Conditions: Ovary Cancer Cervix Cancer Endometrium Cancer Bladder Cancer Prostate Cancer Esophagus Cancer Lung Cancer, Nonsmall Cell Squamous Cell Carcinoma of the Head and Neck
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 5
Healthy volunteers: no

Brief summary:
The purpose of the trial is to evaluate efficacy and safety of continued treatment with tisotumab vedotin.

Detailed description:
This is an open-label, multicenter trial to collect long-term safety and efficacy data and to provide ongoing access to tisotumab vedotin for patients with solid tumors who have completed a tisotumab vedotin base trial.

Arms:
arm 1: All patients will be administered tisotumab vedotin (HuMax-TF-ADC) in 21 day treatment cycles.

Interventions: intervention 1: Tisotumab Vedotin
Intervention descriptions: intervention 1: All patients in the trial will be administered tisotumab vedotin (HuMax-TF-ADC).

Protocol document:
Prot_000.pdf: 
Document Name: GCT1015-03 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
Confidential 
1 
PROTOCOL AND SUMMARY OF PROTOCOL 
AMENDMENTS 
A multi-center, open-label trial investigating the efficacy and 
safety of continued treatment with tisotumab vedotin in 
patients with solid tumors known to express tissue factor 
Protocol no.: 
GCT1015-03 
ClinicalTrials.gov Identifier 
NCT03245736 
Sponsor: 
Genmab A/S 
Collaborators: 
Seattle Genetics, Inc. 
EudraCT No.: 
2016-004743-37 
IND No.: 
115906 
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 
 
 


Document Name: GCT1015-03 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
Confidential 
2 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................. 2 
1 
OVERVIEW OF PROTOCOL AMENDMENTS .................................................. 3 
2 
SUMMARY OF PROTOCOL AMENDMENTS .................................................... 4 
3 
REDACTED PROTOCOL VERSION 5.0, LATEST VERSION ......................... 6 
 
 


Document Name: GCT1015-03 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
Confidential 
3 
1 OVERVIEW OF PROTOCOL AMENDMENTS 
 
Protocol Version  
Issue Date 
Final 1.0 
13 Dec 2016 
Final 2.0 (incorporating Protocol Amendment 1) 
22 Dec 2016 
Final 3.0 (incorporating Protocol Amendment 2) 
27 Jul 2017 
Final 4.0 (incorporating Protocol Amendment 3) 
30 Nov 2017 
Final 5.0 (incorporating Protocol Amendment 4) 
24 Sep 2018 
 
 


Document Name: GCT1015-03 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
Confidential 
4 
2 SUMMARY OF PROTOCOL AMENDMENTS 
This trial was initiated according to the Final Protocol 1.0 dated 13 December 2016. There were 
4 amendments to the protocol, with subsequent updated protocol versions: 
Amendment No. 
Issue Date 
Key Changes 
Amendment 1 
22 December 2016 
. One CTCAE grade 3 event of 
conjunctivitis had already been reported in the GEN702 
trial. Following the cut-off date of 31 May 2016, 
3 additional CTCAE grade 3 events of conjunctivitis and 
1 CTCAE grade 4 event of keratitis were reported with 
tisotumab vedotin. The purpose of this protocol 
amendment was to modify the dose modification and the 
mitigation plan for ocular events accordingly, including 
mandatory preventive eye therapy. 
Amendment 2 
27 July 2017 
The protocol for one of the base trials, GEN702, had been 
modified to change the treatment schedule from the 3Q4W 
administration to that in the GEN701 trial, ie, 2.0 mg/kg 
dose 1Q3W. The change was due to ocular AEs observed 
with the 3Q4W schedule and, therefore, additional 
measurements were also implemented to the Mitigation 
Plan for Ocular Adverse Events, and a requirement of 
urgent reporting of non-serious grade 2 ocular events to 
the FDA was added. These additional measurements and 
the required reporting for ocular events were also 
implemented in the GEN701 trial. In order to align with 
the base protocols GEN701 and GEN702, Protocol 
Amendment 2 was also prepared for the GCT1015-03 
trial. 
Amendment 3 
30 November 2017 
The main purpose of this Protocol Amendment 3 was to 
align with a recent amendment in one of the base 
protocols: GEN701 Protocol Amendment 14. 
During the conduct of GEN701 no clinically relevant 
bleeding events had been observed in subjects treated with 
tisotumab vedotin. As a result, the protocol was amended 
in the areas of inclusion and exclusion criteria as well as 
prohibited medication sections to allow subjects on 
anticoagulation therapy to enter the trial if all other 
inclusion and exclusion criteria were met. To maintain 
alignment with GEN701, these changes were implemented 
in this amendment for GCT1015-03.  
Based on the available safety profile for tisotumab vedotin 
at the time of the protocol amendment, a number of AESIs 
had been defined in the GEN701 Protocol Amendment 14. 
These AESIs were added accordingly in this GCT1015-03 
Amendment 3.  
Additionally, the safety section was revised to include 
reporting requirements for non-serious grade ≥3 AEs and 
non-serious grade ≥2 ocular AEs, medication errors and/or 
overdose, and pregnancies. 


Document Name: GCT1015-03 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
Confidential 
5 
Amendment No. 
Issue Date 
Key Changes 
Amendment 4 
24 September 2018 
The main purpose of this Protocol Amendment 4 was to 
include the option for an independent central radiology 
review as part of the efficacy assessments, in addition to 
the investigator assessments.  
This was considered a non-substantial amendment as it did 
not have any impact on subject safety or the scientific 
value of the trial. In addition, there was no impact on the 
ICF and the subject’s rights in relation to personal data. 
The first subject was included in this trial when Final Protocol 3.0, incorporating Protocol 
Amendment 2, dated 27 July 2017, was in effect. 
 
 


Document Name: GCT1015-03 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
Confidential 
6 
3 REDACTED PROTOCOL VERSION 5.0, LATEST VERSION 


    
 
Protocol No. GCT1015-03 
Continued treatment with tisotumab vedotin 
 
Final 5.0 (incorporating Amendment 4), 24 Sep 2018 
 
Page 1 of 65 
 
 
 
A MULTI-CENTER, OPEN-LABEL TRIAL INVESTIGATING THE EFFICACY 
AND SAFETY OF CONTINUED TREATMENT WITH TISOTUMAB VEDOTIN IN 
PATIENTS WITH SOLID TUMORS KNOWN TO EXPRESS TISSUE FACTOR 
 
 
Investigational Product: 
Tisotumab vedotin 
 
 
 
Protocol Number: 
GCT1015-03 
Trial Phase:  
II 
 
Regulatory Agency Identifying Number(s): 2016-004743-37 
 
Version and Date: 
Final 1.0, 13 December 2016 
Final 2.0 (incorporating Protocol Amendment 1), 22 December 2016 
Final 3.0 (incorporating Protocol Amendment 2), 27 Jul 2017 
Final 4.0 (incorporating Protocol Amendment 3), 30 Nov 2017 
Final 5.0 (incorporating Protocol Amendment 4), 24 Sep 2018 
 
 
Sponsor: 
 
Genmab A/S 
Kalvebod Brygge 43 
DK-1560 Copenhagen V 
Denmark 
Sponsor Medical Officer: 
 
Clinical Research Organization (CRO): 
 
 
  
 
United Kingdom 
 
 
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP) as set forth in the 
International Council for Harmonisation (ICH) guidelines on GCP (ICH E6(R2)), and applicable local 
regulatory requirements. 
 
CONFIDENTIAL 
 
 
This document is a confidential communication of Genmab A/S. Acceptance of this document constitutes agreement by 
the recipient that no unpublished information contained herein shall be published or disclosed without prior written 
approval, except that this document may be disclosed to the appropriate Institutional Review Board(s)/Independent 
Ethics Committee(s) under the condition that they keep it confidential. 


 
 
Protocol No. GCT1015-03 
Continued treatment with tisotumab vedotin 
 
Final 5.0 (incorporating Amendment 4), 24 Sep 2018 
 
 
Page 2 of 65 
SIGNATURES 
Sponsor Approval 
 
Protocol: 
GCT1015-03, Version 5.0 (24-Sep-2018) 
 
 
Protocol Title: A multi-center, open-label trial investigating the efficacy and safety of 
continued treatment with tisotumab vedotin in patients with solid tumors 
known to express tissue factor 
 
 
 
 
 
 
 
 
Vice President Medical, Genmab A/S 
Name 
 
Title 
 
 
 
 
Signature 
 
Date 
 
 


Protocol No. GCT1015-03 
Continued treatment with tisotumab vedotin 
Final 5.0 (incorporating Amendment 4), 24 Sep 2018 
Page 3 of 65 
1.
SYNOPSIS
NAME OF SPONSOR: Genmab A/S 
PROTOCOL No.: GCT1015-03 
NAME OF TRIAL TREATMENT: Tisotumab vedotin 
TITLE OF TRIAL: A multi-center, open-label trial investigating the efficacy and safety of continued 
treatment with tisotumab vedotin in patients with solid tumors known to express tissue factor 
TRIAL CENTERS: The trial will be performed in Europe and the United States of America, at the sites 
participating in the base trials. 
TRIAL PERIOD: The trial will continue until Marketing Authorization in the 
country of an individual is granted or the sponsor stops the development of 
tisotumab vedotin. 
PHASE OF 
DEVELOPMENT: 
Phase II 
PLANNED TRIAL DATES: Until Marketing Authorization or end of clinical development program. 
OBJECTIVES:  
Primary Objective: 
To collect long-term safety data from patients with solid tumors who have been treated with tisotumab vedotin 
and completed any base trial (i.e., GEN701 or GEN702) 
Secondary Objective:  
To further evaluate the anti-tumor activity of tisotumab vedotin 
TRIAL DESIGN AND METHODOLOGY: 
This is an open-label, multicenter trial to collect long-term safety and efficacy data and to provide ongoing 
access to tisotumab vedotin for patients with solid tumors who have completed a tisotumab vedotin base trial. 
Patients demonstrating clinical benefit but who have been withdrawn from the base tisotumab vedotin for 
reasons that are not considered critical and unmanageable for the safety of the patients (as evaluated by the 
investigator and/or the sponsor) can also enter this protocol. For patients who received tisotumab vedotin as a 
single-agent in the base trial, tisotumab vedotin will be given according to the dosing level and schedule 
administered in the base trial at the time of exiting. In the Treatment Phase, investigators will monitor and 
assess the patients for response to treatment and for disease progression. Any serious adverse events (SAEs) 
non-serious grade ≥ 2 ocular adverse events (AEs), non-serious grade ≥ 3 AEs, overdose and/or medication 
errors, and pregnancies should be reported to the Safety Clinical Research Organization by trial site personnel 
within 24 hours of their knowledge of the event. All (S)AEs should be reported from the time the patient has 
signed the informed consent form until the End-of-Trial (EOT) Visit, or until the patient withdraws consent or 
starts subsequent anti-cancer therapy, whichever occurs first. 
An EOT Visit will occur 30 days after the last administration of trial drug. However, if a patient is unable to 
return to the site at that time or if the patient is scheduled to start subsequent treatment, this visit should be 
performed as soon as possible after the last administration of trial drug. 
TRIAL POPULATION AND MAIN CRITERIA FOR INCLUSION/EXCLUSION:  
Patients must have completed the base trial and have not received any other anti-cancer treatment prior to 
inclusion in GCT1015-03, and they must not have experienced radiographic disease progression or clinical 
signs of symptoms of instability requiring urgent intervention. Screening laboratory samples and computerized 
tomography (CT)-scan do not need to be repeated if these were performed as part of the base trial within the 
required timeframes (21 days and four weeks, respectively, before Cycle 1 Day 1 of the current trial). 
Inclusion Criteria: 
•
Patients must have either:
a)
completed the base trial and have shown a clinical benefit of stable disease (SD) or better and have
never met any withdrawal criteria as defined in the tisotumab vedotin base protocol, or
b)
not completed treatment as defined in the base protocol for reasons that are not considered critical


 
 
Protocol No. GCT1015-03 
Continued treatment with tisotumab vedotin 
 
Final 5.0 (incorporating Amendment 4), 24 Sep 2018 
 
 
Page 4 of 65 
and unmanageable for the safety of the patient (as evaluated by the investigator and/or the sponsor) 
and the patient clearly showed response of partial response (PR) or better. 
• Patients must not have experienced radiographic disease progression or clinical signs of symptoms of 
instability requiring urgent intervention. 
• Patients must not have received any other anti-cancer treatment (including surgery, radiation or systemic 
chemotherapy) since the base trial. 
• Acceptable renal function defined as: Glomerular filtration rate (Cockcroft-Gault) > 45 mL/min. 
• Acceptable liver function defined as: alanine aminotransferase and aspartate aminotransferase ≤ 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 (hematologic support is allowed if administered at least one week before 
scheduled Cycle 1 Day 1) defined as: hemoglobin ≥ 5.6 mmol/L (~ 9 g/dL; an absolute value > 8 g/dL is 
allowed if stable [> 4 weeks] during the base trial), absolute neutrophil count ≥ 1500/µL (1.5 109/L); 
platelet count ≥ 75 109/L. 
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
• A negative serum pregnancy test (if female and aged between 18-55 years old).  
• Patients, both females and males, of reproductive potential must agree to use adequate contraception 
during and for six months after the last infusion of tisotumab vedotin. Adequate contraception for women 
is defined as hormonal birth control or an intrauterine device (safe hormonal contraceptives include 
contraceptive pills, implants, transdermal patches, hormonal vaginal devices or injections with prolonged 
release). In countries where two highly effective methods of contraception are required this will be an 
inclusion criterion. Male patients must be willing to use a latex condom during any sexual contact with 
females of childbearing potential during and for six months after the last infusion of tisotumab vedotin, 
even after having undergone a successful vasectomy. In order to be considered as sterilized or infertile, a 
patient must have undergone surgical sterilization (vasectomy/bilateral tubectomy; hysterectomy and 
bilateral ovariectomy) or be postmenopausal (12 months or more with no period prior to enrolment).  
• Following receipt of verbal and written information about the trial, patients must provide signed informed 
consent before any trial-related activity is carried out. 
• Acceptable coagulation status as defined in the applicable base protocol:   
o 
GEN701: Acceptable coagulation status: International normalized ratio (INR) ≤ 1.2 (without 
anticoagulant therapy), and activated partial thromboplastin time (aPTT) ≤ 1.25 ULN; patients on 
stable doses of therapeutic anti-coagulative treatment for ≥ 8 weeks (e.g., warfarin) must have an 
INR < 3. 
o 
GEN702: Acceptable coagulation status defined as: INR ≤ 1.2 (without anticoagulant therapy), and 
aPTT ≤ ULN. 
Exclusion Criteria:  
• Presence of CTCAE (Common Terminology Criteria for Adverse Events) grade ≥ 2 peripheral 
neuropathy. 
• Clinically significant active viral, bacterial or fungal infection requiring intravenous treatment with anti-
infective therapy that has been administered less than two weeks prior to first dose in this trial, or oral 
treatment with anti-infective therapy that has been administered less than one week prior to first dose in 
this trial; prophylactic anti-infective therapy which is given without clinical symptoms is allowed. 
• Ongoing acute or chronic inflammatory skin disease. 
• Women who are breast feeding. 
NUMBER OF SUBJECTS: Any patient who has completed the treatment period of one of the base tisotumab 
vedotin trials (e.g., GEN701, GEN702) and has shown a clinical benefit of SD or better, or not completed 
treatment as defined in the base protocol for reasons that are not considered critical and unmanageable for the 
safety of the patient and the patient clearly showed response of PR or better, and who wishes to continue 
treatment with tisotumab vedotin may participate in GCT1015-03. It is estimated that approximately 25 patients 


 
 
Protocol No. GCT1015-03 
Continued treatment with tisotumab vedotin 
 
Final 5.0 (incorporating Amendment 4), 24 Sep 2018 
 
 
Page 5 of 65 
will enter the trial. 
TRIAL TREATMENT(S): Patients will be treated with the tisotumab vedotin dosing regimen followed by the 
patient in the base trial. Preventive eye therapy should be administered in relation to infusions. Reduced dose 
can be administered in accordance with the mitigation strategies or at the discretion of the treating physician 
based on individual patient observed toxicity profile and quality of life evaluation, and after consultation and 
agreement by the Genmab Medical Officer. 
Tisotumab vedotin will be administered as an intravenous infusion on Day 1 of each 21-day cycle (once every 
three weeks [1Q3W]).  
Each patient’s dose will be calculated based on the patient’s weight (measured at first dosing visit within a 
cycle) rounded to the nearest kilogram, i.e., assigned dose in mg/kg × body weight in kg. For patients whose 
body mass index (BMI) is greater than 30 kg/m2, the investigator should use a weight that, based on the 
patient’s height, corresponds to a maximum BMI of 30. 
DURATION OF TREATMENT: Tisotumab vedotin will be administered over a minimum of 30 minutes. 
Patients will be treated with tisotumab vedotin until the investigator determines that the patient is no longer 
benefitting from treatment (i.e., disease progression or unacceptable toxicity has occurred), the trial is 
terminated by the sponsor, the patient withdraws consent, or for other reasons as defined in this protocol. 
TRIAL EVALUATIONS:  
Primary Variable:  
• Adverse events. 
Secondary Variable: 
• Objective response rate assessed by tumor shrinkage (according to the Response Evaluation Criteria In Solid 
Tumors version 1.1 [RECIST 1.1]) including change in PSA for patients with prostate cancer or CA 125 for 
patients with ovarian cancer. 
STATISTICAL METHODS: Given the low expected number of patients and the heterogeneity between 
patients entering this trial with regards to dosing regimen, indication and response to treatment in the base trial, 
no formal statistical analyses are planned. Instead, all endpoints will only be listed. All enrolled patients will be 
included in the listings. 
DATE AND VERSION: Final 4.0, 30 Nov 2017 
 


