Clinical trial NCT03657043
Conditions: Ovarian Cancer Fallopian Tube Cancer Peritoneal Cancer
Keywords: Platinum-resistant Antibody drug conjugate Tisotumab vedotin PROC Seattle Genetics
Sponsor: Seagen Inc.
Start date: 2019-03-20; Completion date: 2022-02-08
Enrollment: 98 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial will study tisotumab vedotin to find out what its side effects are and to see if it works for platinum-resistant ovarian cancer (PROC). It will test different doses of tisotumab vedotin that are given at different times. It will also compare the side effects and ability to treat tumors of these different doses and schedules. In this study, there will be a safety run-in group of approximately 12 patients that will look at a dose-dense treatment schedule. In a dose-dense schedule, smaller doses are given more frequently. In addition to the safety run-in patients, there will be three groups in the study. One group will get tisotumab vedotin once every 3 weeks (21-day cycles). The two other groups will get tisotumab vedotin once a week for 3 weeks followed by 1 week off (28-day cycles).

Detailed description:
The study objectives are to evaluate the safety, antitumor activity, and pharmacokinetics of tisotumab vedotin (TV) administered every 3 weeks or on Days 1, 8, and 15 of every 4-week cycle (3Q4W) for patients with epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer that has relapsed within 6 months of the completion of platinum-based treatment and determined to be platinum resistant. All patients must have PROC and be eligible for single agent chemotherapy.

The safety run-in period will evaluate the safety of a weekly schedule. The highest dose level that is considered safe will be the recommended phase 2 dose (RP2D) and will be used in Part A. In Part A, participants will be randomized in a 1:1 ratio to receive tisotumab vedotin intravenously (IV) every 3 weeks (Q3W regimen) or the safety run-in RP2D on Days 1, 8, and 15 of every 4-week cycle (weekly regimen; 3Q4W) if a RP2D has been identified. Participants who enroll in Part B will receive tisotumab vedotin on Days 1, 8, and 15 of every 4-week cycle (weekly regimen) at a pre-specified dose level, if the dose level is considered safe and tolerable in the safety run-in period.

Arms: arm 1: 28-day, 3 dose cycle arm 2: 21-day, single dose cycle arm 3: 28-day, 3 dose cycle arm 4: 28-day, 3 dose cycle
Interventions: intervention 1: tisotumab vedotin
Intervention descriptions: intervention 1: Intravenous (IV) infusion

Protocol documents:
Prot_000.pdf: 


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PROTOCOL SYNOPSIS
Protocol Number 
SGNTV-002
Version 
Amendment 4, 24 Aug 2020
Phase
2
Product Name
Tisotumab vedotin
Study Name
innovaTV 208
Sponsor
Seattle Genetics, Inc.
21823 30th Drive SE
Bothell, WA 98021, USA
Protocol Title
Open Label Phase 2 Study of Tisotumab Vedotin for Patients with Platinum-Resistant Ovarian Cancer with a 
Safety Run-in of a Dose-Dense Regimen
Study Objectives
The study objectives are to evaluate the safety, antitumor activity, and pharmacokinetics of tisotumab vedotin 
(TV) administered every 3 weeks (Q3W) or on Days 1, 8, and 15 of every 4-week cycle (3Q4W [dose-dense 
regimen]) for patients with epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer that has 
relapsed within 6 months of the completion of platinum-based treatment (hereafter collectively referred to as 
platinum-resistant ovarian cancer and abbreviated as PROC).
Primary Outcome Measures
●
(Safety Run-In) Safety and tolerability of a dose-dense regimen of tisotumab vedotin, as measured by 
incidence of dose limiting toxicities (DLTs) or other unacceptable toxicities.
●
(Parts A and B) Confirmed objective response rate (ORR) using Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1
Secondary Outcome Measures (Parts A and B)
●
Safety and tolerability of tisotumab vedotin as measured by type, incidence, severity, seriousness, and 
relatedness of adverse events (AEs)
●
Confirmed and unconfirmed ORR (all responses)
●
Cancer Antigen 125 (CA-125) response rate according to Gynecologic Cancer Intergroup (GCIG) criteria
●
Overall response according to GCIG combined RECIST and CA-125 criteria
●
Duration of response (DOR) 
●
Disease control rate (DCR), proportion of patients with complete response (CR), partial response (PR), or 
stable disease (SD). SD patients will be included if maintained for a minimum of 12 weeks.
●
Time to response (TTR)
●
Progression-free survival (PFS)
●
Overall survival (OS)
●
Pharmacokinetic (PK) parameters and the incidence of antitherapeutic antibodies (ATA)
Additional (Parts A and B)
●
Tissue Factor (TF) expression-response relationship
●
Biomarkers of biological activity and resistance and predictive biomarkers of response
●
In Part A and B US patients only, patient-reported outcomes as measured by an NCI PRO-CTCAE 
questionnaire customized to focus on visual symptoms, gastrointestinal symptoms, and bleeding, as well 
as Patient-Reported Outcomes Measurement Information System (PROMIS) version 2.0, short form 6b 
and other questions added by the sponsor.


