (4 
patients); general physical health deterioration (2 patients); dyspnea (1 patient); metastases to the 
central nervous system (1 patient) and oesophageal cancer metastatic (1 patient). 
Safety data from clinical trials with tisotumab vedotin have demonstrated that tisotumab vedotin is 
tolerable. Furthermore, the safety profile in the cervical cohort of GEN701 part II was comparable to 
the profile observed for other indications.  
Three categories of Adverse Events of Special Interest (AESI) have been identified in relation to 
treatment with tisotumab vedotin: 
 Ocular AEs: AEs of grade 1-2 conjunctivitis are frequently reported in relation to treatment 
with tisotumab vedotin. Severe cases (common terminology criteria for adverse events 
[CTCAE]  grade 3) of conjunctivitis and keratitis have been observed, however 
implementation of a comprehensive mitigation plan and preventive measures (please refer to 
Section 7.2.1) have substantially reduced both the frequency and severity of conjunctival 
toxicity in GEN701 part II.  
 AEs of peripheral neuropathy (including preferred terms as: neuropathy peripheral; peripheral 
sensory neuropathy; peripheral motor neuropathy; polyneuropathy): Peripheral neuropathy is 
a well-known adverse reaction to treatment with chemotherapeutics (including cisplatin and 
taxanes) as well as MMAE-based ADCs and is frequently reported in relation to treatment 
with tisotumab vedotin. The majority of the reported cases are grade 1-2; however peripheral 
neuropathy was the leading cause of permanently discontinuation of IMP in GEN701 part II. 
A mitigation plan, including dose reduction and dose delay, is in place in order to prevent 
onset of peripheral neuropathy as well as deterioration of pre-existing conditions (please refer 
to Section 7.2.2). 
 AEs of bleeding: Bleeding events are considered AESI due to the mode of action of IMP. In 
line with non-clinical findings, no major impact on activated partial thromboplastin time 
(aPTT) or prothrombin time (PT) has until now been found for tisotumab vedotin treated 
patients. Epistaxis was the most common reported AE in GEN701 part II, however, nearly all 
of the cases were grade 1. Excluding epistaxis, no causal relation to tisotumab vedotin has 
been established for the majority of the reported bleeding events. One patient in the squamous 
cell carcinoma of the head and neck indication experienced an event of grade 5 pharyngeal 
hemorrhage in GEN701 part I (the event was evaluated as most likely due to the patient’s 
baseline disease, however, a causal relationship to trial drug could at that point in time not 
completely be ruled out). 
For further details of adverse events observed in relation to treatment with tisotumab vedotin please 
refer to Investigator’s Brochure. 


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2.1.4.2 Summary of Efficacy and Concentration Data  
Preliminary efficacy in GEN701 cervical cancer expansion cohort – first 34 patients: 
In GEN701 part II (as of 16-May-2018), 11 patients (32% [95% CI, 17% to 51%]) experienced a best 
overall response of partial response (PR), including 9 (26% [95% CI, 13% to 44%]) patients who had 
a confirmed response according to RECIST v1.1 based on investigator assessment. The median 
duration of response (DOR) in the confirmed responders was 5.5 months [95% CI, 3.0 months to 
9.6 months]. 
Concentration data: 
 
 
2.2 
Rationale 
Tisotumab vedotin is an ADC targeting TF-expressing tumors through intracellular delivery of the 
potent and clinically validated agent MMAE. TF is expressed in a wide variety of tumors including 
the gynecological cancers of the ovary and cervix, genito-urethral tumors, squamous cell carcinoma 
of the head and neck, lung cancers, tumors in the gastrointestinal tract, breast cancer, malignant 
melanoma and pancreatic cancer. TF is expressed on the membrane of neoplastic cells as well as on 
tumor-associated endothelial cells. Furthermore, expression of TF on tumor cells has been associated 
with negative overall survival or disease-free survival as described in several indications, including 
ovarian and bladder cancer. 
Tisotumab vedotin binds efficiently to human TF-expressing cells and is rapidly internalized into 
tumor cells where it undergoes lysosomal degradation resulting in release of the cytotoxic payload. 
MMAE-mediated tumor cell killing is the dominant mechanism of action of tisotumab vedotin. Upon 
lysosomal degradation, tisotumab vedotin can induce bystander killing as a result of diffusion of free 
MMAE over the cell membrane, leading to cytotoxicity against neighboring tumor cells. In a bio-
distribution study in xenograft models, tisotumab vedotin effectively accumulated in TF-positive, but 
not TF-negative tumors. 
High, differential levels of TF expression have been observed in multiple cancers including cervical 
cancer; as such tisotumab vedotin is an attractive candidate as an anti-cancer therapy in cervical 
cancer.  
First-line (1L) treatment for recurrent or metastatic cervical cancer is comprised of bevacizumab 
combined with paclitaxel+platinum (cisplatin or carboplatin) or paclitaxel+topotecan. Despite a 48% 
objective response rate (ORR) and a median overall survival (OS) of approximately 18 months, 
unfortunately almost all patients relapse after this 1L treatment (Tewari et al., 2014). For second line 
(2L) therapy, no approved therapy is available and patients are often treated with single agent 
modalities including, but not limited to: pemetrexed, topotecan, docetaxel, nab-paclitaxel, vinorelbine 
and in some cases bevacizumab. A meta-analysis of single agent treatment demonstrates a response 
rate of 10.7% (95% CI: 8.0%-13.3%) (57 responders out of 535 patients) and median overall survivals 
(OS) of approximately 7 months (Table 2-1). 


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Table 2-1 
Reported Response Rates for Second-Line (2L) Treatment 
Drug(s) 
Type of 
cervical 
cancer1 
Trial 
phase 
ORR2 
median 
OS (months) 
No. of 
evaluable 
patients 
Reference 
Ixabepilone 
2 
10% 
5.8 
41 
(Burotto et al., 2015) 
Imatinib mesylate 
SCC 
0% 
5 
12 
(Candelaria et al., 2009) 
Topotecan 
0% 
6.5 
15 (2L) 
(Coronel et al., 2009) 
Topotecan 
2 
0% 
NA 
25 
(Fiorica et al., 2009) 
Docetaxel 
9% 
7.0 
23 
(Garcia et al., 2007) 
Gefitinib 
SCC 
2 
0% 
3 
28 
(Goncalves et al., 2008) 
Paclitaxel 
SCC 
2 
10% 
20 
(Homesley et al., 2008) 
Systemic 2L therapy in 
hospital 
13% 
9.3 
53 
(McLachlan et al., 2017) 
Pemetrexed 
2 
15% 
7.4 
27 
(Miller et al., 2008) 
Bevacizumab 
SCC 
2 
11% 
7.3 
46 
(Monk et al., 2009) 
Vinorelbine 
SCC 
2 
14% 
NA 
44 
(Muggia et al., 2004) 
Doxil 
SCC 
2 
11% 
8.9 
26 
(Rose et al., 2006) 
Cetuximab 
2 
0% 
6.7 
35 
(Santin et al., 2011) 
Gemcitabine 
Non SCC 
2 
5% 
6.5 
22 
(Schilder et al., 2005) 
Paclitaxel3+Carboplatin 
52% 
NA 
23 
(Torfs et al., 2012) 
Paclitaxel4+Carboplatin 
0% 
NA 
13 
Pembrolizumab 
2 
13% 
NA 
82 
(Schellens et al., 2017) 
1: AC: adenocarcinoma; SCC: squamous cell carcinoma; 2: ORR: overall response rate; patients who receive a complete 
or partial response; 3:  dose dense; 4: weekly 
 
2.3 
Benefit-risk Assessment 
Data from GEN701 part II demonstrate substantial efficacy of tisotumab vedotin in previously treated 
patients with recurrent or metastatic cervical cancer along with a manageable safety profile. The safety 
profile of tisotumab vedotin in the cervical cohort was comparable to the profile observed for other 
indications.  
Given the lack of effective therapies for 2L+ patients, these preliminary safety and efficacy data 
suggest a positive benefit-risk profile and warrant further investigation of tisotumab vedotin in a larger 
cohort of previously treated patients with recurrent or metastatic cervical cancer as a novel anti-cancer 
therapy for this population of high unmet need. 
Risks are addressed in Section 2.1.4.1. 




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4 
TRIAL DESIGN 
4.1 
Description of Trial Design 
This is a single arm, international, multicenter trial of tisotumab vedotin in patients with recurrent or 
metastatic cervical cancer who have received at least one prior line of systemic therapy. Eligible 
patients will be treated with IV tisotumab vedotin 2.0 mg/kg 1Q3W. Imaging will be obtained every 
6 weeks for the first 30 weeks and then every 12 weeks thereafter, calculated from the date of first 
IMP dosing. Imaging should continue until the patient experiences IRC verified disease progression, 
begins a new anti-cancer therapy, withdraws from the trial or dies, whichever comes first. For patients 
who achieve a response, a repeat scan must be obtained no earlier than 4 weeks (28 days) after the 
first scan to confirm the response. Survival status will be assessed every 60 days (7 days), beginning 
from the day of last IMP dose, or more frequently around the time of a database lock. Approximately 
100 patients will be enrolled in the trial.  
The design of the trial is shown in Figure 4-1.  
 
Figure 4-1 Trial Design 
4.2 
Trial Design Rationale 
Data from GEN701 part II demonstrate substantial efficacy of tisotumab vedotin in previously treated 
patients with recurrent or metastatic cervical cancer along with a manageable safety profile. Among 
the first 34 cervical cancer patients in the expansion cohort of GEN701 there were 9 confirmed 
responses (26%) which suggest a substantial improvement over available treatment options in this 


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population of great medical need. In addition, substantial tumor regression in this setting can be 
presumed to be attributed to treatment with tisotumab vedotin. 
Based on the above, it is warranted to further study the efficacy and safety of tisotumab vedotin in a 
larger cohort of previously treated patients with recurrent or metastatic cervical cancer using a single-
arm study design. 
In order to minimize any bias in progression assessments, patients who discontinue the IMP due to a 
non-progression event (e.g. toxicity), will be required to continue imaging (according to the 
Q6W/Q12W schedule) until radiographic progression is verified by the independent review 
committee (IRC) and/or a new anti-cancer therapy is initiated. 
4.3 
Dose and Schedule Rationale 
Patients in this trial will be treated with 2.0 mg/kg 1Q3W. The 2.0 mg/kg dose was identified as the 
Recommended Phase 2 Dose in GEN701 part I and was further evaluated in multiple dose expansion 
cohorts during which additional safety and efficacy data were collected. Please refer to the 
Investigator’s Brochure. 
4.4 
End of Trial and Treatment Discontinuation Definitions 
4.4.1 End of Trial 
The trial is considered completed when the last patient dies or withdraws from the trial OR tisotumab 
vedotin is commercially available. However, maximal trial duration is 5 years (starting from when the 
first patient signs the ICF).  
4.4.2 Treatment Discontinuation 
Treatment should continue until the patient fulfills one of the treatment discontinuation criteria (please 
see Section 8.1).  
4.4.3 Trial Termination 
The sponsor reserves the right to close the trial site or terminate the trial at any time for any reason at 
the sole discretion of the sponsor. Trial sites will be closed upon trial completion.  
The investigator may initiate trial site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a trial site by the sponsor or investigator may include but are not 
limited to: 
 Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or local 
health authorities, the sponsor's procedures, or GCP guidelines. 
 Inadequate recruitment of patients by the investigator. 
 Discontinuation of further tisotumab vedotin development. 
o If the development of the tisotumab vedotin is discontinued, and trial closure is necessary, 
sponsor will ensure provisioning of post trial treatment for ongoing trial patients. 


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5 
TRIAL POPULATION 
5.1 
Inclusion Criteria 
Each patient must satisfy all of the following criteria to be enrolled in the trial. 
1. Patients with extra-pelvic metastatic or recurrent cervical cancer with squamous cell, 
adenocarcinoma or adenosquamous histology, that: 
a. Have experienced disease progression during or after treatment with: 
i. Paclitaxel+cisplatin or carboplatin 
OR 
ii. Paclitaxel+topotecan, 
 
in combination with bevacizumab unless patients are ineligible for bevacizumab 
treatment according to local standards. 
b. Have received no more than 2 prior systemic treatment regimens for recurrent or 
metastatic cervical cancer. Chemotherapy administered in the adjuvant or neoadjuvant 
setting, or in combination with radiation therapy should not be counted as a prior 
systemic treatment regimen. 
c. Are not candidates for curative therapy, including but not limited to, radiotherapy or 
exenterative surgery. 
2. Measurable disease according to RECIST v1.1 as assessed by IRC. 
3. Age ≥ 18 years. 
4. Acceptable renal function: Calculated (Cockcroft-Gault) Glomerular Filtration Rate (GFR) 
> 50 mL/min. 
5. Acceptable liver function: Alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) ≤ 3 times the upper limit of normal (ULN) (if liver tumor/metastases are present, then 
≤ 5  ULN is allowed); bilirubin ≤ 1.5  ULN, except in patients diagnosed with Gilbert’s 
syndrome, direct bilirubin ≤ 2  ULN. 
6. Acceptable hematological status: Hemoglobin ≥ 5.6 mmol/L (9.0 g/dL), absolute neutrophil 
count (ANC) ≥ 1500/µL (1.5109/L); platelet count ≥ 100109/L assessed at least 2 weeks 
after transfusion with blood products and/or growth factor support.  
7. Acceptable coagulation status: 
a. For patients not on anti-coagulation therapy: 
i. Activated partial thromboplastin time (aPTT) ≤ 1.25 ULN. 
ii. International normalized ratio (INR) ≤ 1.2 
b. For patients on anti-coagulation therapy: 
i. aPTT ≤ 1.25 ULN. 
ii. INR: Patients on anti-coagulants that require laboratory assessments for dose 
titration (warfarin or other Vitamin K dependent anti-coagulant agents) must 


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be on a steady dose (no active titration) for ≥ 4 weeks prior to first planned 
administration of tisotumab vedotin and must have an INR ≤ 2.5 for 
eligibility.  
iii. Patients on anti-coagulants that do not require laboratory assessments for dose 
titration do not need to be on a steady dose for ≥ 4 weeks prior to first planned 
administration of tisotumab vedotin.  
iv. Concurrent chronic use of prophylactic AcetylSalicylic Acid (ASA, e.g., 
aspirin) is prohibited for patients on any type of anti-coagulation therapy. 
 
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 prior to the first 
planned administration of IMP.  
9. Life expectancy of at least three months. 
10. A negative serum pregnancy test for patients of reproductive potential. Patients that are 
postmenopausal or permanently sterilized (please refer to Section 10.1.5 for definitions), can 
be considered as not having reproductive potential. 
11. Patients of reproductive potential must agree to use adequate contraception during and for 6 
months after the last IMP administration. Adequate contraception is defined as highly effective 
methods of contraception (please refer to Section 10.1.5 for more information). In countries 
where two highly effective methods of contraception are required this will be an inclusion 
criterion. 
12. All patients 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 IMP. 
13. All patients must provide a fresh or archival biopsy prior to the first planned administration of 
IMP, unless determined it is unfeasible after sponsor medical review. For specific tissue 
requirements, please refer to Section 9.7.3. 
14. Following receipt of verbal and written information about the trial, patients must provide 
signed informed consent before any trial-related activity is carried out. 
5.2 
Exclusion Criteria 
Any patient who meets any of the following criteria will be excluded from participating in the trial. 
1. Patients with primary neuroendocrine or sarcomatoid histologies. 
2. Hematological:  
a. Known past or current coagulation defects leading to an increased risk of bleeding. 
b. Diffuse alveolar hemorrhage from vasculitis. 
c. Known bleeding diathesis. 
d. Ongoing major bleeding. 
e. Trauma with increased risk of life-threatening bleeding. 
f. History of severe head trauma or intracranial surgery within 8 weeks of trial entry. 


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3. Cardiovascular: 
a. Clinically significant cardiac disease including unstable angina, acute myocardial 
infarction 6 months prior to screening. 
b. Any medical history of congestive heart failure (Grade III or IV as classified by the 
New York Heart Association). 
c. Any medical history of decreased cardiac ejection fraction of < 45%. 
d. A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a 
QTc interval >450 msec). 
e. A complete left bundle branch block (defined as a QRS interval ≥ 120 msec in left 
bundle branch block form) or an incomplete left bundle branch block. 
4. Central nervous system: Any history of intracerebral arteriovenous malformation, cerebral 
aneurysm, or stroke (transient ischemic attack > 1 month prior to screening is allowed). 
5. Ophthalmological: Active ocular surface disease at baseline. Patients with any prior episode 
of cicatricial conjunctivitis or Steven Johnson syndrome are ineligible. 
6. Other cancer: Known past or current malignancy other than inclusion diagnosis, except for: 
Non-invasive basal cell or squamous cell skin carcinoma; noninvasive, superficial bladder 
cancer; any curable cancer with a complete response (CR) of ≥ 5 years duration. 
a. Brain metastases are allowed if the following criteria are met: Definitive therapy (for 
example: surgery or stereotactic brain radiotherapy) has been completed > 8 weeks 
before the first dose of IMP; no evidence of clinical or radiologic progression of the 
brain metastases; patients have completed perioperative corticosteroid therapy or 
steroid taper. NOTE: Chronic steroid therapy is acceptable provided that the dose is 
stable for 1 month prior to screening. 
7. Surgery/procedures: Major surgery within 4 weeks or minor surgery within 7 days prior to the 
first IMP administration. Patients who have planned major surgery during the treatment period 
must be excluded from the trial. 
8. Peripheral neuropathy grade > 2. 
9. Prior therapy: 
a. Any prior treatment with MMAE-derived drugs. 
b. Radiotherapy within 21 days prior to the first administration of IMP. Patients must 
have recovered from all clinically significant radiation-related toxicities. At least 42 
days must have elapsed from the last administration of chemo-radiotherapy. 
c. Small molecules, chemotherapy, immunotherapy, monoclonal antibodies, or any 
experimental agents (not specified in this protocol) within 28 days prior to the first 
administration of IMP. 
10. Other: 
a. Ongoing significant, uncontrolled medical condition. 
b. Clinically significant active viral, bacterial or fungal infection requiring IV or oral 
treatment with antimicrobial therapy ending less than 7 days prior to first IMP 
administration. 
c. Clinically relevant bilateral hydronephrosis which cannot be alleviated by ureteral 
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d. Patients with clinical symptoms or signs of gastrointestinal obstruction and who 
require parental hydration and/or nutrition. 
e. Inflammatory bowel disease including Crohn's disease and colitis ulcerosa 
f. Ongoing acute or chronic inflammatory skin disease. 
g. Inflammatory lung disease including moderate and severe asthma and chronic 
obstructive pulmonary disease (COPD) requiring chronic medical therapy.  
11. Known seropositivity of human immunodeficiency virus; known medical history or ongoing 
hepatitis B or C infection. 
12. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (dosing 
exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive 
therapy within 7 days prior to the first dose of tisotumab vedotin. 
13. Patient is pregnant, breast feeding or intends to conceive children starting from date of signed 
ICF and continuing until  6 months after the last dose of trial treatment. 
14. Patient has any condition for which, in the opinion of the investigator, participation would not 
be in the best interest of the patient (e.g. compromise the well-being) or that could prevent, 
limit, or confound the protocol-specified assessments. 
15. Patient has known allergies, hypersensitivity, or intolerance to tisotumab vedotin or its 
excipients (please refer to the Investigator's Brochure). 
5.3 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical trial but are not 
subsequently entered in the trial. Minimal information about the patient and the reason for screen 
failure should be recorded in the eCRF in order to meet  the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements. 
Individuals who do not meet the criteria for participation in this trial (screen failures) may be 
rescreened. The rescreening must be approved by the sponsor to ensure that the safety of the patient 
is not compromised. 
Upon rescreening, all eligibility criteria must be re-assessed by investigator. 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 is met: Previous submitted/IRC 
evaluated CT/MRI scans are valid for rescreening purposes as long as the scanning acquisition date is 
≤ 28 days prior to cycle 1 day 1. Already completed Health Related Quality of Life (HRQL) 
questionnaires and baseline ophthalmological evaluations are valid as long as they have been 
completed ≤ 28 days prior to cycle 1 day 1. Blood samples taken during the previous screening process 
are valid for rescreening purposes as long as they are fulfilling the initial timelines as indicated in 
Table 1-1. If previously approved for eligibility, the same tumor biopsy sample is valid for rescreening 
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6 
TREATMENT 
6.1 
Treatment Assignment 
6.1.1 Patient Numbering 
After signing the informed consent form (ICF), a screening number is assigned to the patient. Patients 
that meet the eligibility criteria and are enrolled will be assigned a patient number.  
6.1.2 Treatment Assignment 
This is an open-label single-arm trial and all patients will be assigned to the same treatment (Section 
6.2). 
Trial participation begins once written informed consent is obtained. 
6.2 
Dosage and Administration 
6.2.1 IMP 
Tisotumab vedotin at 2.0 mg/kg will be administered as an IV infusion over a minimum of 30 minutes 
on day 1 of each treatment cycle (one treatment cycle is 21 days). It is recommended that the infusion 
completes within 60 minutes. 
Each patient’s dose will be calculated based on the patient’s weight (please refer to Section 9.3.2 for 
more 
details 
on 
assessment 
of 
weight) 
rounded 
to 
the 
nearest 
kilogram, 
i.e., 2.0 mg/kg × body weight in kg. For patients who weigh >100 kg, the calculation of IMP dose 
should be normalized to 100 kg (i.e., 2.0 mg/kg × 100 kg = 200 mg). 
Preventive eye therapy must be administered in relation to each infusion as described below. 
6.2.2 Pre-medication 
MANDATORY Prophylaxis of Ocular Adverse Events: 
In order to prevent ocular adverse events, all patients must adhere to the below ocular pre-medication 
guidelines: 
 Use of preservative-free lubricating eye drops during the whole treatment phase of the trial (i.e. 
from first dose of IMP until 30 days after last dose of IMP).  
 Application of steroid eye drops during the first 3 days of each treatment cycle (i.e. first drop to 
be given prior to start of infusion; continue treatment for 72h thereafter).  
 Administration of local ocular vasoconstrictor before infusion. If the patient does not tolerate 
ocular vasoconstrictors due to adverse reactions, continued treatment with these may be stopped 
at the discretion of the investigator and following discussion with the sponsor’s Medical Officer.  
 Use of eye cooling pads during the infusion. 
 It is recommended not to wear contact lenses during the whole treatment phase of the trial. 