 
 
Protocol No. GCT1015-03 
Continued treatment with tisotumab vedotin 
 
Final 5.0 (incorporating Amendment 4), 24 Sep 2018 
 
 
Page 6 of 65 
2. 
TABLE OF CONTENTS 
1. 
SYNOPSIS .................................................................................................................. 3 
2. 
TABLE OF CONTENTS .......................................................................................... 6 
3. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS......................... 10 
4. 
ETHICS .................................................................................................................... 12 
4.1 
Ethics Committee ...................................................................................................... 12 
4.2 
Ethical Conduct of the Trial ...................................................................................... 12 
4.3 
Patient Information and Consent ............................................................................... 12 
5. 
INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE ............ 13 
6. 
INTRODUCTION ................................................................................................... 14 
6.1 
Background ................................................................................................................ 14 
6.2 
Benefit/Risk Assessment ........................................................................................... 15 
6.3 
Trial Rationale ........................................................................................................... 15 
6.4 
Dose Rationale ........................................................................................................... 16 
7. 
TRIAL OBJECTIVES AND ENDPOINTS .......................................................... 17 
8. 
INVESTIGATIONAL PLAN ................................................................................. 18 
8.1 
Overall Trial Design and Plan ................................................................................... 18 
8.2 
Schedule of Activities ................................................................................................ 19 
8.3 
End of Trial Definition .............................................................................................. 21 
8.4 
Number of Patients .................................................................................................... 21 
8.5 
Trial Population ......................................................................................................... 21 
8.5.1 
Inclusion Criteria ....................................................................................................... 21 
8.5.2 
Exclusion Criteria ...................................................................................................... 23 
8.5.3 
Discontinuation Criteria ............................................................................................ 23 
8.5.4 
Screen Failures .......................................................................................................... 25 
9. 
TREATMENT ......................................................................................................... 26 
9.1 
Identity of Investigational Medicinal Product ........................................................... 26 
9.2 
Treatment Administered ............................................................................................ 26 
9.3 
Preparation/Handling/Storage/Accountability ........................................................... 27 
9.3.1 
Trial Treatment Preparation ....................................................................................... 27 
9.3.2 
Trial Treatment Storage and Accountability ............................................................. 27 
9.3.3 
Trial Treatment Storage ............................................................................................. 28 
9.3.4 
Trial Treatment Accountability ................................................................................. 28 
9.4 
Treatment of Infusion-Related Reactions .................................................................. 28 
9.5 
Dose Modification ..................................................................................................... 28 
9.5.1 
Dose Modification and Mitigation Plan for Skin Toxicity ........................................ 28 
9.5.2 
Mitigation Plan for Mucositis .................................................................................... 29 


 
 
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Continued treatment with tisotumab vedotin 
 
Final 5.0 (incorporating Amendment 4), 24 Sep 2018 
 
 
Page 7 of 65 
9.5.3 
Dose Modification and Mitigation Plan for Peripheral Neuropathy and Neutropenia30 
9.5.4 
Dose Modifications and Mitigation Plan for Ocular Adverse Events ....................... 30 
9.5.5 
Dose Modification for QTcF Changes in the Electrocardiogram .............................. 34 
9.5.6 
Dose Modification for Increased Liver Enzymes ...................................................... 34 
9.5.7 
Precautions ................................................................................................................ 34 
9.6 
Prior and Concomitant Therapy ................................................................................ 34 
9.6.1 
Excluded Concomitant Medications .......................................................................... 35 
9.7 
Treatment Compliance .............................................................................................. 35 
10. 
TRIAL ASSESSMENTS ......................................................................................... 36 
10.1 
Screening Assessments .............................................................................................. 36 
10.1.1 
Demographics ............................................................................................................ 36 
10.1.2 
Medical History ......................................................................................................... 36 
10.1.3 
Height and Weight ..................................................................................................... 36 
10.1.4 
ECOG Performance Status ........................................................................................ 36 
10.1.5 
Neuropathy Assessment ............................................................................................ 36 
10.1.6 
Skin Assessments ...................................................................................................... 36 
10.1.7 
Ophthalmological Evaluation .................................................................................... 37 
10.2 
Efficacy Assessments ................................................................................................ 37 
10.3 
Safety Assessments ................................................................................................... 37 
10.3.1 
Adverse Events .......................................................................................................... 37 
10.3.2 
Vital Signs ................................................................................................................. 38 
10.3.3 
Electrocardiograms .................................................................................................... 38 
10.3.4 
Clinical Safety Laboratory Assessments ................................................................... 38 
11. 
ASSESSMENT AND REPORTING OF ADVERSE EVENTS .......................... 39 
11.1 
Definitions ................................................................................................................. 39 
11.1.1 
Adverse Event ........................................................................................................... 39 
11.1.2 
Serious Adverse Event............................................................................................... 39 
11.1.3 
Adverse Events of Special Interest ............................................................................ 39 
11.2 
Adverse Event Reporting........................................................................................... 40 
11.3 
Events Requiring Immediate Reporting .................................................................... 40 
11.3.1 
Serious Adverse Events, Non-serious Grade ≥ 3 Adverse Events, Non-serious Grade ≥ 2 
Ocular Events, Overdose and/or Medication Errors, and Pregnancies ...................... 40 
11.3.2 
Overdose and Medication Errors ............................................................................... 41 
11.3.3 
Pregnancy .................................................................................................................. 41 
11.3.4 
Suspected Unexpected Serious Adverse Reactions ................................................... 42 
11.4 
Reporting of Adverse Events after Termination of Trial Participation ..................... 42 
11.5 
Timelines for Reporting............................................................................................. 42 
11.6 
Recording Instructions ............................................................................................... 43 


 
 
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Continued treatment with tisotumab vedotin 
 
Final 5.0 (incorporating Amendment 4), 24 Sep 2018 
 
 
Page 8 of 65 
11.6.1 
Start Date and Time ................................................................................................... 43 
11.6.2 
End Date and Time .................................................................................................... 44 
11.6.3 
Diagnosis ................................................................................................................... 44 
11.6.4 
Information about Infusion-Related Reactions .......................................................... 44 
11.6.5 
Relationship to IMP ................................................................................................... 44 
11.6.6 
Serious Event ............................................................................................................. 44 
11.6.7 
Intensity ..................................................................................................................... 44 
11.6.8 
Outcome .................................................................................................................... 44 
11.6.9 
Action Taken with IMP ............................................................................................. 45 
11.7 
Follow-up on Adverse Events ................................................................................... 45 
11.8 
Safety Surveillance .................................................................................................... 45 
12. 
STATISTICAL CONSIDERATIONS ................................................................... 46 
12.1 
Sample Size Estimation ............................................................................................. 46 
12.2 
Statistical Analyses .................................................................................................... 46 
12.2.1 
Efficacy Analyses ...................................................................................................... 46 
12.2.2 
Safety Analyses ......................................................................................................... 46 
12.2.3 
Other Analyses .......................................................................................................... 46 
12.2.4 
Interim Analyses ........................................................................................................ 46 
13. 
MONITORING PROCEDURES/QUALITY ASSURANCE .............................. 47 
13.1 
Data Collection .......................................................................................................... 47 
13.2 
Data Management ...................................................................................................... 47 
13.3 
Trial Monitoring ........................................................................................................ 47 
13.4 
Inspections and Auditing Procedures ........................................................................ 48 
14. 
TRIAL MANAGEMENT AND MATERIALS..................................................... 49 
14.1 
Data Collection .......................................................................................................... 49 
14.2 
Source Documents Maintenance ............................................................................... 49 
14.3 
Record Maintenance .................................................................................................. 50 
14.4 
Confidentiality ........................................................................................................... 50 
15. 
ADMINISTRATION PROCEDURES .................................................................. 52 
15.1 
Regulatory Approval ................................................................................................. 52 
15.2 
Protocol Amendments ............................................................................................... 52 
15.3 
Protocol Adherence and Deviations .......................................................................... 52 
15.4 
Publication Policy ...................................................................................................... 53 
15.5 
Contractual and Financial Details .............................................................................. 53 
15.6 
Insurance, Indemnity and Compensation .................................................................. 53 
15.7 
Termination of the Trial ............................................................................................ 54 
15.8 
Investigator Trial File Management .......................................................................... 54 
16. 
REFERENCE LIST ................................................................................................ 55 


 
 
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Continued treatment with tisotumab vedotin 
 
Final 5.0 (incorporating Amendment 4), 24 Sep 2018 
 
 
Page 9 of 65 
17. 
APPENDICES .......................................................................................................... 57 
17.1 
Appendix 1: ECOG Performance Status Scale .......................................................... 57 
17.2 
Appendix 2: Highly Effective Methods of Contraception ......................................... 58 
17.3 
Appendix 3: Declaration of Helsinki ......................................................................... 60 
 
 
LIST OF TABLES 
Table 1: 
Trial Flow Chart - 1Q3W Treatment Scheme ...................................................... 19 
Table 2: 
Trial Treatment Details ........................................................................................ 27 
Table 3: 
Timeframes for Reporting SAEs, Non-serious Grade ≥ 2 Ocular AEs and 
Pregnancies ........................................................................................................... 43 
 
 


 
 
Protocol No. GCT1015-03 
Continued treatment with tisotumab vedotin 
 
Final 5.0 (incorporating Amendment 4), 24 Sep 2018 
 
 
Page 10 of 65 
3. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Term 
Definition 
1Q3W 
Once every 3 weeks 
ADC 
Antibody drug conjugate 
AE 
Adverse event  
AESI 
Adverse event of special interest 
aPTT 
Activated partial thromboplastin time 
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
CMV 
Cytomegalovirus  
CRO 
Clinical research organization 
CRPC 
Castration-resistant prostate cancer 
CT 
Computerized tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450  
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EOT 
End-of-Trial  
EU 
European Union 
FVII, FIX, FX 
Factor VII, factor IX, factor X 
FVIIa, FIXa, FXa 
Activated factor VII/factor IX/factor X 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation  
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
MMAE 
Monomethyl auristatin E  
NCI 
National Cancer Institute  
PAR-2 
Protease activated receptor 2 
P-gp 
P-glycoprotein 


 
 
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Continued treatment with tisotumab vedotin 
 
Final 5.0 (incorporating Amendment 4), 24 Sep 2018 
 
 
Page 11 of 65 
Term 
Definition 
PR 
Partial response 
PSA 
Prostate specific antigen 
QTcF 
QT interval as corrected by Fridericia’s formula 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SCCHN 
Squamous cell carcinoma of the head and neck 
SD 
Stable disease 
SUSAR 
Suspected unexpected serious adverse reaction 
TF 
Tissue factor 
ULN 
Upper limit of normal 
US/USA 
United States/United States of America 
WMA 
World Medical Association 


 
 
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4. 
ETHICS 
4.1 
Ethics Committee 
This trial will be conducted in compliance with independent ethics committee 
(IEC)/institutional review board (IRB) and International Council for Harmonisation (ICH) 
Good Clinical Practice (GCP) Guidelines - including Title 21 Part 56 of the United States of 
America (USA) Code of Federal Regulations (CFR) relating to IRBs and GCP as described 
in the United States Food and Drug Administration (FDA) CFR (21 CFR § 50, 56, 312), in 
accordance with applicable regulations regarding clinical safety data management (E2A, 
E2B(R3)), European Community directives 2001/20, 2001/83, 2003/94 and 2005/28 as 
enacted into local law, and with ICH guidelines regarding scientific integrity (E4, E8, E9 and 
E10). In addition, this trial will adhere to all local regulatory requirements, and requirements 
for data protection. 
Before initiating a trial, the investigator/institution must have written and dated 
approval/favorable opinion from the IEC/IRB for the trial protocol/amendment(s), written 
informed consent form (ICF), any consent form updates, patient recruitment procedures (e.g., 
advertisements), and any written information to be provided to patients and a statement from 
the IEC/IRB that they comply with GCP requirements. The IEC/IRB approval must identify 
the protocol version as well as the documents reviewed. 
4.2 
Ethical Conduct of the Trial 
This trial will be conducted in accordance with the ICH Guideline for GCP E6 (R2); FDA 
CFR (21 CFR § 50, 56, 312), Declaration of Helsinki (Fortaleza 2013) (Appendix 3) and all 
applicable regulatory requirements. 
4.3 
Patient Information and Consent 
The investigator will explain the benefits and risks of participation in the trial to each patient 
and will obtain written informed consent. Written informed consent must be obtained prior to 
the patient entering the trial and before initiation of any trial-related procedure (including 
administration of trial drug).  
The IEC/IRB-approved information and consent form that is used must be in language 
readily understood by the patient. Each patient’s original consent form, personally signed and 
dated by the patient and by the person who conducted the informed consent discussion, will 
be retained by the investigator. The investigator will supply all enrolled patients with a copy 
of their signed informed consent. 
The consent form may need to be revised during the trial, should important new information 
become available that may be relevant to the safety and procedures of the patient. In this 
instance approval should always be given by the IEC/IRB and existing patients informed of 
the changes and reconsented. This is documented in the same way as previously described. 
The investigator should, with the consent of the patient, inform the patient’s primary 
physician about participation in the clinical trial. 


 
 
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5. 
INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE 
The trial will be performed in Europe and the United States of America, at the sites 
participating in the base trials.  
No Coordinating Investigator or Data Monitoring Committee will be involved in this trial. 
Laboratory tests will be performed at the sites; no central facilities are required for this trial.  
Investigational Medicinal Product (IMP) will be supplied by 
. 
Overall trial management and clinical operations will be performed by 
. 
Serious adverse event (SAE) reporting and Pharmacovigilance will be managed by 
. 
Data management and statistical analysis will be performed by 
. 
 
Sponsor: 
Genmab A/S 
Kalvebod Brygge 43 
DK-1560 Copenhagen V 
Denmark 
 
Clinical Research Organization (CRO): 
 
  
 
United Kingdom  
 
Safety Reporting/Pharmacovigilance CRO: 
 
 
 
 
Sponsor Medical Officer: 
 
Vice President, Medical 
 
 
Sponsor Drug Safety: 
 
Vice President, Head of Drug Safety 
 
Data Management and Statistical Analysis CRO: 
 
 
 
Belgium 


 
 
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6. 
INTRODUCTION 
Tisotumab vedotin (HuMax®-TF-ADC) is an antibody drug conjugate (ADC) composed of a 
human monoclonal immunoglobulin (Ig) 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.  
6.1 
Background 
Human TF (thromboplastin, CD142 or coagulation factor III) is a 43-47 kDa, single chain, 
transmembrane glycoprotein. Tissue factor is the main initiator of the extrinsic pathway of 
blood coagulation, which starts when TF binds to serine protease factor VII (FVII) or 
activated factor VII (FVIIa). The TF:FVIIa complex initiates blood coagulation by 
proteolytic cleavage of factor X (FX) to activated factor X (FXa), and factor IX (FIX) to 
activated factor IX (FIXa), eventually leading to thrombin generation and the formation of a 
clot. In addition, the TF:FVIIa complex can initiate an intracellular signaling cascade by 
proteolytic activation of protease activated receptor 2 (PAR-2), resulting in release of pro-
angiogenic factors and pro-inflammatory mediators such as vascular endothelial growth 
factor and interleukin-8. 
Under pathological conditions, membranous TF can be aberrantly expressed. TF is present on 
neoplastic cells as well as tumor associated endothelial cells in a variety of solid cancers. 
Indications where tumor cells are known to express TF include gynecological and 
genito-urethral tumors, squamous cell carcinoma of head and neck (SCCHN), lung cancers, 
tumors in the gastrointestinal tract, breast cancer, malignant melanoma and pancreatic cancer 
(Ohta et al., 2002; Akashi et al., 2003; Khorana et al., 2007; Uno et al., 2007; Patry et al., 
2008; Yokota et al., 2009; Cocco et al., 2011). 
Expression of TF on tumor cells has been associated with negative overall survival or disease 
free survival as described in several indications, including ovarian, bladder and pancreatic 
cancer (Nitori et al., 2005; Han et al., 2006; Patry et al., 2008). Experimental studies suggest 
that tumor cells may benefit from both TF procoagulant activity and TF-induced PAR-2 
signaling, for example through enhanced metastatic potential, angiogenesis and cell survival 
(Ruf and Mueller, 1996; Kasthuri et al., 2009). Furthermore, monoclonal antibodies that 
inhibited either TF:FVIIa intracellular signaling or TF procoagulant capacity could reduce 
tumor growth in vivo (Versteeg et al., 2008). 
Constitutive TF expression is mostly restricted to sub-endothelial cells (such as pericytes, 
smooth muscle cells and fibroblasts) that only interact with blood borne FVIIa when vascular 
integrity is compromised (Drake et al., 1989). Tissue factor is expressed in the vessel walls of 
a wide range of organs, with moderate to high levels observed in the brain, heart, intestine, 
kidney, lung, placenta, uterus, and testes. The expression pattern suggests that TF provides 
additional hemostatic protection to these organs. In addition, TF expression has been 
described in epithelial cells in a number of organs including the skin, kidney and lung 
(Flössel et al., 1994; Drake et al., 1989; Imokawa et al., 1997). Under pathological, 
inflammatory conditions TF is aberrantly expressed, including but not limited to bullous 