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Study Population
All patients must have PROC, defined as progression within 6 months from completion of platinum-containing 
therapy, and must be eligible for single agent chemotherapy. Safety run-in patients may have received more 
than 1 systemic treatment regimen for PROC. Patients eligible for Parts A and B patients must have received 1
to 3 prior anticancer lines of therapy overall, including at least 1 line of therapy containing bevacizumab or a
biosimilar to bevacizumab.
Patients must have measurable disease at baseline according to RECIST v1.1. An Eastern Cooperative 
Oncology Group (ECOG) performance status of 0 or 1 and adequate cardiovascular, central nervous system 
(CNS), renal, and hematological function (including coagulation parameters) are required at baseline. Patients 
may not have active bleeding conditions, uncontrolled pleural/pericardial effusions, uncontrolled tumor-related 
pain, peripheral neuropathy ≥ Grade 2, or ocular surface disease at the time of enrollment. Tumor TF expression 
will not be evaluated at screening or required for enrollment.
Number of Planned Patients
Approximately 222 patients may be enrolled in the study. This includes approximately 12 patients in the safety 
run-in phase as well as approximately 30 patients in each of 2 Part A cohorts with a possible expansion of up to 
approximately 70 additional patients in one of the 2 Part A cohorts. Part B will enroll approximately 80 patients
including approximately 60 patients who have received 1 to 3 prior lines of therapy, including bevacizumab
treatment.
Study Design
This is an open-label, phase 2 study with an initial safety run-in period. The safety run-in period will evaluate 
the safety of a dose-dense schedule and will start at a 0.9 mg/kg dose level. If 0.9 mg/kg is considered safe and 
tolerable, the dose level will be escalated to 1.2 mg/kg. Otherwise it will be de-escalated to 0.65 mg/kg. Each 
dose level will enroll approximately 6 patients. Patients who do not complete the DLT period will be replaced.
A dose level is considered safe and tolerable if no more than 1 patient experiences a DLT among 6 patients 
during the DLT period. The highest dose level that is considered safe will be the recommended phase 2 dose 
(RP2D) and will be used in Part A. If no RP2D for the dose-dense schedule is identified, Part A will be a single 
arm of the Q3W regimen and Part B will not enroll.
In Part A, 60 patients will be randomized in a 1:1 ratio to receive tisotumab vedotin 2.0 mg/kg intravenously 
(IV) every 3 weeks (Q3W regimen) or the safety run-in RP2D on Days 1, 8, and 15 of every 4-week cycle 
(dose-dense regimen; 3Q4W) if a RP2D has been identified. Randomization will be stratified by first line vs. 
second line PROC and histology (serous vs. non-serous).
Based upon antitumor activity and safety data, one Part A treatment arm may be expanded to enroll up to an 
additional 70 patients to further characterize safety and antitumor activity of tisotumab vedotin for patients with 
PROC. The analysis to support expansion will be conducted when approximately 30 patients per arm have at 
least one post-baseline response assessment per RECIST v1.1 or have discontinued from the study or started 
subsequent cancer therapy.
Part B will enroll approximately 80 patients with PROC including approximately 60 patients who have received
1 to 3 prior lines of therapy, including bevacizumab treatment. Part B will further characterize the long-term 
efficacy, safety, and PK of 0.9 mg/kg tisotumab vedotin on Days 1, 8, and 15 of every 4-week cycle 
(dose-dense regimen) if the 0.9 mg/kg dose level is considered safe and tolerable in the safety run-in period.
Enrollment in this cohort may discontinue when Part A begins enrollment.
Interim futility analysis will be performed on Part B after at least 20 patients with 1 to 3 prior lines of therapy,
including bevacizumab treatment, have been treated and had at least one response assessment post-baseline. The 
Bayesian predictive probability approach will be used to assess the futility criteria. Based on activity and safety 
data, together with the predictive probability of success (PPoS), a cohort may be stopped early by the sponsor. 
A cohort may also be discontinued at any point at the discretion of the sponsor.
On a periodic basis, a Safety Monitoring Committee (SMC) will monitor the safety of patients participating in 
the trial. The SMC will be responsible for evaluating the results of safety analyses and will make 