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Please refer to the Preparation and Administration Guide for more detailed instructions. 
Please note that prophylactic pre-medication does not qualify as an intervention when assessing 
CTCAE grading of treatment emergent ocular adverse events. 
Please refer to Section 7.2.1.1 for more information about mitigation of ocular adverse events. 
6.2.3 Supportive Care 
Prophylaxis of alopecia: 
Suggest using the DigniCap Scalp Cooling System according to guidelines 
(https://www.dignicap.com/) to prevent chemo-induced hair loss. 
Prophylaxis of recurrent infusion related reactions (IRRs):  
In case of an IRR ≥ grade 2, the patient should be pre-medicated prior to next infusion of IMP 
(antihistamine, acetaminophen and corticosteroids are recommended). 
Please refer to Section 7.2.2 for more information about mitigation of IRRs. 
Prophylaxis of nausea: 
Prophylactic treatment with anti-emetics is strongly suggested for patients experiencing an adverse 
event of nausea after cycle 1.  
Prophylaxis of recurrent neutropenia: 
In case of an AE of neutropenia grade 3 or grade 4, growth factor support (G-CSF) should be given 
prophylactically for subsequent IMP administrations. 
Please refer to Section 7.2.2 for more information about mitigation of AEs of neutropenia. 
6.3 
Compliance 
The IMP will be administered in the controlled environment of a clinical research center, and the 
direct observation of the administration of the IMP by the trial staff will ensure compliance with trial 
requirements. The date and time of each IMP administration must be captured in the eCRF.  
6.4 
Concomitant Medications and Therapies  
6.4.1 Permitted Concomitant Medications and Therapies 
Anti-coagulation therapy is permitted. Patients being treated with anti-coagulation therapy that 
requires laboratory assessments for dose titration (warfarin or other Vitamin K dependent 
anticoagulant agents) should have their doses adjusted to target an INR  2.5. Coagulation parameters, 
including aPTT, PT and INR, must be measured locally prior to each infusion of tisotumab vedotin as 
per the protocol flowchart (Table 1-1). 
6.4.2 Permitted Concomitant Therapy Requiring Caution and/or Action 
Drugs and substances known to be strong CYP3A and/or P-gp inhibitors according to the FDA’s list 
of drug interactions should be avoided if possible (FDA, 2016). If administered, the patient must be 
closely observed for potential adverse reactions. 


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6.4.3 Prohibited Concomitant Therapy 
Patients must be instructed not to take any medications, including over-the-counter products, without 
first consulting with the investigator. 
The following is prohibited: 
 Chronic prophylactic treatment with AcetylSalicylic Acid (ASA, e.g., aspirin) in combination 
with any other anti-coagulation therapy.  
 Radiotherapy.   
o Radiation therapy of a symptomatic solitary non-target lesion IS allowed. 
 Small molecules, chemotherapy, immunotherapy, monoclonal antibodies, other MMAE-derived 
drugs or any experimental agents (not specified in this protocol). 
6.5 
IMP Information 
6.5.1 Physical Description of the IMP 
Tisotumab vedotin is presented as a lyophilized cake for reconstitution in water for injection and is 
intended for dosing by the intravenous route by infusion after dilution in physiological saline solution. 
It will be manufactured and provided under the responsibility of the sponsor. A list of excipients can 
be found in the Investigator’s Brochure. 
6.5.2 Packaging 
Tisotumab vedotin will be supplied to the trial site pharmacy as bulk supply cartons.  
The IMP will be supplied in vials containing 40 mg of tisotumab vedotin as lyophilized powder. The 
powder must be reconstituted with 4 mL water for injection leading to a 10 mg/mL solution.  
The IMP will not be dispensed in child-resistant packaging. 
6.5.3 Labeling 
Labeling will be in accordance with the EU Guidelines to Good Manufacturing Practice, Annex 13, 
Investigational Medicinal Products, and any other applicable local regulatory requirements. For 
further details, see the trial specific preparation and administration guideline. 
6.5.4 Preparation, Handling and Storage 
Tisotumab vedotin (lyophilized vials) must be stored in a refrigerator at 2°C to 8°C.  
The dose of tisotumab vedotin for administration must be prepared by the trial site pharmacy using 
aseptic technique.  
The reconstituted tisotumab vedotin must be diluted into 0.9% NaCl 100 mL infusion bag according 
to the dose calculated for the patient. 
A 0.2 µm in-line filter must be used for the infusion. The entire 100 mL infusion volume from the 
prepared infusion bag needs to be administered, no dead volume is provided. 


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Please refer to the administration and preparation manual for instructions on storage, preparation and 
infusion. 
6.5.5 Drug Accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing of IMP 
in a drug accountability log. Drug accountability will be noted by the field monitor during trial site 
visits and at the completion of the trial.  
It is forbidden to use the IMP for purposes other than as defined in this protocol. 
When drug accountability has been verified and a copy of the completed drug accountability log has 
been received by sponsor, the investigator will dispose all used and unused trial treatment and 
packaging in accordance with the guidance in the administration and preparation manual and local 
regulations. 
6.5.6 Handling of Other Trial Treatment 
Not applicable. 
6.6 
Technical Complaint Handling 
A technical complaint is defined as any suspicion of a product defect related to manufacturing, 
labeling, or packaging, i.e. any dissatisfaction relative to the identity, quality, durability, or reliability 
of a product, including its labeling or package integrity. A technical complaint may have an impact 
on the safety and efficacy of the product. Timely, accurate, and complete reporting and analysis of 
technical complaint information from trials are crucial for the protection of patients, investigators, and 
the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has established 
procedures in conformity with regulatory requirements worldwide to ensure appropriate reporting of 
technical complaint information; all trials conducted by the sponsor or its affiliates will be conducted 
in accordance with those procedures. 
6.6.1 Procedures 
All initial technical complaints must be reported to the sponsor by the trial site personnel within 
24 hours after being made aware of the event. 
If the defect is combined with a SAE, the trial site personnel must report the technical complaint to 
the sponsor according to the SAE reporting timelines (Section 10.3). A sample of the suspected 
product must be maintained for further investigation if requested by the sponsor. 
6.6.2 Contacting Sponsor Regarding Product Quality 
The names (and corresponding telephone numbers) of the individuals who must be contacted 
regarding technical complaint issues are listed on the contact information page(s), which will be 
provided as a separate document. 


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7 
DOSE MODIFICATIONS AND SAFETY MANAGEMENT GUIDELINES 
7.1 
Dose Modification Guidance 
7.1.1 Dose Reduction 
For patients who do not tolerate the protocol-specified dosing schedule, dose reductions are permitted 
in order to allow the patient to continue treatment with tisotumab vedotin. Dose reductions must be 
preapproved by the sponsor’s Medical Officer unless allowed according to the mitigation plans 
specified in the protocol (please refer to Section 7.2). 
In case any dose reduction of tisotumab vedotin is needed, the dose must be reduced according to the 
guidelines provided below (Table 7-1). 
Table 7-1 
Dose Modification Scheme 
Previous dose of tisotumab vedotin 
Reduced dose of tisotumab vedotin 
 2.0 mg/kg 
 1.3 mg/kg 
 1.3 mg/kg 
 0.9 mg/kg* 
* No more than 2 dose reductions of tisotumab vedotin will be permitted. If an AE recurs after the second dose reduction 
of IMP, then the patient must permanently discontinue IMP treatment.  
7.1.2 Dose delay 
For any dose delay due to adverse events, dosing with tisotumab vedotin can be resumed immediately 
after the adverse event has improved (please refer to Section 7.2 for handling adverse events with a 
protocol mitigation plan). Treatment with tisotumab vedotin must be permanently discontinued for 
any dose delay > 12 weeks, (i.e. 84 days calculated from the intended day of the next scheduled dose), 
unless approved by the sponsor.  






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 Use of eye cooling pads during the infusion. 
 It is recommended not to wear contact lenses during the whole treatment phase of the trial.  
Please refer to the Preparation and Administration Guide for more detailed instructions.  
7.2.1.2 Guidelines for Treatment Prescribed by the Ophthalmologist 
Ocular symptom 
(CTCAE grading) 
Treatment guideline 
(The length of treatment is to be decided by the local ophthalmologist) 
Conjunctivitis gr 1 
Frequent dosing of preservative-free topical steroid drops is 
recommended. 
Conjunctivitis gr 2 
Frequent dosing (every second hour) of preservative-free topical steroid 
drops in conjunction with preservative free antibiotic prophylaxis such 
as chloramphenicol is recommended. 
Conjunctivitis gr 3 
Frequent dosing (every second hour) of preservative-free topical steroid 
drops in conjunction with preservative free antibiotic prophylaxis such 
as chloramphenicol is recommended. 
Keratitis gr 1 
Frequent dosing of preservative-free topical steroid drops is 
recommended. 
Keratitis gr 2 
Frequent dosing (every second hour) of preservative-free topical steroid 
drops in conjunction with preservative free antibiotic prophylaxis such 
as chloramphenicol is recommended. 
Conjunctival   
ulceration: Any grade 
Frequent dosing (every second hour) of preservative-free topical steroid 
drops in conjunction with preservative free antibiotic prophylaxis such 
as chloramphenicol is recommended. 








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 Any dose delay > 12 weeks calculated from the intended day of the next scheduled dose, unless 
approved by the sponsor. 
 
IMP discontinuation criteria for other adverse events: 
 Any grade pulmonary or CNS hemorrhage. 
 Second occurrence of a grade 3 infusion related reaction (despite pre-medication). 
 First occurrence of a ≥ grade 4 infusion related reaction. 
 First occurrence of mucositis ≥ grade 4. 
 First occurrence of peripheral neuropathy ≥ grade 4. 
 Any dose delay > 12 weeks calculated from the intended day of the next scheduled dose, unless 
approved by the sponsor. 


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8 
DISCONTINUATION, FOLLOW-UP AND COMPLETION 
8.1 
Discontinuation of Treatment 
A patient’s trial treatment must be discontinued if one of the following criteria is met: 
 Radiographic disease progression verified by IRC. 
 Death. 
 Unacceptable AEs requiring treatment discontinuation.  
 Investigator believes that it is in the best interest of the patient to stop treatment. 
 Withdrawal of consent. 
If IMP treatment is permanently discontinued for other reasons than IRC verified disease progression, 
every effort should be made to continue tumor assessments as outlined in Table 1-1. 
 
Discontinuation and safety follow-up visit: 
When IMP treatment is permanently discontinued, investigators will perform a treatment 
discontinuation visit and a safety follow-up visit. The treatment discontinuation visit should be 
performed as soon as possible after permanent discontinuation of IMP (preferably within 7 days after 
treatment discontinuation has been decided) and will include most assessments performed during 
screening (Table 1-1). The safety follow-up visit should be performed 30 days (±5 days) after the 
patient has received the last dose of IMP (Table 1-1).  
 
Survival follow-up: 
All patients will be followed until death or withdrawal from the trial. Information about survival status 
and initiation of any new anti-cancer therapy should be collected every 60 days (±7days) (or more 
frequently around the time of a database lock), beginning from the day of last IMP dose. Survival 
follow-up can be performed by telephone contact (the patient or a family member may give the 
requested information) or during a routine visit, if such a visit is scheduled for other reasons not related 
to this trial. This should be documented in the medical records. 
 
8.2 
Withdrawal from the Trial 
A patient may withdraw from the trial for any of the following reasons: 
 Withdrawal of consent to participate. 
 Investigator decision. 
 Lost to follow-up. 
Optional research samples collected from patients that withdraw from the trial will be retained and 
used in accordance with the patient’s original separate informed consent unless this consent is revoked 
(see Section 8.3). 


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8.3 
Withdrawal from the Optional Research Samples 
The patient may revoke their consent for optional research samples at any time. In this case, the 
optional research samples will be destroyed and no further testing will take place. To initiate the 
sample destruction process, the investigator must notify the sponsor of withdrawal of consent for the 
optional research samples and to request sample destruction. The sponsor will then initiate the process 
for sample destruction. If requested, the investigator will receive written confirmation from the 
sponsor that the samples have been destroyed. 
8.4 
Withdrawal from the Use of Samples in Future Research 
The patient may withdraw consent for use of samples for research (Section 13.2.5). In this case, 
samples previously collected will be destroyed after they are no longer needed for the clinical trial. 
Details of the sample retention for research are presented in the main ICF. 
8.5 
Follow-up for Safety Evaluations 
A safety follow-up visit must be performed 30 days (± 5 days) after the patient has received the last 
IMP dose (Table 1-1). Please see Section 8.1 for further details.  
8.6 
Lost to Follow-up 
For patients whose status is unclear because they fail to appear for trial visits without stating an 
intention to withdraw consent, the investigator must show "due diligence" by contacting the patient, 
family or family physician as agreed in the ICF and by documenting in the source documents steps 
taken to contact the patient, e.g. dates of telephone calls, registered letters, etc. A patient must not be 
considered lost to follow-up until due diligence has been completed (where possible, 3 telephone calls 
and, if necessary, a certified letter to the patient’s last known mailing address or local equivalent 
methods). Patients lost to follow-up must be recorded as such on the appropriate disposition eCRF.  


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9 
TRIAL ASSESSMENTS 
9.1 
Demography and Baseline Assessments 
9.1.1 Demographics 
Demographic details must be assessed and recorded in the eCRF at screening. 
9.1.2 Medical History 
Medical history is defined as all relevant past and all current medical conditions/diseases (besides 
cervical cancer) occurring prior to the patient signing the ICF.  
9.1.3 Concomitant Medication 
Investigators may prescribe concomitant medications or treatments deemed necessary to provide 
adequate supportive care except for those medications identified as “prohibited” (Section 6.4.3).  
The patient should be told to notify the trial site about any new medications she is taking. All 
medications and significant non-drug therapies (including physical therapy, herbal/natural 
medications and blood transfusions) administered during the trial must be recorded in the eCRF from 
28 days prior to the first dose of IMP and up to 30 days after the last dose of IMP. Thereafter only 
new anti-cancer therapy(s) will be collected. 
9.1.4 
Prior Cancer Therapy and Surgery 
All anti-cancer therapies (including surgery, radiotherapy, chemo-radiotherapy, systemic treatment 
regimens etc.), received by the patient, from the time of the initial cervical cancer diagnosis until 
enrollment in this trial, should be reported in the appropriate section of the eCRF.  
9.2 
Efficacy assessments 
9.2.1 Tumor imaging:  
Tumor response will be assessed both locally and centrally according to RECIST v1.1 criteria 
(Eisenhauer et al., 2009). All tumor imaging data obtained locally (including unscheduled scans) 
during the trial should be submitted to the Imaging CRO for review by the IRC. Data obtained from 
central IRC review will be used in the analysis and reporting of trial results.  
Tumor imaging is strongly preferred to be acquired by computed tomography (CT). For the abdomen 
and pelvis, contrast-enhanced magnetic resonance imaging (MRI) may be used when CT with 
iodinated contrast is contraindicated, or when mandated by local practice. A contrast enhancing MRI 
is the preferred modality for imaging the brain (if contraindicated, an MRI without contrast or CT 
with/without contrast is acceptable). The same imaging modality and ideally the same scanner should 
be used throughout the trial to optimize the reproducibility of the assessment and preserve the accuracy 
of the assessment of response or progression. 
Combined PET/CT may be used only if the CT portion is of similar diagnostic quality to CT alone. 
At the discretion of the investigators, FDG-PET scans may be performed to document disease 


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progression as per RECIST v1.1 (Eisenhauer et al., 2009). Localized CT, MRI or X-rays must be 
acquired for assessment of skeletal lesions not visible on other images. 
Chest X-rays and ultrasound should not be used to measure tumor lesions. 
9.2.1.1 Baseline Imaging Assessments 
Baseline imaging assessments will be performed during the screening period (≤ 28 days prior to cycle 
1 day 1). Any imaging assessments already completed for regular radiographic evaluation of the 
patient’s cancer disease can be considered as the baseline images for this trial as long as they are of 
diagnostic quality and have been obtained ≤ 28 days prior to cycle 1 day 1. The following assessments 
are required at baseline: 
 Chest X-ray   
o The chest X-ray (CXR) should be locally evaluated: If the CXR shows evidence of metastatic 
disease, a CT of the chest must be obtained and submitted to the Imaging CRO for evaluation 
of measurable disease and should continue to be obtained for evaluation of response. If the 
CXR does not show any evidence of metastatic disease, further imaging of the chest does not 
need to continue. 
o Chest CT images may be used for evaluation of baseline chest/lung metastasis instead 
of CXR if such images have been obtained ≤ 28 days prior to cycle 1 day for reasons 
not related to this trial.  
 
 Abdomen and pelvis CT or MRI scan.  
o The CT/MRI scan of the abdomen and pelvis must be submitted to the Imaging CRO for 
evaluation of measurable disease and should continue to be obtained for evaluation of response.  
 
 If clinically indicated, CT or MRI of other areas of malignant disease (e.g. neck or brain) must be 
performed and submitted to the Imaging CRO for evaluation of measurable disease and should 
continue to be obtained for evaluation of response.  
 
Determination of measurable disease: 
All patients must have measurable disease as defined by RECIST v1.1 using conventional imaging 
techniques such as CT or MRI. Measurable disease is defined as at least one target lesion that can be 
accurately measured in at least one dimension. If using a CT with a slice thickness of less than 5 mm 
or MRI, non-lymph node lesions must measure ≥10 mm in the longest diameter and lymph nodes must 
measure ≥15 mm in the shortest diameter. Lymph nodes that measure less than 10 mm in the short 
axis are deemed “non-pathologic.” Lymph nodes that measure >10 mm but <15 mm should be 
classified as non-target lesions. It is strongly recommended that MRI is used for evaluation of lesion(s) 
present within an irradiated field. Tumors within a previously irradiated field will be designated as 
“non-target” lesions unless progression is documented or a biopsy is obtained to confirm persistence 
at least 90 days following completion of radiation therapy. Biopsy confirmation MAY be considered 
for either target or non-target lesions if the lesion(s) measures <30 mm or if the treating physician 


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determines it is clinically indicated. If a biopsy is performed on a previously irradiated lesion, a MRI 
scan (CT if MRI is contraindicated) should be obtained as baseline evaluation after the biopsy 
procedure. 
Baseline images must be submitted to the Imaging CRO in order to verify that the patient meets the 
inclusion criterion of measurable disease. The baseline imaging will undergo expedited review by the 
IRC (approximately within 3 days starting from the time of image receipt and once all queries issued 
by the Imaging CRO have been resolved). Baseline images should be submitted for IRC review as 
soon as possible after the screening process has been initiated in order to prevent any delay of first 
dosing. The results of the central IRC baseline review will be directly communicated to the trial site.  
9.2.1.2 Post-baseline Imaging Assessments 
Imaging assessments must be performed every 6 weeks (±7 days) for the first 30 weeks and every 12 
weeks (±7 days) thereafter, calculated from the date of first IMP dosing. Imaging should continue 
until the patient experiences IRC verified disease progression, begins a new anti-cancer therapy, 
withdraws from the trial or dies, whichever comes first. For patients who achieve a response, a repeat 
scan must be obtained no earlier than 4 weeks (28 days) after the first scan to confirm the response. 
For stable disease (SD), measurements must have met the SD criteria at least 5 weeks after the first 
dose of trial treatment. Time points for radiographic evaluation should be calendar based and does not 
depend on cycle visits i.e. radiological evaluation must be performed regardless of IMP administration 
delays.  
 NOTE: For patients who permanently discontinue IMP for other reasons than IRC verified 
disease progression (e.g. adverse events), every effort should be made to continue on-trial 
radiological evaluation as outlined in Table 1-1. 
All post-baseline images must be submitted to the Imaging CRO for review by the IRC. Post-baseline 
images (except cases of locally determined disease progression – please see details for expedited 
review below) will be read on an ongoing basis as detailed in the CRO Imaging Manual. Results of 
post-baseline readings will not be communicated to the trial sites (unless the site requests verification 
of suspected progressive disease). 
Additional imaging assessments may be performed at any time during the trial at the investigator’s 
discretion to support the efficacy evaluations for a patient, as necessary. If any supplemental 
radiological evaluation is performed off-schedule, subsequent imaging assessments must be 
performed in accordance with the original imaging schedule (please refer to Table 1-1). All 
supplemental images must be submitted to the Imaging CRO for review.  
Determination of Disease Progression 
In case disease progression is determined by the local investigator, the images must be transferred to 
the Imaging CRO for expedited review by the IRC. The investigator seeking an expedited review 
should indicate this request to the Imaging CRO on a designated form. In all instances, the process at 
the Imaging CRO will ensure that the central IRC reviewers remain blinded to the results of the local 
assessment and any potential expedited nature of the review. The result of the central IRC review will 
be communicated directly to the trial site.  
NOTE: Every effort should be made to continue the patient on IMP treatment during the IRC review 
period, as long as it is clinically acceptable. 


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In case progressive disease is verified by IRC: 
If the central IRC review verifies disease progression, the patient must permanently discontinue IMP 
treatment. No subsequent tumor assessments are required. 
In case progressive disease not is verified by the IRC: 
If the central IRC review does not verify disease progression, every effort must be made to continue 
IMP treatment, as long as it is clinically acceptable. Patients should continue on-trial radiological 
evaluation. 
9.2.2 Survival Status 
Survival status will be assessed every 60 days (± 7 days), beginning from the day of last IMP dose 
and continues until the patient dies or withdraws from the trial. Survival status may be requested more 
frequently around the time of a database lock. Patients who are not or whose designated family 
members are not available for this assessment should be entered as “lost to follow-up” (Section 8.6).  
9.3 
Clinical Safety Assessments 
9.3.1 Physical Examination 
A complete physical examination will at a minimum include general appearance of the following body 
systems: Lymph node regions, mouth and throat, lungs, cardiovascular, abdomen, extremities 
(including muscular-skeletal system), neurological system and skin.   
9.3.2 Body Measurements 
Height should be measured at screening. Body weight should be measured as indicated in Table 1-1.  
The patient’s body weight should be measured and used to calculate the dose of tisotumab vedotin for 
infusion. Please note that the weight measurement that is used for calculation of dose should be the 
weight/value that is recorded in the eCRF. The following rules for weight measurements apply:  
 The body weight that is used for calculation of dose must be measured at the trial site ≤ 7 days 
prior to the infusion.   
 If the measured weight does not fluctuate more than 10% from the baseline weight (i.e., the last 
weight measurement taken before first dosing of tisotumab vedotin), the baseline weight may be 
used for calculation of IMP dose. 
9.3.3 Vital Signs 
Vital signs (including temperature, blood pressure and heart rate) must be measured according to 
Table 1-1. The patient should be resting for at least 10 minutes before vital signs are measured. 
Temperature should be measured as an oral, axillary, rectal or ear temperature. Within each visit, 
preferably the same equipment should be used for vital sign measurements. On IMP administration 
days, vital signs must be measured no longer than 30 minutes before infusion start. 