 
 
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pemphigoid, urticaria (primarily on eosinophils, Marzano et al., 2009; Marzano et al., 2011; 
Cugno et al., 2009), inflammatory gastrointestinal diseases including Crohn’s disease and 
ulcerative colitis (More et al., 1993) and lung diseases including acute respiratory distress 
syndrome (Bastarache et al., 2007). 
Broad expression of TF was confirmed in a tissue cross reactivity trial. Binding of 
HuMax-TF-ADC was observed on e.g. epithelial cells in organs, including but not limited to 
skin, breast, lungs, gastrointestinal tract, kidney, liver and eye. Staining in glomeruli, islet 
cells in pancreas, peripheral nerves, cardiomyocytes, smooth myocytes (esophagus, stomach 
and prostate) and processes of glial cells in grey matter was also observed 
. 
Tisotumab vedotin shows excellent anti-tumor activity in vitro and in vivo. Efficient tumor 
cell killing is thought to rely on tisotumab vedotin binding to TF on the cell surface of tumor 
cells followed by rapid internalization and lysosomal processing of MMAE (GMB1015-087 
available upon request). Subsequent intracellular release of MMAE results in tumor cell 
killing by disruption of the microtubule network. In addition, MMAE can exert so called 
bystander toxicity by diffusion to neighboring tumor cells or tumor stromal cells. The 
cytotoxic effect mediated via MMAE release in target cells is believed to be the main 
mechanism of action of HuMax-TF-ADC. In vitro studies demonstrated that tisotumab 
vedotin and unconjugated HuMax-TF also induce antibody-dependent, cell-mediated 
cytotoxicity and inhibition of TF:FVIIa signaling. The contribution of these mechanisms to 
tumor cell killing remains unknown. 
For the most comprehensive nonclinical and clinical information regarding tisotumab 
vedotin, refer to the latest version of the Investigator’s Brochure for tisotumab vedotin. 
6.2 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of tisotumab vedotin can be found in the Investigator’s 
Brochure.  
6.3 
Trial Rationale 
Tisotumab vedotin is currently being developed as a treatment agent for solid tumors known 
to express TF in the GEN701 and GEN702 trials. The present trial is designed to collect 
long-term safety and certain efficacy data from patients treated with tisotumab vedotin who 
have completed one of the base trials and want to continue treatment with tisotumab vedotin. 
Patients demonstrating clinical benefit but who have been withdrawn from the base 
tisotumab vedotin trials for reasons that are not considered critical and unmanageable for the 
safety of the patient (as evaluated by the investigator and/or the sponsor) can also enter this 
protocol. The patients should have shown continued benefit from tisotumab vedotin 
treatment in the base trial. The present trial will continue until Marketing Authorization in 
the country of an individual patient is granted or the sponsor stops the development of 
tisotumab vedotin. 


 
 
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6.4 
Dose Rationale 
The patients will continue on the dose and schedule given in the relevant base trial. Reduced 
dose can be administered in accordance with the mitigation strategies (Section 9.4 to 9.5.6) 
or at the discretion of the treating physician based on individual patient observed toxicity 
profile and after consultation and agreement by the Genmab Medical Officer. 


 
 
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7. 
TRIAL OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 The primary objective of the trial is to 
collect long-term safety data from 
patients with solid tumors who have been 
treated with tisotumab vedotin and 
completed any base trial (i.e., GEN701 or 
GEN702)  
 
 Adverse events 
Secondary  
 To further evaluate the anti-tumor 
activity of tisotumab vedotin 
 
 Objective response rate assessed by 
tumor shrinkage (according to the 
Response Evaluation Criteria In Solid 
Tumors version 1.1 [RECIST 1.1]) 
including change in prostate specific 
antigen (PSA) for patients with prostate 
cancer and CA 125 for patients with 
ovarian cancer 
 


 
 
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8. 
INVESTIGATIONAL PLAN 
8.1 
Overall Trial Design and Plan 
This is an open-label, multicenter trial to collect long-term safety and efficacy data and to 
provide ongoing access to tisotumab vedotin for patients with solid tumors who have 
completed a tisotumab vedotin base trial. Patients demonstrating clinical benefit but who 
have been withdrawn from the base tisotumab vedotin trials for reasons that are not 
considered critical and unmanageable for the safety of the patient (as evaluated by the 
investigator and the sponsor) can also enter this protocol. For patients who received 
tisotumab vedotin as a single-agent in the base trial, tisotumab vedotin will be given 
according to the dosing level and schedule administered in the base trial at the time of 
exiting. Reduced dose can be administered in accordance with the mitigation strategies 
(Section 9.4 to 9.5.6) or at the discretion of the treating physician based on individual patient 
observed toxicity profile and after consultation and agreement by the Genmab Medical 
Officer. Patients will be treated with the tisotumab vedotin dosing regimen followed by the 
patient in the base trial, until the investigator determines that the patient is no longer 
benefitting from treatment (i.e., disease progression or unacceptable toxicity has occurred), 
the trial is terminated by the sponsor, the patient withdraws consent, or for other reasons as 
defined in this protocol. 
In the Treatment Phase, investigators will monitor and assess the patients for response to 
treatment and for disease progression. Timing and assessments are outlined in the Schedule 
of Activities (Table 1). Any SAEs, non-serious grade ≥ 2 ocular AEs, non-serious grade ≥ 3 
AEs, overdose and/or medication errors, and pregnancies should be reported to the Safety 
CRO by trial site personnel within 24 hours of their knowledge of the event. All (S)AEs 
should be reported from the time the patient has signed the ICF until the End-of-Trial (EOT) 
Visit, or until the patient withdraws consent or starts subsequent anti-cancer therapy, 
whichever occurs first. 
An EOT Visit will occur 30 days after the last administration of trial drug. However, if a 
patient is unable to return to the site at that time or if the patient is scheduled to start 
subsequent treatment, this visit should be performed as soon as possible after the last 
administration of trial drug.  
  


 
 
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8.2 
Schedule of Activities 
Table 1: 
Trial Flow Chart - 1Q3W Treatment Scheme 
Procedure 
Screening 
(up to 21 days 
before Day 1) 
Treatment Period 
Cycle 1 – X 
(21-day cycle ± 7 days) 
Day 1 
End-of-Trial Visit 
(30 days after last dose 
+ 1 week) 
Comments 
Informed consent  
X 
 
 
 
Eligibility criteria 
X 
 
 
 
Demography 
X 
 
 
 
Height 
X 
 
 
 
Weight 
X 
X 
 
To be taken at screening and at start of each 
treatment cycle 
Pregnancy test 
X 
X 
 
To be taken at screening and at start of each 
treatment cycle for women of childbearing potential 
Vital signs 
X 
X 
 
Blood pressure pulse, heart rate and temperature 
taken at screening and before and after treatment 
ECG 
X 
X 
 
To be taken at screening and before each treatment  
ECOG performance status 
X 
 
 
 
Neuropathy assessment 
X 
 
 
 
Skin assessment 
X 
 
 
 
Ophthalmology evaluation 
X 
X 
X 
To be performed according to the schedule in the 
base protocol. Patients experiencing ocular 
symptoms must be referred to an ophthalmologist 
for prompt review (preferably within 72 hours and 
no later than within 1 week). 
Laboratory sampling 
X 
X 
X 
Local laboratories will be used. Screening 
laboratory samples do not need to be repeated if 
performed at the base trial. Details on laboratory 
samples are provided in Section 10.3.4. 


 
 
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Procedure 
Screening 
(up to 21 days 
before Day 1) 
Treatment Period 
Cycle 1 – X 
(21-day cycle ± 7 days) 
Day 1 
End-of-Trial Visit 
(30 days after last dose 
+ 1 week) 
Comments 
Trial drug administration 
 
X 
 
Treatment administration schedule to follow the 
treatment schedule in the base protocol. 
Preventive eye therapy 
 
X 
 
Preventive eye therapy to be administered in 
relation to infusions as detailed in Section 9.5.4. 
Response assessment 
(CT-scan, PSA, CA 125)  
X 
X 
X 
Last CT-scan of base trial to be used at screening if 
less than 4 weeks old, otherwise a new CT-scan 
needs to be obtained. Then, to be performed every 
6 weeks (at the end of every second cycle) during 
Treatment Period, and response to be confirmed 
4 weeks later.  
Response assessments will be recorded in the 
eCRF. 
PSA will be performed for CRPC patients. 
CA 125 will be performed for patients with ovarian 
cancer. 
Radionuclide bone scan 
 
X 
 
For patients with CRPC, assessment of bone 
metastases by radionuclide bone scan every 
12 weeks is recommended, but frequency should be 
based on local standards. If there is suspicion of 
progression, another bone scan will be performed 
twelve weeks later. 
AE/SAE review 
X 
X 
X 
 
Concomitant medication  
X 
X 
X 
   
1Q3W=once every 3 weeks; AE=adverse event; CT=computerized tomography; CRPC=castration-resistant prostate cancer; ECG=electrocardiogram; 
ECOG=Eastern Cooperative Oncology Group; eCRF=electronic case report form; PSA=prostate specific antigen; SAE=serious adverse event 


 
 
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8.3 
End of Trial Definition 
The trial is considered completed when tisotumab vedotin has been granted Marketing 
Authorization in the specific country and the last patient has been transferred to an approved 
treatment or sponsor stops the development of tisotumab vedotin. 
8.4 
Number of Patients 
Any patient who has completed the treatment period of one of the base tisotumab vedotin 
trials (e.g., GEN701,  GEN702) and has shown a clinical benefit of stable disease (SD) or 
better, or not completed treatment as defined in the base protocol for reasons that are not 
considered critical and unmanageable for the safety of the patient and the patient clearly 
showed response of partial response (PR) or better, and who wishes to continue treatment 
with tisotumab vedotin and fulfills the enrolment (inclusion and exclusion) criteria can 
participate in this trial. It is estimated that approximately 25 patients will enter the GCT1015-
03 trial. 
8.5 
Trial Population 
Eligibility in GCT1015-03 requires that patients must have completed the base trial and have 
not received any other anti-cancer treatment prior to inclusion in the current trial, and they 
must not have experienced radiographic disease progression or clinical signs of symptoms of 
instability requiring urgent intervention. Screening laboratory samples and computerized 
tomography (CT)-scan do not need to be repeated if these were performed as part of the base 
trial within the required timeframes (21 days and four weeks, respectively, before Cycle 1 
Day 1 of the current trial). Prospective approval of protocol deviations to recruitment and 
enrolment criteria, also known as protocol waivers or exemptions, are not permitted.  
The inclusion and exclusion criteria for enrolling patients in GCT1015-03 are described 
below. If there is a question about the inclusion or exclusion criteria below, the investigator 
should consult with the appropriate sponsor representative before enrolling a patient in the 
trial. 
8.5.1 Inclusion Criteria 
Patients MUST satisfy all of the following entry criteria before they will be allowed to 
participate in the trial: 
1. Patients must have either: 
a) completed the base trial and have shown a clinical benefit of SD or better and have 
never met any withdrawal criteria as defined in the tisotumab vedotin base protocol, 
or 
b) not completed treatment as defined in the base protocol for reasons that are not 
considered critical and unmanageable for the safety of the patient (as evaluated by the 
investigator and/or the sponsor) and the patient clearly showed response of PR or 
better. 


 
 
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2. Patients must not have experienced radiographic disease progression or clinical signs of 
symptoms of instability requiring urgent intervention. 
3. Patients must not have received any other anti-cancer treatment (including surgery, 
radiation or systemic chemotherapy) since the base trial. 
4. Acceptable renal function defined as: Glomerular filtration rate (Cockcroft-Gault) 
> 45 mL/min. 
5. Acceptable liver function defined as: 
a) Alanine aminotransferase and aspartate aminotransferase ≤ 3 times the upper limit of 
normal (ULN); if liver tumor/metastases are present, then ≤ 5 × ULN is allowed, 
b) Bilirubin ≤ 1.5 × ULN, except in patients diagnosed with Gilbert’s syndrome, direct 
bilirubin ≤ 2 × ULN. 
6. Acceptable hematological status (hematologic support is allowed if administered at least 
one week before scheduled Cycle 1 Day 1) defined as: 
a) Hemoglobin ≥ 5.6 mmol/L (~ 9 g/dL). An absolute value > 8 g/dL is allowed if stable 
(> 4 weeks) during the base trial. 
b) Absolute neutrophil count ≥ 1500/µL (1.5 ×109/L). 
c) Platelet count ≥ 75 × 109/L. 
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
8. A negative serum pregnancy test (if female and aged between 18-55 years old). 
9. Patients, both females and males, of reproductive potential must agree to use adequate 
contraception during and for six months after the last infusion of tisotumab vedotin.  
a) Adequate contraception for women is defined as hormonal birth control or an 
intrauterine device (safe hormonal contraceptives include contraceptive pills, 
implants, transdermal patches, hormonal vaginal devices or injections with prolonged 
release). In countries where two highly effective methods of contraception are 
required this will be an inclusion criterion (refer to Appendix 2). 
b) Male patients must be willing to use a latex condom during any sexual contact with 
females of childbearing potential during and for six months after the last infusion of 
tisotumab vedotin, even after having undergone a successful vasectomy.  
c) In order to be considered as sterilized or infertile, a patient must have undergone 
surgical sterilization (vasectomy/bilateral tubectomy; hysterectomy and bilateral 
ovariectomy) or be postmenopausal (12 months or more with no period prior to 
enrolment). 


 
 
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10. Following receipt of verbal and written information about the trial, patients must provide 
signed informed consent before any trial-related activity is carried out. 
11. Acceptable coagulation status as defined in the applicable base protocol: 
 GEN701: Acceptable coagulation status: international normalized ratio (INR) 
≤ 1.2 (without anticoagulant therapy) and activated partial thromboplastin time 
(aPTT) ≤ 1.25 ULN; patients on stable doses of therapeutic anti-coagulative 
treatment for ≥ 8 weeks (e.g., warfarin) must have an INR < 3. 
 GEN702: Acceptable coagulation status defined as: INR ≤ 1.2 (without 
anticoagulant therapy) and aPTT ≤ ULN. 
8.5.2 Exclusion Criteria 
If any of the following apply, the patient MUST NOT enter the trial: 
1. (Exclusion criterion removed in Amendment 3) 
2. Presence of CTCAE (Common Terminology Criteria for Adverse Events) grade ≥ 2 
peripheral neuropathy. 
3. Clinically significant active viral, bacterial or fungal infection requiring: 
o Intravenous treatment with anti-infective therapy that has been administered less 
than two weeks prior to first dose in this trial, or 
o Oral treatment with anti-infective therapy that has been administered less than one 
week prior to first dose in this trial. 
o Prophylactic anti-infective therapy, which is given without clinical symptoms is 
allowed. 
4. Ongoing acute or chronic inflammatory skin disease. 
5. Women who are breast feeding. 
Pregnant women must not take part in this trial and will be considered as screening 
failures.  
8.5.3 Discontinuation Criteria  
8.5.3.1 
Discontinuation of Trial Treatment  
A patient’s trial treatment should be discontinued if:  
 The investigator believes that for safety reasons (e.g., unacceptable toxicity) it is in the 
best interest of the patient to discontinue trial treatment.  
 Any unacceptable toxicities as defined in Section 9.5.  
 The patient becomes pregnant.  
 Disease progression.  


 
 
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 The patient (or the patient’s representative) withdraws consent for administration of trial 
drug.  
 The patient is unable to adhere to the trial visit schedule or comply with protocol 
requirements.  
 The patient received concurrent (non-protocol) anti-cancer therapy or any other 
investigational agent.  
 The patient receives exclusionary medication as described in Section 9.6.1.  
8.5.3.2 
Discontinuation from the Trial  
The sponsor will make every effort to ensure patients are followed up for completion of 
safety assessment in the trial. Patients will be withdrawn from the trial for the following 
reasons:  
 Trial medication is withdrawn  
 Withdrawal of consent  
 Lost to follow-up  
 Death  
 Sponsor terminates the trial  
If a patient withdraws from the trial, an EOT Visit should be performed, preferably 30 days 
after last treatment.  
When a patient withdraws consent for trial participation before completing the trial, the 
reason for withdrawal is to be documented in the electronic case report form (eCRF) and in 
the source document.  
8.5.3.3 
Lost to Follow-Up  
A patient will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the trial site.  
The following actions must be taken if a patient fails to return to the clinic for a required trial 
visit:  
 The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the patient wishes to and/or should continue in the 
trial.  
 In cases in which the patient is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the patient (where possible, three telephone 
calls and, if necessary, a certified letter to the patient’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the patient’s 
medical record.  