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recommendations to the sponsor. Ongoing, real-time review of patient safety and serious adverse events (SAEs) 
will also be conducted by the sponsor’s Drug Safety department throughout the study.
During the safety run-in period, the SMC will assess tolerability and safety of tisotumab vedotin (refer to SMC 
charter for additional details) at the end of the DLT period for each dose level. Ad hoc meetings of the SMC 
may be convened prior to the safety evaluation period if safety data indicate.
An individual’s dose may be modified based upon treatment-related AEs. Response will be assessed every 
6 weeks for the first 6 months, every 12 weeks for the next 6 months, and then every 6 months after that. 
RECIST v1.1 will be used by the investigator to score responses for primary and secondary endpoints as well as 
progression. Objective responses will be confirmed with repeat scans at least 4 weeks after the first 
documentation of response. The study will be closed 3 years after the last patient is enrolled or when no patients 
remain in long-term follow-up, whichever comes first. Additionally, the sponsor may terminate the study at any 
time.
Investigational Product, Dose, and Mode of Administration
For the dose-dense regimen, tisotumab vedotin will be administered at a dose of 0.9 mg/kg or 1.2 mg/kg as a 
30–60 minute IV infusion on Days 1, 8, and 15 of every 4-week cycle. For patients weighing more than 100 kg, 
dosing will be capped at 90 mg or 120 mg for the 0.9 or 1.2 mg/kg doses, respectively, per infusion. If the dose 
for the dose-dense regimen is de-escalated to 0.65 mg/kg, the maximum dose will be capped at 65 mg per 
infusion.
For the Q3W regimen, tisotumab vedotin will be administered at a dose of 2.0 mg/kg as a 30–60 minute IV 
infusion on Day 1 of each 3-week treatment cycle. For patients weighing more than 100 kg, dosing will be 
capped at 200 mg per infusion.
Duration of Treatment
Patients will continue to receive study treatment until disease progression, unacceptable toxicity, investigator 
decision, consent withdrawal, start of a subsequent anti-cancer therapy, study termination by the sponsor, 
pregnancy, or death, whichever comes first.
Efficacy Assessments
Antitumor activity will be assessed by radiographic tumor imaging at protocol-specified time points. Response 
assessment for primary and secondary efficacy endpoints will be evaluated by the investigator using 
RECIST v1.1. Patients will be followed for response assessments until disease progression, subsequent cancer 
therapy, consent withdrawal, study termination by the sponsor, or death, whichever comes first.
In addition to radiographic tumor assessments, expression level of CA-125 will also be monitored to assess 
response rate by CA-125 and the combination response of ORR/CA-125 as secondary endpoints.
Pharmacokinetic and Immunogenicity Assessments
Patient serum and plasma samples will be obtained for tisotumab vedotin PK and ATA evaluation at protocol
specified- time points. Concentrations of tisotumab vedotin, total antibody, and monomethyl auristatin 
E (MMAE) will be measured in plasma and ATA in serum.
Biomarker Assessments 
Blood and fresh and/or archival tumor samples will be collected at protocol-specified time points. Biomarker 
analysis will not be utilized for patient selection. Biomarker assessments in tumor tissue may include, but are 
not limited to: measurement of TF protein, mRNA expression, disease subtype, tumor immune 
microenvironment, and tumor mutational load. Assessments in blood may include, but are not limited to: cancer 
markers such as CA-125, cytokine measurements, abundance and phenotypes of immune cell subsets, and 
circulating nucleic acids. Methods of analysis may include immunohistochemistry (IHC), PCR and T-cell 
receptor beta chain sequencing, multiplex immune histofluorescence, mutation and gene expression profiling, 
Next Generation Sequencing, flow cytometry, and proteomic methodologies such as enzyme-linked 
immunosorbent assay (ELISA) and microvesicle- assessment.