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9.3.4 Electrocardiograms 
One 12-lead ECG must be performed at screening. Three 12-lead ECGs must be performed before 
and after each administration of IMP, at additional time points during cycle 1 (please refer to Table 
1-2) and at the treatment discontinuation visit.  
All patients should be resting for at least 10 minutes prior to obtaining the ECG. In case any 
irregularity (e.g., vomiting or cough) occurs during the recording of the ECG, the ECG should be 
repeated. All ECG recordings should be performed with at least 2 minutes apart in accordance with 
the ECG Specifications Manual issued by the ECG CRO. 
The ECG recordings should be locally evaluated by investigator (the investigator may delegate this 
task to a cardiologist, if applicable) in order to exclude any safety concerns. The ECGs must 
furthermore be transmitted to the ECG CRO for central review. The results from the central review 
will be used in the analyses and reporting of trial results.   
9.3.5 ECOG 
The Eastern Cooperative Oncology Group (ECOG) performance status will be assessed by the 
investigator as indicated in Table 1-1. Performance status will be scored using the ECOG performance 
status scale index (Table 9-1). 
Table 9-1 
ECOG performance status 
Score  
Score  
0 
Fully active, able to carry out all normal activity without restriction. 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light housework, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair. 
5 
Dead. 
9.3.6 Eye Examination and Ophthalmological Evaluation 
Eye examination: Eye examination should be assessed by investigator as indicated in Table 1-1 and 
should include a visual inspection of the eye orbit and conjunctiva and control of normal eye 
movement. The patient should furthermore be asked about any ocular symptoms (e.g. itchy eyes, 
sticky eyelids, eye secretion, blurry vision etc.) 
Ophthalmological evaluation: All patients must have their eyes evaluated by an ophthalmologist 
during screening as indicated in Table 1-1. Patients experiencing ocular symptoms or patients with 
abnormal ocular findings at the eye examination (assessed by investigator) must be referred to an 
ophthalmologist for prompt review (preferably within 72 hours and no later than within one week) 
any time during trial. The ophthalmologist’s evaluation should be recorded in the eCRF. 


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9.4 
Pharmacokinetics 
9.4.1 Evaluations 
Blood samples for assessment of tisotumab vedotin and MMAE will be drawn in accordance with the 
PK flowchart (see Table 1-2). Two assays will be used for tisotumab vedotin, one detecting tisotumab 
vedotin only and one detecting tisotumab vedotin and non-conjugated tisotumab. In addition a third 
assay will be used to determine free MMAE in circulation. 
Samples will be used to evaluate the PK of tisotumab vedotin. Remaining samples collected for 
analyses of tisotumab vedotin plasma concentration may also be used to evaluate other safety, 
efficacy, or biomarker lab parameters to address concerns arising during the trial. 
9.4.2 Analytical Procedures 
Plasma samples will be analyzed to determine concentrations of conjugated and non-conjugated 
tisotumab vedotin, as well as MMAE, using validated methods.  
9.5 
Clinical Laboratory Assessments 
Central Laboratory 
The tests detailed in Table 9-2 will be drawn and shipped for centralized testing and results will be 
reported to the investigators by the central laboratory as described in the laboratory manual. Central 
laboratory values will be used for assessment of eligibility (except for INR, aPTT and PT values which 
exclusively should be measured locally) and will also be used in the analyses and reporting of the trial 
results. Central laboratory values must be reviewed by investigator prior to first dosing.  






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enable the identification of biomarkers predictive of response to tisotumab vedotin. Tumor biopsies 
must be provided at screening, unless deemed unfeasible after sponsor medical review. Fresh biopsy 
material is preferred, but archival biopsies (FFPE blocks or slides) are also acceptable. Please note 
that any open biopsy must be performed > 7 days prior to the first IMP administration (refer to 
exclusion criteria Section 5.2). Potential mechanisms of tumor response and resistance as well as 
treatment-induced changes in the tumor immune microenvironment, may be monitored if post-
treatment tumor biopsies are also obtained. Optional tumor biopsies may also be collected if patients 
have unscheduled biopsies or tumor tissue resection during the course of the trial. 
9.7.1.1 Protein Expression Analyses 
TF expression and expression of other proteins related to cervical cancer biology or tisotumab 
vedotin’s mechanism of action (for example; Ki-67 as a measure of proliferative index) 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. 
9.7.1.2 RNA Expression Analyses 
RNA sequencing and/or focused profiling may be performed on tumor biopsies to determine TF RNA 
expression levels, and to evaluate expression of other genes such as MDR1, MDR6, Ki67 and VEGF 
associated with cervical cancer biology and/or response to MMAE/tubulin-disrupting agents for 
exploratory biomarker analyses. RNA profiling, including a focused gene panel, may also be utilized 
to characterize the immune profile within the tumor microenvironment (T cell, B cell, dendritic cells, 
macrophage, and other immune infiltrates within the tumor) and to determine whether tisotumab 
vedotin has an effect on these immune profiles. 
9.7.1.3 DNA Analyses 
Tumor biopsies may also be analyzed using Next Generation Sequencing (NGS) for DNA mutations, 
copy number variations, microsatellite instability, insertions, deletions, , and/or rearrangements in 
genes associated with tissue factor, tisotumab vedotin’s proposed mechanism of action, or cervical 
cancer biology such as tissue factor (F3 gene), -tubulin subtypes and genes involved in apoptosis 
regulation like PTEN and BCL2. In order to confirm genomic alterations found in tumor material, a 
normal sample (PBMC) may also be sequenced. 
9.7.2 Biomarker Assessments in Blood Samples 
Biomarker assessments will also be performed using whole blood samples to investigate potential 
pharmacodynamic markers such as circulation TF, and to explore the relationship to efficacy and/or 
mechanism of action of tisotumab vedotin. Assessments will be performed according to flow-chart 
(Table 1-1) in order to enable correlation analyses with response to treatment or disease progression.  
9.7.2.1 Protein Expression Analyses 
Protein levels of circulating TF and other proteins related to cervical cancer or tisotumab vedotin’s 
mechanism of action may be measured so changes associated with the mechanism of action of 
tisotumab vedotin can be monitored. 


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9.7.2.2 Cell-free DNA/RNA (cfDNA/RNA) and Tumor-derived DNA (ctDNA) Analyses 
Circulating cell-free DNA and/or RNA (cfDNA/RNA), including circulating tumor-derived DNA 
(ctDNA) and/or exosomal RNA (exoRNA), may be measured and analyses such as RNA expression 
levels, DNA mutations, copy number variations, microsatellite instability, indels, and/or 
rearrangements in genes may be performed to evaluate the association of such biomarkers with 
tisotubmab vedotin’s mechanism of action, patient response, or cervical cancer disease biology.  
9.7.3 Sample collections 
Samples for biomarker analyses will be collected as specified in Table 1-1. 
A tumor biopsy sample must be provided at screening, unless deemed unfeasible after sponsor medical 
review. A fresh biopsy is preferred, but archival tissue is also acceptable. The most recent archived 
biopsy should be used. Formalin-fixed, paraffin-embedded (FFPE) blocks or 10 slides with 5 micron 
sections should be provided. 
If it is determined at any time before trial completion that additional material is needed from a FFPE 
tumor sample for the successful completion of the protocol-specified analyses, the sponsor may 
request that additional material be retrieved from existing samples. Also, based on emerging scientific 
evidence relating to a potential correlation between a biomarker and treatment efficacy and/or safety 
the sponsor may request additional material from previously collected tumor samples during the 
clinical trial or for a period of 5 years after trial completion for a retrospective analysis. In this case, 
such analyses would be specific to research related to the IMP or diseases being investigated in the 
clinical trial. 
9.7.4 Additional Analyses 
In addition to the biomarker analyses listed above, other biomarkers deemed relevant to gain further 
knowledge about the pathological mechanism of the disease or about tisotumab vedotin (i.e. mode of 
action related effect or safety of the IMP) may be measured, based on newly emerging data from other 
ongoing trials and/or literature data. Biomarker samples may further be used to help address emerging 
issues and to enable the development of safer, more effective, and, ultimately, individualized therapy.  
Moreover, biomarker analyses are dependent upon the availability of appropriate biomarker assays 
and clinical response rates. Biomarker analysis may be deferred or not performed, if during or at the 
end of the trial, it becomes clear that the analysis will not have sufficient scientific value for biomarker 
evaluation, or if there are not enough samples or responders to allow for adequate biomarker 
evaluation. In the event the trial is terminated early or shows poor clinical efficacy, completion of 
biomarker assessments is based on justification and intended utility of the data. 
9.8 
Pharmacogenomic (DNA) Evaluations  
For those patients who have signed a separate consent for pharmacogenomics research, DNA/RNA 
samples (tumor and/or whole blood) may be analyzed for DNA/RNA aberrations such as gene 
expression levels, mutations, copy number variations, microsatellite instability, insertions, deletions, 
and/or rearrangements in genes as described in previous biomarker sections. A whole blood sample 
containing normal cells (PBMC) may also be evaluated to confirm the tumor specificity of any 


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genomic alterations that are identified. The consent and provision of samples used for genomic 
research is separate, voluntary, and has no influence on participation in the trial. 
DNA/RNA samples may be used for research related to tisotumab vedotin or evaluation of cervical 
cancer. Pharmacogenomic research may consist of the analysis of one or more candidate genes or of 
the analysis of genetic markers throughout the genome in relation to tisotumab vedotin clinical 
endpoints. 
If pharmacogenomic research evaluations are performed, the results will be reported in a separate 
report. 
9.9 
Patient Reported Outcomes 
The following health related quality of life questionnaires must be completed at the screening visit, 
on day 1 of cycle 2 and 4 and at the treatment discontinuation visit: 
EORTC-QLQ-C30 
The QLQ-C30 is a validated questionnaire developed by the European Organization for Research and 
Treatment of Cancer (EORTC) to assess the quality of life of cancer patients in multicultural clinical 
research settings (Aaronson et al., 1993).  
EORTC-QLQ-CX24 
The EORTC-QLQ-CX24 is a validated questionnaire developed by the European Organization for 
Research and Treatment of Cancer (EORTC) to assess the quality of life in patients who are treated 
for cervical cancer both in clinical trials and in clinical practice (Greimel et al., 2006). 
Both questionnaires should be completed by the patient as first thing upon arrival for a visit (i.e. before 
any disease/treatment dialog with study nurse/treating physician or initiation of other preparations for 
the trial/IMP infusion). 


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


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AESIs are defined on the basis of an ongoing review of the safety data. AESIs are discussed further 
in Section 2.1.4.1 and in the Investigator’s Brochure. 
10.1.4 Definition of Overdose of Tisotumab Vedotin 
For this trial, an overdose of tisotumab vedotin will be defined as any dose ≥ 10% of the indicated 
dose. 
10.1.5 Definition of Reproductive Potential and Contraception 
In this trial, patients are considered to have reproductive potential, UNLESS they are post-menopausal 
or permanently sterile.  
 A postmenopausal state is defined as no menses, in patients > 45 years of age, for 12 months 
without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-menopausal state in patients 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 patients 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 IMP.  
Patients of reproductive potential must agree to use adequate contraception during and for 6 months 
after the last IMP administration. Adequate contraception is defined as highly effective methods of 
contraception (Table 10-1). Birth control methods are considered highly effective if they have a failure 
rate of less than 1% per year, when used consistently and correctly. For more information please refer 
to Appendix 1. 


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Table 10-1 
Highly Effective Methods of Contraception 
 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation: 
o 
Oral 
o 
Intravaginal 
o 
Transdermal 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o 
Oral 
o 
Injectable 
o 
Implantable1 
 
Intrauterine device1 
 
Intrauterine hormone-releasing system1 
 
Bilateral tubal occlusion1 
 
Vasectomized partner1, 2 
 
Sexual abstinence3 
1 
Contraception methods that in the context of this guidance are considered to have low user dependency. 
2 
Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner 
of the woman of child-bearing potential trial participant and that the vasectomized partner has received medical 
assessment of the surgical success. 
3 
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 treatments. 
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 patient. 
Table adapted from ‘Recommendations related to contraception and pregnancy testing in clinical trials. Advisory non-
binding guidance represented at the CTFG-meeting in Rome 2014’ (UK MHRA., 2014). 
10.1.6 Definition of Infusion Related Reactions 
An infusion related reaction is defined as an adverse events with onset during or < 24 hours after IMP 
infusion, that is considered caused by the infusion of tisotumab vedotin. Examples of infusion related 
reactions are: Redness around injection site, rash, flushing, bronchospasm, chills etc. 
 
10.2 Reporting 
Adverse Event Reporting Period: 
All AEs must be reported from the time the patients signs the ICF until 30 days after last IMP dose. 
For patients who start any new anti-cancer therapy (other than IMP) during the AE reporting period, 
only AEs that are related to IMP should be reported. Any medical condition (signs, symptoms and 
diagnosis) occurring prior to signing the ICF, should be recorded as medical history.  
Please note:  The intensity of the AE, the suspected relationship to IMP treatment, action taken with 
IMP and the outcome of the AE should be assessed at each visit (or more frequently, if necessary). 
Instructions for reporting changes in an ongoing AE during a patient's participation in the trial are 
provided in the instructions that accompany the AE eCRF. 
 


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The following Adverse Events must be reported to the Safety CRO within 24 hours:  
 All serious adverse events (SAEs). 
 All ocular AEs, independent of grading and seriousness. 
 All events of overdose and/or medication errors with tisotumab vedotin, whether associated with 
an adverse event or not.  
 Any event of pregnancy. 
 
Table 10-2 Timeframes and Documents for Reporting of Adverse Events to the Safety CRO 
 
Initial Reports 
Follow-up Information on a Previous Report 
Type of 
Event 
Time 
Frame 
Documents 
Type of 
Event 
Time 
Frame 
Document 
All AEs 
reportable to 
the Safety 
CRO 
24 hours 
Safety Reporting 
Form (SRF)* 
All AEs 
reportable to 
the Safety 
CRO 
3 days 
CDS DCF 
Site DCF 
Overdose/ 
medication 
errors 
24h 
Safety Reporting 
Form (SRF)* 
Overdose/ 
medication 
errors 
3 days 
CDS DCF 
Site DCF 
Pregnancy 
24 hours 
Pregnancy Form 
Pregnancy 
3 days 
CDS DCF 
* A supplemental AESI Form must be filled in for all AESI qualifying for safety reporting. CDS=Corporate Drug Safety; 
DCF=Data Clarification Form.  
Completed Safety Reporting Forms or Pregnancy Forms must immediately be forwarded to the Safety 
CRO 
 
 
If you have access to a secured email you may forward completed safety reporting forms or 
pregnancy forms to: 
Email: 
 
If you do not have access to a secured email, please forward completed safety reporting forms or 
pregnancy forms to: 
Fax:  Europe: 
, US: 
 
 
Trial sites should make every effort to respond to follow-up queries from sponsor within 3 working 
days. 


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10.2.1 Pre-existing Conditions 
In this trial, a pre-existing condition (i.e. a disorder present before the AE reporting period has started 
and noted on the medical history form, please refer to Section 9.1.2) should not be reported as an AE. 
If a pre-existing condition worsens during the AE reporting period, the event must be reported as an 
AE. 
10.2.2 Diagnosis 
The diagnosis/underlying cause of an AE should be recorded rather than symptoms of the AE. If no 
diagnosis is available each sign and symptom must be recorded as individual AEs. 
10.2.3 Disease Progression or Death 
Progression of malignancy radiologically documented by RECIST, should not be reported as an AE. 
However, all hospitalizations caused by disease progression should be reported as an SAE.  
All deaths, except death caused by disease progression, should be reported as SAEs. 
Please note that specific clinical manifestations of disease progression (e.g., “malignant 
pleural effusion”, “spinal bone metastases”, “lymphadenopathy”, “brain metastases”) that 
meet the criteria for an SAE should be reported as the adverse event diagnosis rather than 
the unspecific term “disease progression”. If no specific clinical symptoms meet the serious 
criteria, then it is acceptable to report “disease progression” as the diagnosis of the adverse 
event. 
10.2.4 Unrelated Procedures 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
reported as AEs. A medical condition for which an unscheduled procedure was performed, must 
however be reported if it meets the definition of an AE. For example, an acute appendicitis must be 
reported as the AE and not the appendectomy. 
10.2.5 Laboratory test abnormalities 
Laboratory abnormalities that induce clinical signs or symptoms, require concomitant therapy or 
require changes in trial treatment must be reported as an AE. Whenever possible, a diagnosis, rather 
than a symptom should be provided (e.g. anemia instead of low hemoglobin). Laboratory 
abnormalities that meet the criteria for AEs must be followed until they have returned to normal or an 
adequate explanation of the abnormality is found. When an abnormal laboratory or test result 
corresponds to a sign/symptom of an already reported AE, it is not necessary to separately record the 
laboratory/test result as an additional event. 
NOTE: A CTCAE grade 3 or 4 laboratory value abnormality does not automatically indicate an SAE. 


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10.2.6 Start Date and Time 
Start date for an (S)AE is the date of occurrence of the first symptom of the disease, e.g. if chest pain 
occurs on 01 April 2016 and the patient is hospitalized with myocardial infarction on 04 April 2016, 
then the onset date of the SAE myocardial infarction is 01 April 2016. 
10.2.7 Infusion-Related Reactions (IRRs) 
For all adverse events with onset during or < 24 hours after IMP infusion, the investigator must assess 
whether the AE is considered caused by the infusion (please refer to Section 10.1.6 for a definition of 
IRRs). 
10.2.8 Seriousness Criteria 
Indicate whether or not the AE is determined to be “serious” based on the criteria defined in Section 
10.1.2. 
10.2.9  Intensity 
The investigator will use the National Cancer Institute’s CTCAE version 5.0 to describe the intensity 
of AEs.  
Changes in intensity of an ongoing AE should be assessed at each visit or more frequent if deemed 
necessary and should be reported in the eCRF (please refer to the instructions that accompany the AE 
eCRF for more information). 
10.2.10 Relationship to the Investigational Medicinal Product 
The investigator must assess whether or not the event is related to treatment with tisotumab vedotin. 
The relationship is to be judged using the following terms: 
 Related 
 Not related 
“An AE related to tisotumab vedotin” (i.e. a suspected adverse reaction) is an event for which there 
is a reasonable possibility that the tisotumab vedotin caused the AE, meaning there is evidence to 
suggest a causal relationship between tisotumab vedotin and the AE. 
Please note: If the relationship changes over time, the last judgment by the investigator should be 
reported. Relatedness has to be assessed and reported from the first time the AE is being reported. 
10.2.11 Action Taken with the Investigational Medicinal Product 
The action taken with the IMP in relation to an adverse event must be noted as: 
 Dose not changed 
 Dose reduced 
 Drug interrupted 
 Drug withdrawn  
 Not applicable 


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10.2.12  Outcome 
The outcome of the AE must be judged by investigator using the following terms: 
 Fatal 
 Not recovered/not resolved 
 Recovering/resolving 
 Recovered/resolved 
 Recovered with sequelae /resolved with sequelae 
 Unknown 
10.2.13 End Date and Time 
The end date should be filled in if the outcome of an event is fatal, recovered/resolved or recovered 
with sequelae/resolved with sequelae.  
10.3 Events Requiring Immediate Reporting 
10.3.1 Serious Adverse Events and Ocular Adverse Events  
 All serious AEs must be reported to the Safety CRO within 24h. 
 All ocular AEs, independent of grading and seriousness, must be reported to the Safety CRO 
within 24h. 
All SAEs and all ocular AEs must be reported from the trial site to the sponsor no later than 24 hours 
following a) the patient visit at which such AE was reported, noted or recognized; or b) the principal 
investigator’s or any investigator personnel’s receipt of the test results or c) other information at, or 
from which, such development was reported, noted or recognized. 
Please refer to Section 10.2 for an overview of AE reporting timelines. 
10.3.2 Overdose and Medication Errors 
For this trial, an overdose of tisotumab vedotin will be defined as any dose ≥ 10% of the indicated 
dose. All cases of overdose with tisotumab vedotin must be reported to sponsor as protocol deviations 
and to the eCRF and Safety CRO as an AE (whether or not associated with an AE). Reporting to the 
Safety CRO should be completed within 24 hours of knowledge of the event.  
Medication errors and uses outside what is foreseen in the protocol, including misuse and abuse of 
tisotumab vedotin, must be reported as protocol deviations to sponsor and to the eCRF and Safety 
CRO as an AE (whether or not associated with an AE). Reporting to the Safety CRO should be 
completed within 24 hours of knowledge of the event.  
Rescue medication to reverse the action of tisotumab vedotin is not available. In case of overdose, 
medication errors, misuse and/or abuse of tisotumab vedotin, patients should receive supportive care 
according to local guidelines and potential adverse events should be treated symptomatically. 


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In the event of an overdose, the investigator should: 
i. 
Contact the sponsor’s Medical Officer immediately. 
ii. 
Obtain a plasma sample for PK analysis if requested by the sponsor’s Medical Officer 
(determined on a case-by-case basis). 
iii. 
Closely monitor the patient for any AE and laboratory abnormalities until tisotumab vedotin 
can no longer be detected systemically. 
 
10.3.3 Pregnancy 
Any pregnancy must be reported to the Safety CRO within 24 hours of learning of its occurrence. 
Pregnant trial patients must immediately permanently discontinue IMP treatment. The pregnancy 
should be followed-up to determine outcome (including premature termination) and status of mother 
and child. The child should be followed at least to the age of one month. Pregnancy complications 
and elective terminations for medical reasons must be reported as an AE or SAE. Spontaneous 
abortions must be reported as an SAE. Any SAE occurring in association with a pregnancy brought 
to the investigator’s attention after the patient has completed the trial and considered by the 
investigator as possibly related to the IMP, must be promptly reported to the Safety CRO.  
10.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) 
The sponsor has a legal responsibility to notify, as appropriate and according to local regulations, both 
the local regulatory authority and other regulatory agencies about the safety of the product under 
clinical investigation. Prompt notification of SAEs by the investigator to the sponsor is essential so 
that legal obligations and ethical responsibilities towards the safety of patients are met. 
The sponsor will ensure that all relevant information about Suspected Unexpected Serious Adverse 
Reactions (SUSARs) is recorded and reported as soon as possible, but within a maximum of 15 days 
(fatal or life-threatening SUSARs within a maximum of seven days) of first knowledge by the sponsor 
or designee, to the competent regulatory authorities and/or to the ethics committee according to the 
applicable local regulatory requirements. Relevant follow–up information of fatal or life-threatening 
SUSARs will be communicated subsequently within an additional eight days. 
The investigator must be aware of local reporting regulations to the IEC/IRB. The safety CRO will 
either supply the investigator with the reports which must be passed on to the IEC/IRB or report 
directly to the IEC/IRB, depending on local regulations. 
10.5 Follow-Up on Adverse Events 
All AEs must be followed until they are resolved or until the safety follow-up visit, whichever comes 
first. However, IMP related AESIs qualifying for safety reporting and all SAEs (independent of 
causality) still ongoing after the safety follow-up visit should be followed on a regular basis, according 
to the investigator’s clinical judgment, until the event has been resolved or until the investigator 
assesses it as chronic and all queries have been resolved. 