 
 
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8.5.4 Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical trial but are 
not subsequently entered in the trial. Only information about demography, reason for screen 
failure including eligibility criteria not met, and any SAEs will be collected. 


 
 
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9. 
TREATMENT 
9.1 
Identity of Investigational Medicinal Product 
Tisotumab vedotin is presented as a lyophilized powder for reconstitution in water for 
injection and is intended for dosing by the intravenous route by infusion after dilution in 
physiological saline solution.  
The final composition of the drug product after reconstitution is 10 mg/mL tisotumab vedotin 
formulated in a mixture of histidine, sucrose and mannitol at pH 6.0. 
9.2 
Treatment Administered 
The investigator must ensure that the trial drug will be used only in accordance with the 
protocol. 
Tisotumab vedotin will be administered as an intravenous infusion on Day 1 of each 21-day 
cycle (once every three weeks [1Q3W]).  
Each patient’s dose will be calculated based on the patient’s weight (measured at first dosing 
visit within a cycle) rounded to the nearest kilogram, i.e., assigned dose in mg/kg × body 
weight in kg. For patients whose body mass index (BMI) is greater than 30 kg/m2, the 
investigator should use a weight that, based on the patient’s height, corresponds to a 
maximum BMI of 30. 
The dose is calculated according to the following formula if BMI is greater than 30 kg/m2: 
Dose (mg) = x (mg/kg) * 30 (kg/m2) * height (m) * height (m) 
Tisotumab vedotin will be administered over a minimum of 30 minutes. If infusion-related 
events emerge, refer to Section 9.4. The infusion is complete when the infusion line has been 
flushed with a minimum 15 mL saline. Preventive eye therapy should be administered in 
relation to infusions as detailed in Section 9.5.4. 


 
 
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Table 2: 
Trial Treatment Details 
 
1Q3W Treatment Scheme 
Trial Treatment Name: 
Tisotumab vedotin 
Dosage Formulation: 
Vials containing tisotumab vedotin as lyophilized powder for 
reconstitution 
Unit Dose Strength(s)/ 
Dosage Level(s): 
Each vial contains 40 mg of tisotumab vedotin as lyophilized powder 
to be reconstituted with 4 mL water for injection leading to a 10 
mg/mL solution. 
Route of Administration: 
Intravenous infusion 
Dosing Instructions: 
2.0 mg/kg or if dose reduced continue the same dose as in base 
protocol. If patient toxicity profile warrants reduced dose, this can be 
introduced (see Section 9.5) 
Packaging and Labeling: 
Trial treatment will be provided in boxes containing 4 vials each. 
Each box/vial will be labeled as required per country requirement 
with multi-language labels. 
Each vial will have a unique vial ID number. 
1Q3W=once every 3 weeks 
 
9.3 
Preparation/Handling/Storage/Accountability  
9.3.1 Trial Treatment Preparation  
The dose of tisotumab vedotin for administration must be prepared by the site pharmacy 
using aseptic technique. Tisotumab vedotin will be supplied to the site pharmacy as bulk 
supply cartons.  
The reconstituted tisotumab vedotin should be diluted into a 0.9% NaCl 100 mL infusion bag 
according to the dose assigned to the patient.  
The infusion must be completed within 24 hours after the tisotumab vedotin vials have been 
reconstituted. An 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.  
Please refer to the Preparation and Administration of Tisotumab Vedotin (HuMax-TF-ADC) 
/ IMP Manual for instructions on storage, preparation and infusion. 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.  
9.3.2 Trial Treatment Storage and Accountability  
It is forbidden to use investigational trial drug material for purposes other than as defined in 
this protocol.  


 
 
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9.3.3 Trial Treatment Storage  
Tisotumab vedotin will be stored at 2-8°C in a secure area with restricted access.  
9.3.4 Trial Treatment Accountability  
The trial drug must exclusively be used for the investigation specified in this protocol and it 
will only be accessible to authorized staff. The investigator or designee must confirm and 
document the receipt of the trial drug.  
The IMP vials must be kept at the pharmacy. Throughout the trial, all used and unused 
material will be accounted for on vial ID level in the eCRF. Documented destruction of drugs 
and containers should be coordinated at the clinical site. 
9.4 
Treatment of Infusion-Related Reactions 
Patients should be monitored during infusion. 
 If an infusion-related reaction occurs, the infusion should be interrupted and appropriate 
medical management instituted. The infusions may be restarted at the investigator’s 
discretion. 
 Patients who have experienced prior infusion-related CTCAE grade ≥ 3 reactions in the 
trial should be pre-medicated before all subsequent infusions with an antihistamine 
and/or acetaminophen and/or corticosteroid at the investigator’s discretion.  
 If anaphylaxis occurs, administration of trial drug should be discontinued immediately 
and permanently, and appropriate medical therapy should be administered. 
9.5 
Dose Modification  
Reduced dose can be administered at the discretion of the treating physician based on 
individual patient observed toxicity profile and after consultation and agreement by Sponsor 
Medical Officer. 
9.5.1 Dose Modification and Mitigation Plan for Skin Toxicity 
 Patients’ information will include information about potential skin toxicity. 
 Investigators will be trained in skin monitoring and action to findings. Patients should be 
referred to a dermatologist as deemed relevant. 


 
 
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Skin toxicity should be handled according to the following instructions (based on CTCAE 
grading): 
Macular-papular skin rash grade 1 
Continue dosing of tisotumab vedotin as planned, treat 
with a potent topical steroid (betamethasone valerate or 
equivalent) once daily for up to one week, facial areas 
with a moderate topical steroid (hydrocortisone 
butyrate 0.1% or equivalent) twice daily for up to one 
week; thereafter, every other day for a maximum of 
three weeks. 
Macular-papular skin rash grade 2 
Postpone dosing of tisotumab vedotin until skin rash 
has decreased to grade 1, then continue dosing of 
tisotumab vedotin as planned. Treat the skin rash with a 
potent topical steroid (betamethasone valerate or 
equivalent) once daily for up to one week; facial areas 
with a moderate topical steroid (hydrocortisone 
butyrate 0.1% or equivalent) twice daily, followed by 
dosing once every other day for a maximum of three 
weeks. 
Macular-papular skin rash 
grade ≥ 3 
Stop dosing (patient withdrawal), and treat the skin 
rash with a potent topical steroid (betamethasone 
valerate or equivalent) once daily for up to one week, 
followed by dosing once every other day for a 
maximum of three weeks. 
Macular-papular skin rash 
grade ≥ 3 (covering ≥ 30% of body 
surface area) 
Withdraw patient permanently 
Toxic Epidermal Necrolysis, 
Steven Johnson and cutaneous 
vasculitis grade ≥ 3 
Withdraw patient permanently 
Treatment-related bullous 
dermatitis grade 1 or skin bullae 
(blister) ≥ 0.5 cm 
Withdraw patient permanently 
 
9.5.2 Mitigation Plan for Mucositis 
 Patients with CTCAE grade 3 mucositis: hold dosing until mucositis improves to grade 2 
and treat according to local practice. 
 Withdrawal criteria for mucositis: 
o Patients with CTCAE grade ≥ 4 mucositis: the patient should be withdrawn from 
treatment. 


 
 
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9.5.3 Dose Modification and Mitigation Plan for Peripheral Neuropathy and 
Neutropenia  
Peripheral neuropathy should be managed using a combination of dose delay and 
reduction, and should be managed according to the following instructions (based on 
CTCAE grading): 
New or worsening grade 2 or 3 
neuropathy 
Hold dose until neuropathy improves to grade ≤ 1, and 
then restart at 2/3 of the initial dose until end of trial 
treatment. 
Peripheral neuropathy grade 4   
Stop dosing, and the patient should be withdrawn from 
treatment. 
Neutropenia should be managed by dose delays and dose reductions (based on CTCAE 
grading) 
Neutropenia grade 3 or 4 
Dosing should be held for grade 3 or 4 neutropenia 
until resolution to grade ≤ 2 
Growth factor support should be considered for 
subsequent cycles   
Recurrent neutropenia grade 4 
despite the use of growth factors 
Discontinuation or dose reduction of trial drug to 2/3 of 
the initial dose until end of trial treatment may be 
considered after discussion with the Genmab Medical 
Officer 
 
9.5.4 Dose Modifications and Mitigation Plan for Ocular Adverse Events 
Events of conjunctivitis and keratitis have been reported in patients treated with tisotumab 
vedotin. To prevent occurrence and ensure appropriate handling, events should be prevented 
and managed as described below. 
Ocular toxicity mitigation plan 


 
 
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Ocular toxicity mitigation plan 
Preventive measures for all patients: 
 Use of preservative-free lubricating eye drops from the start of trial treatment until the end 
of treatment. 
 Avoid use of contact lenses while treated with tisotumab vedotin. 
 Use of refrigerator-based eye cooling pads during infusion, e.g. THERA PEARL Eye 
Mask or similar. To be applied immediately before infusion in accordance with the 
instructions provided with the eye cooling pads. 
 Administration of local ocular vasoconstrictor before infusion (brimonidine tartrate 
0.2% eye drops or similar, 3 drops in each eye immediately prior to start of infusion; 
otherwise to be used in accordance with the product prescribing information). 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 Genmab Medical Officer. 
 Application of steroid eye drops for 3 days from the day of infusion (dexamethasone 
0.1% eye drops or equivalent, 1 drop in each eye 3 times daily for 3 days [first drop to be 
given before start of infusion], otherwise to be used in accordance with the product 
prescribing information). 
 
Grading: All ocular events of should be graded according to both: 
 Ophthalmological grading based on the objective eye-examination findings performed by 
the ophthalmologist. 
 CTCAE grading system based on National Cancer Institute (NCI) CTCAE version 4.03 
(NCI-CTCAE v4.03, 2010) assessed by the investigator. 
Conjunctivitis should be handled according to the following instructions (based on 
CTCAE grading) 
Conjunctivitis grade 1 
Hold dosing until the event is managed effectively 
by topical treatment initiated by the ophthalmologist 
(according to treatment guidelines below). When the 
event is managed effectively the patient can be 
re-treated with the same dose of trial drug as being 
administered prior to the event onset. 
First occurrence of conjunctivitis 
grade 2 
Hold dosing. Topical treatment should be initiated by 
the ophthalmologist (according to treatment guidelines 
below). When the event has improved to grade ≤ 1, 
dosing of trial drug can be resumed at a reduced dose 
(please refer to dose modification scheme below). 
Second occurrence of conjunctivitis 
grade 2 
Hold dosing and topical treatment should be initiated 
by the ophthalmologist (according to treatment 
guidelines below). When the event is grade ≤ 1, dosing 
of trial drug can be resumed at a further reduced dose 


 
 
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Ocular toxicity mitigation plan 
(please refer to dose modification scheme below). 
> 3rd occurrence of conjunctivitis 
grade 2 
Hold dosing and topical treatment should be initiated 
by the ophthalmologist (according to treatment 
guidelines below). When the event is grade ≤ 1, dosing 
of trial drug should not be further reduced but resumed 
at 0.9 mg/kg. 
First occurrence of conjunctivitis 
grade ≥ 3  
Hold dosing. Topical treatment should be initiated by 
the ophthalmologist (according to treatment guidelines 
below). When the event has improved to grade ≤ 1, 
dosing of trial drug can be resumed at a reduced dose 
(please refer to dose modification scheme below). 
Second occurrence of 
conjunctivitis grade ≥ 3 (despite 
dose reduction) 
Permanently discontinue treatment with trial drug. 
> 2nd occurrence of conjunctivitis 
grade > 3  
Permanently discontinue treatment with trial drug. 
Keratitis should be handled according to the following instructions (based on CTCAE 
grading) 
First occurrence of keratitis 
grade ≤ 2 
 
Hold dosing until the event is managed effectively by 
topical treatment (according to treatment guidelines 
below) initiated by the ophthalmologist. When the 
event is ≤ grade 1, dosing of trial drug can be resumed 
at a reduced dose (please refer to dose modification 
scheme below). 
Second occurrence of keratitis 
grade ≤ 2 
 
 
Hold dosing and topical treatment (according to 
treatment guidelines below) should be initiated by the 
ophthalmologist. When the event is grade ≤ 1, dosing 
of trial drug can be resumed at a further reduced dose 
(please refer to dose modification scheme below). 
Third occurrence of keratitis 
grade ≤ 2 (despite dose reductions)  
Permanently discontinue treatment with trial drug. 
Keratitis grade ≥ 3 
Permanently discontinue treatment with trial drug. 
Conjunctival ulceration should be handled according to the following instructions (based 
on CTCAE grading) 
If an ophthalmological evaluation 
reveals fluorescent patches or 
conjunctival ulceration of any 
grade 
 
Hold dose until conjunctivitis/conjunctival ulceration is 
managed effectively by topical treatment (according to 
treatment guidelines below). When the event is 
managed effectively, dosing of trial drug can be 
resumed at a reduced dose (please refer to dose 


 
 
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Ocular toxicity mitigation plan 
modification scheme below). 
If symptoms do not stabilize/improve after dose 
reduction, the patient must permanently discontinue 
treatment with trial drug. 
Other Eye Toxicity should be handled according to the following instructions (based on 
CTCAE grading) 
Ophthalmological evaluation 
reveals conjunctival/corneal 
scarring 
Permanently discontinue treatment with trial drug. 
Any grade of symblepharon 
Permanently discontinue treatment with trial drug. 
Any dose delay related to ocular 
toxicity exceeding 12 weeks  
Permanently discontinue treatment with trial drug 
following discussion with the Genmab Medical Officer. 
 
Treatment guidelines  
Ocular symptom  
Treatment guideline  
(The length of treatment should be decided by the local 
ophthalmologist) 
Conjunctivitis: CTCAE grade 1 
The local ophthalmologist should prescribe frequent 
dosing of preservative-free topical steroid drops 
Conjunctivitis: CTCAE grade 2 
The local ophthalmologist should prescribe frequent 
dosing (every 2nd hour) of preservative-free topical 
steroid drops in conjunction with preservative-free 
antibiotic prophylaxis such as chloramphenicol 
Conjunctivitis: CTCAE grade 3 
The local ophthalmologist should prescribe frequent 
dosing (every 2nd hour) of preservative-free topical 
steroid drops in conjunction with preservative-free 
antibiotic prophylaxis such as chloramphenicol 
Keratitis: CTCAE grade 1 
The local ophthalmologist should prescribe frequent 
dosing of preservative-free topical steroid drops 
Keratitis: CTCAE grade 2 
The local ophthalmologist should prescribe frequent 
dosing (every 2nd hour) of preservative-free topical 
steroid drops in conjunction with preservative-free 
antibiotic prophylaxis such as chloramphenicol 
Conjunctival ulceration: any grade 
The local ophthalmologist should prescribe frequent 
dosing (every 2nd hour) of preservative-free topical 
steroid drops in conjunction with preservative-free 
antibiotic prophylaxis such as chloramphenicol 
 
Dose modification scheme: 
Previous dose of tisotumab vedotin 
Reduced dose of tisotumab vedotin 


 
 
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2.0 mg/kg 
1.3 mg/kg 
1.3 mg/kg 
0.9 mg/kg 
0.9 mg/kg 
0.9 mg/kg* 
*If the patient is already being treated with tisotumab vedotin (HuMax-TF-ADC) 0.9 mg/kg every 
3rd week, the dose of tisotumab vedotin (HuMax-TF-ADC) should not be reduced further. 
 