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Safety Assessments
Safety assessments will include the surveillance and recording of AEs, physical examination findings, eye 
examinations, vital signs, electrocardiograms (ECGs), concomitant medications, pregnancy testing, and 
laboratory tests. Safety assessments will be performed while the patient continues to receive treatment. 
On a periodic basis, a safety monitoring committee (SMC) will monitor the safety of patients participating in 
the trial.
Statistical Methods
The primary analysis of the study will be performed when all treated patients have been followed for at least 
6 months or come off study, whichever comes first. Patients enrolled in the safety run-in and Parts A and B of 
the study will be summarized separately.
Safety measurements will be summarized by descriptive statistics based on the safety analysis set. The safety 
analysis set will include all patients who received any amount of study treatment.
The primary endpoint of Parts A and B is the confirmed ORR per RECIST v1.1. The confirmed ORR will be 
estimated for each cohort based on the full analysis set, comprising all patients who received any amount of 
study treatment. The 95% exact confidence intervals (CIs) using the Clopper-Pearson method will be provided.
Interim futility analysis will be performed on Part B after at least 20 patients with 1 to 3 prior lines of therapy, 
including bevacizumab, have been treated and had at least one response assessment post-baseline. The Bayesian 
predictive probability approach will be used to determine the futility criteria. Based on activity and safety data, 
together with the PPoS, a cohort may be stopped early by the sponsor. A cohort or Part may also be 
discontinued at any point at the discretion of the sponsor.
For a sample size of 30 patients (Part A) and 60 patients (Part B with 1 to 3 prior lines of therapy, including 
bevacizumab treatment) per cohort (or 100 patients, if a treatment arm from Part A is expanded), assuming the 
confirmed ORR is between 20% and 40%, the 2-sided 95% exact CIs are summarized below:
Confirmed ORR
95% Exact CI (N=30)
95% Exact CI (N=60)
95% Exact CI (N=100)
15%
(4%, 31%)
(7%, 27%)
(9%, 24%)
20%
(8%, 39%)
(11%, 32%)
(13%, 29%)
30%
(15%, 49%)
(19%, 43%)
(21%, 40%)
40%
(23%, 59%)
(28%, 53%)
(30%, 50%)