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10.6 Warnings and Precautions 
No evidence available at the time of the approval of this trial protocol indicated that special warnings 
or precautions were appropriate, other than those noted in the provided Investigator’s Brochure. 
Additional safety information collected between Investigator’s Brochure updates will be 
communicated in the form of investigator notifications. This information will be included in the 
patient informed consent and must be discussed with the patient during the trial as needed. 
10.7 Data Monitoring Committee 
This trial will institute a data monitoring committee (DMC), which will function independently of all 
other individuals associated with the conduct of this clinical trial, including the trial site investigators 
participating in the trial. The DMC will consist at a minimum of two physicians with appropriate 
disease area qualifications and, where applicable, a statistician.  The functions and responsibilities of 
the DMC will be described in the DMC Charter, which will be approved by the DMC. During the trial 
the DMC may meet at regular intervals or ad hoc, as defined in the DMC charter. 


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11 STATISTICS 
The Statistical Analysis Plan (SAP) will be developed and finalized before database lock. This section 
is a summary of the planned statistical analyses of the primary and secondary endpoints. 
The primary analysis of the trial will be based on a data cutoff approximately 6 months after all 
responders have experienced their first response as assessed by the investigator per RECIST v1.1. 
All data will be listed. Baseline is defined as the latest available measurement made before the first 
treatment with tisotumab vedotin. 
11.1 Analysis Sets 
11.1.1 Full Analysis Set 
The full analysis set (FAS) comprises all patients who received at least one dose of trial treatment. 
11.1.2 Safety Set 
The safety set includes all patients who received at least one dose of trial treatment; thus, the full 
analysis set and the safety set is identical. 
11.2 Patient Demographics and Baseline Characteristics 
Demographic and other baseline data including disease characteristics will be listed and summarized 
descriptively for the safety set.  
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. 
Relevant medical histories and current medical history at baseline will be summarized separately by 
system organ class and preferred term. 
11.3 Treatments 
The safety set will be used for the analyses below. Categorical data will be summarized as frequencies 
and percentages. For continuous data, mean, standard deviation, median, 25th and 75th percentiles, 
minimum, and maximum will be presented.  
The duration of exposure in months to tisotumab vedotin as well as the dose intensity (computed as 
the ratio of actual cumulative dose received and actual duration of exposure) will be summarized by 
means of descriptive statistics using the safety set.  
The number of patients with dose adjustments (delay, reductions or permanent discontinuation) and 
the reasons will be summarized and all dosing data will be listed. 
Concomitant medications and significant non-drug therapies prior to and after the start of the trial 
treatment will be listed and summarized according to the anatomical therapeutic chemical (ATC) 
classification system. 
11.4 Primary Objective 
Determine the anti-tumor efficacy in patients with cervical cancer.   


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11.4.1 Endpoint 
 Confirmed objective response rate (ORR) based upon RECIST v1.1, assessed by the independent 
review committee (IRC). 
Confirmed ORR is defined (based on IRC verified CT scan results) as a best overall response (PR or 
better) confirmed by a subsequent best overall response of PR or better at least four weeks later. 
11.4.2 Statistical Hypothesis, Model and Method of Analysis 
The following statistical hypotheses will be tested to address the primary efficacy objective: 
𝐻0: 𝜃≤11%   𝑣𝑠.   𝐻𝐴: 𝜃> 11% 
where θ is the objective response rate. The test will be performed as an exact test at a one-sided 2.5% 
alpha level. 
In addition an exact 95% two-sided confidence interval for the objective response rate will be provided 
using the Clopper-Pearson method. 
The analysis will be performed on the FAS with an ITT approach so that any patients with missing 
information regarding response to treatment will be counted as non-responders. 
11.4.3 Handling of Missing Values/Censoring/Discontinuations 
Any patients with missing information regarding response to treatment will be counted as non-
responders. 
11.4.4 Supportive and Sensitivity Analyses 
ORR including unconfirmed responders will also be analyzed as a supportive analysis. 
Subgroup analyses will be provided by histology (adenocarcinoma, adeno-squamous and squamous 
cell carcinoma), prior radiation for localized disease (Y/N), bevacizumab (Y/N), prior lines of therapy, 
response to last therapy (Y/N) and by TF expression in biopsy as measured by IHC (details to be 
specified in the SAP). 
Because of the lower expected number of patients per center, no center effect will be investigated, but 
subgroup analyses by region (EU/US) will be done to assess regional consistency of treatment effects. 
Further confirmed ORR, as assessed by the investigator, will be analyzed and summarized in the same 
way. 
11.5 Secondary Objectives 
11.5.1 Secondary Efficacy Objectives 
 Evaluate tumor response durability. 
 Evaluate clinical response. 


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11.5.1.1 Secondary Efficacy Endpoints 
Duration of response (DOR) based upon RECIST v1.1, assessed by the IRC  
Duration of response (DOR) only applies to the subset of patients in the FAS whose best overall 
response is CR or PR according to RECIST v1.1 (Eisenhauer et al., 2009), based on tumor response 
data per IRC review. The start date is the date of first documented response of CR or PR (i.e. the start 
date of response, not the date when response was confirmed), and the end date is defined as the date 
of the first documented disease progression verified by IRC or death. Patients continuing without 
disease progression or death will be censored and the censoring date will be the date of the last 
adequate tumor assessment prior to data cut-off/start of new anti-cancer therapy. The data cut-off is 
the date defining the data to be included in the analysis. All data up to and including this date will be 
included. In case of progression after >2 missed visits, censoring will be done at last adequate tumor 
assessment date. DOR will be listed and summarized for all patients in the FAS with confirmed best 
overall response of CR or PR. 
DOR distribution will be estimated using the Kaplan-Meier method, and the survival curve, median 
and 95% confidence interval of the median will be presented. 
Confirmed ORR based upon RECIST v1.1, assessed by the investigator  
Investigator assessed confirmed ORR will be analyzed as described for the primary endpoint. 
DOR based upon RECIST v1.1, assessed by the investigator  
Investigator assessed DOR will be analyzed as described for IRC assessed DOR. 
Time to response (TTR) based upon RECIST v1.1, assessed by the IRC and by the investigator 
Time to response (TTR), whether assessed by IRC or investigator, is defined as the time from the date 
of the first IMP administration to the first documented response of either CR or PR, which must be 
subsequently verified by the IRC (although date of initial response is used, not date of confirmation). 
CR and PR are based on tumor response data as per blinded independent central review and according 
to RECIST 1.1 (Eisenhauer et al., 2009). 
All patients in the FAS will be included in TTR calculations. Patients without a confirmed CR or PR 
will be censored and the censoring date will be the date of the last adequate tumor assessment prior to 
cut-off/start of new anti-cancer therapy. TTR will be listed and summarized. 
Progression free survival (PFS) based upon RECIST v1.1, assessed by the IRC and by the 
investigator 
Progression free survival (PFS) is defined as the time from the date of the first IMP administration to 
the date of the first documented disease progression or death due to any cause. PFS will be assessed 
via blinded independent central review according to RECIST 1.1 (Eisenhauer et al., 2009). PFS will 
be censored if no PFS event is observed before the first to occur between: (i) the analysis cut-off date, 
and (ii) the date when a new anti-cancer therapy is started. The censoring date will be the date of the 
last adequate tumor assessment prior to cut-off/start of new anti-cancer therapy. In case of progression 


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after >2 missed visits, censoring will be done at last adequate tumor assessment date prior to the 
missed visits. 
PFS will be analyzed in the FAS population. The PFS distribution will be estimated using the Kaplan-
Meier method, and the Kaplan-Meier curve, median and 95% confidence interval of the median will 
be presented.  
Six and 12 months PFS rates (i.e. percentage of patients with PFS ≥ 6 months and ≥ 12 months 
respectively) will be summarized. 
Overall Survival (OS) 
Overall survival  is defined as the time from the date of the first IMP administration to the date of 
death due to any cause. If a patient is not known to have died, then OS will be censored and the 
censoring date will be the latest date the patient was known to be alive (on or before the cut-off date).  
OS will be analyzed in the FAS population. The OS distribution will be estimated using the Kaplan-
Meier method, and the Kaplan-Meier curve, median, first and third quartiles and 95% confidence 
interval of the median will be presented. 
Six and 12 months OS rates (i.e. percentage of patients with OS ≥ 6 months and ≥ 12 months 
respectively) will be summarized. 
11.5.1.2 Supportive Analyses of Secondary Efficacy Objectives and Endpoints 
Subgroup analyses will be provided as for the primary endpoint (Section 11.4.4). 
11.5.2 Safety Objectives 
The secondary safety objective is: 
 Assess safety and tolerability. 
11.5.2.1 Analysis Set and Grouping for the Analyses 
For all safety analyses, the safety set will be used. 
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment period: from day of patient’s informed consent to the day before first IMP 
administration. 
2. On-treatment period: from day of first dose of trial medication to 30 days after last IMP 
administration. 
3. Post-treatment: From 31 days after last IMP administration. 
11.5.2.2 Adverse Events 
Summary tables for AEs will include only AEs that started or worsened during the on-treatment 
period, the treatment-emergent AEs.  


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The incidence of treatment-emergent AEs (new or worsening from baseline) will be summarized by 
system organ class and or preferred term, severity (based on CTCAE version 5.0 grades), type of AE 
and relationship to trial treatment  
SAEs, non-serious AEs, AEs leading to withdrawal and AEs of special interest (AESI) during the on-
treatment period will be tabulated.  
All deaths (on-treatment and post-treatment) will be summarized.  
All AEs, deaths and SAEs (including those from the pre and post-treatment periods) will be listed and 
those collected during the pre-treatment and post-treatment period will be flagged. 
Further summaries of AEs, including summaries of AESIs will be specified in the statistical analysis 
plan. 
11.5.2.3 Laboratory Abnormalities 
Grading of laboratory values will be assigned programmatically as per the National Cancer Institute’s 
CTCAE version 5.0. The calculation of CTCAE grades will be based on the observed laboratory 
values only, clinical assessments will not be taken into account. 
CTCAE grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
For laboratory tests where grades are not defined by the CTCAE, results will be categorized as 
low/normal/high based on laboratory normal ranges. 
The following summaries will be generated separately for hematology and biochemistry tests: 
 Listing of all laboratory data with values flagged to show the corresponding CTCAE grades, if 
applicable, and the classifications relative to the laboratory normal ranges. 
 For continuous variables for both the raw value and change from baseline: 
o Summary tables by visit with mean, standard deviation (SD), median, min and max. The tables 
should include summaries of the last value as well as of the highest and the lowest value. 
o Box plots by visit. 
 For categorical variables: 
o Summary tables with frequencies of each response.  
 For laboratory tests where grades are defined by the CTCAE: 
o Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline. 
o Shift tables using CTCAE grades to compare baseline to the worst on-treatment value. 
 For laboratory tests where grades are not defined by the CTCAE: 
o Shift tables using the low/normal/high/ (low and high) (or other project-specific) classification 
to compare baseline to the worst on-treatment value. 


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11.5.2.4 Other Safety Data 
ECG 
12-lead ECGs including PR, QRS, QT, QTcF, and RR intervals will be obtained for each patient 
during the trial. ECG data will be read and interpreted centrally.  
Categorical analysis of QT/QTc interval data based on the number of patients meeting or exceeding 
predefined limits in terms of absolute QT/QTc intervals or changes from baseline will be presented. 
In addition, a listing of these patients will be produced. 
Vital Signs 
Data on vital signs will be tabulated and listed; notable values will be flagged. 
Immunogenicity (anti-drug antibodies) of tisotumab vedotin: 
Data on immunogenicity will be tabulated and listed; notable values will be flagged. 
11.5.3 Pharmacokinetics 
The plasma concentrations will be summarized by sampling time points, listed and presented 
graphically. Values below limit of quantification will be counted as having a value of half the lower 
limit of quantification. 
11.5.3.1 Data Handling Principles 
Missing concentration values will be reported as is in data listings. Concentration values below the 
lower limit of quantitation will be handled as LLOQ/2 in summary statistics, and reported as is in data 
listings. Any missing concentration data will not be imputed. 
11.5.4 Biomarkers 
The biomarker assessments are intended to evaluate potential pharmacodynamic markers, and to 
identify markers predictive of response or resistance to tisotumab vedotin. Since this clinical trial is 
not designed to address specific biomarkers-related statistical hypotheses, the analysis of these data 
should be viewed as exploratory and hypotheses generating. 
Biomarkers, including disease progression markers, may be listed, tabulated, and plotted when 
deemed appropriate.  Analyses will be stratified by clinical covariates or molecular subgroups using 
the appropriate statistical methods (e.g., parametric or non-parametric, univariate or multivariate, 
analysis of variance, or survival analysis) depending on the endpoint and the hypotheses. Baseline 
biomarker levels, or changes in biomarker levels, will be assessed for correlation with response and 
other clinical endpoints to identify responsive or resistant subgroups, as well as biomarkers or 
pathways attenuated following treatment with tisotumab vedotin.   
Additional analyses that may be performed after the completion of the end-of-trial clinical trial report 
and will be documented in separate reports. These analyses may include, but are not limited to, the 
meta-analysis of data from this trial combined with data from other trials or the analysis of biomarkers 
generated from samples collected during the trial but analyzed after the database lock and completion 


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of the clinical trial report. The data analysis will be described in an addendum of the statistical analysis 
plan or in a stand-alone analysis plan document, as appropriate. 
Planned analyses are based on the availability of clinically valid assays and may be deferred if 
emerging trial data shows no likelihood of providing useful scientific information. 
11.5.5 Resource Utilization 
Not applicable. 
11.5.6 Patient-reported Outcomes 
Endpoints on patient-reported outcomes will be summarized and listed. 
11.6 Exploratory Objectives 
 Assess biomarkers related to clinical response. 
 Assess potential pharmacodynamic biomarkers. 
 Assess Health Related Quality of Life (HRQL). 
Please see Section 11.5.4 for a high level description of the planned biomarker analyses. Further 
details on those analyses and the summary of the HRQL measures will be described in the Statistical 
Analysis Plan. 
11.7 Interim Analyses 
No formal interim analyses are planned. The primary analysis of the trial will be based on a data cutoff 
approximately 6 months after all responders have experienced their first response as assessed by the 
investigator per RECIST v1.1. 
Since patients will be treated until disease progression or withdrawal some patients may be still be 
ongoing at that time point and in that case the entire trial will be reported again when the last patient 
completes the trial.   
11.8 Sample Size Calculation 
In GEN701 there were 9 confirmed responders among the first 34 cervical cancer patients (26%).  
Applying a one-sided exact binomial test at the 0.025 significance level, the planned sample size of 
100 patients provides ≥80% power to reject an ORR of 11%, the combined ORR for available second-
line therapies (Section 2.2), or less for true ORRs in the range 21% - 25%, representing clinically 
relevant improvements over available second-line treatments (Table 11-1).  
Table 11-1 
Power for a range of clinically relevant true confirmed ORRs 
True ORR 
21% 
22% 
23% 
24% 
25% 
Power 
80% 
86 
91% 
94% 
96% 




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The following data may be recorded directly into the eCRF and could be considered source data:  
 Race and ethnicity. 
12.3 Case Report Form Completion 
Case report forms are provided for each patient in electronic format.  
Electronic data capture (EDC) will be used for this trial. The trial data will be transcribed by trial site 
personnel from the source documents onto an electronic CRF, and transmitted in a secure manner to 
the sponsor within the timeframe agreed upon between the sponsor and the trial site. The electronic 
file will be considered to be the CRF. 
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any such 
worksheets will become part of the patient's source documentation. All data relating to the trial must 
be recorded in eCRFs prepared by the sponsor. Data must be entered into eCRFs in English. Trial site 
personnel should make every effort to enter data into the eCRF no later than 5 working days after 
granted trial enrollment and/or after each patient visit. 
The investigator must verify that all data entries in the eCRFs are accurate and correct. 
All eCRF entries, corrections, and alterations must be made by the investigator or other authorized 
trial site personnel. If necessary, queries will be generated in the EDC tool. 
If corrections to an eCRF are needed after the initial entry into the eCRF, this can be done in three 
different ways: 
 Trial site personnel can make corrections in the EDC tool at their own initiative or as a response 
to an auto query (generated by the EDC tool). 
 The monitor can generate a query for resolution by the trial site personnel. 
 The clinical data manager can generate a query for resolution by the trial site personnel. 
 The sponsor can generate a query for resolution by the trial site personnel. 
12.4 Data Quality Management 
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate trial sites, review of protocol procedures with the investigator and trial 
site personnel before the trial, and periodic monitoring visits by the sponsor and direct transmission 
of clinical laboratory data from a central laboratory, ECG and scan data from a central imaging vendor 
into the sponsor's data base. Written instructions will be provided for collection, handling, storage, 
and shipment of samples.  
Guidelines for eCRF completion will be provided and reviewed with trial site personnel before the 
start of the trial. The sponsor will review eCRFs for accuracy and completeness during on-site 
monitoring visits and after transmission to the sponsor; any discrepancies will be resolved with the 
investigator or designee, as appropriate. After upload of the data into the trial database they will be 
verified for accuracy and consistency with the data sources. 


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12.5 Record Retention 
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs and 
all source documents, as well as a source document location list, that support the data collected from 
each patient, as well as all trial documents as specified in ICH/GCP (R2) guideline Section 8, Essential 
Documents for the Conduct of a Clinical Trial (ICH, 2016), and all trial documents as specified by 
the applicable regulatory requirements. 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 or by an agreement with the 
sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the responsibility 
of keeping the trial records, custody must be transferred to a person who will accept the responsibility. 
The sponsor must be notified in writing of the name and address of the new custodian. Under no 
circumstance shall the investigator relocate or dispose of any trial documents before having obtained 
written approval from the sponsor. 
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this trial, the investigator/institution must permit access to such reports. 


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13 ETHICS 
13.1 Trial-Specific Design Considerations 
Potential patients will be fully informed of the risks and requirements of the trial and, during the trial, 
patients will be given any new information that may affect their decision to continue participation. 
Only patients who are fully able to understand the risks, benefits, and potential AEs of the trial, and 
provide their consent voluntarily will be enrolled. 
The total blood volume to be collected is considered to be within the normal range allowed for this 
patient population over the time frame of the trial. 
13.2 Regulatory Ethics Compliance 
13.2.1 Investigator Responsibilities 
The investigator is responsible for ensuring that the trial is performed in accordance with the protocol, 
ICH GCP E6 (R2), and applicable regulatory and country-specific requirements (ICH, 2016). 
GCP is an international ethical and scientific quality standard for designing, conducting, recording, 
and reporting trials that involve the participation of human subjects. Compliance with this standard 
provides public assurance that the rights, safety, and well-being of trial subjects are protected, 
consistent with the principles that originated in the Declaration of Helsinki (The World Medical 
Association, 2013), and that the trial data are credible. 
13.2.2 Independent Ethics Committee or Institutional Review Board 
This trial will be undertaken only after the IEC/IRB has given full approval of the final protocol, 
amendments (if any, excluding the ones that are purely administrative, with no consequences for 
patients, data or trial conduct), the ICF, applicable recruiting materials, and patient compensation 
programs, and the sponsor has received a copy of this approval. This approval letter must be dated 
and must clearly identify the IEC/IRB and the documents being approved. 
Approval for the collection of optional samples for research and for the corresponding ICF must be 
obtained from the IEC/IRB. Approval for the protocol can be obtained independent of this optional 
research component.  
For all protocol amendments (excluding the ones that are purely administrative, with no consequences 
for patients, data or trial conduct), the amendment and applicable ICF revisions must be submitted 
promptly to the IEC/IRB for review and approval before implementation of the change(s).  
Where applicable, interim reports on the trial and/or reviews of trial progress will be submitted by the 
investigator to the IEC/IRB at intervals stipulated in the IEC/IRB guidelines. 
At the end of the trial, the investigator (or sponsor where required) will notify the IEC/IRB about the 
trial completion. 
13.2.3 Informed Consent 
Each patient must give written consent according to local requirements after the nature of the trial has 
been fully explained. The ICFs must be signed before performance of any trial-related activity. The 


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ICF that is used must be approved by both the sponsor and by the reviewing IEC/IRB and be in a 
language that the patient can read and understand. The informed consent must be in accordance with 
principles that originated in the Declaration of Helsinki, current ICH GCP E6(R2) guidelines, 
applicable regulatory requirements, and sponsor policy. 
Before enrollment in the trial, the investigator or an authorized member of the trial site personnel must 
explain to potential patients the aims, methods, reasonably anticipated benefits, and potential hazards 
of the trial, and any discomfort participation in the trial may entail. Patients will be informed that their 
participation is voluntary and that they may withdraw consent to participate at any time. They will be 
informed that choosing not to participate will not affect the care that the patient will receive for the 
treatment of his or her disease. Patients 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 patient identification register for the purposes of long-term follow-
up if needed and that their records may be accessed by health authorities and authorized sponsor 
personnel without violating the confidentiality of the patient, to the extent permitted by the applicable 
law(s) or regulations. By signing the ICF the patient is authorizing such access, including permission 
to obtain information about his or her survival status, and agrees to allow his or her trial physician to 
recontact the patient for the purpose of obtaining consent for additional safety evaluations, if needed, 
and subsequent disease-related treatments, or to obtain information about his or her survival status. 
The patient will be given sufficient time to read the ICF and the opportunity to ask questions. After 
this explanation and before entry into the trial, consent must be appropriately recorded by means of 
the patient's personally dated signature. After having obtained the consent, a copy of the ICF must be 
given to the patient. 
Patients will be asked for consent to provide optional samples for research where local regulations 
permit. After informed consent for the trial is appropriately obtained, the patient will be asked to sign 
and personally date a separate ICF indicating agreement to participate in the optional research 
component (Section 13.2.5). Refusal to participate in the optional research will not result in 
ineligibility for the trial. A copy of this signed ICF will be given to the patient. 
13.2.4 Privacy of Personal Data 
The collection and processing of personal data from patients enrolled in this trial will be limited to 
those data that are necessary to fulfill the objectives and purposes of the trial. 
These data must be collected and processed with adequate precautions to ensure confidentiality and 
compliance with applicable data privacy protection laws and regulations. Appropriate technical and 
organizational measures to protect the personal data against unauthorized disclosures or access, 
accidental or unlawful destruction, or accidental loss or alteration must be put in place. Sponsor 
personnel whose responsibilities require access to personal data agree to keep the identity of patients 
confidential. 
The informed consent obtained from the patient includes explicit consent for the processing of 
personal data for the purpose of the trial and for the investigator/institution to allow direct access to 
his or her original medical records (source data/documents) for trial-related monitoring, audit, 
IEC/IRB review, and regulatory inspection. This consent also addresses the transfer of the data to 
other entities and to other countries. 