9.5.5 Dose Modification for QTcF Changes in the Electrocardiogram 
Prolongation of QTcF interval during the trial should be managed as follows: 
 For CTCAE grade 1 QTcF interval prolongation (450 to 480 msec): check electrolytes 
(calcium, magnesium and potassium) prior to next dosing, but no dose adjustment or 
dosing hold is required. 
 For CTCAE grade 2 QTcF interval prolongation (481 to 500 msec): hold dosing until 
improvement to grade 1 or lower and check electrolytes (calcium, magnesium and 
potassium) and substitute until normal levels; then dose can be restarted and 
electrocardiograms (ECGs) should be performed at least every other day.  
If the QTcF interval prolongation is not related to electrolyte abnormality, hold dosing until 
improvement to grade 1 or lower; then next infusions may be restarted at half of the initial 
infusion rate; ECGs should be performed at least every other day. 
 For CTCAE grade 3 QTcF interval prolongation (≥ 501 msec on at least two separate 
ECGs): stop dosing. Then, check electrolytes (calcium, magnesium and potassium) and 
substitute until normal levels; ECGs should be performed at least daily; consider 
obtaining cardiology consult. 
9.5.6 Dose Modification for Increased Liver Enzymes 
In case of CTCAE grade ≥ 3 liver enzymes increase is not resolved (decreased to grade 2 or 
lower) at time of dosing, the site must contact Genmab Medical Officer before the next 
dosing of the patient, in order to decide whether there should be any dose adjustment, delay 
or withdrawal of the patient. 
9.5.7 Precautions  
Patients receiving the following therapy three weeks after the last treatment with tisotumab 
vedotin should be monitored closely for adverse reactions:  
 Drugs and substances known to be strong cytochrome P450 3A4 (CYP3A4) and 
P-glycoprotein (P-gp) inhibitors (e.g., amiodarone, boceprevir, clarithromycin, 
conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, 
verapamil, voriconazole) should not be administered during the trial period.  
9.6 
Prior and Concomitant Therapy 
Any medication or therapy other than tisotumab vedotin is considered concomitant 
medication and should be recorded in the eCRF with the following information:  


 
 
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 Start date  
 Route of administration  
 Stop date of administration or ongoing at trial termination  
 Indication/reason for use 
 The total daily dose should be filled in whenever possible 
Prior concomitant medication includes that given within one month prior to screening. 
Concomitant medication includes medication given from the Screening Visit until 30 days 
after the last dose of tisotumab vedotin, or until the patient withdraws consent or starts 
subsequent anti-cancer therapy, whichever occurs first.  
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as “excluded” (see 
Section 9.6.1).  
Patients must be instructed not to take any medications, including over-the-counter products, 
without first consulting the investigator.  
Concomitant medication which is ongoing at end of trial of the base protocol should be 
entered again at the time of signing informed consent (start date should be the original start 
date). 
9.6.1 Excluded Concomitant Medications 
The following medications are considered exclusionary during the trial. The sponsor must be 
notified if a patient receives any of these during the trial.  
 Any investigational anti-cancer therapy.  
 Drugs and substances known to be strong CYP3A4 and/or P-gp inhibitors (e.g., 
amiodarone, boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, 
itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, 
posaconazole, saquinavir, telaprevir, telithromycin, verapamil, voriconazole) should not 
be administered during the trial period.  
 Dietary supplements are allowed during the trial period, except when known to be strong 
CYP3A4 inhibitors as judged by treating physician. 
9.7 
Treatment Compliance 
Tisotumab vedotin will be administered by trial site personnel, who will monitor patient 
compliance. 


 
 
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10. 
TRIAL ASSESSMENTS 
Trial procedures will be performed as outlined in the Schedule of Activities (Table 1). A 
description of the different assessments is provided below.  
10.1 
Screening Assessments 
All screening procedures must be performed within 21 days before the first dose of tisotumab 
vedotin in the GCT1015-03 trial, except for the CT-scan that may be performed within 
four weeks. Screening laboratory samples and CT-scan do not need to be repeated if these 
were performed as part of the base trial within the required timeframes for the current trial. 
Magnetic resonance imaging can be performed instead of a CT-scan if used in the base trial. 
The screening evaluations may be carried out over more than one visit. Written informed 
consent and any locally required privacy act document authorization must be obtained prior 
to performing any protocol-specific procedures, including screening evaluations.  
10.1.1 
Demographics 
Date of birth (day and month will be anonymized if required by local regulations); ethnicity, 
race and gender will be recorded in the eCRF. 
10.1.2 
Medical History 
The Medical History recorded in the applicable base protocol will be the Medical History in 
this trial as well, i.e., no new Medical History will be collected.  
10.1.3 
Height and Weight 
Height (without shoes) must be measured at screening and recorded in the eCRF rounded to 
nearest centimeter. Body weight (without overcoat and shoes) will be measured at screening 
and at first treatment visit within a treatment cycle, and will be recorded in the eCRF rounded 
to nearest kilogram. If body weight is assessed seven days or less before the day of the 
planned dosing at Day 1, this value can be used. 
10.1.4 
ECOG Performance Status 
The ECOG performance status scale (Appendix 1) will be used and will be assessed by the 
investigator at screening. 
10.1.5 
Neuropathy Assessment 
A standard scheme for assessment of peripheral neuropathy will be used at screening. 
Patients should not be included in this trial if they have CTCAE grade ≥ 2 peripheral 
neuropathy. 
10.1.6 
Skin Assessments 
Development of skin reactions at the end of the base trial will be assessed at screening of the 
GCT1015-03 trial. Patients should not be included in this trial if they have ongoing acute or 
chronic inflammatory skin disease.  


 
 
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10.1.7 
Ophthalmological Evaluation  
Ophthalmological evaluations should be performed at screening and during the trial as 
indicated in the trial flow chart.  
The ophthalmological evaluation should include collection of medical ophthalmological 
history (at screening only), visual acuity assessment, Shirmer’s test, slit-lamp examination, 
measurement of ocular pressure and funduscopic.  
Patients experiencing ocular symptoms during the trial must be referred to an 
ophthalmologist for prompt review (preferably within 72 hours and no later than within 
one week). 
10.2 
Efficacy Assessments 
Investigator assessment of disease control, by CT-scan, will be collected during screening, 
and during the Treatment Period until disease progression or the EOT Visit, whichever 
occurs first. At screening, the last CT-scan of the base protocol may be used if it is performed 
less than four weeks before Cycle 1 Day 1 of the current trial. Assessments every six weeks 
(at the end of every second cycle), which are consistent with the schedule for standard of 
care, are recommended (however, based on local standards, disease monitoring can also be as 
frequent as every four weeks or as infrequent as every 12 weeks). Disease response or 
progression should be evaluated by the investigator according to the current published 
RECIST 1.1 (Eisenhauer et al., 2009) and recorded in the eCRF. Scans may also be sent for 
an independent, central imaging review. If reduction of target lesions ≥ 30% in size is 
observed, a repeat CT-scan will be performed after four weeks to confirm the response. In 
the case of SD, measurements must have met the SD criteria at least once after study entry at 
a minimum interval (in general not less than six weeks) that is defined in the study protocol. 
Patients with prostate cancer must be clinically refractory and resistant to hormone therapy 
(castration-resistant prostate cancer [CRPC]) as documented by progression, and can be 
evaluated based on PSA and/or bone metastases according to the Prostate Cancer Working 
Group Guideline (Scher et al., 2008). Assessment of bone metastases by radionuclide bone 
scan every 12 weeks is recommended, but frequency should be based on local standards. If 
there is suspicion of progression, another bone scan will be performed twelve weeks later. 
Patients with prostate cancer will be evaluated according to RECIST 1.1 in combination with 
PSA. 
For patients with ovarian cancer, blood samples for CA 125 assessment will be drawn for 
local analysis. Patients with ovarian cancer will be evaluated according to RECIST 1.1 in 
combination with CA 125. 
10.3 
Safety Assessments 
10.3.1 
Adverse Events 
Adverse events will be assessed and reported at each visit. Adverse events will be graded 
according to the NCI-CTCAE version 4.03 (NCI-CTCAE v4.03, 2010). 
Details on AEs monitoring and reporting are provided in Section 11. 


 
 
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10.3.2 
Vital Signs 
Vital signs including temperature, blood pressure and heart rate should be recorded at each 
visit. Within each visit, preferably the same equipment shall be used for vital signs 
measurements. Vital signs should be assessed just before and no longer than 30 minutes 
before infusion start, and within 30 minutes after the infusions.  
10.3.3 
Electrocardiograms  
Single 12-lead ECG will be obtained as outlined in the Schedule of Activities (Table 1) using 
a local ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals. ECG results will not be recorded in the eCRF except for clinically 
significant results that must be reported as an AE.  
10.3.4 
Clinical Safety Laboratory Assessments  
Laboratory tests should be collected as outlined in the Schedule of Activities (Table 1) and 
assessed in accordance with local standards. Screening laboratory samples do not need to be 
repeated if these were performed as part of the base trial within 21 days before Cycle 1 Day 1 
of the current trial. Laboratory results will not be recorded in the eCRF except for clinically 
significant results that must be reported as an AE. If a laboratory result is deemed to be an 
AE, this should be reported in the eCRF including the laboratory value and the relevant 
reference range. Retesting is required only if clinical symptoms appear. 
A blood sample for pregnancy test will be drawn at the Screening Visit and at the start of 
each treatment cycle from all women of childbearing potential. 
The following safety laboratory tests should be collected: 
Hematology 
Erythrocytes, hemoglobin, hematocrit, leukocytes, neutrophils, lymphocytes, monocytes, 
eosinophils, basophils, neutrophils (absolute), lymphocytes (absolute), monocytes (absolute), 
eosinophils (absolute), basophils (absolute) and reticulocytes. 
Coagulation 
Prothrombin time (INR), aPTT and prothrombin time (sec).  
Biochemistry 
Sodium, potassium, calcium, magnesium, albumin, glucose, creatinine, creatinine clearance 
(Cockcroft-Gault), uric acid, blood urea nitrogen, aspartate aminotransferase, alanine 
aminotransferase, alkaline phosphatase, bilirubin (total), lactate dehydrogenase, creatinine 
kinase and C-reactive protein. 
Serology (only at screening) 
Hepatitis B surface antigen, anti-hepatitis B core antigen, anti-hepatitis C virus, 
cytomegalovirus (CMV) IgG, CMV IgM, human papilloma virus screening, CMV DNA, 
hepatitis C virus RNA (qualitative). 


 
 
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11. 
ASSESSMENT AND REPORTING OF ADVERSE EVENTS 
11.1 
Definitions 
11.1.1 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical trial patient, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.  
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of a medicinal product. 
11.1.2 
Serious Adverse Event 
An AE that meets one or more of the following criteria/outcomes is classified as serious 
(AEs not meeting the below mentioned criteria are classified as non-serious): 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
 Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
 Is a congenital anomaly/birth defect. 
 Medically important. 
 Results in death. 
 Is life-threatening.  
The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
Elective surgery overnight for convenience or other scheduled hospitalization periods that 
were planned before the patient was included in this trial are not to be reported as AEs. 
Medical and scientific judgment must be exercised in deciding whether an AE is believed to 
be “medically important”. Medically important events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may 
require intervention to prevent one of the other outcomes listed in the definition above. 
11.1.3 
Adverse Events of Special Interest 
Based on the currently available safety profile for tisotumab vedotin, the below listed events 
are regarded as adverse events of special interest (AESIs): 
 Bleeding-related events 
 Neuropathy 
 Ocular events (conjunctivitis, ulceration, keratitis, symblepharon) 


 
 
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11.2 
Adverse Event Reporting  
The investigator must report all directly observed AEs and all AEs reported by the patient. A 
general type of question should be used similar to “Do you have any health problems?" or 
“Have you had any health problems since your last visit?" 
All AEs must be reported from the time the patient signs the ICF until 30 days after the last 
dose of tisotumab vedotin, or until the patient withdraws consent or starts subsequent anti-
cancer therapy, whichever occurs first. 
Any AE (signs, symptoms and diagnosis) occurring prior to signing the ICF must be 
recorded in the applicable base protocol eCRF. 
Registration of Adverse Events in the eCRF:  
 All AEs must be recorded in the eCRF.  
 Grade 3 and 4 abnormal laboratory test results must be reported as AEs when these are 
assessed as clinically significant by the reporting investigator. 
Reporting of Adverse Events to the Safety CRO:  
 All SAEs 
 Ocular grade ≥ 2 AEs 
 All non-serious grade ≥ 3 AEs 
 All events of overdose and/or medication errors, independent of intensity, must be 
reported as AEs to the Safety CRO.  
 Any event of pregnancy must be reported as an AE to the Safety CRO. 
Please refer to Section 11.5 for an overview of AE reporting timelines. 
All deaths (including deaths due to disease progression) should be reported as an SAE. 
11.3 
Events Requiring Immediate Reporting 
11.3.1 
Serious Adverse Events, Non-serious Grade ≥ 3 Adverse Events, 
Non-serious Grade ≥ 2 Ocular Events, Overdose and/or Medication Errors, and 
Pregnancies  
Serious adverse events, non-serious grade ≥ 3 AEs, non-serious grade ≥ 2 ocular AEs, 
overdose and/or medication errors, and pregnancies must be reported from the investigational 
site to the Safety CRO no later than 24 hours following (a) the patient visit at which such AE 
was reported, noted or recognized; or (b) the principal investigator’s or any investigator 
personnel’s receipt of the test results or other information at, or from which, such 
development was reported, noted or recognized.  
Completed SAE Report Forms, Non-serious Grade 3 Adverse Event Report Forms, 
Non-serious Grade 2 Ocular Adverse Event Report Forms or Pregnancy Forms must 
immediately be forwarded to the Safety CRO 
. 
 


 
 
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11.3.2 
Overdose and Medication Errors 
An overdose is defined as a patient receiving a dose of the IMP in excess of that specified in 
this protocol. All cases of overdose must be recorded in the eCRF and reported to the Safety 
CRO as an AE within 24 hours of knowledge of the event. 
Medication errors and uses outside what is foreseen in the protocol, including misuse and 
abuse of the product, must be recorded in the eCRF and reported to the Safety CRO as an AE 
within 24 hours of knowledge of the event.  
Overdose, medication errors, misuse and abuse do not automatically make an AE serious, but 
if the consequences are serious, for example death or hospitalizations, the event is serious 
and must be reported as an SAE (see Section 11.5). 
Rescue medication to reverse the action of tisotumab vedotin is not available. In case of 
overdose, medication errors, misuse and/or abuse of the IMP, patients should receive 
supportive care according to local guidelines, and potential side effects of tisotumab vedotin 
should be treated symptomatically. 
In the event of an overdose, the investigator should: 
i. 
Closely monitor the patient for any AE and laboratory abnormalities. 
ii. 
Contact the Medical Monitor immediately. 
iii. 
Obtain a plasma sample for PK analysis if requested by the Medical Monitor 
(determined on a case-by-case basis). 
iv. 
Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
11.3.3 
Pregnancy 
Any pregnancy that occurs during trial participation must be reported. Pregnant trial patients 
must be withdrawn from treatment immediately, whereas male patients may continue in the 
trial should pregnancy of female partners occur. In this case, a separate informed consent will 
be obtained from the female partner for collection of information regarding the pregnancy. 
 
If you have access to a secured email, you may forward completed SAEs, non-serious grade 3 
AEs, non-serious grade 2 ocular events forms or pregnancy forms to: 
 
If you do not have access to a secured email, please forward completed SAEs, non-serious 
grade 3 AEs, non-serious grade 2 ocular events forms or pregnancy forms to: 
 
 


 
 
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Each pregnancy must be reported to the Safety CRO within 24 hours of learning of its 
occurrence using the Pregnancy Form. The pregnancy must be followed up to determine 
outcome (including premature termination) and status of mother and child. The child must be 
followed at least to the age of one month. 
Pregnancy complications and elective terminations for medical reasons must be reported as 
an AE or SAE. Spontaneous abortions must be reported as an SAE. Any SAE occurring in 
association with a pregnancy brought to the investigator’s attention after the patient has 
completed the trial and considered by the investigator as possibly related to the IMP must be 
promptly reported to the Safety CRO. 
11.3.4 
Suspected Unexpected Serious Adverse Reactions  
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 should be aware of local reporting regulations to the IEC/IRB. The Safety 
CRO will either supply the investigator with the reports which should be passed on to the 
IEC/IRB or report directly to the IEC/IRB depending on local regulations. 
11.4 
Reporting of Adverse Events after Termination of Trial Participation  
Any suspected IMP-related SAE, non-serious grade ≥ 2 ocular AEs and non-serious 
grade ≥ 3 AEs occurring at any time after the patient has terminated trial participation, should 
be emailed to the Safety CRO at 
 if there is access to a 
secured email, or if there is no access to a secured email, faxed to 
 
.  
11.5 
Timelines for Reporting  
The required timeframes and reporting forms for reporting SAEs, non-serious grade ≥ 3 AEs, 
non-serious grade ≥ 2 ocular AEs, overdose and/or medication errors and pregnancies are 
presented in Table 3.  
All new information regarding SAEs, non-serious grade ≥ 3 AEs, non-serious grade ≥ 2 
ocular AEs, overdose and/or medication errors and pregnancies (initial and follow-up) must 
be reported from sites to the Safety CRO within 24 hours. Sites must respond to follow-up 
queries from the Safety CRO within 3 days.  