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TABLE OF CONTENTS
PROTOCOL SYNOPSIS .......................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.......................................................................10 
1 
INTRODUCTION.........................................................................................................................................12 
1.1 
Patient Population...............................................................................................................................12 
1.2 
Tissue Factor ......................................................................................................................................12 
1.2.1 
Role of Tissue Factor in Malignancy ...................................................................................13 
1.3 
Tisotumab Vedotin .............................................................................................................................14 
1.3.1 
Mechanism of Action...........................................................................................................14 
1.3.2 
Preclinical Experience with Tisotumab Vedotin ..................................................................14 
1.3.3 
Clinical Experience With Tisotumab Vedotin......................................................................14 
1.4 
Benefit Risk Assessment ....................................................................................................................20 
2 
OBJECTIVES ...............................................................................................................................................21 
3 
INVESTIGATIONAL PLAN .......................................................................................................................22 
3.1 
Summary of Study Design..................................................................................................................22 
3.1.1 
Dose-Limiting Toxicity........................................................................................................24 
3.2 
Discussion and Rationale for Study Design........................................................................................25 
3.2.1 
Method of Assigning Patients to Treatment Groups ............................................................26 
3.2.2 
Rationale for Selection of Doses ..........................................................................................26 
3.2.3 
Retreatment ..........................................................................................................................27 
3.2.4 
Blinding and Unblinding......................................................................................................27 
4 
STUDY POPULATION................................................................................................................................27 
4.1 
Inclusion Criteria ................................................................................................................................27 
4.2 
Exclusion Criteria...............................................................................................................................29 
4.3 
Childbearing Potential ........................................................................................................................32 
4.4 
Removal of Patients From Therapy or Assessment............................................................................32 
4.4.1 
Discontinuation of Study Treatment ....................................................................................32 
4.4.2 
Patient Withdrawal From Study ...........................................................................................32 
5 
TREATMENTS ............................................................................................................................................32 
5.1 
Treatments Administered....................................................................................................................32 
5.2 
Investigational Product.......................................................................................................................33 
5.2.1 
Description ...........................................................................................................................33 
5.2.2 
Dose and Administration......................................................................................................33 
5.2.3 
Dose Modifications ..............................................................................................................34 
5.3 
Mitigation Plans for Specific Adverse Events....................................................................................35 
5.3.1 
Ocular Adverse Events.........................................................................................................35 
5.3.2 
Infusion-Related Reactions ..................................................................................................39 
5.3.3 
Other Adverse Events...........................................................................................................39 
5.3.4 
Storage and Handling...........................................................................................................41 
5.3.5 
Packaging and Labeling .......................................................................................................41 
5.3.6 
Preparation ...........................................................................................................................41 
5.4 
Required Ocular Premedication and Preventive Eye Therapy............................................................42 
5.5 
Concomitant Therapy .........................................................................................................................42 
5.5.1 
Required Concomitant Therapy ...........................................................................................43 
5.5.2 
Allowed Concomitant Therapy ............................................................................................43 
5.5.3 
Prohibited Concomitant Therapy .........................................................................................44 
5.6 
Management of Adverse Reactions ....................................................................................................44 
5.6.1 
Management of Infusion Reactions......................................................................................44 
5.6.2 
Management of Overdose ....................................................................................................45 
5.7 
Treatment Compliance .......................................................................................................................45 
6 
STUDY ACTIVITIES...................................................................................................................................45 
6.1 
Schedule of Events .............................................................................................................................45 


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6.2 
Screening Visit (Days [–28] to 1).......................................................................................................46 
6.2.1 
Baseline Visit (Days –7 to Day 1)........................................................................................46 
6.3 
Treatment Period (Q3W Regimen only).............................................................................................47 
6.3.1 
Day 1 (±1 day), All treatment cycles (exceptions noted) .....................................................47 
6.3.2 
Cycle 1 and 2, Day 2 ............................................................................................................48 
6.3.3 
Cycle 1 and 2, Day 3 ............................................................................................................48 
6.3.4 
Cycle 1 Day 8 (±1 day) ........................................................................................................48 
6.3.5 
Cycle 1 and 2, Day 15 ..........................................................................................................48 
6.3.6 
Cycle 2, Day 8 (±1 day) .......................................................................................................49 
6.4 
Treatment Period (Dose-Dense Regimen only)..................................................................................49 
6.4.1 
Day 1 (±1 day), All Treatment Cycles (Exceptions Noted) .................................................49 
6.4.2 
Cycles 1 and 2, Day 2...........................................................................................................50 
6.4.3 
Cycles 1 and 2, Day 3...........................................................................................................50 
6.4.4 
All Treatment Cycles, Day 8 (±1 day) (Exceptions Noted) .................................................50 
6.4.5 
All Treatment Cycles, Day 15 (±1 day) (Exceptions Noted) ...............................................51 
6.4.6 
Cycle 1, Day 17....................................................................................................................51 
6.4.7 
Cycle 1, Day 22 (±1 day) .....................................................................................................52 
6.5 
Response Assessments .......................................................................................................................52 
6.6 
End of Treatment Visit (30 to 37 days after last dose of study drug) .................................................52 
6.7 
Follow-up (Every 12 weeks ±1 week)................................................................................................53 
6.8 
End of Study/End of Follow-up..........................................................................................................53 
7 
STUDY ASSESSMENTS.............................................................................................................................53 
7.1 
Screening/Baseline Assessments ........................................................................................................53 
7.1.1 
Biopsy Collection.................................................................................................................54 
7.2 
Response/Efficacy Assessments.........................................................................................................54 
7.3 
Pharmacokinetic and Immunogenicity Assessments ..........................................................................55 
7.4 
Patient-Reported Outcomes Assessments...........................................................................................55 
7.5 
Biomarker Studies ..............................................................................................................................56 
7.5.1 
Protein Markers in Blood .....................................................................................................56 
7.5.2 
Characterization of Tumor Tissue........................................................................................56 
7.6 
Biospecimen Repository.....................................................................................................................57 
7.7 
Safety Assessments.............................................................................................................................57 
7.7.1 
Vital Signs............................................................................................................................58 
7.7.2 
Clinical Laboratory Tests .....................................................................................................58 
7.7.3 
Physical Examination...........................................................................................................59 
7.7.4 
Ophthalmological Exam.......................................................................................................59 
7.7.5 
Eye Examination ..................................................................................................................59 
7.7.6 
Pregnancy Testing................................................................................................................59 
7.7.7 
Electrocardiogram ................................................................................................................59 
7.7.8 
Adverse Events.....................................................................................................................60 
7.8 
Appropriateness of Measurements......................................................................................................66 
8 
DATA QUALITY CONTROL AND QUALITY ASSURANCE ................................................................66 
8.1 
Site Training and Monitoring Procedures...........................................................................................66 
8.2 
Data Management Procedures ............................................................................................................67 
8.3 
Access to Source Data ........................................................................................................................67 
8.4 
Accuracy and Reliability of Data........................................................................................................67 
8.5 
Quality Assurance Procedures............................................................................................................68 
8.6 
Data Handling and Record Keeping ...................................................................................................68 
8.6.1 
Data Handling ......................................................................................................................68 
8.6.2 
Investigator Record Retention..............................................................................................68 
9 
DATA ANALYSIS METHODS...................................................................................................................68 
9.1 
Determination of Sample Size............................................................................................................68 
9.2 
Study Endpoint Definitions ................................................................................................................69 
9.2.1 
Confirmed ORR ...................................................................................................................69 