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The patient has the right to request through the investigator access to his or her personal data and the 
right to request rectification of any data that are not correct or complete. 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 the data processor agreement 
and applicable laws and regulations. The investigator will inform- and work together with the sponsor 
when handling such requests. 
Exploratory DNA, biomarker, PK and immunogenicity research is not conducted under standards 
appropriate for the return of data to patients. In addition, the sponsor cannot make decisions as to the 
significance of any findings resulting from exploratory research. Therefore, exploratory research data 
will not be returned to patients or investigators, unless required by law or local regulations. Privacy 
and confidentiality of data generated in the future on stored samples will be protected by the same 
standards applicable to all other clinical data. 
13.2.5 Long-term Retention of Samples  
If it is determined at any time before trial completion that additional material is needed from a FFPE 
tumor sample for the successful completion of the protocol-specified analyses, the Sponsor may 
request that additional material be retrieved from existing samples. Also, based on emerging scientific 
evidence relating to a potential correlation between a biomarker and treatment efficacy and/or safety 
the sponsor may request additional material from previously collected tumor samples during the 
clinical trial or for a period of 5 years after trial completion for a retrospective analysis. In this case, 
such analyses would be specific to research related to the IMP or diseases being investigated in the 
clinical trial. 


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14 ADMINISTRATIVE PROCEDURES 
14.1 Protocol Amendments 
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by the 
sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the 
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or when 
the relevant competent authority has raised any grounds for non-acceptance, except when necessary 
to eliminate immediate hazards to the patients, in which case the amendment must be promptly 
submitted to the IEC/IRB and relevant competent authority. Documentation of amendment approval 
by the investigator and IEC/IRB must be provided to the sponsor. When the change(s) involves only 
logistic or administrative aspects of the trial, the IRB (and IEC where required) only needs to be 
notified. 
During the course of the trial, in situations where a departure from the protocol is unavoidable, the 
investigator or other physician in attendance will contact the appropriate sponsor representative (see 
contact information page(s) provided separately). Except in emergency situations, this contact must 
be made before implementing any departure from the protocol. In all cases, contact with the sponsor 
must be made as soon as possible to discuss the situation and agree on an appropriate course of action. 
The data recorded in the eCRF and source documents will reflect any departure from the protocol, 
and the source documents will describe this departure and the circumstances requiring it. 
14.2 Regulatory Documentation 
14.2.1 Regulatory Approval/Notification 
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities in 
each respective country, if applicable. A trial may not be initiated until all local regulatory 
requirements are met. 
14.3 Patient Identification, Enrollment, and Screening Logs 
The investigator agrees to complete a patient identification and enrollment log to permit easy 
identification of each patient during and after the trial. This document will be reviewed by the sponsor 
trial site contact for completeness. 
The patient identification and enrollment log will be treated as confidential and will be filed by the 
investigator in the Investigator Site file and will never be transferred to the Sponsor or any third 
parties. To ensure patient confidentiality, no copy will be made. All reports and communications 
relating to the trial will identify patients by their patient number (or screening number if not enrolled). 
The investigator must also complete a patient screening log, which reports on all patients who were 
seen to determine eligibility for inclusion in the trial. 
14.4 Monitoring 
The sponsor will use a combination of monitoring techniques remote and on-site monitoring to 
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The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will record 
dates of the visits in a trial site visit log that will be kept at the trial site. The first post-initiation 
monitoring visit will be performed shortly after the first patient has been enrolled. At these visits, the 
monitor will compare 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 source 
of original data required to complete the eCRFs 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 and monitor access must be discussed with the trial site 
personnel.  
Direct access to source documentation (medical records) must be allowed for the purpose of verifying 
that the data recorded in the eCRF are consistent with the original source data. Findings from this 
review of eCRFs and source documents will be discussed with the trial site personnel. The sponsor 
expects that, during monitoring visits, the relevant trial site personnel will be available, the source 
documentation will be accessible, and a suitable environment will be provided for review of trial-
related documents. The monitor will meet with the investigator on a regular basis during the trial to 
provide feedback on the trial conduct. 
In addition to on-site monitoring visits, remote contacts will 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 trial site.  
Central monitoring will take place for data identified by the sponsor as requiring central review. 
14.5 On-Site Audits 
Representatives of the sponsor's clinical quality assurance department may visit the trial site at any 
time during or after completion of the trial to conduct an audit of the trial in compliance with 
regulatory guidelines and company policy. These audits will require access to all trial records, 
including source documents, for inspection and comparison with the eCRFs. Patient privacy must, 
however, be respected. The investigator and trial site personnel are responsible for being present and 
available for consultation during routinely scheduled trial site audit visits conducted by the sponsor 
or its designees.  
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part of 
a national GCP compliance program or to review the results of this trial in support of a regulatory 
submission. The investigator must immediately notify the sponsor if he or she has been contacted by 
a regulatory agency concerning an upcoming inspection. 
14.6 Publication 
All information, including but not limited to information regarding tisotumab vedotin or the sponsor's 
operations (e.g. patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not previously 
published, and any data, including pharmacogenomic or biomarker research data, generated as a result 
of this trial, are considered confidential and remain the sole property of the sponsor. The investigator 
agrees to maintain this information in confidence and use this information only to accomplish this 
trial, and will not use it for other purposes without the sponsor's prior written consent. 


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The investigator understands that the information developed in the trial will be used by the sponsor in 
connection with the continued development of tisotumab vedotin, and thus may be disclosed as 
required to other clinical investigators or regulatory agencies. To permit the information derived from 
the clinical trials to be used, the investigator is obligated to provide the sponsor with all data obtained 
in the trial. 
The results of the trial will be reported in a CTR generated by the sponsor and will contain eCRF data 
from all trial sites that participated in the trial. Recruitment performance or specific expertise related 
to the nature and the key assessment parameters of the trial will be used to determine a coordinating 
investigator. Results of pharmacogenomic or biomarker analyses performed after the CTR has been 
issued will be reported in a separate report and will not require a revision of the CTR. Trial patient 
identifiers will not be used in publication of results. Any work created in connection with performance 
of the trial and contained in the data that can benefit from copyright protection (except any publication 
by the investigator as provided for below) shall be the property of the sponsor as author and owner of 
copyright in such work. 
Consistent with Good Publication Practices and International Committee of Medical Journal Editors 
guidelines, the sponsor in conjunction with any collaborative group(s) shall have the right to publish 
such primary (multicenter) data and information as per the pre-specified 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 abstracts and publications resulting from this trial will be based on ICMJE guidelines, 
patient recruitment efforts and standard operating procedures of the sponsor. 
 
Registration of Clinical Trials and Disclosure of Results 
The sponsor will register and/or disclose the existence of and the results of clinical trials as required 
by law.  
 


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15 REFERENCES 
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Goncalves, A., Fabbro, M., Lhomme, C., Gladieff, L., Extra, J. M., Floquet, A. et al. (2008). A phase 
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(2006). The European Organization for Research and Treatment of Cancer (EORTC) Quality-
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Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. 
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cervical cancer. Int.J Clin Oncol, 13, 62-65. 
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Schellens, J. H. M., Marabelle, A., Zeigenfuss, S., Ding, J., Pruitt, S. K., & Chung, H. C. (2017). 
Pembrolizumab for previously treated advanced cervical squamous cell cancer: Preliminary 
results from the phase 2 KEYNOTE-158 study. Journal of Clinical Oncology, 35, 5514. 
Schilder, R. J., Blessing, J., & Cohn, D. E. (2005). Evaluation of gemcitabine in previously treated 
patients with non-squamous cell carcinoma of the cervix: a phase II study of the Gynecologic 
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(2005). Reduction-alkylation strategies for the modification of specific monoclonal antibody 
disulfides. Bioconjugate Chemistry (Washington, DC), 16, 1282-1290. 
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Improved survival with bevacizumab in advanced cervical cancer. N.Engl.J.Med., 370, 734-
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Fortaleza, Brazil. 
Torfs, S., Cadron, I., Amant, F., Leunen, K., Berteloot, P., & Vergote, I. (2012). Evaluation of 
paclitaxel/carboplatin in a dose dense or weekly regimen in 66 patients with recurrent or 
primary metastatic cervical cancer. Eur.J Cancer, 48, 1332-1340. 
UK MHRA. (2014). Recommendations related to contraception and pregnancy testing in clinical 
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Appendix 1 Recommendations Related to Contraception and Pregnancy Testing in Clinical 
Trials 
 
 
 
 
 


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Appendix 2 INVESTIGATOR AGREEMENT 
 
 
1. I have carefully read this protocol entitled “A Single arm, Multicenter, International Trial of 
Tisotumab Vedotin (HuMax®-TF-ADC) in Previously Treated, Recurrent or Metastatic 
Cervical Cancer” and agree that it contains all the necessary information required to conduct 
the trial. I agree to conduct this trial as outlined in the protocol. 
2. I understand that this trial will not be initiated without approval of the appropriate 
Institutional Review Committee/Independent Ethics Committee (IRB/IEC), and that all 
administrative requirements of the governing body of the Institution will be complied with 
fully. 
3. Informed written consent will be obtained from all participating patients in accordance with 
institutional guidelines, FDA requirements as specified in Title 21 CFR, Part 50, the 
European Union Directive 2001/20/EC and its associated Detailed Guidances, European 
Union GCP Directive 2005/28/EC (replaced by 536/2014), the Declaration of Helsinki and 
in the guideline on good clinical practice. 
4. I will enroll patients who meet the protocol criteria for entry. 
5. I understand that my signature on each completed electronic Case Report Form (eCRF) 
indicates that I have carefully reviewed the complete set of eCRFs and accept full 
responsibility for the contents thereof.  
6. I understand that the information presented in this trial protocol is confidential, and I hereby 
assure that no information based on the conduct of the trial will be released without prior 
consent from the Sponsor unless this requirement is superseded by the Food and Drug 
Administration, a Competent Authority of the European Union or another Regulatory 
Authority. 
 
 
 
 
 
Investigator: 
 
 
 
 
Name: ____________________________ 
 
Site : ___________________________ 
 
 
 
 
Signature: __________________________  
Date:____________________________ 
 
 
 





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Page 1 of 38 
 
TPL N°: eTPL SA-02-01 
TPL Version: 02 
Of SOP SA-02.08 
TPL Effective Date: 31 Mar 2016 
 
 
Statistical Analysis Plan 
 
 
 
 
Sponsor:  
Genmab 
Protocol Title:  
A 
Single 
arm, 
Multicenter, 
International 
Trial 
of 
Tisotumab Vedotin (HuMax®-TF-ADC) in Previously 
Treated, Recurrent or Metastatic Cervical Cancer 
Protocol Version: 
V7.0 17-Jun-2019 
Trial Code: 
GCT1015-04 
 
 
 
For 
 
Author: 
, Senior 
 
Reviewer: 
, Principal 
 
 
For Sponsor: 
Approver: 
, 
, Biostatistics 
Reviewers: 
, 
 Biostatistics 
, 
, Medical 
 
 
, 
, Translational Research 
 
 
, 
, Translational Research 
 
 
, 
, Drug Safety Physician 
, 
, Pharmacology 
Genmab - GCT1015-04                                                                   Version: 5.0
Approved in Vault: 11/1/2019


 
 
Confidential 
 
 
 
Page 2 of 38 
 
TPL N°: eTPL SA-02-01 
TPL Version: 02 
Of SOP SA-02.08 
TPL Effective Date: 31 Mar 2016 
 
Table of Contents 
 
1. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................... 4 
2. 
INTRODUCTION ........................................................................................... 6 
3. 
TRIAL DESIGN AND OBJECTIVES ................................................................. 6 
3.1 
Trial Objectives ........................................................................................ 6 
3.1.1 
Primary Objectives ............................................................................ 6 
3.1.2 
Secondary Objectives ........................................................................ 6 
3.1.3 
Exploratory Objective ........................................................................ 6 
3.2 
Trial Design ............................................................................................. 6 
3.3 
Sample Size Justification ........................................................................... 7 
4. 
GENERAL ANALYSIS DEFINITIONS .............................................................. 7 
4.1 
Trial Period and Visit Window Definitions ..................................................... 7 
4.1.1 
Trial Periods ..................................................................................... 7 
4.1.2 
Visit Windows ................................................................................... 8 
4.2 
Planned Analyses ..................................................................................... 8 
4.3 
Definition of Populations (Analysis Sets) ..................................................... 8 
4.3.1 
Full Analysis Set ................................................................................ 8 
4.3.2 
Safety Set ........................................................................................ 8 
4.4 
Subgroup Definitions ................................................................................ 8 
4.5 
Treatment Assignment and Treatment Arms ................................................ 9 
4.6 
Calculated Variables ................................................................................. 9 
4.7 
Partial/Missing Dates .............................................................................. 10 
4.8 
Methods to Be Used For Handling Missing Data .......................................... 11 
4.8.1 
Primary Endpoint ............................................................................ 11 
4.8.2 
Pharmacokinetics ............................................................................ 11 
4.8.3 
Biomarkers (TF expression, cTF) ....................................................... 11 
4.8.4 
Health Related Quality of Life ............................................................ 11 
4.9 
Changes to Protocol ............................................................................... 11 
5. 
TRIAL SUBJECTS ........................................................................................ 12 
5.1 
Disposition of Subjects ........................................................................... 12 
5.2 
Protocol Deviations ................................................................................ 12 
5.3 
In- and Exclusion Criteria ........................................................................ 12 
6. 
DEMOGRAPHIC CHARACTERISTICS ............................................................ 13 
7. 
BASELINE DISEASE CHARACTERISTICS ..................................................... 13 
8. 
MEDICAL AND SURGICAL HISTORY............................................................ 14 
9. 
PRIOR ANTI-CANCER THERAPIES .............................................................. 14 
10. 
SUBSEQUENT ANTI-CANCER THERAPIES ................................................ 14 
11. 
PROCEDURES ......................................................................................... 14 
12. 
PRIOR AND CONCOMITANT MEDICATIONS ............................................ 15 
13. 
EFFICACY EVALUATION .......................................................................... 15 
13.1 
Primary Objective .................................................................................. 15 
13.1.1 
Confirmed Objective Response Rate based upon RECIST v1.12, assessed 
by the independent review committee (IRC) .................................................... 15 
Genmab - GCT1015-04                                                                   Version: 5.0
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13.2 
Secondary Efficacy Objectives ................................................................. 16 
13.2.1 
Duration of confirmed response ........................................................ 16 
13.2.2 
Time to Confirmed Response ............................................................ 17 
13.2.3 
Progression-Free Survival ................................................................. 17 
13.2.4 
Overall Survival .............................................................................. 17 
13.3 
Supportive Analyses of Secondary Efficacy Objectives ................................ 18 
13.4 
Anti-tumor Activity ................................................................................. 18 
13.5 
Follow-up Time ...................................................................................... 18 
14. 
PHARMACOKINETICS (PK) ..................................................................... 18 
15. 
SAFETY EVALUATION ............................................................................. 18 
15.1 
Extent of Exposure ................................................................................. 18 
15.2 
Secondary Safety Objectives ................................................................... 18 
15.2.1 
Adverse events ............................................................................... 18 
15.2.2 
Deaths and Serious Adverse Events ................................................... 20 
15.2.3 
Clinical Laboratory Data ................................................................... 20 
15.2.4 
Ophthalmology results ..................................................................... 21 
15.2.5 
Other Safety Data ........................................................................... 22 
15.2.5.1 
ECG ........................................................................................ 22 
15.2.5.2 
Immunogenicity (anti-drug antibodies) of tisotumab vedotin .......... 23 
15.2.6 
Pregnancy Test ............................................................................... 23 
16. 
EXPLORATORY OBJECTIVES ................................................................... 23 
16.1 
TF expression ........................................................................................ 23 
16.2 
Circulating TF ........................................................................................ 24 
16.3 
Health Related Quality of Life (HRQL) ....................................................... 24 
16.3.1 
EORTC-QLQ-C30 ............................................................................. 24 
16.3.2 
EORTC-QLQ-CX24 ........................................................................... 26 
17. 
REFERENCES .......................................................................................... 28 
18. 
LIST OF TABLES/GRAPHS/LISTINGS ..................................................... 29 
18.1 
List of Statistical Tables .......................................................................... 29 
18.2 
List of Graphs ........................................................................................ 31 
18.3 
List of Derived Data Listings .................................................................... 32 
19. 
VERSION HISTORY ................................................................................. 33 
Genmab - GCT1015-04                                                                   Version: 5.0
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1. List of Abbreviations and Definition of Terms 
 
Abbreviation 
Term 
ADA 
Anti-drug antibody 
ADC 
Antibody-drug conjugate 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CI 
Confidence Interval 
CONSORT 
Consolidated Standards of Reporting Trials 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
Deoxyribonucleic Acid 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
FAS 
Full Analysis Set 
FPFV 
First Patient First Visit 
FU 
Follow-Up 
GFR 
Glomerular Filtration Rate 
HRQL 
Health Related Quality of Life 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
IOC 
Intraocular 
IRC 
Independent Review Committee 
ITT 
Intention to Treat 
IV 
Intravenous 
LPLV 
Last Patient Last Visit 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
Genmab - GCT1015-04                                                                   Version: 5.0
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MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMAE 
Monomethyl Auristatin E 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
PK 
Pharmacokinetics 
PR 
Partial Response 
PT 
Preferred Term 
QTc 
Corrected QT 
RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SAF 
Safety Set 
SD 
Standard Deviation 
SOC 
System Organ Class 
TF 
Tissue Factor 
TNM 
Tumor Nodes Metastasis 
TTR 
Time to Response 
ULN 
Upper Limit of Normal 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
Genmab - GCT1015-04                                                                   Version: 5.0
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2. 
Introduction 
This Statistical Analysis Plan was written for the clinical trial GCT1015-04 conducted in 
eight countries (Belgium, Czech Republic, Denmark, Germany, Italy, Spain, Sweden and 
the United States). The ICH guideline E3 “Structure and Content of Clinical Study Reports” 
was used as a guide to the writing of the plan. 
3. Trial Design and Objectives 
3.1 Trial Objectives 
3.1.1 Primary Objectives 
 
Determine the anti-tumor efficacy in subjects with cervical cancer. 
3.1.2 Secondary Objectives 
 
Evaluate tumor response durability. 
 
Evaluate clinical response. 
 
Assess safety and tolerability. 
3.1.3 Exploratory Objective 
 
Assess biomarkers related to clinical response. 
 
Assess potential pharmacodynamic biomarkers. 
 
Assess Health Related Quality of Life (HRQL). 
3.2 Trial Design 
The trial design is available in section 4 Trial Design of the protocol.  
Figure 1. Overview of trial design
 
Genmab - GCT1015-04                                                                   Version: 5.0
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3.3 Sample Size Justification 
In GEN701 there were 9 confirmed responders among the first 34 cervical cancer subjects 
(26%). 
Applying a one-sided exact binomial test at the 0.025 significance level, the planned 
sample size of 100 subjects provides ≥ 80% power to reject an ORR of 11%, the combined 
ORR for available second-line therapies (See section 2.2 of the protocol), or less for true 
ORRs in the range 21% - 25%, representing clinically relevant improvements over 
available second-line treatments (See Table 1). 
Table 1. Power for a range of clinically relevant true confirmed ORRs 
True ORR 
21% 
22% 
23% 
24% 
25% 
Power 
80% 
86% 
91% 
94% 
96% 
4. General Analysis Definitions 
Data will be analyzed using SAS (Version 9.4 or higher). For graphs R (RStudio) can be 
used in addition.  
Descriptive statistics will be tabulated as follows:  
 
Categorical data will be summarized in contingency tables presenting frequencies 
and percentages. 
 
Continuous data will be summarized using number of non-missing values (n), 
mean, standard deviation (SD), median, minimum and maximum values. 
 
Time to event parameters will be described using Kaplan-Meier estimates: 
Median time along with 95% confidence interval of the median. First and third 
quartiles will also be added when specified. 
The study being a single arm trial, the tables will be created with one treatment arm. 
All data will be listed by subject number and visit (if applicable). Data from scheduled and 
unscheduled visit will be included in listings. Listings will include all data from all subjects 
unless specified otherwise. Population flag for FAS will be included.  
In general, in plots where subject data are grouped together (e.g. boxplots), the ticks on 
the time-axis will denote the nominal visit numbers (e.g. Scr, C1D1, C2D1, …). 
Unscheduled visit data will not be included. 
In tables and listings presenting data by visit, the visit names (Screening, Cycle 1 Day 1, 
Cycle 2 Day 1, …, Treatment discontinuation, Safety Follow-up, and Survival Follow-up) 
will be used or their abbreviated term (Scr, C1D1, C1D2, …, Treat discont, Saf FU, and 
Surv FU). Unscheduled visit data will not be tabulated unless specified otherwise. 
In tables and listings presenting coded data (e.g. medical history, concomitant medication, 
adverse events …), the dictionary and the version used will be mentioned in the footnote. 
4.1 Trial Period and Visit Window Definitions 
4.1.1 Trial Periods 
The overall observation period will be divided into three mutually exclusive segments: 
Pre-treatment period will be defined as the period from the day of subject’s informed 
consent to the day before first IMP administration. 
Genmab - GCT1015-04                                                                   Version: 5.0
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On-treatment period will be defined as the period from day of first dose of IMP to 30 days 
after last IMP administration. 
Post-treatment period will be defined as the period after the On-treatment period (i.e. 
from 31 days after last IMP administration) and until death, lost to follow-up or withdrawal 
from the trial. 
4.1.2 Visit Windows 
Visit windows are defined in the protocol. Those will not be used in the analysis to avoid 
excluding important data due to dates outside visit windows. Tables will assume that 
observations are from the recorded visit irrespective of the date specified. 
4.2 Planned Analyses 
No formal interim analyses are planned. The primary reporting of the trial will be based 
on a data cut off approximately 6 months after all responders have experienced their first 
response as assessed by the investigator per RECIST v1.1 (cut-off date). 
Since subjects will be treated until they met one of the discontinuation criteria, some 
subjects may still be ongoing at the time of primary analysis. In that case the entire trial 
will be reported again including all available data (no cut-off date applied) when the last 
subject dies or when tisotumab vedotin becomes available in the subjects country, 
whichever comes first. However, maximum trial duration is 5 years (starting from when 
the first subject signed the ICF). 
4.3 Definition of Populations (Analysis Sets) 
4.3.1 Full Analysis Set  
The Full Analysis Set (FAS) comprises all subjects who received at least one dose of IMP. 
4.3.2 Safety Set 
The Safety Set (SAF) includes all subjects who received at least one dose of IMP. Since 
the full analysis set and the safety set are identical, all safety analyses will use the term 
full analysis set as the analysis population. 
 
Data from subjects who were screened but never started treatment or from screening 
failures will be listed, but will not be included in any of the analyses and summary tables. 
4.4 Subgroup Definitions 
Subgroup analyses for the following baseline factors are planned as supportive analyses 
of ORR: 
 
Histology (Squamous or Non-squamous) 
 
Prior radiation administered to the pelvis (Yes or No) 
 
Prior lines of systemic regimen (1 or 2). Systemic regimen refers to systemic 
regimen administered in the extra-pelvic metastatic or recurrent setting in this 
document.  
 