 
 
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Please note that any SAE should be reported on an SAE Report Form, any non-serious grade 
≥ 3 AE should be reported on a Non-serious Grade 3 Adverse Event Report Form, any 
non-serious grade ≥ 2 ocular AE should be reported on a Non-serious Grade 2 Ocular 
Adverse Event Report Form, and any pregnancy should be reported on a Pregnancy Form. 
Overdose and medication errors have no specific reporting form and should be reported on 
the SAE Report Form regardless of seriousness. If the event is serious, the serious criteria 
tick box should be ticked, and if the event is non-serious, the serious criteria tick box shall be 
left blank. 
Table 3: Timeframes for Reporting SAEs, Non-serious Grade ≥ 3 AEs, Non-serious 
Grade ≥ 2 Ocular AEs, Overdose and/or Medication Errors and Pregnancies 
 
Initial Reports 
Follow-up Information on a Previous 
Report 
Type of Event 
Time Frame 
Documents 
Time Frame 
Documents 
SAE 
24 hours* 
SAE Report Form 3 days* 
24 hours* 
CDS SAE DCF 
Site SAE DCF 
Non-serious grade 
≥ 3 AE 
24 hours* 
Non-serious Grade 
3 Adverse Event 
Report Form 
3 days* 
24 hours* 
CDS SAE DCF  
Site SAE DCF 
Grade ≥ 2 ocular 
AE 
24 hours* 
Non-serious Grade 
2 Ocular Adverse 
Event Report 
Form 
3 days* 
24 hours* 
CDS SAE DCF 
Site SAE DCF 
Overdose and/or 
Medication Errors 
24 hours* 
SAE Report Form 3 days* 
24 hours* 
CDS SAE DCF 
Site SAE DCF 
Pregnancy 
24 hours* 
Pregnancy Form 
3 days 
Updated Pregnancy 
Form 
AE=adverse event; CDS=Corporate Drug Safety; DCF=Data Clarification Form; SAE=serious adverse event 
* No later than 24 hours following a) the patient visit at which such AE was reported, noted or recognized; or 
b) the principal investigator’s or any investigator personnel’s receipt of the test results or other information at, 
or from which, such development was reported, noted or recognized. 
 
11.6 
Recording Instructions 
11.6.1 
Start Date and Time 
Start date for (S)AEs 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, the onset date of the SAE myocardial infarction is 01 April 2016.  


 
 
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Time should be filled in if event starts on a dosing day or if the duration of the event is less 
than 24 hours. 
11.6.2 
End Date and Time 
End date should be filled in if the outcome of an event is fatal, recovered/resolved, or 
recovered/resolved with sequelae.  
Time should be filled in if the duration of the event is less than 24 hours. 
11.6.3 
Diagnosis 
The diagnosis of an AE should be recorded if available. If no diagnosis is available each sign 
and symptom should be recorded as individual AEs. 
Study Disease: 
Signs and symptoms, which according to the investigator are expected and well-known 
consequences of the indication, both in intensity and frequency, should not be reported as 
AEs or SAEs. Any unexpected change in the intensity or frequency should be reported as an 
AE (or SAE, if applicable). 
11.6.4 
Information about Infusion-Related Reactions 
Information on whether AEs are infusion-related or not must be reported in the eCRF. 
11.6.5 
Relationship to IMP 
The investigator must assess whether or not the event is related to the IMP. 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. 
11.6.6 
Serious Event  
The investigator must indicate whether or not the AE is determined to be “serious” based on 
what is defined in Section 11.1. 
11.6.7 
Intensity 
The investigator should use the NCI-CTCAE version 4.03 to describe the severity of the AE 
(NCI-CTCAE v4.03, 2010). 
The grade assigned by the investigator should be the most severe that occurred during the AE 
period. 
11.6.8 
Outcome 
The outcome of the AE must be judged by the investigator by the following terms: 
 Fatal  
 Not recovered/not resolved  
 Recovered/resolved  


 
 
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 Recovered/resolved with sequelae  
 Recovering/resolving  
 Unknown 
11.6.9 
Action Taken with IMP 
The action taken with the IMP should be recorded as: 
 Dose not changed 
 Dose reduced 
 Dose interrupted  
 Drug withdrawn  
 Not applicable  
 Unknown  
11.7 
Follow-up on Adverse Events 
All AEs should be followed until they are resolved or until 30 days after the last dose of 
tisotumab vedotin, until the patient withdraws consent or starts subsequent anti-cancer 
therapy, whichever occurs first. Serious adverse events, related non-serious grade ≥ 2 ocular 
AEs and non-serious grade ≥ 3 AEs that are ongoing after trial participation 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. 
11.8 
Safety Surveillance 
Reported individual SAEs, non-serious grade ≥ 3 AEs and non-serious grade ≥ 2 ocular AEs 
will be evaluated by the sponsor upon receipt. Analysis of aggregated safety data across trials 
will be performed on an ongoing basis. If new safety issues are identified, actions will be 
taken as appropriate, including update of the Investigator’s Brochure. Safety data obtained in 
this specific trial will be reported in the Development Safety Update Report. 


 
 
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12. 
STATISTICAL CONSIDERATIONS 
12.1 
Sample Size Estimation 
Since the trial will include all patients willing to continue on treatment after completing other 
tisotumab vedotin trials (i.e., GEN701 and GEN702), no sample size determination can be 
made. It is expected that approximately 25 patients will enter the GCT1015-03 trial.  
12.2 
Statistical Analyses 
Given the low expected number of patients and the heterogeneity between patients at 
entering this trial with regards to dosing regimen, indication and response to treatment in the 
lead in trial, no formal statistical analyses are planned. Instead, all endpoints will only be 
listed. All enrolled patients will be included in the listings. 
12.2.1 
Efficacy Analyses  
Anti-tumor activity endpoints will be listed.  
12.2.2 
Safety Analyses  
Safety endpoints will be listed.  
12.2.3 
Other Analyses  
Not applicable. 
12.2.4 
Interim Analyses  
As this trial may be ongoing for a very long time, potentially several interim analyses may 
become relevant. Given that it is an open-label trial with no formal hypotheses, this will not 
require any formal methods such as control of the alpha level. It will simply consist of lists of 
what has been observed so far with tisotumab vedotin during the trial conduct. 


 
 
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13. 
MONITORING PROCEDURES/QUALITY ASSURANCE 
The sponsor has ethical, legal and scientific obligations to conduct this trial in accordance 
with established research principles and ICH GCP guidelines E6(R2). As such, in order to 
fulfill these obligations and to monitor trial progress, the sponsor's monitors or 
representatives will visit the investigative sites during the trial conduct, in addition to 
maintaining telephone and written communication. On-site visits, telephone calls and regular 
review of the eCRFs will be conducted in order to assess patient enrolment, compliance with 
protocol procedures, completeness and accuracy of data entered on the eCRFs, verification of 
eCRF data against original source documents and occurrence of AEs. The investigator must 
provide the monitor, sponsor representative and auditors/inspectors with full access to all 
source and trial documents.  
13.1 
Data Collection 
As part of the responsibilities assumed by participating in the trial, the investigator agrees to 
maintain adequate and accurate case histories for the patients treated under this protocol. 
Case histories include eCRFs and supporting data including, but not limited to, signed and 
dated ICFs, progress notes, hospital charts, nurse’s notes, diary cards or other worksheets 
provided to patients, laboratory reports, ECG readings, etc. 
Patient demographics and key/essential disease baseline characteristics thought to affect 
outcome, i.e., stratification variables and other prognostic factors, may be collected, as 
available, for all patients who provide written informed consent. For patients who provided 
informed consent and were not entered into the trial, the reason the patient was not entered, 
i.e., did not meet one or more inclusion criteria, met one or more exclusion criteria, or other 
(e.g., lost to follow-up, consent withdrawn), may also be collected. 
13.2 
Data Management 
Data management will be performed by 
. Data collected during the trial will be recorded 
in the patient’s eCRF by the investigational site staff.  
13.3 
Trial Monitoring 
Sponsor or sponsor assigned monitors will conduct regular site visits to the investigational 
facilities for the purpose of monitoring various aspects of the trial. The investigator must 
agree to sponsor-authorized personnel having direct access to the clinical (or associated) files 
and clinical trial supplies (dispensing and storage areas) for all trial patients considered for 
trial entry for the purpose of verifying entries made in the eCRF, and assist with their 
activities, if requested. Adequate time and space for monitoring visits should be made 
available by the investigator. 
The site must complete the electronic eCRFs in a timely manner and on an ongoing basis to 
allow regular review by the trial monitor. Further instruction will be provided in the eCRF 
Completion Guidelines. 
The monitor will discuss the conduct and progress of the trial with the investigator and other 
site staff. The investigator must cooperate with the monitor to ensure that corrective action is 


 
 
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taken to resolve any problems noted in the course of the monitoring, and that the preventive 
measures are put into place to prevent recurrence of issues. In cases where compliance is not 
achieved, shipment(s) of the trial drug to the investigator will be discontinued and trial 
participation by that investigator will be terminated. 
13.4 
Inspections and Auditing Procedures 
Before, during and after the trial, the sponsor or its representative may conduct audits at the 
investigative sites including, but not limited to, drug supply, presence of required documents, 
the informed consent process, and comparison of eCRFs with source documents. All medical 
records (progress notes) must be available for audit. The investigator agrees to participate in 
audits conducted at a convenient time in a reasonable manner. 
Government regulatory authorities may also inspect the investigator. The investigator or 
designee should contact the sponsor/
 immediately if this occurs. He/she must cooperate 
fully with regulatory authorities or other audits conducted at a convenient time in a 
reasonable manner. The investigator will forward to the sponsor a copy of any inspection 
records received. 
 


 
 
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14. 
TRIAL MANAGEMENT AND MATERIALS 
14.1 
Data Collection 
All data entered in the eCRF should be documented at the site. During each trial visit, a 
physician participating in the trial will maintain progress notes in the patient’s medical 
records to document all significant observations. At a minimum, these notes will contain: 
 That the patient has consented and is found eligible for the trial (as applicable). 
 The date of the visit and the corresponding day or visit in the trial schedule (e.g., 
screening, Day 1, Day 15, etc.). 
 General condition and status remarks by the patient, including any significant medical 
findings. The severity, frequency, duration and resolution of any reported AE, and the 
investigator's assessment as to whether or not the reported AE is trial drug-related. 
 Changes in concomitant medications or dosages. 
 A general reference to the procedures completed. 
 The signature or initials of all physicians making an entry in the medical record (progress 
notes). 
In addition, any contact with the patient via telephone or other means that provides 
significant clinical information will also be documented in the medical record (progress 
notes), as described above.  
Information from the medical records (progress notes) and other source documents will be 
promptly transcribed to the appropriate section of the eCRF. 
Changes to information in the medical record (progress notes), and other source documents 
will be initialed and dated on the day the change is made by the investigator or designee. If 
the reason for the change is not apparent, a brief explanation for the change will be written 
adjacent to the change. 
Details on data validation, data transfers, origin and destination on the data, access to the 
transferred data, timing of the transfer and any actions that may be triggered by real-time 
review of those data will be documented in the data management plan. 
14.2 
Source Documents Maintenance 
Source documents contain the results of original observations and activities of a clinical 
investigation. Source documents include, but are not limited to, medical records (progress 
notes), clinical and office charts, laboratory notes, pharmacy dispensing records, recorded 
data from automated instruments, photographic negatives, microfilm or magnetic media, 
x-rays, computer printouts, patient files and records kept at the pharmacy, laboratories and 
medico-technical departments involved in the clinical trial. There should only be one source 
defined at any time for any data element. 
All source documents from this trial will be maintained by the investigator and made 
available for inspection by authorized persons. The original signed informed consent for each 


 
 
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patient shall be filed with records kept by the investigator and a copy shall be given to the 
patient. 
14.3 
Record Maintenance 
All data derived from the trial will remain the property of Genmab A/S. 
Records must be retained in accordance with the ICH Guidelines on GCP (R2). All essential 
trial documents including records of patients, source documents, eCRFs and trial drug 
inventory must be kept on file. 
USA FDA regulations (21 CFR 312.62[c]) require that records and documents pertaining to 
the conduct of this trial and the distribution of investigational drug, including eCRFs, consent 
forms, laboratory test results and medical inventory records, must be retained by the 
Principal Investigator for two years after marketing application approval. If no application is 
filed, these records must be kept two years after the investigation is discontinued and the 
USA FDA and the applicable national and local health authorities are notified. The sponsor 
or their representative will notify the Principal Investigator of these events. 
The investigator will not dispose of any records relevant to this trial without written 
permission from the sponsor, and will provide the sponsor the opportunity to collect such 
records. The investigator shall take responsibility for maintaining adequate and accurate hard 
copy source documents of all observations and data generated during this trial. Such 
documentation is subject to inspection by the sponsor, its representatives and regulatory 
authorities. 
If an investigator moves, withdraws from an investigation or retires, the responsibility for 
maintaining the records may be transferred to another person who will accept responsibility. 
Notice of transfer must be made to and agreed by the sponsor. 
14.4 
Confidentiality 
All information obtained during the conduct of the trial with respect to the patient’s state of 
health will be regarded as confidential. For disclosure of any such information, an agreement 
will be obtained in writing.  
The investigator must ensure that each patient’s anonymity is maintained. On eCRFs and 
other documents submitted to the sponsor or the CRO, patients must not be identified. 
Instead, patients will only be known by the unique patient number allocated to them in order 
to ensure confidentiality on all trial documentation. Patients will retain this unique number 
throughout the trial. The investigator will keep a separate log of these codes. 
In order to comply with government regulatory guidelines and to ensure patient safety, it may 
be necessary for the sponsor and its representative, 
 personnel, the local research review 
board, or the USA FDA to review patients’ medical records as they relate to this trial. Only 
the patient’s unique number on the eCRFs will identify him/her, but their full names may be 
made known to a drug regulatory authority or other authorized government or health care 
officials, if necessary, and to personnel designated by the sponsor. 
Documents that are not for submission to the sponsor (e.g., consent forms) will be 
maintained by the investigator in strict confidence, except to the extent necessary to allow 


 
 
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monitoring by the sponsor and designee, and auditing by regulatory authorities. No 
documents identifying patients will leave the investigative site and patient identity will 
remain confidential in all publications related to the trial. 


 
 
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15. 
ADMINISTRATION PROCEDURES 
15.1 
Regulatory Approval 
Genmab A/S or their appointed agents will be responsible for ensuring that appropriate 
regulatory authority approvals are obtained, according to local country requirements. 
No patient may enter the trial until this approval has been obtained. A copy of the approval 
(where one is provided, according to local country requirements) will be provided to the 
investigator and to the IEC(s)/IRB(s). 
15.2 
Protocol Amendments 
In accordance with ICH Topic E6(R2) Guideline for GCP, the investigator should not 
implement any deviation from, or changes of the protocol without agreement by the sponsor 
and documented approval from the IEC/IRB of a protocol amendment, except where 
necessary to eliminate an immediate hazard(s) to trial patients, or when the change(s) 
involves only logistical or administrative aspects of the trial (e.g., change in monitor(s), 
change of telephone number(s)).  
Any change to the protocol must be handled as a protocol amendment. Any potential 
amendment must be approved by the sponsor. A written amendment must be submitted to the 
appropriate regulatory authorities and to the IEC/IRB assuming this responsibility. The 
investigator must await IEC/IRB approval of protocol amendments before implementing the 
changes, except where necessary to eliminate apparent immediate hazard to patients. In these 
cases, the IEC/IRB must be notified within five days of the change. 
All amendments to the protocol must be approved in writing by both the appropriate 
regulatory authorities and the IEC/IRB, except for administrative amendments, which require 
notification but not written approval. Once approved, the protocol amendment will be 
distributed to all recipients of the original protocol, with instructions to append the 
amendment to the protocol. 
If, in the judgment of the local IEC/IRB, the investigator and/or sponsor, the protocol 
amendment alters the trial design, procedures and/or increases the potential risk to the 
patient, the currently approved written ICF will require modification. The modified ICF must 
also be reviewed and approved by the sponsor, appropriate regulatory authorities, and the 
IEC/IRB. In such cases, repeat informed consent must be obtained from patients enrolled in 
the trial before participation continues. 
15.3 
Protocol Adherence and Deviations 
The protocol must be read thoroughly and the instructions must be followed. However, 
exceptions will be made in emergency situations when the protection, safety and well-being 
of the patient requires immediate intervention based on the judgment of the investigator or a 
responsible, appropriately trained and credentialed professional(s) designated by the 
investigator as a sub-investigator.  
In the event of a significant protocol deviation due to an emergency, accident or error, the 
investigator or designee must contact the Medical Monitor at the earliest possible time by 


 
 
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telephone. This allows for an early joint decision to be made as to whether or not the patient 
should continue in the trial. The investigator, the sponsor and the Medical Monitor will 
document this decision. 
15.4 
Publication Policy 
The sponsor acknowledges the investigator’s right to publish the entire results of the trial, 
regardless of the outcome, in accordance with the Uniform Requirements for Manuscripts 
Submitted to Biomedical Journals of the International Committee of Medical Journal Editors 
(http://www.icmje.org/icmje-recommendations.pdf, updated December 2014). 
The international Coordinating Investigator will, together with the sponsor, decide on the 
publication strategy and has the right to publish and present the results and methods as first 
author of multicenter publications. Co-authorship will be decided by the sponsor and the 
international Coordinating Investigator and will be limited to a number of persons who have 
contributed substantially in the design, analysis and conduct of the trial or the writing and 
presentation of results. The sponsor will have representation in the list of authors. 
Publications are subject to the following conditions: 
 No publication before the completion of the trial at all participating sites without written 
agreement with the sponsor. 
 All proposed publications and presentations, including any modifications or amendments, 
shall be submitted to the sponsor for its review at least 30 days before such presentation or 
publication is submitted to any third party. 
 Publications shall not disclose any sponsor confidential information and property (not 
including the trial results, which can be published as described elsewhere in this section). 
15.5 
Contractual and Financial Details 
The investigator (and/or, as appropriate, the hospital administrative representative) and the 
sponsor will sign a clinical trial agreement prior to the start of the trial, outlining overall 
sponsor and investigator responsibilities in relation to the trial. The contract should describe 
whether costs for pharmacy, laboratory and other protocol-required services are being paid 
directly or indirectly. Financial Disclosure Statements will need to be completed, as 
requested by FDA CFR 21 part 54. 
15.6 
Insurance, Indemnity and Compensation 
Genmab A/S undertakes to maintain an appropriate clinical trial insurance policy. 
Deviations from the trial protocol - especially the prescription of a dose other than that 
scheduled in the trial protocol, other modes of administration, other indications and longer 
treatment periods - are not permitted and shall not be covered by the statutory patient 
insurance scheme. 