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9.2.2 
Confirmed and Unconfirmed ORR ......................................................................................69 
9.2.3 
CA-125 Response Rate ........................................................................................................69 
9.2.4 
Combined RECIST/CA-125 Overall Response ...................................................................69 
9.2.5 
Disease Control Rate............................................................................................................70 
9.2.6 
Duration of Response ...........................................................................................................70 
9.2.7 
Time to Response.................................................................................................................71 
9.2.8 
Progression-Free Survival ....................................................................................................71 
9.2.9 
Overall Survival ...................................................................................................................71 
9.3 
Statistical and Analytical Plans ..........................................................................................................71 
9.3.1 
General Considerations ........................................................................................................71 
9.3.2 
Patient Disposition ...............................................................................................................73 
9.3.3 
Patient Characteristics ..........................................................................................................74 
9.3.4 
Efficacy Analyses.................................................................................................................74 
9.3.5 
Pharmacokinetic and Immunogenicity Analyses..................................................................74 
9.3.6 
Biomarker Analyses .............................................................................................................74 
9.3.7 
Patient-Reported Outcomes Analyses ..................................................................................74 
9.3.8 
Safety Analyses....................................................................................................................75 
9.3.9 
Interim Analyses ..................................................................................................................76 
10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY CONSIDERATIONS .................77 
10.1 Informed Consent ...............................................................................................................................77 
10.2 Ethical Review....................................................................................................................................78 
10.3 Regulatory Considerations..................................................................................................................78 
10.3.1 
Investigator Information.......................................................................................................78 
10.3.2 
Protocol Amendments and Study Termination ....................................................................78 
10.4 Study Documentation, Privacy, and Records Retention .....................................................................79 
10.5 Clinical Trial Agreement ....................................................................................................................79 
11 REFERENCES..............................................................................................................................................80 
APPENDIX A: SCHEDULE OF EVENTS .........................................................................................................83 
APPENDIX B: PK, ATA, AND BIOMARKER SAMPLING TIME POINTS...................................................87 
APPENDIX C: OCULAR SAFETY MEASURES..............................................................................................89 
APPENDIX D: PATIENT-REPORTED OUTCOMES SURVEYS (PARTS A AND B US PATIENTS ONLY)
.......................................................................................................................................................................91 
APPENDIX E: PERFORMANCE STATUS SCALES CONVERSION.............................................................96 
APPENDIX F: GUIDANCE ON CONTRACEPTION .......................................................................................97 
APPENDIX G: RECIST CRITERIA SUMMARY (VERSION 1.1)...................................................................98 
APPENDIX H: NEW YORK HEART ASSOCIATION CLASSIFICATION ....................................................99 
APPENDIX I: CALCULATION OF PREDICTIVE PROBABILITY OF SUCCESS......................................100 
APPENDIX J: INVESTIGATOR SIGNATURE PAGE....................................................................................101 
APPENDIX K: DOCUMENT HISTORY..........................................................................................................102 