Response to last systemic regimen (Yes or No) 
 
Prior first line combination of Paclitaxel + Cisplatin/Carboplatin + Bevacizumab 
or Paclitaxel + Topotecan + Bevacizumab (Yes or No) 
 
ECOG (0 or 1) 
Genmab - GCT1015-04                                                                   Version: 5.0
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 
Age (< 50, >=50 to <65 or >=65) 
 
Region (EU or US) 
4.5 Treatment Assignment and Treatment Arms 
This is an open-label single-arm trial and all subjects will be assigned the same treatment. 
Tisotumab vedotin at 2.0 mg/kg will be administered as an IV infusion over a minimum of 
30 minutes on day 1 of each treatment cycle (one treatment cycle is 21 days). It’s 
recommended that the infusion completes within 60 minutes. 
Each subject’s dose will be calculated based on the subject’s weight (please refer to section 
9.3.2 of the protocol for more details on assessment of weight) rounded to the nearest 
kilogram, i.e., 2.0 mg/kg x body weight in kg. For subjects who weigh >100 kg, the 
calculation of IMP dose should be normalized to 100 kg (i.e., 2.0 mg/kg x 100 kg = 200 
mg). 
Preventive eye therapy must be administered in relation to each infusion as described in 
section 6.2.2 of the protocol. 
4.6 Calculated Variables 
 
Baseline is defined as the latest available measurement made before the first 
treatment with tisotumab vedotin. Measurements done on the same date as 
the first IMP administration will be considered as done before the first IMP 
administration unless specified otherwise. For PK variables, the first IMP 
administration will be time 0. 
 
Change from baseline is defined as the post-baseline value – baseline value. 
 
Percent change from baseline is defined as the 100*(post-baseline value – 
baseline value)/baseline value. When the baseline value=0, the percent 
change from baseline will be missing. 
 
Time (in months) from last systemic regimen to start of IMP: (start date of 
IMP – end date of last systemic regimen)/30.4375. 
 
Time (in months) from biopsy to start of IMP: (start date of IMP – date the 
biopsy was obtained)/30.4375. 
 
Duration of exposure (months): (end date of IMP – start date IMP + 1) / 
30.4375, End date of IMP related to min (last IMP intake date +20 days, last 
contact date, date of death, cut-off date). 
 
Actual cumulative dose (mg): sum of all actual doses administered. 
 
Planned cumulative dose (mg): 2.0 mg x weight x number of cycles reached. 
If weight >100 kg, 100 kg will be used in the calculation (i.e. corresponding 
to a dose of 200 mg per cycle). 
 
Dose intensity (mg/kg/3 weeks): (actual cumulative dose received (mg/kg) / 
(last dose date of IMP + 21 – start date of IMP) ) * 21 days. 
 
Relative dose intensity (%): 100 * actual dose intensity (mg/kg/3 weeks) / 
planned dose intensity (2 mg/kg/3 weeks). 
 
Follow-up time (months): max (last contact date, date of death) – start date 
of IMP + 1) / 30.4375. 
 
Genmab - GCT1015-04                                                                   Version: 5.0
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4.7 Partial/Missing Dates 
Partial or missing dates in general will not be imputed (medical history, previous cancer 
treatment). 
For the calculation of the time (in months) from the date the biopsy was obtained to start 
date of IMP and the time (in months) from end date of last systemic regimen to start date 
of IMP, the following imputation rules will be applied when respectively the date the biopsy 
was obtained or the end date of last systemic regimen is incomplete: 
 
If the day is missing: first day of the month 
 
If the day and month are missing: first day of July. 
 
If the day and month are missing and if the year is the same as the start year 
of IMP: leave missing. 
For the assignment to prior or concomitant medication the following rules will be applied 
in case of incomplete or missing dates: 
 
If end date is missing, the end date will be set to the last contact date. 
 
If end date is incomplete: if the day is missing: the end date will be imputed 
with the last day of the month; if the day and month are missing: the end 
date will be imputed with min (31 December of the year, last contact date, 
date of death). 
 
If start date is missing: if the (imputed) end date is before the date of first 
IMP administration, the start date will remain missing; if the (imputed) end 
date is after or on the date of first IMP administration, the start date will be 
imputed by the date of first IMP administration. 
 
If start date is incomplete: the start date will be imputed as minimum of last 
day/last month and the (imputed) end date. 
The imputed dates will only be used for the assignment to prior or concomitant and will 
not be used in any other calculation and will not be listed. 
For the assignment of adverse events (AE) the following rules will be applied in case of 
incomplete or missing start date: 
 
If end date is before the date of first IMP administration, the start date will 
remain missing/incomplete (medical history);  
 
If start date is missing and end date is after or on the date of first IMP 
administration or the end date is missing, the start date will be imputed by 
the date of first IMP administration (AE). 
 
If start date is incomplete and end date is after or on the date of first IMP 
administration or the end date is missing, the start date will be imputed as 
follows: if the day is missing and if the start date and date of first dose share 
the same month and year, the missing start day will be imputed as the day 
of first dose. If the start date month is after the month of first dose, day will 
be imputed as the first (i.e. 01-MMM-YY); if the day and month are missing 
and if the start date and date of first dose share the same year, day and 
month will be imputed as the day and month of first dose. If the start date 
year is after the year of first dose, the month and day will be imputed as 
January first (i.e. 01-JAN-YY) (AE). 
The imputed date will only be used for the assignment of the treatment emergent flag and 
will not be used in any other calculation (unless specified otherwise) and will not be listed. 
Genmab - GCT1015-04                                                                   Version: 5.0
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4.8 Methods to Be Used For Handling Missing Data 
All available data will be included in data listings and/or tabulations.  
No imputation of missing data is planned for safety endpoints, PK or biomarker endpoints. 
If outliers are detected, a robustness analysis where the outlier effect is reduced or 
eliminated may be considered. 
4.8.1 Primary Endpoint 
Any subjects with missing information regarding response to treatment will be counted as 
non-responders. This also includes subjects with response that cannot be confirmed 
according to RECIST v1.1 criteria. 
4.8.2 Pharmacokinetics 
Missing concentration values will be reported as is in data listings. Concentration values 
below the lower limit of quantification will be handled as LLOQ/2 in summary statistics, 
and reported as is in data listings. Any missing concentration data will not be imputed. 
4.8.3 Biomarkers (TF expression, cTF) 
Missing data for TF expression or cTF will be reported as is in data listings, and will not be 
included in any summary charts or graphs. TF expression or cTF values below the lower 
limit of quantification will be handled as LLOQ/2 in summary statistics, and reported as is 
in data listings. Any missing TF expression or cTF data will not be imputed. 
4.8.4 Health Related Quality of Life 
Missing data at an individual item level will not be imputed, however the following rule will 
be used for the computation of the scores at the scale level (per the EORTC guideline). 
For a particular scale, if at least half of the items from the scale have been answered then 
use the items that were completed and apply the standard equations (per EORTC 
guideline; see in section 16.3 for more details) for calculating the scale score (ignore items 
with missing values when making the calculations). If less than half of the items from the 
scale have been answered then set the scale score to missing (For single-item measures, 
the score will then be set to missing). 
4.9 Changes to Protocol 
Some subgroup analyses were updated compared to the ones planned in the protocol: 
- 
 Histology which was planned for three subgroups (Adenocarcinoma, adeno-
squamous and squamous cell carcinoma) will be done for two subgroups 
(Squamous and Non-squamous).  
- 
Prior radiation for localized disease has been updated to Prior radiation 
administered to the pelvis.  
- 
Bevacizumab (Yes and No) has been updated to Prior first line combination of 
Paclitaxel + Cisplatin/Carboplatin + Bevacizumab or Paclitaxel + Topotecan + 
Bevacizumab.  
- 
Prior lines of therapy has been updated to Prior lines of systemic regimen 
administered in the extra-pelvic metastatic or recurrent setting (1 and 2).  
- 
Response to last therapy has been updated to response to last systemic therapy.  
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- 
TF expression in biopsy as measured by IHC has been removed. Based on the 
available data from GEN701, it was observed that there is rarely a scenario where 
the subject is Tissue Factor “negative”.  Therefore, a simply positive to negative 
comparison is insufficient. This analysis is then out of the scope of this clinical SAP. 
- 
Additional subgroup analyses have been added for ECOG and age. 
Regarding the efficacy endpoint time to response, it was decided to analyse it only for the 
FAS population restricted to subjects with a confirmed response using descriptive 
statistics.  
For the efficacy endpoint progression free survival, it was decided to present the PFS rates 
at 3 and 6 months rather than at 6 and 12 months. 
Regarding the pharmacokinetic data, the plasma concentrations will be listed. No further 
summary is planned. 
For the adverse events, it was decided to remove the tabulation of non-serious AEs, as 
tabulations for all AEs and serious AEs were considered to provide sufficient information. 
The deaths won’t be tabulated in a separate table to avoid duplication of information; on-
treatment deaths will be recorded on the AE form and tabulated in the fatal AEs tabulation; 
and the post-treatment deaths will be included in the overall survival analyses. 
Regarding the laboratory data, summary tables for continuous parameters were removed 
and information was presented in box plots. 
No analysis is planned for the vital signs data while the protocol mentioned a table and a 
listing. 
5. Trial Subjects 
5.1 Disposition of Subjects 
Screening failures including failure reason, protocol version and re-screening information 
will be presented in a listing. Subjects screened but never started IMP will also be listed. 
The frequency of subjects with ongoing treatment and the frequency of subjects who 
discontinued from treatment will be summarized for the full analysis set (FAS) together 
with the reasons for treatment discontinuation. The frequency of subjects ongoing in the 
study and the frequency of subjects discontinued from study (combining the ones who 
withdrew from study (including subjects who withdrew consent, subjects withdrawn by 
investigator and lost to follow-up subjects) and the ones who died) will be also given for 
the full analysis set (FAS). 
The details of the ‘other reason’ will be included in the listing together with the reason for 
not attending the treatment discontinuation visit and the safety follow-up visit. 
Subject dispositions will also be presented in flow diagram in accordance with the current 
CONSORT statement1. 
5.2 Protocol Deviations 
Important protocol deviations will be summarized for the FAS. The details of all deviations 
will be listed. 
Protocol deviations will be defined in the protocol deviations plan. 
5.3 In- and Exclusion Criteria 
Listing of all in- and exclusion criteria not met will be provided for the FAS. 
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6. Demographic Characteristics 
Descriptive statistics with respect to subject characteristics at baseline will be displayed 
for the FAS.  
The variables to be summarized are: 
 
Age (years, continuous and categorical: age<50 years and age ≥50 years 
including also subcategory age ≥65 years) 
 
Region (EU or US) 
 
Race (White, Black or African American, Native Hawaiian or other Pacific 
Islander, Asian, American Indian or Alaska native, Other) 
 
Ethnic origins (Hispanic or Latino, Not Hispanic or Latino) 
 
Weight (kg) 
Details of the other categories mentioned above will be added to the listings. 
7. Baseline Disease Characteristics 
Descriptive statistics with respect to subject disease characteristics at baseline will be 
displayed for the FAS. 
 
ECOG performance status score. (Note: at entry, only subjects with an ECOG 
performance status of 0 and 1 are allowed). 
 
Recurrent disease at time of screening (Yes, No). 
 
Site(s) of disease at time of screening (Cervix, Uterus, Vagina, Bladder, 
Rectum, Pelvic lymph nodes, Extra-pelvic lymph nodes, Liver, Bowel, Lung, 
Bone, Other). 
 
Histology (Squamous cell carcinoma, Adenocarcinoma, Adenosquamous 
carcinoma) 
 
Time (in months) from last systemic regimen* to start date of IMP 
Descriptive statistics for the following subgroup data will also be displayed for the FAS. 
 
Prior radiation administered to the pelvis (Yes or No) 
 
Prior lines of systemic regimen* (1 or 2) 
 
Response to last systemic regimen* (Yes or No) 
 
Prior first line combination of Paclitaxel + Cisplatin/Carboplatin + 
Bevacizumab  or Paclitaxel + Topotecan + Bevacizumab* (Yes or No) 
Lastly, descriptive statistics with respect to biopsy information will be displayed for the 
FAS. 
 
Biopsy provided (Yes, No) at screening 
 
Type of Biopsy (Before vs After last systemic regimen*) 
 
Time from the date the biopsy was obtained to start of IMP (months) 
* Given in the setting of recurrent or extra-pelvic metastatic cervical cancer. 
Tumor classification (TNM) and Tumor stage (FIGO) at time of diagnosis, and details of 
the other categories mentioned above will be added to the listings.  
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8. Medical and Surgical History 
Medical conditions and Surgeries will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). 
The medical conditions (separately for ongoing and past conditions) and the surgeries will 
be tabulated separately by system organ class (SOC) and preferred term (PT) for the FAS. 
SOC and PT (within SOC) will be ordered by decreasing frequency. As mentioned in the 
Adverse Events section, the adverse events collected during the pre-treatment period will 
be tabulated together with the medical history. 
All details will be listed. 
9. Prior Anti-cancer Therapies 
All prior anti-cancer therapies, except for radiation therapies and surgeries, will be listed 
and tabulated by anatomical therapeutic chemical (ATC) code level 3 and active ingredient 
(WHO-DD dictionary). ATC class and active ingredient (within ATC class) will be ordered 
by decreasing frequency. 
In addition, subjects with prior lines of systemic regimen administered in the extra-pelvic 
metastatic or recurrent setting will be summarized for the following: 
 
Number of subjects who received 1 vs 2 systemic regimens 
 
The best response to the last systemic regimen 
 
Number of subjects with 1st line systemic regimen by combination of drugs 
 
Number of subjects with 2nd line systemic regimen by combination of drugs 
 
Number of subjects with Paclitaxel + Cisplatin/Carboplatin + Bevacizumab or 
Paclitaxel + Topotecan + Bevacizumab as 1st line systemic therapy 
Prior radiation therapies and prior cancer surgeries will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). The prior cancer surgeries will be presented 
by system organ class and preferred term (both levels ordered by decreasing frequency). 
The prior cancer radiation therapies will be summarized by setting (Early-stage disease, 
locally advanced disease, and palliative) and preferred term (ordered by decreasing 
frequency). 
All details will be listed. 
10. 
Subsequent Anti-Cancer Therapies 
All subsequent anti-cancer therapies will be listed and tabulated by anatomical therapeutic 
chemical (ATC) code level 3 and active ingredient (WHO-DD dictionary). ATC class and 
active ingredient (within ATC class) will be ordered by decreasing frequency. 
In addition, subsequent systemic cancer therapies will also be summarized by combination 
of drugs. The combination “Other” will also be detailed by a summary of the standardized 
procedure name. 
All details will be listed. 
11. 
Procedures 
Procedures will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
All procedures will be listed. 
 
Genmab - GCT1015-04                                                                   Version: 5.0
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12. 
Prior and Concomitant Medications 
Prior and Concomitant medications will be classified according to World Health 
Organization Drug Dictionary (WHO-DD dictionary). 
Medications will be reported according to the following two distinct categories: 
- 
Prior when they start and end before the first day of IMP 
- 
Concomitant when they start before the first day of IMP and stop or continue after 
the first day of IMP, or when they start on or after the first day of IMP. 
The number and percentage of subjects receiving a concomitant medication will be 
displayed by third Anatomical Therapeutic Chemical class (ATC 3) and active ingredient 
for the FAS.  
ATC class and active ingredient (within ATC class) will be ordered by decreasing frequency. 
Prior medications will only be listed. 
A listing of all medications recorded on the (prior and) concomitant medications eCRF page 
will provide details including indication, dose, route, frequency, and start and stop dates.  
Prior and Concomitant medications will be split in two listings. 
13. 
Efficacy Evaluation  
Efficacy results will be presented on the full analysis set (FAS).  
13.1 Primary Objective 
Determine the anti-tumor efficacy in subjects with cervical cancer. 
13.1.1 Confirmed Objective Response Rate based upon RECIST v1.12, assessed 
by the independent review committee (IRC) 
Confirmed objective response rate (ORR) is defined (based on IRC verified scan results) 
as an overall response (PR or better) confirmed by a subsequent overall response of PR or 
better at least four weeks later*. Of note, the best overall response is the best response 
recorded from the start of the treatment until disease progression/recurrence or start of 
new anti-cancer therapy. 
[* The following sequences will be counted as confirmed response: 
 
CR-CR = CR confirmed 
 
CR-PR = PD (confirmed) - because of reappearance of disease. Imaging charter 
must make sure that prior scan is corrected to PR if believed when seeing the 
following scan to be only PR at subsequent scan. This way CR-PR should not occur 
if the reader interprets this as a PR confirmed, it would be corrected to PR-PR in 
this case. Otherwise it would be CR-PD which would qualify as confirmed SD if 
minimum duration criteria for SD met. 
 
PR-PR = PR confirmed 
 
PR-CR = PR confirmed 
NB: Intermediate missing (NE) scan evaluations between the response scan and the 
confirmation scan are allowed, e.g. the sequences PR-NE-PR and PR-NE-NE-PR will be 
considered PR confirmed. 
In all cases the scan that confirms the first scan with CR/PR must occur no sooner than 4 
weeks after the first scan. 
Genmab - GCT1015-04                                                                   Version: 5.0
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A subject with sequences that qualify both as PR confirmed and CR confirmed, e.g. PR-PR-
CR-CR would be considered a CR confirmed. 
If PR or CR are not confirmed, the response will be SD when on or after 35 days and NE 
when before 35 days. The 35 days takes into account the minimal 6-weeks duration +/- 
1 week window.] 
The following statistical hypotheses will be tested to address the primary efficacy 
objective: 
H0: θ ≤ 11% vs. HA: θ > 11% 
where θ is the ORR. The test will be performed as an exact test at a one-sided 2.5% alpha 
level. 
In addition an exact 95% two-sided confidence interval for the ORR will be provided using 
the Clopper-Pearson method. 
The analysis will be performed on the FAS with an ITT approach so that any subjects with 
missing information regarding response to treatment will be counted as non-responders. 
See section 4.8 for detailed information of handling of missing values. 
Best overall response will be summarized descriptively. Subjects with no post-baseline 
data will be identified by NE for best response. 
ORR including unconfirmed responders will also be analyzed as a supportive analysis. 
In addition, confirmed ORR will be analyzed by subgroup (as described in section 4.4) 
using a forest plot. 
Further confirmed ORR as well as confirmed and unconfirmed ORR, as assessed by the 
investigator, will be analyzed and summarized in the same way. 
13.2 Secondary Efficacy Objectives 
Evaluate tumor response durability and evaluate clinical response. 
13.2.1 
Duration of confirmed response 
Duration of response (DOR) only applies to the subset of subjects in the FAS whose 
confirmed best overall response is CR or PR according to RECIST v1.12, based on tumor 
response data per IRC review. The start date is the date of first documented response of 
CR or PR (i.e. the start date of response, not the date when response was confirmed), and 
the end date is defined as the date of the first documented disease progression verified 
by IRC or death.  
Subjects continuing without disease progression or death will be censored and the 
censoring date will be the date of the last adequate tumor assessment prior to data cut-
off/start of new anti-cancer therapy. In case of progression after ≥2 missed scans, 
censoring will be done at last adequate tumor assessment date prior to the missed scans. 
Reason of censoring will be summarized.  
DOR (months) will be listed for all subjects in the FAS with confirmed best overall response 
of CR or PR, and presented graphically as well as summarized using survival analysis 
methods:  
 
Kaplan-Meier curves 
 
Kaplan-Meier estimate of the median time, the first and third quartiles, along 
with approximate 95% confidence interval of the median (the default 
conftype=loglog in SAS proc lifetest will be used), and the range. 
Genmab - GCT1015-04                                                                   Version: 5.0
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Six months DOR rate (i.e. percentage of subjects with DOR ≥6 months) and 95% CI will 
also be summarized using Kaplan-Meier estimates. 
13.2.2 
Time to Confirmed Response 
Time to response (TTR) is defined as the time (months) from the date of the first IMP 
administration to the first documented response of either CR or PR, which must be 
subsequently verified by the IRC (although date of initial response is used, not date of 
confirmation). CR and PR are based on tumor response data as per IRC review and 
according to RECIST v1.12. 
TTR will be summarized in the FAS population restricted to subjects with a confirmed 
response using descriptive statistics. 
13.2.3 
Progression-Free Survival 
Progression free survival (PFS) is defined as the time (months) from the date of the first 
IMP administration to the date of the first documented disease progression or death due 
to any cause. PFS will be assessed via IRC review according to RECIST v1.12. 
PFS will be censored if no PFS event is observed before the first to occur between: (i) the 
analysis cut-off date, and (ii) the date when a new anti-cancer therapy is started.  The 
censoring date will be the date of the last adequate tumor assessment prior to cut-off/start 
of new anti-cancer therapy. In case of progression after ≥2 missed scans, censoring will 
be done at last adequate tumor assessment date prior to the missed scans. 
PFS will be analyzed in the FAS population and presented graphically as well as 
summarized using survival analysis methods:  
 
Kaplan-Meier curves 
 
Kaplan-Meier estimate of the median time, the first and third quartiles, along 
with approximate 95% confidence interval of the median (the default 
conftype=loglog in SAS proc lifetest will be used). 
Three and 6 months PFS rates (i.e. percentage of subjects with PFS ≥3 months and ≥6 
months respectively) and 95 %CI will also be summarized using Kaplan-Meier estimates. 
13.2.4 
Overall Survival 
Overall survival (OS) is defined as the time (months) from the date of the first IMP 
administration to the date of death due to any cause.  
If a subject is not known to have died, then OS will be censored and the censoring date 
will be the latest date the subject was known to be alive (on or before the cut-off date). 
OS will be analyzed in the FAS population and presented graphically as well as summarized 
using survival analysis methods:  
 
Kaplan-Meier curves 
 
Kaplan-Meier estimates of the median time, the first and third quartiles, along 
with approximate 95% confidence interval of the median (the default 
conftype=loglog in SAS proc lifetest will be used). 
Six and 12 months OS rates (i.e. percentage of subjects with OS ≥6 months and ≥12 
months respectively) and 95% CI will also be summarized using Kaplan-Meier estimates. 
 
 
Genmab - GCT1015-04                                                                   Version: 5.0
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13.3 Supportive Analyses of Secondary Efficacy Objectives 
Investigator assessment of DOR, TTR and PFS, based upon RECIST v1.12, will be analyzed 
in the same way as the corresponding IRC review based endpoints (except Kaplan-Meier 
curves which will only be presented for IRC review). 
Concordance between IRC review and Investigator assessment will be summarized at a 
patient level for confirmed ORR and confirmed BOR. 
13.4 Anti-tumor Activity 
Anti-tumor activity measured by tumor shrinkage (based on sum of the diameter(s) of all 
target lesions from the radiological scan evaluations) will be listed and summarized 
descriptively using individual subject plots: 
 
Waterfall plot and spider plot summarizing the percent change from baseline 
of the sum of diameter(s) of all target lesions (using response data as 
assessed by IRC). 
 