 
 
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15.7 
Termination of the Trial 
This trial may be terminated by the sponsor. The trial may also be terminated prematurely at 
any time when agreed to by both the investigators and the sponsor as being in the best 
interests of patients, and justified on either medical or ethical grounds. In terminating the 
trial, Genmab A/S, 
 and the investigator will ensure that adequate consideration is given 
to the protection of the patients’ interests. 
15.8 
Investigator Trial File Management 
The investigator is responsible for assuring that the Investigator Trial File is maintained. The 
Investigator Trial File will contain, but will not be limited to, the information listed below: 
(1) 
Investigator’s Brochure; 
(2) 
Current signed version of the protocol and any previous versions of the protocol; 
(3) 
Protocol amendments (if applicable); 
(4) 
Operations Manual (if applicable); 
(5) 
Current ICF (blank) and any previous versions of the ICF; 
(6) 
Curricula Vitae of investigator(s) and sub-investigator(s) and a photocopy of their 
respective license(s) where required by law; original USA FDA Form 1572 (for all 
studies conducted under USA Investigational New Drug [IND] regulations), signed by 
all Principal investigators. The names of any sub-investigators must appear on this 
form. Investigators must also complete all regulatory documentation as required the 
ICH GCP and by local or national regulations; 
(7) 
Documentation of CA/IEC/IRB approval of the protocol, the ICF, any protocol 
amendments, and any ICF revisions; 
(8) 
All correspondence between the investigator, IEC/IRB, and the sponsor/designee 
relating to trial conduct; 
(9) 
Laboratory certification(s); 
(10) Patient management logs (screening log, etc.); 
(11) Monitoring log; 
(12) Trial drug invoices; 
(13) Delegation log; 
(14) Source document location list. 
 


 
 
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16. 
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Cugno M, Marzano AV, Tedeschi A, et al. Expression of tissue factor by eosinophils in 
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Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-47 
Flössel C, Luther T, Müller M, et al. Immunohistochemical detection of tissue factor (TF) on 
paraffin sections of routinely fixed human tissue. Histochem. 1994 Jul;101(6):449-53 
Hamblett KJ, Senter PD, Chace DF, et al. Effects of drug loading on the antitumor activity of 
a monoclonal antibody drug conjugate. Clin Cancer Res. 2004 Oct 15;10(20):7063-70 
Han LY, Landen CN Jr, Kamat AA, et al. Preoperative serum tissue factor levels are an 
independent prognostic factor in patients with ovarian carcinoma. J Clin Oncol. 2006 Feb 
10;24(5):755-61 
Imokawa S, Sato A, Hayakawa H, et al. Tissue factor expression and fibrin deposition in the 
lungs of patients with idiopathic pulmonary fibrosis and systemic sclerosis. Am J Respir Crit 
Care Med. 1997 Aug;156(2 Pt 1):631-6 
Kasthuri RS, Taubman MB, and Mackman N. Role of tissue factor in cancer. J Clin Oncol. 
2009 Oct 10;27(29):4834-8 
Khorana AA, Ahrendt SA, Ryan CK, et al. Tissue factor expression, angiogenesis, and 
thrombosis in pancreatic cancer. Clin Cancer Res. 2007;13:2870-5 
Marzano AV, Tedeschi A, Berti E, et al. Activation of coagulation in bullous pemphigoid 
and other eosinophil-related inflammatory skin diseases. Clin Exp Immunol. 2011 
Jul;165(1):44-50 
Marzano AV, Tedeschi A, Fanoni D, et al. Activation of blood coagulation in bullous 
pemphigoid: role of eosinophils, and local and systemic implications. Br J Dermatol. 2009 
Feb;160(2):266-72 


 
 
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More K, Sim R, Hudson M, et al. Immunohistochemical study of tissue factor expression in 
normal intestine and idiopathic inflammatory bowel disease. J Clin Pathol. 1993 
Aug;46(8):703-8 
National Cancer Institute. Common Terminology Criteria for Adverse Events v4.0. NCI, 
NIH, DHHS. May 29, 2009. NIH publication # 09-7473. Updated to v4.03 on June 14, 2010. 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
Nitori N, Ino Y, Nakanishi Y, et al. Prognostic significance of tissue factor in pancreatic 
ductal adenocarcinoma. Clin Cancer Res. 2005 Apr 1;11(7):2531-9 
Ohta S, Wada H, Nakazaki T, et al. Expression of tissue factor is associated with clinical 
features and angiogenesis in prostate cancer. Anticancer Res. 2002;22:2991-6 
Patry G, Hovington H, Larue H, et al. Tissue factor expression correlates with disease-
specific survival in patients with node-negative muscle-invasive bladder cancer. Int J 
Cancer. 2008;122:1592-7 
Ruf W, Mueller BM. Tissue factor in cancer angiogenesis and metastasis. Curr Opin 
Hematol. 1996 Sep;3(5):379-84 
Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with 
progressive prostate cancer and castrate levels of testosterone: Recommendations of the 
Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26:1148-59 
Sun MM, Beam KS, Cerveny CG, et al. Reduction-alkylation strategies for the modification 
of specific monoclonal antibody disulfides. Bioconjug. Chem. 2005;16:1282-90  
Uno, K, Homma S, Satoh T, et al. Tissue factor expression as a possible determinant of 
thromboembolism in ovarian cancer. Br J Cancer. 2007;96:290-5 
Versteeg HH, Schaffner F, Kerver M, et al. Inhibition of tissue factor signaling suppresses 
tumor growth. Blood. 2008 Jan 1;111(1):190-9 
Yokota, N, Koizume S, Miyagi E, et al. Self-production of tissue factor-coagulation factor 
VII complex by ovarian cancer cells. Br J Cancer. 2009;101:2023-9 


 
 
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17. 
APPENDICES 
17.1 
Appendix 1: ECOG Performance Status Scale 
These scales and criteria are used by doctors and researchers to assess how a patient's disease 
is progressing, assess how the disease affects the daily living abilities of the patient, and 
determine appropriate treatment and prognosis. 
 
ECOG PERFORMANCE STATUS* 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance 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 house work, 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 
ECOG=Eastern Cooperative Oncology Group 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. 
Am J Clin Oncol 5:649-655, 1982. 
 


 
 
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17.2 
Appendix 2: Highly Effective Methods of Contraception 
For countries where 2 highly effective methods of contraception are required, the following 
definitions are provided (ICH M3). 
Highly effective method of contraception / birth control as defined in ICH (M3) 
Methods of birth control which result in a low failure rate (i.e., less than 1% per year) when 
used consistently and correctly such as implants, injectables, combined oral contraceptives, 
some intrauterine devices (IUDs), sexual abstinence or vasectomized partner. 
Barrier Contraceptive 
A contraceptive device that physically prevents sperm from entering the endometrial cavity 
and fallopian tubes (e.g., male condom, female condom or diaphragm). 
Acceptable forms of effective contraception include: 
(1) 
Established use of oral, injected or implanted hormonal methods of contraception. (Safe 
hormonal contraceptives include contraceptive pills, implants, transdermal patches, 
hormonal vaginal devices or injections with prolonged release.) [The decision to allow 
use of hormonal contraceptives should be based on the Investigational Medicinal 
Product’s metabolism and potential for interactions, pharmacology and the adverse 
event profile (e.g. vomiting)]. 
(2) 
Placement of an intrauterine device or intrauterine system. [Consideration should be 
given to the type of device or system being used, as there are higher failure rates 
quoted for certain types, e.g. steel or copper wire] 
(3) 
Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. [The use of 
barrier contraceptives should always be supplemented with the use of a spermicide. 
The following should be noted: 
 Failure rates indicate that, when used alone, the diaphragm and condom are not 
highly effective forms of contraception. Therefore the use of additional spermicides 
does confer additional theoretical contraceptive protection. 
 However, spermicides alone are inefficient at preventing pregnancy when the whole 
ejaculate is spilled. Therefore, spermicides are not a barrier method of 
contraception and should not be used alone.] 
(4) 
Male sterilization (with the appropriate post-vasectomy documentation of the absence 
of sperm in the ejaculate). [For female subjects on the study, the vasectomized male 
partner should be the sole partner for that subject]. 
(5) 
True abstinence: When this is in line with the preferred and usual lifestyle of the 
subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception]. 


 
 
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Two forms of highly effective contraception 
For certain studies, e.g. in the event of teratogenicity or lack of adequate reproductive 
toxicity data, there is a requirement for 2 forms of highly effective contraception. In this 
situation, subjects should be instructed to use 2 different forms of effective contraception 
(e.g. from the list above). 


 
 
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17.3 
Appendix 3: Declaration of Helsinki 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53th WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
Preamble 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving 
human subjects to adopt these principles.  
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health 
of my patient will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the patient's best interest when providing medical 
care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician's knowledge 
and conscience are dedicated to the fulfilment of this duty. 
5. Medical progress is based on research that ultimately must include studies involving 
human subjects. 
6. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best proven 
interventions must be evaluated continually through research for their safety, effectiveness, 
efficiency, accessibility and quality. 


 
 
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7. Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
8. While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects. 
9. It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. The responsibility for the protection of research subjects 
must always rest with the physician or other health care professionals and never with the 
research subjects, even though they have given consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable international 
norms and standards. No national or international ethical, legal or regulatory requirement 
should reduce or eliminate any of the protections for research subjects set forth in this 
Declaration. 
11. Medical research should be conducted in a manner that minimises possible harm to the 
environment. 
12. Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications. Research on 
patients or healthy volunteers requires the supervision of a competent and appropriately 
qualified physician or other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14. Physicians who combine medical research with medical care should involve their patients 
in research only to the extent that this is justified by its potential preventive, diagnostic or 
therapeutic value and if the physician has good reason to believe that participation in the 
research study will not adversely affect the health of the patients who serve as research 
subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
Risks, Burdens and Benefits  
16. In medical practice and in medical research, most interventions involve risks and 
burdens. 
Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful assessment 
of predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected by 
the condition under investigation. 
Measures to minimise the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher.  


 
 
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18. Physicians may not be involved in a research study involving human subjects unless they 
are confident that the risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive proof 
of definitive outcomes, physicians must assess whether to continue, modify or immediately 
stop the study.          
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive to 
the health needs or priorities of this group and the research cannot be carried out in a 
non-vulnerable group. In addition, this group should stand to benefit from the knowledge, 
practices or interventions that result from the research. 
Scientific Requirements and Research Protocols  
21. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal experimentation. 
The welfare of animals used for research must be respected. 
22. The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, potential conflicts 
of interest, incentives for subjects and information regarding provisions for treating and/or 
compensating subjects who are harmed as a consequence of participation in the research 
study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This committee 
must be transparent in its functioning, must be independent of the researcher, the sponsor and 
any other undue influence and must be duly qualified. It must take into consideration the 
laws and regulations of the country or countries in which the research is to be performed as 
well as applicable international norms and standards but these must not be allowed to reduce 
or eliminate any of the protections for research subjects set forth in this Declaration.  
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse 
events. No amendment to the protocol may be made without consideration and approval by 


 
 
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the committee. After the end of the study, the researchers must submit a final report to the 
committee containing a summary of the study’s findings and conclusions.  
Privacy and Confidentiality  
24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
Informed Consent  
25. Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members or 
community leaders, no individual capable of giving informed consent may be enrolled in a 
research study unless he or she freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, any 
possible conflicts of interest, institutional affiliations of the researcher, the anticipated 
benefits and potential risks of the study and the discomfort it may entail, post-study 
provisions and any other relevant aspects of the study. The potential subject must be 
informed of the right to refuse to participate in the study or to withdraw consent to participate 
at any time without reprisal. Special attention should be given to the specific information 
needs of individual potential subjects as well as to the methods used to deliver the 
information. 
After ensuring that the potential subject has understood the information, the physician or 
another appropriately qualified individual must then seek the potential subject’s freely-given 
informed consent, preferably in writing. If the consent cannot be expressed in writing, the 
non-written consent must be formally documented and witnessed.     
All medical research subjects should be given the option of being informed about the general 
outcome and results of the study. 
27. When seeking informed consent for participation in a research study the physician must 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent must be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
28. For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. These 
individuals must not be included in a research study that has no likelihood of benefit for them 
unless it is intended to promote the health of the group represented by the potential subject, 
the research cannot instead be performed with persons capable of providing informed 
consent, and the research entails only minimal risk and minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is 
able to give assent to decisions about participation in research, the physician must seek that 
assent in addition to the consent of the legally authorised representative. The potential 
subject’s dissent should be respected. 


 
 
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30. Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research group. In such 
circumstances the physician must seek informed consent from the legally authorised 
representative. If no such representative is available and if the research cannot be delayed, 
the study may proceed without informed consent provided that the specific reasons for 
involving subjects with a condition that renders them unable to give informed consent have 
been stated in the research protocol and the study has been approved by a research ethics 
committee. Consent to remain in the research must be obtained as soon as possible from the 
subject or a legally authorised representative. 
31. The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek informed 
consent for its collection, storage and/or reuse. There may be exceptional situations where 
consent would be impossible or impracticable to obtain for such research. In such situations 
the research may be done only after consideration and approval of a research ethics 
committee. 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following circumstances: 
        Where no proven intervention exists, the use of placebo, or no intervention, is 
acceptable; or 
        Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention is 
necessary to determine the efficacy or safety of an intervention and the patients who receive 
any intervention less effective than the best proven one, placebo, or no intervention will not 
be subject to additional risks of serious or irreversible harm as a result of not receiving the 
best proven intervention.  
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention 
identified as beneficial in the trial. This information must also be disclosed to participants 
during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject. 


 
 
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36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a 
duty to make publicly available the results of their research on human subjects and are 
accountable for the completeness and accuracy of their reports. All parties should adhere to 
accepted guidelines for ethical reporting. Negative and inconclusive as well as positive 
results must be published or otherwise made publicly available. Sources of funding, 
institutional affiliations and conflicts of interest must be declared in the publication. Reports 
of research not in accordance with the principles of this Declaration should not be accepted 
for publication. 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the patient or a legally authorised representative, may use an 
unproven intervention if in the physician's judgement it offers hope of saving life, 
re-establishing health or alleviating suffering. This intervention should subsequently be made 
the object of research, designed to evaluate its safety and efficacy. In all cases, new 
information must be recorded and, where appropriate, made publicly available.  
 