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LIST OF IN-TEXT TABLES
Table 1: 
Frequency of conjunctivitis* by CTCAE toxicity grading before and after Dec-2016 – subjects 
dosed Q3W....................................................................................................................................17 
Table 2: 
Objectives and corresponding endpoints .......................................................................................22 
Table 3: 
Dose modification scheme: Dose-dense regimen..........................................................................34 
Table 4: 
Dose modification scheme: Q3W regimen....................................................................................34 
Table 5: 
Dose modification and toxicity management guidelines – ocular AEs .........................................36 
Table 6: 
Dose modification and toxicity management for infusion-related reactions .................................39 
Table 7: 
Dose modification and toxicity management for other AEs associated with tisotumab vedotin...40 
Table 8: 
Overall response by RECIST and CA-125 criteria........................................................................70 
Table 9: 
PPoS based on responses among the first 20 patients pretreated with bevacizumab.....................76 
Table 10: 
Operating characteristics of predictive probability design ............................................................77 
LIST OF IN-TEXT FIGURES
Figure 1: 
Frequency of the conjunctivitis* by CTCAE toxicity grading before and after Dec-2016 –
subjects dosed Q3W ......................................................................................................................18 
Figure 2: 
Study design ..................................................................................................................................24 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
3Q4W
three times every 4 weeks
ADC
antibody-drug conjugate
AE
adverse event
AESI
adverse events of special interest
ALT
alanine aminotransferase
ASA
acetylsalicyclic acid
AST
aspartate aminotransferase
ATA
antitherapeutic antibodies
AUC
area under the curve
β-hCG
beta human chorionic gonadotropin 
CA 125
Cancer antigen 125
Cmax
maximum concentration
CBC
complete blood count
CFR
Code of Federal Regulations
CI
confidence interval
CNS
central nervous system
CR
complete response
CRF
case report form
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DCR
disease control rate
DILI
drug-induced liver injury
DLT
dose limiting toxicity
DOR
duration of response
DVT
deep vein thrombosis
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EE
efficacy-evaluable
EGFR
epidermal growth factor receptor
ELISA
enzyme-linked immunosorbent assay
EOT
end of treatment
FAS
full analysis set
FIX
Factor IX
FVII
Factor VII
FX
Factor X
GCIG
Gynecologic Cancer Intergroup
HgbA1c
hemoglobin A1c
ICH
International Council for Harmonisation 
IEC
independent ethics committee
IHC
immunohistochemistry
IND
investigational new drug
INR
international normalized ratio
IRB
institutional review board
IRR
infusion-related reaction
IV
intravenous


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MDRD
Modification of Diet in Renal Disease
MMAE
monomethyl auristatin E
MRI
magnetic resonance imaging
NCI CTCAE
National Cancer Institute’s Common Terminology Criteria for Adverse Events
OMP
ocular mitigation plan
ORR
objective response rate
OS
overall survival
PAR-2
protease activated receptor 2
PBMC
peripheral blood mononuclear cells
PD
progressive disease
PD-L1
Programmed Death-Ligand 1
PE
pulmonary embolism
PFS
progression-free survival
PK
pharmacokinetic
PPoS
predictive probability of success
PR
partial response
PROC
platinum-resistant ovarian cancer
PT
prothrombin time
aPTT
active partial thromboplastin time
Q3W
every 3 weeks
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SAP
statistical analysis plan
Scr
serum creatinine
SD
stable disease
SMC
Safety Monitoring Committee
TF
Tissue Factor
TTR
time to response
TV
tisotumab vedotin
ULN
upper limit of normal
VEGF
vascular endothelial growth factor