Swimlane plot showing the time to progression (or censoring) for each subject 
indicating also overall responses as well as withdrawal reason (using response 
data as assessed by IRC). Swimlane plot will be also repeated restricted to 
subjects with confirmed response. 
13.5 Follow-up Time 
The follow-up time (months) will be summarized using descriptive statistics. 
14. 
Pharmacokinetics (PK) 
The plasma concentrations will be summarized as described below.  
Values below limit of quantification will be counted as having a value of half the lower limit 
of quantification. See section 4.8 for detailed information of handling of missing values. 
Plasma concentrations (HuMax-TF, HuMax-TF-ADC and MMAE) data will be listed. 
15. 
Safety Evaluation 
15.1 Extent of Exposure 
The duration of exposure to IMP (months), the number of doses received and the 
cumulative dose (mg/kg), as well as the actual and relative dose intensities will be 
summarized by means of descriptive statistics using the FAS. 
The number of subjects with dose reductions will be summarized together with the 
reasons. 
Details of the other reason category as well as all dosing data will be listed. 
15.2 Secondary Safety Objectives 
Assess safety and tolerability of tisotumab vedotin. 
15.2.1 Adverse events 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be graded according to the National Center Institute Common 
Terminology Criteria for AEs (NCI-CTCAE criteria [v5.0]3). 
Genmab - GCT1015-04                                                                   Version: 5.0
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Summary tables for AEs described below will only include AEs that are treatment-
emergent, i.e. AEs that started or worsened (taking into account the dates of grade 
changes) during the on-treatment period.  
Adverse events collected during the pre-treatment period will be tabulated together with 
the medical history (by SOC and PT) and will be included in the AE listings (marked with 
a flag). Adverse events collected during the post-treatment period will be tabulated 
separately from the treatment-emergent AEs and will be included in the AE listings 
(marked with a flag).  
See section 4.1.1 for definition of pre-treatment, on-treatment and post-treatment 
periods. 
Missing or partial AE start date will be estimated in order to include events in summary 
tables in case of doubt (see section 4.7 for more details). 
A summary table will present the number and percentage of subjects with at least one: 
 
Adverse event (AE) 
 
AE related to tisotumab vedotin 
 
Grade ≥3 AE 
 
Grade ≥3 AE related to tisotumab vedotin 
 
Serious AE 
 
Serious AE related to tisotumab vedotin 
 
AE leading to drug withdrawal 
 
AE leading to drug interruption 
 
AE leading to dose reduction 
 
Fatal AE 
 
Fatal AE related to tisotumab vedotin 
In addition, tabulations of the number of subjects who experienced AEs as well as severity 
grade of the events will be presented by preferred term (ordered by decreasing frequency). 
Subjects will only be counted once for each preferred term. In case a subject experienced 
the same event more than once, the worst severity grade will be presented. 
The following tabulations will be presented: 
 
All AEs 
 
All AEs (Occurrence >=10%) 
 
AEs related to tisotumab vedotin 
 
AEs leading to drug withdrawal 
 
AE leading to drug interruption 
 
AE leading to dose reduction 
All adverse events will also be summarized by severity grade, system organ class and 
preferred term (ordered by decreasing frequency of SOC and by decreasing frequency of 
preferred term within a SOC). 
AE of special interest will be summarized grouped by AESI category (Ocular AE, Peripheral 
neuropathy, Bleeding event), preferred term and severity grade.  
Genmab - GCT1015-04                                                                   Version: 5.0
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The AESI categories will be defined using MedDRA SMQ lists provided by sponsor at the 
time of the analysis programming. The AESI indicator per eCRF data will only be used as 
a data monitoring tool. 
In addition, time to onset of first AESI event (for subjects with at least one event), total 
number of AESI events, total number and percentage of AESI events with outcome of 
resolution, and time to resolution of each AESI event (for events which are resolved) will 
be summarized by AESI category (Ocular AE, Ocular Surface Disease, Peripheral 
Neuropathy, Bleeding Event) using descriptive statistics. AESI events with partial start 
date will be imputed accordingly to the rules described in section 4.7. 
Time to onset of first AESI event will also be presented graphically by AESI category 
(Ocular AE, Ocular Surface Disease, Peripheral Neuropathy, Bleeding Event) using Kaplan-
Meier curves (one plot with one line for each AESI category); subjects with no AESI will 
be censored at the end of the treatment period. 
Adverse events of special interest will also be presented graphically using lines plots. Plots 
will be performed individually for each subject and will show the reported AESI by category 
on a time-based x-axis (arrow will be used to show ongoing AEs). Plots will also include 
lines to show start date in the study (i.e. informed consent date) and last contact date of 
subject, as well as start and end dates of on-treatment period. Colors will be added for 
the grades (worst grade). 
Lastly, the number of subjects who reported hypersensitivity, number of subjects who 
reported infusion related reactions and number of subjects who reported anaphylaxis will 
be summarized by ADA status (As per definition described in section 15.2.5.2).  
Listings of all AEs (including those from the pre and post-treatment periods) will be 
provided including the subject identifier, verbatim, preferred term, system organ class, 
duration of the event, severity, action taken, outcome, causality, date of onset, days since 
the first dose, and days since the last dose. The AEs collected during the pre-treatment 
and post-treatment periods will be flagged. 
15.2.2 Deaths and Serious Adverse Events  
Serious adverse events (SAEs), SAEs (Occurrence >=2%), SAEs related to tisotumab 
vedotin, fatal AEs, Grade ≥3 AEs, and Grade ≥3 AEs related to tisotumab vedotin will be 
summarized grouped by severity grade (except fatal AEs and Grade ≥3 AEs) and preferred 
term (ordered by decreasing frequency). Serious adverse events will also be summarized 
by severity grade, system organ class and preferred term (ordered by decreasing 
frequency of SOC and by decreasing frequency of preferred term within a SOC). 
In addition, listings of serious AEs and fatal AEs will be provided similarly to the listing of 
all AEs. 
All deaths (on-treatment and post-treatment) will be listed together with the primary 
reason of death. 
15.2.3 Clinical Laboratory Data 
The following laboratory parameters are measured: 
 
Hematology parameters: Platelets, red blood cell count (including RBC 
indices, i.e. Mean corpuscular volume (MCV), mean corpuscular hemoglobin 
(MCH), mean corpuscular hemoglobin concentration (MCHC) and % 
reticulocytes), hemoglobin, hematocrit, white blood cell count with differential 
(i.e. Neutrophils, lymphocytes, monocytes, eosinophils and basophils) 
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 
Coagulation factors: prothrombin time, international normalized ratio and 
activated partial thromboplastin time. 
 
Biochemistry parameters: Sodium, potassium, magnesium, creatinine (GFR 
calculation), calcium, blood urea nitrogen, AST, ALT, alkaline phosphatase, 
albumin, glucose, total bilirubin, direct bilirubin, lactate dehydrogenase, uric 
acid, C-reactive protein, s-Ferritin and total creatinine kinase. 
Grading of laboratory values (hematology and biochemistry) will be assigned 
programmatically as per the NCI-CTCAE criteria [v5.0]³. The calculations of CTCAE grades 
will be based on the observed laboratory values only, clinical assessments will not be taken 
into account. CTCAE grade 0 will be assigned for all non-missing values not graded as 1 
or higher. For laboratory tests where grades are not defined by the CTCAE, results will be 
categorized as low/normal/high based on laboratory normal ranges.  
All laboratory assessments will be converted to the corresponding international system of 
unit. 
All summaries described below will be generated separately for hematology, coagulation 
and biochemistry tests. 
For continuous laboratory tests, box plots will be presented for actual values and for 
changes from baseline by visit for each parameter. 
For all laboratory tests where grades are defined by the CTCAE grading, shift tables from 
the baseline CTCAE grade to the highest post-baseline CTCAE grade (during on-treatment 
period) will be produced.  
For the calculation of the maximum CTCAE grade, both scheduled and unscheduled values 
available post-baseline (during on-treatment period) will be used.  
Shift tables will be produced based on normal ranges (Low/Normal/High) for all laboratory 
tests (even the ones defined in the NCI-CTCAE grading guidelines). These tables will 
summarize the number of subjects with each baseline category (Low/Normal/High) and 
changes to the worst high and worst low category (Low/Normal/High). Both scheduled and 
unscheduled values available post-baseline (during the on-treatment period) will be used. 
The following subject data listings will be produced for all laboratory parameters where 
CTCAE grades are defined: 
 
Listing of subjects with laboratory abnormalities of CTCAE grade 3 or 4. 
 
Listing of all laboratory data including CTCAE grades (if applicable) as well as 
classifications relative to laboratory normal ranges. 
All other laboratory parameters will be listed by laboratory parameter and subject including 
the classifications relative to the laboratory normal ranges. 
In addition, the frequency of subjects with incidence of drug induced liver laboratory 
abnormalities (defined as subjects meeting or exceeding the following predefined limits: 
ALT > 3xULN and Total Bilirubin > 2xULN, AST > 3xULN and Total Bilirubin > 2xULN, AST 
and/or ALT > 3xULN and Total Bilirubin > 2xULN, AST and/or ALT > 3xULN and Total 
Bilirubin > 2xULN and ALP < 1.5xULN) will be summarized descriptively and listed. Total 
bilirubin and/or ALP measurements concurrent or within 21 days subsequent to ALT/AST 
elevation will be included for the assessment of the incidence.  
 
15.2.4 Ophthalmology results 
Genmab - GCT1015-04                                                                   Version: 5.0
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Eye examination results (Normal / Abnormal / Not done) will be tabulated over time for 
visual inspection of eye orbit, eye movement and conjunctiva. In addition, frequency of 
subjects going from normal result at baseline to abnormal result at any post-baseline visits 
(all together) and at treatment discontinuation visit and safety follow-up (individually) will 
also be summarized. 
The frequency of subjects with normal or abnormal findings at the baseline 
ophthalmological evaluation will be summarized separately for subjects with and without 
a reported treatment-emergent ocular AE (MedDRA SMQ lists to be defined by sponsor). 
The baseline ophthalmological evaluation is considered abnormal if one of the 
ophthalmological tests included (i.e. Visual acuity, Schrimer’s tear test, SLIT lamp, IOC 
pressure, fundoscopy) is recorded as abnormal in either of the eyes. In addition, the 
frequency of subjects with an abnormal finding at the baseline evaluation will be 
summarized for each ophthalmological test separately (Pooling results from both eyes, i.e. 
abnormal if abnormal in one of the eyes). 
Lastly, ophthalmological results will be summarized for the FAS restricted to subjects with 
a reported treatment-emergent ocular AE as a shift table from baseline to any post-
baseline visit (for overall ophthalmological evaluation and for each test separately). 
All results from the ophthalmological tests will also be listed for subjects with at least one 
abnormal finding. A flag for subjects who develop a treatment emergent ocular AE will be 
added in the listing. 
15.2.5 Other Safety Data 
15.2.5.1 
ECG 
ECG interpretation (Normal / Abnormal) and ECG measurements (HR, RR, QT, QTcF, PR 
and QRS) will be tabulated/summarized by visit and ECG time point (Before IMP 
administration and End of IMP administration (+15 min)). The three 12-lead ECG 
performed at each visit/time point will be combined as one measurement using the 
average of the three results (for ECG measurements), and the worst outcome of the three 
results for ECG interpretation.  
Categorical analysis of QT and QTcF interval data based on the number of subjects meeting 
or exceeding predefined limits in terms of absolute QT and QTcF intervals (>450 ms or 
>480 ms or >500 ms) or changes from baseline (change of >30 ms or >60 ms) will be 
presented at baseline and at any post-baseline visit. 
Additionally, categorical analysis of PR interval data based on the number of subjects 
meeting or exceeding predefined limits in terms of absolute PR (>200 ms or >220 ms) or 
changes from baseline (change of >25%) will also be presented at baseline and at any 
post-baseline visit.  
Lastly, categorical analysis of QRS interval data based on the number of subjects meeting 
or exceeding predefined limits in terms of absolute QRS (>110 ms or >120 ms) or changes 
from baseline (change of >25%) will also be presented at baseline and at any post-
baseline visit. 
A listing of these subjects will be produced. 
QTcF will also be presented graphically using a mean-SE plot for change from baseline 
values. 
 
Genmab - GCT1015-04                                                                   Version: 5.0
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15.2.5.2 
Immunogenicity (anti-drug antibodies) of tisotumab vedotin 
Data on immunogenicity (anti-drug antibodies) of tisotumab vedotin will be summarized 
as described below. 
Titers of tisotumab vedotin will be listed. 
Positive/negative host immune response to tisotumab vedotin will be tabulated at baseline 
and at any post-baseline visit. For post-baseline results, a subject will be considered 
positive if negative at baseline and at least one positive post-baseline result, or positive 
at baseline and at least one positive post-baseline result with a titer higher than baseline. 
Of note, subjects with no post-baseline ADA assessment will have a missing ADA status. 
All details will be listed.  
Of note, ADA positivity requires confirmation in 2 assay steps. First step has many false 
positive; the second assay step (confirmation) ensures specificity of the assay. Only 
confirmed ADA positivity results will be considered as positive. The others will be negative. 
Presence of neutralizing antibodies (positive/negative) will be presented in the listing. 
For ADA-positive subjects, all ADA assessments should be listed together with their PK 
value. 
The effect of immunogenicity will be assessed for efficacy through a swimlane plot for NAb 
positive subjects. The plot will examine timing, frequency and nature of ADA occurrence 
(i.e. the plot will summarize titer values, ADA and NAb status over time as well as 
progression free survival and best overall response, individually for each subject). 
In addition, information from NAb positive subjects will be detailed in individual case 
narratives. This will include but not limited to ADA test results, ADA titer, and key safety 
and efficacy data by date or study day. 
15.2.6 Pregnancy Test 
All positive pregnancy test data will be listed. 
16. 
Exploratory Objectives 
Asses biomarkers related to clinical response, assess potential pharmacodynamic 
biomarkers, and assess Health Related Quality of Life (HRQL). 
16.1 TF expression 
TF expression (membrane H-score, membrane total % TF expression, cytoplasmic H-score 
and cytoplasmic total % TF expression) at baseline will be summarized for all subjects 
using descriptive statistics. 
Median TF expression will be presented for each best clinical response category (SD, PR, 
CR, PD), and also for subjects who derived clinical benefit (SD, PR, CR) versus those with 
progressive disease (PD). 
In addition, TF expression will also be summarized by confirmed BOR first using descriptive 
statistics, and then graphically using box plots of actual values. 
All analyses based on responses in this section will be duplicated using first response data 
as assessed by investigator and then using response data as assessed IRC. 
Additional evaluations of TF expression with other trial data may be performed for 
exploratory purposes.  
Genmab - GCT1015-04                                                                   Version: 5.0
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16.2 Circulating TF 
Circulating TF (cTF) will be measured from whole blood samples. 
 
 
 
Actual values and percent change from baseline of cTF will be graphed per visit using 
mean-SE plots, overall and by confirmed BOR (one line per response and one line for all).  
Actual values and percent change in cTF will be calculated and summarized per visit using 
descriptive statistics, overall and by confirmed BOR. 
Median percent change in cTF will be presented per visit for those subjects with clinical 
benefit (SD, PR, CR) and compared to those subjects with progressive disease (PD). 
All analyses based on responses in this section will be duplicated using first response data 
as assessed by investigator and then using response data as assessed IRC.  
16.3 Health Related Quality of Life (HRQL) 
The analysis of health related quality of life will be assessed through EORTC-QLQ-C30 
questionnaire together with the EORTC-QLQ-CX24 questionnaire (additional module for 
subjects treated for cervical cancer). 
16.3.1EORTC-QLQ-C30 
The EORTC-QLQ-C30 questionnaire consists of both multi-item scales and single items 
measures. These include 5 functional scales, 3 symptom scales, a global health status/QoL 
scale, and 6 single items. Each of the multi-item scales includes a different set of items 
(i.e. no item occurs in more than one scale). 
The questionnaire is composed of 30 questions for which the answers ranges either from 
1 (Not at all) to 4 (Very much) for items 1 to 28, or from 1 (Very poor) to 7 (Excellent) 
for items 29 to 30. 
All of the scales and single-item measures range in score from 0 to 100, with a high scale 
score representing a higher response level (e.g. a high level of functioning, a high QoL, or 
a high level of symptomatology/problems). 
The principle for scoring the scales is the same in all cases: 
1. Estimate the average of the items that contribute to the scale; this is the raw score 
Genmab - GCT1015-04                                                                   Version: 5.0
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2. Use a linear transformation to standardise the raw score, so that scores range from 
0 to 100; a higher score represents a higher (“better”) level of functioning, or a 
higher (“worst”) level of symptoms. 
Table 1 Scoring the EORTC-QLQ-C30 
 
Table 1 summarizes the different scales and component items. 
For all scales, the RawScore (RS) is the mean of the component items: 
 
 
Then for Functional scales: 
 
and for Symptoms scales/items and Global health status/QoL: 
 
 
See section 4.8 for detailed information of handling of missing values. 
Genmab - GCT1015-04                                                                   Version: 5.0
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The 15 scores computed from EORTC-QLQ-C30 questionnaire will be summarized using 
descriptive statistics (n, mean and SD) at baseline, and at each scheduled visit for actual 
values and changes from baseline. 
In addition, compliance and completeness to the questionnaire, as defined below, will also 
be summarized. Compliance will be presented overall and by visit, while completeness will 
only be presented by visit. 
Compliance (percentage) will be computed on a subject level as the number of visits for 
which the subject filled in the questionnaire (at least one item answered) divided by the 
number of visits scheduled for HRQL data taking into account which visit the subject 
reached. Of note, all screening visits have been pooled as one visit. 
Compliance will also be computed on a visit level as how many subjects filled in the 
questionnaire (at least one item answered) divided by the total number of subjects who 
reached that visit. 
Completeness will be computed on a visit level as how many subjects filled in the 
questionnaire (at least one item answered) divided by the total number of subjects in the 
FAS population, regardless of subject drop-outs. 
All details including answers to individual questions will be listed. 
16.3.2 EORTC-QLQ-CX24 
The cervical cancer module is meant for use among cervical cancer subjects varying in 
disease stage and treatment modality. It should always be complemented by the QLQ-
C30. 
The EORTC-QLQ-CX24 is composed of 24 questions for which the answers range from 1 
(Not at all) to 4 (Very much). 
Table 2 Scoring the EORTC-QLQ-CX24 
 
Table 2 summarizes the different scales and component items. 
The scoring system is similar to the one for EORTC-QLQ-C30 and fully described in the 
previous section 16.3.1. See section 4.8 for detailed information of handling of missing 
values. 
As for the EORTC-QLQ-C30, the 9 scores computed from EORTC-QLQ-CX24 questionnaire 
will be summarized using descriptive statistics at baseline, and at each scheduled visit for 
Genmab - GCT1015-04                                                                   Version: 5.0
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actual values and changes from baseline. In addition, compliance and completeness to the 
questionnaire will also be summarized as described in the previous section 16.3.1. 
All details including answers to individual questions will be listed. 
 
Genmab - GCT1015-04                                                                   Version: 5.0
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17. 
References 
1. 
http://www.consort-statement.org/  
2. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). European journal of cancer (Oxford, 
England: 1990). 2009;45(2):228-247. 
3. CTCAE 5.0. Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0. 
Published: November 27, 2017. U.S.DEPARTMENT OF HEALTH AND HUMAN 
SERVICES. 
National 
Institutes 
of 
Health. 
National 
Cancer 
Institute. 
https://ctep.cancer.gov/protocoldevelopment/electronic applications/docs/CTCAE v
5 Quick Reference 5x7.pdf 
4. EORTC-QLQ-C30 Scoring Manual.  
https://www.eortc.be/qol/files/SCManualQLQ-C30.pdf 
5. EORTC-QLQ-CX24 Scoring Manual. 
http://www.eortc.be/qol/files/ScoringInstructions/CX24_summary.pdf 
 
 
Genmab - GCT1015-04                                                                   Version: 5.0
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18. 
List of Tables/Graphs/Listings 
18.1  List of Statistical Tables 
 
General  
Table 14.01.01: Subject Treatment Disposition 
Table 14.01.02: Subject Study Disposition 
Table 14.01.03: Important Protocol Deviations 
Table 14.01.04: Demographic and Baseline Disease Characteristics 
Table 14.01.05: Baseline Biopsy Information 
Table 14.01.06.01: Medical History and Pre-Treatment Adverse Events – Resolved prior to C1D1 – By SOC and PT 
Table 14.01.06.02: Medical History and Pre-Treatment Adverse Events – Ongoing – By SOC and PT 
Table 14.01.06.03: Surgical History – By SOC and PT 
Table 14.01.07.01: Prior Systemic Regimen in Extra-pelvic Metastatic or Recurrent Setting 
Table 14.01.07.02: Prior Anti-Cancer Therapies – By ATC level 3 and Active Ingredient 
Table 14.01.07.03: Prior Cancer Radiations– By Setting and PT 
Table 14.01.07.04: Prior Cancer Surgeries – By SOC and PT 
Table 14.01.08.01: Anti-Cancer Therapies after Tisotumab Vedotin Treatment 
Table 14.01.08.02: Anti-Cancer Therapies after Tisotumab Vedotin Treatment – By ATC level 3 and Active 
Ingredient 
Table 14.01.09: Concomitant Medications – By ATC level 3 and Active Ingredient 
 
Efficacy Evaluation 
Table 14.02.01.01: Confirmed Objective Response Rate (Assessed by IRC and Investigator) 
Table 14.02.01.02: Objective Response Rate including Unconfirmed Response (Assessed by IRC and Investigator) 
Table 14.02.02: Duration of and Time to Confirmed Response (Assessed by IRC and Investigator) 
Table 14.02.03: Progression-Free Survival (Assessed by IRC and Investigator) 
Table 14.02.04: Overall Survival 
Table 14.02.05: Concordance/Discordance of Confirmed Response Assessment per IRC vs Investigator 
Table 14.02.06: Follow-up Time 
 