 

SAP_001.pdf: 


 
 
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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 Multi-center, Open-Label Trial Investigating the 
Efficacy and Safety of Continued Treatment with 
Tisotumab Vedotin in Patients with Solid Tumors Known 
to Express Tissue Factor 
Protocol Version: 
Final version 5.0, dd. 24 September 2018 
Trial Code: 
GCT1015-03 
 
 
 
For 
: 
Author: 
, Senior Biostatistician 
Reviewer: 
, Associate Director, Biostatistics 
 
For Sponsor: 
Reviewers:  
- 
, Biostatistician 
- 
, Director, Clinical Research Scientist 
 
Genmab - GCT1015-03                                                                   Version: 2.0
Approved in Vault: 1/18/2019


 
 
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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 ........................................................................................... 5 
3. 
TRIAL DESIGN AND OBJECTIVES ................................................................. 5 
3.1 
Trial Objectives ........................................................................................ 5 
3.1.1 
Primary Objective .............................................................................. 5 
3.1.2 
Secondary Objective .......................................................................... 5 
3.2 
Trial Design ............................................................................................. 5 
3.3 
Sample Size Justification ........................................................................... 5 
4. 
GENERAL ANALYSIS DEFINITIONS .............................................................. 5 
4.1 
Trial Period and Visit Window Definitions ..................................................... 6 
4.1.1 
Trial Periods ..................................................................................... 6 
4.1.2 
Visit Windows ................................................................................... 6 
4.2 
Planned Analyses ..................................................................................... 6 
4.3 
Definition of Populations (Analysis Sets) ..................................................... 6 
4.3.1 
Enrolled Population ............................................................................ 6 
4.4 
Subgroup Definitions ................................................................................ 6 
4.5 
Treatment Assignment and Treatment Arms ................................................ 6 
4.6 
Calculated Variables ................................................................................. 6 
4.7 
Partial/Missing Dates ................................................................................ 7 
4.8 
Methods to Be Used For Handling Missing Data ............................................ 7 
4.9 
Changes to Protocol ................................................................................. 7 
5. 
TRIAL PATIENTS .......................................................................................... 7 
5.1 
Disposition of Patients .............................................................................. 7 
5.2 
Protocol Deviations .................................................................................. 7 
5.3 
In- and Exclusion Criteria .......................................................................... 7 
6. 
DEMOGRAPHIC AND BASELINE DISEASE CHARACTERISTICS ...................... 7 
7. 
MEDICAL HISTORY ...................................................................................... 8 
8. 
SUBSEQUENT CANCER THERAPIES .............................................................. 8 
9. 
PRIOR AND CONCOMITANT MEDICATIONS .................................................. 8 
10. 
EFFICACY EVALUATION ............................................................................ 8 
10.1 
Anti-tumor Activity ................................................................................... 8 
10.2 
CA 125 (Ovarian cancer only) .................................................................... 9 
10.3 
ECOG Performance Status ......................................................................... 9 
11. 
SAFETY EVALUATION ............................................................................... 9 
11.1 
Extent of Exposure ................................................................................... 9 
11.2 
Adverse Events ........................................................................................ 9 
11.3 
Deaths and Serious Adverse Events ........................................................... 9 
11.4 
Neuropathy and Skin Assessment ............................................................ 10 
11.5 
Ophthalmological Evaluations .................................................................. 10 
11.6 
Clinical Laboratory Data .......................................................................... 10 
11.7 
Vital Signs and ECG ............................................................................... 10 
11.8 
Pregnancy Test ...................................................................................... 10 
Genmab - GCT1015-03                                                                   Version: 2.0
Approved in Vault: 1/18/2019


 
 
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TPL N°: eTPL SA-02-01 
TPL Version: 02 
Of SOP SA-02.08 
TPL Effective Date: 31 Mar 2016 
 
12. 
REFERENCES .......................................................................................... 10 
13. 
LIST OF TABLES/GRAPHS/LISTINGS ..................................................... 11 
13.1 
List of Statistical Tables .......................................................................... 11 
13.2 
List of Graphs ........................................................................................ 11 
13.3 
List of Derived Data Listings .................................................................... 11 
14. 
VERSION HISTORY ................................................................................. 12 
Genmab - GCT1015-03                                                                   Version: 2.0
Approved in Vault: 1/18/2019


 
 
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TPL N°: eTPL SA-02-01 
TPL Version: 02 
Of SOP SA-02.08 
TPL Effective Date: 31 Mar 2016 
 
1. List of Abbreviations and Definition of Terms 
 
Abbreviation 
Term 
 
 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BP 
Blood Pressure 
bpm 
Beats per Minute 
CA 125 
Cancer Antigen 125 
CRF 
Case Report Form 
CT 
Computed Tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
WHO 
World Health Organization 
 
 
Genmab - GCT1015-03                                                                   Version: 2.0
Approved in Vault: 1/18/2019


 
 
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TPL N°: eTPL SA-02-01 
TPL Version: 02 
Of SOP SA-02.08 
TPL Effective Date: 31 Mar 2016 
 
2. Introduction 
This Statistical Analysis Plan was written for the clinical trial GCT1015-03 conducted in 
Europe and the United States of America. 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 Objective 
 
To collect long-term safety data from patients with solid tumors who have 
been treated with tisotumab vedotin and completed any base trial (i.e., 
GEN701 or GEN702).  
3.1.2 Secondary Objective 
 
To further evaluate the anti-tumor activity of tisotumab vedotin. 
3.2 
Trial Design 
The trial design is available in section 8.1 Overall Trial Design and Plan of the protocol 
final version 5.0 dd. 24 September 2018.  
3.3 
Sample Size Justification 
Since the trial will include all patients willing to continue on treatment after completing 
other tisotumab vedotin trials (i.e., GEN701 and GEN702), no sample size determination 
can be made. It is expected that approximately 25 patients will enter the GCT1015-03 
trial. 
4. General Analysis Definitions 
Data will be analyzed using SAS (Version 9.4 or higher).  
Given the low expected number of patients and the heterogeneity between patients at 
entering this trial with regards to dosing regimen (as followed by the patient in the base 
trial), indication and response to treatment in the base trial, no formal statistical 
analyses are planned. Instead, all endpoints will only be listed. All enrolled patients will 
be included in the listings. 
All data collected in this maintenance trial will be listed by base trial, dosing regimen (as 
followed by the patient in the base trial), indication, patient number and visit (if 
applicable). All listings will include the first IMP administration date in this trial and the 
last IMP administration date at the time of the database snapshot or database lock. 
Whenever applicable the reason for not done will be included in the listings. 
When presenting coded data (e.g. medical history, concomitant medication, adverse 
events), the dictionary and the version used will be mentioned in the footnote. The 
current version of each dictionary will be used. 
In case there will be a need for summary tables, these can be performed using 
descriptive statistics as follows:  
 
Categorical data will be summarized in contingency tables presenting 
frequencies and percentages. 
Genmab - GCT1015-03                                                                   Version: 2.0
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 
Continuous data will be summarized using number of non-missing values (n), 
mean, standard deviation, median, 25th and 75th percentiles, minimum and 
maximum values.  
The following data will be included from the base trials as specified in the respective 
sections below: 
- 
Medical history data 
- 
Local tumor assessments 
- 
Exposure data 
4.1 
Trial Period and Visit Window Definitions 
4.1.1 Trial Periods 
Treatment period will be defined as the period between the date of first IMP 
administration in the base trial and the date of last IMP administration + 30 days or the 
date of the end of trial visit in this trial when available. 
Trial periods will not be used in the analysis as the data is listed only.  
4.1.2 Visit Windows 
Visits will be reported as captured in the eCRF. 
4.2 
Planned Analyses 
As this trial may be ongoing for a very long time, potentially several interim analyses 
may become relevant. Given that it is an open-label trial with no formal hypotheses, this 
will not require any formal methods such as control of the alpha level. It will simply 
consist of lists of what has been observed so far with tisotumab vedotin during the trial 
conduct. 
4.3 
Definition of Populations (Analysis Sets) 
4.3.1 Enrolled Population  
The Enrolled Population consists of all patients who sign the informed consent form 
(ICF).  
4.4 
Subgroup Definitions 
Not defined at the time of final SAP given the objectives and the size of the trial. 
4.5 
Treatment Assignment and Treatment Arms 
Tisotumab vedotin will be administered as an intravenous infusion on Day 1 of each 21-
day cycle (once every three weeks [1Q3W]). 
The dose will be 2.0 mg/kg or if dose reduced in the base trial continue the same dose. 
Dose reductions are allowed according to the protocol section 9.5. 
4.6 
Calculated Variables 
Baseline is defined as the last assessment value before or on the date of the first IMP 
administration in this trial unless specified otherwise. 
Genmab - GCT1015-03                                                                   Version: 2.0
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Date/time of first study treatment in the listings refers to first IMP administration in the 
base trial. 
Study days for visit date, assessment date, date of progression and date of death are 
calculated versus the start of IMP administration in the base trial. 
4.7 
Partial/Missing Dates 
Partial or missing dates will not be imputed as the data will only be listed. All information 
available will be presented. 
4.8 
Methods to Be Used For Handling Missing Data 
All available data will be included in data listings and tabulations.  
No imputation of missing data is planned. 
4.9 
Changes to Protocol 
Summary tables might be created as needed.  
5. Trial Patients 
 
5.1 
Disposition of Patients 
Date of signing the ICF (including additional ICFs), version and date of ICF, base trial, 
last trial drug intake date in the base trial, screening failure and the reason, the primary 
reason for discontinuation of the trial including the reason for ‘other’ and the reason for 
withdrawal by patient, date of progression and date of death will be included.  
A listing of all visits will be created including the reason for unscheduled visits and a flag 
if target/non-target assessment is done. 
5.2 
Protocol Deviations 
The protocol deviations will be listed including a flag for major deviations. 
Protocol violations will be defined in the protocol deviations plan. 
5.3 
Inclusion and Exclusion Criteria 
Listing of all inclusion and exclusion criteria not met together with the protocol version 
will be provided. 
6. Demographic and Baseline Disease Characteristics 
In the listing of demographic characteristics, the variables to be listed are: 
 
Gender (Male/Female) 
 
Age (Years), date of birth 
 
Race (White, Black or African American, Native Hawaiian or other Pacific 
Islander, Asian, American Indian or Alaska native, Other + details) 
 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
 
ECOG performance score (0-5). Note: at entry only patients with an ECOG 
performance score of 0 and 1 are allowed. 
Genmab - GCT1015-03                                                                   Version: 2.0
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 
Childbearing potential (Yes/No and reason) 
 
Cancer type (Ovary, Cervix, Endometrium, Bladder, Prostate, Head and 
neck, Esophagus, Lung) 
7. Medical History 
Medical conditions will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
The medical conditions will be listed including term, system organ class and preferred 
term, start and end date, ongoing flag and started more than 1 year ago flag. 
The medical history from the base trial will be reported. 
8. Subsequent Cancer Therapies 
All subsequent cancer therapies, except for surgeries, will be listed including the 
anatomical therapeutic chemical (ATC) code level 2 and active ingredient (WHO-DD 
dictionary). Surgeries will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and presented including system organ class and preferred term.  
9. Prior and Concomitant Medications 
Prior and Concomitant medications will be classified according to World Health 
Organization Drug Dictionary. 
Medications will be flagged according to the following 3 distinct categories: 
- 
Prior when they start and end before the first day of trial treatment. 
- 
Prior and ongoing when they start before the first day of trial treatment and stop 
or continue after the first day of trial treatment. 
- 
Medications will be reported as concomitant when they start on or after first day 
of trial treatment.  
A listing of all medications recorded on the (prior and) concomitant medications CRF 
page will provide details including indication, dose, route, frequency, start and stop 
dates, prior/concomitant flag, active ingredient and ATC class.  
10. 
Efficacy Evaluation  
10.1 Anti-tumor Activity 
Anti-tumor activity measured by tumor shrinkage (based on sum of the diameter(s) of 
all target lesions from the CT or MRI scan evaluations) will be listed. Details of target 
lesions (method, lesion location and specification, description, longest and shortest 
diameter), non-target lesions (method, lesion location and specification, description, 
lesion status and specification) and new lesions (method, lesion site and specification 
and description) will be included. Response assessments including the target lesion 
overall response, non-target lesion overall response, new lesion status, overall response 
and date of disease progression will be listed in a separate listing. Disease response or 
progression should be evaluated according to the current published RECIST (Response 
Evaluation Criteria In Solid Tumors) version 1.1 (Eisenhauer et al., 20091). Baseline will 
be defined as the last assessment before the first IMP administration in the base 
trial.Local tumor assessment information available from the base trials will be included in 
these listings. 
Genmab - GCT1015-03                                                                   Version: 2.0
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Results obtained from an independent, central imaging review will be included when 
available. 
10.2  CA 125 (Ovarian cancer only) 
CA 125 values over time including the change from baseline from the initial trial will be 
listed. 
10.3 ECOG Performance Status 
ECOG performance status results will be listed.  
11. 
Safety Evaluation 
11.1 Extent of Exposure 
The listing of extent of exposure will include the treatment administration date and start 
and end times, the planned dose and planned total dose, dose adjusted (Yes/No) and 
reason (including AE and details for Other), actual dose administered, the actual volume 
infused, administration interrupted (Yes/No) including times and reason, planned dose 
administered (Yes/No) and reason if not and treatment label identifier. Number of 
infusions in this trial and in total since start in the base trial will be added as well as the 
cumulative dose since start of the treatment in the base trial. 
Exposure information from the base trials will be included in the listing.  
Ocular AE mitigation plan administrations in relation to infusions will be included in this 
listing. 
11.2 Adverse Events 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be graded according to the National Cancer Institute Common 
Terminology Criteria for AEs (NCI CTCAE criteria version 4.03, 2010).  
Adverse events will be listed including the reported term (verbatim), system organ class 
and preferred term, start and end date/time, start and end day relative to the date of 
the start date of treatment in the base trial, outcome, toxicity grade, seriousness, 
relationship to the trial treatment and infusion, action taken and if supporting clinically 
significant laboratory results.  
A flag will be added to mark if the AE occurs before the first IMP administration in this 
trial, or after the last IMP administration in this trial. In addition, flags will be added to 
mark ocular adverse events, overdose and medication errors and adverse events of 
special interest (Bleeding-related events, neuropathy and ocular events). 
11.3 Deaths and Serious Adverse Events  
The same listing as above will be repeated for: 
- 
Serious AEs 
- 
Fatal AEs 
- 
NCI CTCAE Grade 3/4 AEs 
- 
AEs leading to discontinuation of the IMP 
- 
Non-serious grade 2 or higher ocular events. 
Genmab - GCT1015-03                                                                   Version: 2.0
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All deaths will be listed separately including the source CRF page (fatal AEs, reason for 
withdrawal on End of trial form) and the death date.  
11.4 Neuropathy and Skin Assessment 
Neuropathy and skin assessment data will be listed. 
11.5 Ophthalmological Evaluations 
Visual acuity, Schirmer’s tear test, SLIT lamp, Intraocular pressure, Fundoscopy and 
overall evaluation results will be listed. 
11.6 Clinical Laboratory Data 
All laboratory results will be listed including the test name, result, unit and normal 
ranges. Supporting clinically significant laboratory results will be flagged.  
11.7 Vital Signs and ECG 
ECG measurements will be listed including the evaluation (Normal/Abnormal, not 
clinically significant/Abnormal, clinically significant). 
All vital signs results will be listed including a flag for clinically notable values for each of 
the following parameters: 
Clinically notable elevated values 
 
Systolic BP: >=180 mmHg and an increase >=20 mmHg from baseline 
 
Diastolic BP: >=105 mmHg and an increase >=15 mmHg from baseline. 
 
Weight: Increase from baseline of 10% 
 
Heart rate: >=120 bpm with increase from baseline of >=15 bpm 
 
Temperature: >38 °C 
Clinically notable below normal values 
 
Systolic BP: <=90 mmHg and a decrease >=20 mmHg from baseline 
 
Diastolic BP: <=50 mmHg and a decrease >=15 mmHg from baseline 
 
Weight: decrease from baseline of >=10% 
 
Heart rate: <=50 bpm with decrease from baseline of >=15 bpm  
 
Temperature: <35 °C 
11.8 Pregnancy Test 
All pregnancy test data will be listed. 
12. 
References 
1. 
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. 
2. Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for 
patients with progressive prostate cancer and castrate levels of testosterone: 
Recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 
2008; 26:1148-59. 
 
Genmab - GCT1015-03                                                                   Version: 2.0
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13. 
List of Tables/Graphs/Listings 
13.1 List of Statistical Tables 
Not applicable. 
13.2 List of Graphs 
Not applicable. 
13.3 List of Derived Data Listings 
 
General  
Listing 16.02.01.01: Screening Failures  
Listing 16.02.01.02: Patient Disposition 
Listing 16.02.01.03: Visits 
Listing 16.02.01.04: Protocol Deviations 
Listing 16.02.01.05: Inclusion/Exclusion Summary 
Listing 16.02.01.06: Demographic and Baseline Disease Characteristics 
Listing 16.02.01.07: Medical History 
Listing 16.02.01.08: Subsequent Cancer Therapies 
Listing 16.02.01.09: Prior and Concomitant Medications 
 
Efficacy Evaluation 
Listing 16.02.02.01: Target, Non-Target and New Lesions Information (Including all Assessments) 
Listing 16.02.02.02: Response Assessments Based on RECIST 
Listing 16.02.02.03: CA 125 Values  
 
 
Listing 16.02.02.04: ECOG Performance Scores 
 
Safety Evaluation 
 
Listing 16.02.03.01: 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: All Deaths 
Listing 16.02.03.06: NCI CTCAE Grade 3/4 Adverse Events 
Listing 16.02.03.07: Adverse Events Leading to Discontinuation of IMP 
Listing 16.02.03.08: Non-Serious Grade 2 or Higher Ocular Adverse Events 
Listing 16.02.03.09: Neuropathy and Skin Assessments 
Listing 16.02.03.10: Ophthalmological Evaluations 
Listing 16.02.03.11: Laboratory Results 
Listing 16.02.03.12: ECG Results 
Listing 16.02.03.13: Vital Signs 
Listing 16.02.03.14: Pregnancy Data 
 
 
 
Genmab - GCT1015-03                                                                   Version: 2.0
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14. 
Version history 
Version of the SAP and date 
Changes 
Final version 1.0, 3 March 2017 
NA. First final version. 
Final version 2.0, 16 January 
2019 
Updated to reflect changes to the protocol version 
3, 4 and 5: 
- 
Neuropathy and Skin Assessment 
- 
Ophtalmological Evaluations 
- 
Non-serious grade 2 or higher ocular events 
added 
- 
Populations removed 
- 
1Q3W schedule kept only 
Medical 
history, 
exposure 
data 
and 
tumor 
assessments data from the base trials are included. 
Listings on ECOG performance status and all deaths 
added. 
Ocular AE mitigation plan administrations added. 
Since no prostate cancer patients are enrolled, 
prostate specific parameters and listings (PSA and 
Radionuclide bone scan results) are removed. 
Other minor updates were done to clarify some 
sections. 
 
 
 
Genmab - GCT1015-03                                                                   Version: 2.0
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