Safety Evaluation 
 
Table 14.03.01: Extent of exposure to Tisotumab Vedotin 
Table 14.03.02: Summary of Treatment-Emergent Adverse Events 
Table 14.03.03.01: Treatment-Emergent Adverse Events - By PT, and Maximum Severity Grade 
Table 14.03.03.02: Treatment-Emergent Adverse Events - By SOC, PT, and Maximum Severity Grade 
Table 14.03.03.03: Treatment-Emergent Adverse Events (Occurrence >=10%) - By PT, and Maximum Severity 
Grade 
Table 14.03.04: Treatment-Emergent Adverse Events Related to Tisotumab Vedotin - By PT, and Maximum 
Severity Grade 
Table 14.03.05.01: Treatment-Emergent Adverse Events of Special Interest – By AESI category, PT, and Maximum 
Severity Grade 
Table 14.03.05.02.01: Treatment-Emergent Adverse Events of Special Interest - Ocular Adverse Event: Time to 
Onset and Time to Resolution 
Table 14.03.05.02.02: Treatment-Emergent Adverse Events of Special Interest - Ocular Surface Disease: Time to 
Onset and Time to Resolution 
Table 14.03.05.02.03: Treatment-Emergent Adverse Events of Special Interest - Peripheral Neuropathy: Time to 
Onset and Time to Resolution 
Table 14.03.05.02.04: Treatment-Emergent Adverse Events of Special Interest - Bleeding Event: Time to Onset 
and Time to Resolution 
Table 14.03.06: Grade >=3 Treatment-Emergent Adverse Events – By PT 
Table 14.03.07: Grade >=3 Treatment-Emergent Adverse Events Related to Tisotumab Vedotin – By PT 
Table 14.03.08.01: Serious Treatment-Emergent Adverse Events – By PT, and Maximum Severity Grade 
Table 14.03.08.02: Serious Treatment-Emergent Adverse Events – By SOC, PT, and Maximum Severity Grade 
Table 14.03.08.03: Serious Treatment-Emergent Adverse Events (Occurrence >=2%) – By PT, and Maximum 
Severity Grade 
Table 14.03.09: Serious Treatment-Emergent Adverse Events Related to Tisotumab Vedotin – By PT, and 
Maximum Severity Grade 
Table 14.03.10: Treatment-Emergent Adverse Events Leading to Drug Withdrawal – By PT, and Maximum Severity 
Grade 
Table 14.03.11: Treatment-Emergent Adverse Events Leading to Drug Interruption – By PT, and Maximum 
Severity Grade 
Genmab - GCT1015-04                                                                   Version: 5.0
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Table 14.03.12: Treatment-Emergent Adverse Events Leading to Dose Reduction – By PT, and Maximum Severity 
Grade 
Table 14.03.13: Fatal Treatment-Emergent Adverse Events – By PT 
Table 14.03.14: Post-treatment Adverse Events – By PT, and Maximum Severity Grade 
Table 14.03.15: Incidence of Hypersensitivity and Infusion reactions by ADA status 
Table 14.03.16: Hematology Laboratory Results – Shift table from Baseline CTCAE grade to Highest Post-Baseline 
CTCAE grade 
Table 14.03.17.01: Hematology Laboratory Results – Shift Table Baseline vs Worst Highest Post-Baseline 
Abnormality 
Table 14.03.17.02: Hematology Laboratory Results – Shift Table Baseline vs Worst Lowest Post-Baseline 
Abnormality 
Table 14.03.18: Biochemistry Laboratory Results – Shift table from Baseline CTCAE grade to Highest Post-Baseline 
CTCAE grade 
Table 14.03.19.01: Biochemistry Laboratory Results – Shift Table Baseline vs Worst Highest Post-Baseline 
Abnormality 
Table 14.03.19.02: Biochemistry Laboratory Results – Shift Table Baseline vs Worst Lowest Post-Baseline 
Abnormality 
Table 14.03.20: Coagulation Laboratory Results (Local) – Shift table from Baseline CTCAE grade to Highest Post-
Baseline CTCAE grade 
Table 14.03.21.01: Coagulation Laboratory Results (Local) – Shift Table Baseline vs Worst Highest Post-Baseline 
Abnormality 
Table 14.03.21.02: Coagulation Laboratory Results (Local) – Shift Table Baseline vs Worst Lowest Post-Baseline 
Abnormality 
Table 14.03.22: Subject Incidence of Drug Induced Liver Laboratory Abnormalities 
Table 14.03.23: Eye Examination over Time 
Table 14.03.24: Eye Examination - Shift table from Baseline to any Post-Baseline visits 
Table 14.03.25: Ophthalmological Evaluation at Baseline 
Table 14.03.26: Ophthalmological Evaluation – Shift table from Baseline to any Post-Baseline visits – For subjects 
with a reported treatment emergent ocular AE 
Table 14.03.27: ECG over Time 
Table 14.03.28: ECG Categorical Analysis 
Table 14.03.29: Tisotumab Vedotin Immunogenicity 
 
Exploratory Evaluation 
Table 14.04.01.01: Biomarkers – TF expression (Response Data as Assessed by Investigator) 
Table 14.04.01.02: Biomarkers – TF expression (Response Data as Assessed by IRC) 
Table 14.04.02.01: Biomarkers – Circulating TF (Response Data as Assessed by Investigator) 
Table 14.04.02.02: Biomarkers – Circulating TF (Response Data as Assessed by IRC) 
Table 14.04.03.01: Health Related Quality of Life – EORTC-QLQ-C30 
Table 14.04.03.02: Health Related Quality of Life – EORTC-QLQ-C30: Compliance and Completeness 
Table 14.03.04.01: Health Related Quality of Life – EORTC-QLQ-CX24 
Table 14.03.04.02: Health Related Quality of Life – EORTC-QLQ-CX24: Compliance and Completeness 
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18.2 List of Graphs 
 
General  
Graph 14.01.01: Consort Diagram 
 
Efficacy Evaluation 
Graph 14.02.01.01: Confirmed Objective Response Rate (Assessed by IRC) by Subgroup – Forest Plot 
Graph 14.02.01.02: Confirmed Objective Response Rate (Assessed by Investigator) by Subgroup – Forest Plot 
Graph 14.02.02: Duration of Confirmed Response (Assessed by IRC) – Kaplan-Meier Curves 
Graph 14.02.03: Progression-Free Survival (Assessed by IRC) – Kaplan-Meier Curves 
Graph 14.02.04: Overall Survival – Kaplan-Meier Curves 
Graph 14.02.05: Tumor Shrinkage: Best Change in Tumor Size (Assessed by IRC) – Waterfall plot 
Graph 14.02.06: Tumor Shrinkage: Change in Target Lesion Tumor Size over Time (Assessed by IRC) – Spider 
plot 
Graph 14.02.07.01: Anti-Tumor Response per RECIST 1.1 (Assessed by IRC) – For confirmed responders – 
Swimlane plot 
Graph 14.02.07.02: Anti-Tumor Response per RECIST 1.1 (Assessed by IRC) – Swimlane plot 
Graph 14.02.08: Effect of Immunogenicity - For Nab positive subjects – Swimlane plot 
 
Safety Evaluation 
 
Graph 14.03.01.01: Adverse Event of Special Interest – Line plot 
Graph 14.03.01.02: Time to first AESI event – Kaplan-Meier Curves 
Graph 14.03.02.01: Hematology Laboratory Results – Box Plot: Actual Values over time 
Graph 14.03.02.02: Hematology Laboratory Results – Box Plot: Change from Baseline over time 
Graph 14.03.03.01: Biochemistry Laboratory Results – Box Plot: Actual Values over time 
Graph 14.03.03.02: Biochemistry Laboratory Results – Box Plot: Change from Baseline over time 
Graph 14.03.04.01: Coagulation Laboratory Results – Box Plot: Actual Values over time 
Graph 14.03.04.02: Coagulation Laboratory Results – Box Plot: Change from Baseline over time 
Graph 14.03.05: QTcF: Change from baseline – Mean-SE plot 
 
Exploratory Evaluation 
Graph 14.04.01.01.01: Biomarkers – TF Expression – Box plot: Membrane H-score by confirmed BOR (Assessed 
by Investigator) 
Graph 14.04.01.01.02: Biomarkers – TF Expression – Box plot: Membrane H-score by confirmed BOR (Assessed 
by IRC) 
Graph 14.04.01.02.01: Biomarkers – TF Expression – Box plot: Membrane % Total TF Expression by confirmed 
BOR (Assessed by Investigator) 
Graph 14.04.01.02.02: Biomarkers – TF Expression – Box plot: Membrane % Total TF Expression by confirmed 
BOR (Assessed by IRC) 
Graph 14.04.01.03.01: Biomarkers – TF Expression – Box plot: Cytoplasmic H-score by confirmed BOR (Assessed 
by Investigator) 
Graph 14.04.01.03.02: Biomarkers – TF Expression – Box plot: Cytoplasmic H-score by confirmed BOR (Assessed 
by IRC) 
Graph 14.04.01.04.01: Biomarkers – TF Expression – Box plot: Cytoplasmic % Total TF Expression by confirmed 
BOR (Assessed by Investigator) 
Graph 14.04.01.04.02: Biomarkers – TF Expression – Box plot: Cytoplasmic % Total TF Expression by confirmed 
BOR (Assessed by IRC) 
Graph 14.04.02.01.01: Biomarkers – Circulating TF – Actual values – Mean-SE plot (Overall and by confirmed BOR 
as Assessed by Investigator) 
Graph 14.04.02.01.02: Biomarkers – Circulating TF – Actual values – Mean-SE plot (Overall and by confirmed BOR 
as Assessed by IRC) 
Graph 14.04.02.02.01: Biomarkers – Circulating TF – Percent Change from Baseline - Mean-SE plot (Overall and 
by confirmed BOR as Assessed by Investigator) 
Graph 14.04.02.02.02: Biomarkers – Circulating TF – Percent Change from Baseline - Mean-SE plot (Overall and 
by confirmed BOR as Assessed by IRC) 
 
Genmab - GCT1015-04                                                                   Version: 5.0
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18.3 List of Derived Data Listings 
 
General  
Listing 16.02.01.01: Screening Failures 
Listing 16.02.01.02: Subject Disposition 
Listing 16.02.01.03: Protocol Deviations 
Listing 16.02.01.04: In- and Exclusion Criteria not met 
Listing 16.02.01.05: Demographic Characteristics 
Listing 16.02.01.06: Baseline Disease Characteristics 
Listing 16.02.01.07: Medical and Surgical History 
Listing 16.02.01.08.01: Prior Anti-Cancer Therapies 
Listing 16.02.01.08.02: Anti-Cancer Therapies after Tisotumab Vedotin Treatment 
Listing 16.02.01.09: Prior Cancer Radiations 
Listing 16.02.01.10: Prior Cancer Surgeries 
Listing 16.02.01.11: Procedures 
Listing 16.02.01.12.01: Prior Medications 
Listing 16.02.01.12.02: Concomitant Medications 
 
Efficacy Evaluation 
Listing 16.02.02.01.01: Target, non-target and new lesions information – Assessed by IRC 
Listing 16.02.02.01.02: Target, non-target and new lesions information – Assessed by Investigator 
Listing 16.02.02.02.01: Efficacy (Response data) – Assessed by IRC 
Listing 16.02.02.02.02: Efficacy (Response data) – Assessed by Investigator 
Listing 16.02.02.03.01: Efficacy (DOR, TTR, PFS, OS) – Assessed by IRC 
Listing 16.02.02.03.02: Efficacy (DOR, TTR, PFS, OS) – Assessed by Investigator 
 
Safety Evaluation 
 
Listing 16.02.03.01:Tisotumab Vedotin Exposure Data 
Listing 16.02.03.02: Adverse Events 
Listing 16.02.03.03: Serious Adverse Events 
Listing 16.02.03.04: Fatal Adverse Events 
Listing 16.02.03.05: Deaths 
Listing 16.02.03.06: Laboratory Results 
Listing 16.02.03.07: NCI CTCAE Grade >=3 Laboratory Results 
Listing 16.02.03.08: Incidence of Drug Induced Liver Laboratory Abnormalities 
Listing 16.02.03.09: Eye examination results – by Investigator 
Listing 16.02.03.10: Ophthalmology Examination Results (For subjects with at least one abnormal finding at any 
evaluation) – by Ophthalmologist 
Listing 16.02.03.11.01: ECG 
Listing 16.02.03.11.02: QT/QTcF, PR and QRS (For subjects meeting or exceeding the predefined limits) 
Listing 16.02.03.12.01: Plasma Concentrations and Tisotumab Vedotin Immunogenicity 
Listing 16.02.03.12.02: Plasma Concentrations and Tisotumab Vedotin Immunogenicity – ADA-positive subjects 
Listing 16.02.03.13: Tisotumab Vedotin Immunogenicity – Case Narratives (For Nab positive subjects) 
Listing 16.02.03.14: Positive Pregnancy Test 
 
Exploratory Evaluation 
Listing 16.02.04.01: Biomarkers –Circulating TF 
Listing 16.02.04.02: Biomarkers – TF expression 
Listing 16.02.04.03: Health Related Quality of Life 
 
 
 
Genmab - GCT1015-04                                                                   Version: 5.0
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19. 
Version history 
Version 
of 
the 
SAP and date 
Changes 
Final version 1.0, 
MAY2018 
NA. First final version. 
Final version 3.0, 
JAN2019 
[Of 
note, 
final 
version 
2.0 
does 
not exist in the 
Vault due to wrong 
manipulation 
during the approval 
process.] 
Major changes are described below, section by section. Additional 
minor updates were done for clarification or typos. 
Section 4.1.2 Visit windows:  
A paragraph was added to define visit windows for the radiological 
assessments. This will be used for all corresponding outputs 
presented by time points. 
Section 4.4 Subgroup definitions: 
Subgroup analysis by TF membrane H-score (TF+ or TF-) was 
removed as considered out of scope of this SAP based on data 
from GEN701. ROC analysis planned to define TF+ vs TF- was then 
also removed from section 13.1.1. 
Section 4.9 Changes to protocol: 
Section was updated to reflect the changes compared to the most 
up-to-date version of the protocol (Version 6.0). 
Section 9 Prior cancer therapies: 
Additional analyses were added to describe more in details the 
prior systemic treatments received. 
Section 10 New cancer therapies: 
Listing of new cancer therapies has been added. 
Section 11 Procedures: 
New section added to describe the analyses to be performed on 
the procedures data. 
Section 12 Prior and concomitant medications: 
Prior and concomitant medications were divided into three 
exclusive categories: prior (when they start and end before start 
of treatment), prior and ongoing (when they start before start of 
treatment and stop or continue after start of treatment) and 
concomitant (when they start on or after start of treatment). 
In addition, tables will be presented by active ingredient instead 
of generic term since the latter one will not be collected. 
Section 13.1.1 Confirmed ORR: 
Overall response at each time points and best overall response 
will also be summarized descriptively. 
Section 13.2.2 Time to response: 
Genmab - GCT1015-04                                                                   Version: 5.0
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A sentence was added to specify that Kaplan-Meier curves for TTR 
will be presented from bottom-left corner to top-right corner. 
Section 13.4 Anti-Tumor Activity: 
Wording was updated to make it clear that tumor shrinkage tables 
will be repeated by ADA status but corresponding graphs will only 
be presented overall. 
In addition, clear definition of ADA status was added. 
Section 14.2.1 Adverse events: 
Additional analyses were added for the AESI: time to first AESI, 
duration of first AESI, total duration of AESI (per patient), and 
duration of AESI (per event) will be summarized using Kaplan-
Meier methods, for all AESI and for Grade 3 of higher AESI. 
Corresponding conventions were also added. Individual lines plots 
were also added for AESI. 
In 
addition, 
additional 
analyses 
were 
also 
added 
for 
hypersensitivity and infusion reaction events, overall and by ADA 
status. 
Section 14.2.5.1 ECG: 
A graph was added to visually describe QTcF. 
Section 14.2.5.2 Weight and Vital signs: 
A categorical analysis of the vital signs was added to better 
summarize the clinically notable values. 
Section 14.2.5.3 Immunogenicity: 
The wording of the paragraph was updated to better describe all 
analyses planned for the immunogenicity data as the section 
wasn’t initially very much detailed. 
Section 14.2.7 Pharmacokinetics: 
Graphs planned for the PK data were updated from individual 
patient profile plots to a mean concentration plot. 
Section 14.3: Exploratory objectives: 
Some analyses were added for the exploratory objectives: 
sections were added for biomarkers (TF expression and circulating 
TF) and for the HRQL. A subsection describing conventions for 
handling missing biomarkers data was also added in section 4.8. 
 
Final version 4.0, 
SEP2019 
Major changes are described below, section by section. Additional 
minor updates were done for clarification or typos. 
Section 4 General Analysis Definition: 
25th and 75th percentiles were removed from the descriptive 
statistics for continuous data. 
Section 4.1.2 Visit Windows: 
Genmab - GCT1015-04                                                                   Version: 5.0
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“Section 4.1.2.1 Radiological assessment” was removed as no 
efficacy output is presented by visit anymore. 
Section 4.2 Planned Analysis: 
The cut off of the primary reporting of the trial has been aligned 
to the most up-to-date version of the protocol (Version 7.0). 
Section 4.4 Subgroup Definitions: 
Some 
subgroups 
have 
been 
slightly 
updated 
either 
for 
combination of subcategories (Histology), or for a better 
specification of the subgroup itself (For the subgroups related to 
prior cancer therapies). Some new subgroups were added (ECOG 
and Age). 
Section 4.7 Partial/Missing Dates: 
Rules for derivation of partial/missing dates were updated for 
prior/concomitant medications and adverse events to better 
describe all possible cases. 
Section 4.8 Methods to Be Used for Handling Missing Data: 
Sections were added with methods for Biomarkers and Health 
Related Quality of Life missing data. 
Section 4.9 Changes to protocol: 
Section was updated to reflect the changes compared to the most 
up-to-date version of the protocol (Version 7.0). 
Section 5.1 Disposition of Subjects: 
Descriptive analyses for disposition were updated to better 
describe the treatment and study dispositions of subjects. 
Section 6 Demographic Characteristics/Section 7 Baseline 
Disease Characteristics: 
Selection of variables to be presented for demographic and 
baseline disease characteristics data was updated. Presentation of 
the subgroup variables was also added and described in the 
section. 
Section 8 Medical and Surgical History: 
Adverse events collected during pre-treatment period was added 
to the section as they will be combined within the medical history 
summary. 
Section 9 Prior Anti-cancer therapies: 
For tabulations summarized by anatomical therapeutic chemical 
(ATC) code, use of ATC level 2 has been changed to ATC level 3. 
The summary of the prior cancer radiation therapies has been 
updated to present data by setting rather than by system organ 
class. 
The analyses related to the prior systemic treatments were 
updated to better describe treatment regimens received by the 
subjects. 
Genmab - GCT1015-04                                                                   Version: 5.0
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Section 10 Subsequent Anti-cancer Therapy: 
For tabulations summarized by anatomical therapeutic chemical 
(ATC) code, use of ATC level 2 has been changed to ATC level 3. 
In addition, a new analysis was added to present the subsequent 
anti-cancer therapies by combination of drugs as planned for the 
prior anti-cancer therapies. 
Section 11 Procedures: 
Tabulation of procedures was removed. 
Section 12 Prior and Concomitant Medications: 
Definition of prior versus concomitant medications was updated 
into two categories instead of three (“Prior and Ongoing” was 
removed).  
Tabulations of prior medications were removed. For tabulations 
summarized by anatomical therapeutic chemical (ATC) code, use 
of ATC level 2 has been changed to ATC level 3. 
Listing was updated to be produced separately for prior and 
concomitant medications. 
Section 13.1 Primary Objective: 
Summary of overall response by visit has been removed. 
Subgroups analyses have been limited to confirmed objective 
response rate and done using a forest plot rather than tabulations. 
Section 13.2 Secondary Efficacy Objectives: 
Computation of 6 months rate using Kaplan-Meier estimates has 
been added for duration of response. 
Time to response endpoint has been updated to be produced only 
for responders. Corresponding analyses were updated to simple 
descriptive statistics rather than Kaplan-Meier analyses. 
Computations of 6 and 12 months rates for progression-free 
survival using Kaplan-Meier estimates have been updated to 3 and 
6 months. 
A new analysis has been added for the concordance between IRC 
review and Investigator assessment. 
Section 13.4 Anti-tumor Activity: 
Tabulations of tumor shrinkage by time point and corresponding 
mean-SE plots over time have been removed. Spider plots were 
added for tumor shrinkage data. 
Section 13.5 ECOG Performance status: 
The section was deleted as analysis of ECOG post-baseline data 
was removed. 
Section 15.2 Secondary Safety Objectives: 
Genmab - GCT1015-04                                                                   Version: 5.0
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Tabulations of adverse events collected during pre-treatment 
period was removed as they will be combined within the medical 
history summary. 
Content of summary table of TEAEs was slightly updated. 
Tabulations for TEAEs have been updated to be presented by PT 
rather than by SOC and PT. Tabulations for non-serious TEAEs was 
removed while tabulations for TEAEs with occurrence >=10%, 
TEAEs leading to drug interruption, TEAEs leading to drug 
reduction, and serious TEAEs with occurrence >=2% were added. 
The additional analyses for AESIs was limited to time to onset of 
first event (for subjects with at least one event) and time to 
resolution of each event (for events which are resolved) using 
descriptive analyses. 
The number of subjects who reported anaphylaxis was added to 
the hypersensitivity and infusion related reaction incidence table. 
The separate tabulation for deaths was removed to avoid 
duplication of the information. 
Descriptive statistics summary tables of laboratory data over time 
were removed. A new tabulation of drug induced liver 
abnormalities incidence and the corresponding listing have been 
added. 
The ophthalmology analyses were slightly updated to better 
describe the available data. A convention for pooling information 
from both eyes has been added. 
A convention for the handling of triplicates ECG measurements 
has been added. ECG categorical analyses were extended to PR 
and QRS in addition to QT/QTcF. 
All analyses for weight and vital signs have been removed. 
Definition of ADA status was updated for consistency throughout 
the document. Graphical analyses of association between ADA 
status and PK concentrations were removed. 
Listing of physical examination results was removed as no data 
collected as such. 
Section 15.3 Exploratory Objectives: 
Analyses planned for TF expression and circulating TF were 
updated to better describe the data. Analyses presented by 
quartiles were updated to by BOR. A convention for the selection 
of the baseline tumor biopsy when there are multiple records was 
added. 
New analyses for compliance and completeness of the HRQL data 
were added. 
Final version 5.0, 
OCT2019 
Major changes are described below, section by section. Additional 
minor updates were done for clarification or typos. 
 
Genmab - GCT1015-04                                                                   Version: 5.0
Approved in Vault: 11/1/2019


 
 
Confidential 
 
 
 
Page 38 of 38 
 
TPL N°: eTPL SA-02-01 
TPL Version: 02 
Of SOP SA-02.08 
TPL Effective Date: 31 Mar 2016 
 
Section 4.6 Calculated Variables: 
The definitions of dose intensity and relative dose intensity were 
slightly updated. 
Section 15.2.1 Adverse events: 
The following wording was removed: 
Those numbers will include preferred terms such as infusion-
related reaction, hypersensitivity, and anaphylaxis regardless of 
causality within 48 hours of infusion throughout the treatment 
duration. 
Section 15.3 Exploratory Objectives: 
Section numbering was updated to Section 16. 
 
Genmab - GCT1015-04                                                                   Version: 5.0
Approved in Vault: 11/1/2019