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1
INTRODUCTION
1.1
Patient Population
Epithelial cancers of the ovary, fallopian tube, and of peritoneal origin in women exhibit 
similar biology, clinical characteristics and behavior. As such, these are often collectively 
referred to as epithelial ovarian cancer (EOC) in clinical trials and clinical practice.
Despite initial therapy, the vast majority of women with ovarian cancer will relapse and 
require subsequent therapy. Platinum-free interval is a strong predictor of treatment success 
in recurrent ovarian cancer (Pujade-Lauraine 2011). Patients whose disease relapses within 
6 months after platinum-containing therapy are categorized as having platinum-resistant 
disease. At first relapse, approximately 25% of the patients have platinum-resistant ovarian 
cancer (PROC), and the vast majority of patients with recurrent disease will eventually 
develop PROC (Slaughter 2016).
Treatment combining double agent chemotherapy with the VEGF receptor antibody 
bevacizumab has become standard of care for women with PROC, despite a lack of evidence 
that it prolongs overall survival (OS) (Pujade-Lauraine 2014). Ideal patients for 
chemotherapy plus bevacizumab include those women who have received less than 2 prior 
regimens, have not received bevacizumab previously, and have no history of bowel 
obstruction within six months (Pujade-Lauraine 2014). For patients that relapse from or are 
not eligible for this combination treatment, options are limited primarily to single agent
chemotherapy (Pujade-Lauraine 2014).
For patients who relapse after first-line therapy for PROC and are fit enough to receive 
subsequent treatment there is no standard of care. Clinical benefit, as measured by 
progressive-free survival (PFS) and OS, diminishes significantly below even the poor 
prognosis of first-line treatment as the line of therapy increases (Hanker 2012). Thus, there is 
an urgent need for more effective therapies for the treatment of PROC, particularly for
patients previously treated with bevacizumab.
1.2
Tissue Factor
Human Tissue Factor (TF), also called thromboplastin, CD142 or coagulation factor III is a 
43–47 kDa, single chain, transmembrane glycoprotein. TF is the main initiator of the 
extrinsic pathway of blood coagulation, which starts when TF binds to serine protease factor 
VII (FVII) or activated FVIIa. The TF:FVIIa complex initiates blood coagulation by 
proteolytic cleavage of factor X (FX) to FXa, and factor IX (FIX) to 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 proangiogenic factors and proinflammatory 
mediators such as VEGF and interleukin-8.
Constitutive TF expression is mostly restricted to subendothelial cells (such as pericytes, 
smooth muscle cells and fibroblasts) that only interact with blood borne FVIIa when vascular 
integrity is compromised (Drake 1989). TF is expressed in the vessel walls of a wide range of 


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organs, with moderate to high levels observed in the brain, heart, intestine, kidney, lung, 
placenta, uterus, and testes. Its 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 (Drake 1989;
Flossel 1994; Imokawa 1997). Under pathological, inflammatory conditions TF is aberrantly 
expressed, including but not limited to bullous pemphigoid, urticaria (primarily on 
eosinophils), (Cugno 2009; Marzano 2011; Marzano 2009), inflammatory gastrointestinal 
diseases including Crohn’s disease and ulcerative colitis (More 1993), and lung diseases 
including acute respiratory distress syndrome (Bastarache 2007).
1.2.1 Role of Tissue Factor in Malignancy
TF has a central physiological role in initiation of the coagulation cascade but, during 
oncological transformation, it is upregulated and expressed on the membranes of neoplastic 
cells and tumor-associated endothelial cells. Under pathological conditions, membranous TF 
can be aberrantly expressed. The pathological presence of TF in cancer cells promotes tumor
initiated- thrombosis and cancer metastasis (Zhang 2017). Indications where tumor cells are
known to express TF include gynecological and genito-urinary tumors such as cervical, 
ovarian, and prostate cancer as well as squamous cell carcinoma of the head and neck, non
small- cell lung cancer, esophageal and colorectal tumors, breast cancer, malignant 
melanoma, and pancreatic cancer (Akashi 2003; Ohta 2002) (Chen 2010; Clouston 2016a;
Clouston 2016b; Clouston 2016c; Cocco 2011a; Cocco 2011b; Khorana 2007; Sawada 1999;
Uno 2007; Yokota 2009).
TF is expressed widely in ovarian cancer. In one study, TF was expressed in 27 of 32 (84%) 
of newly diagnosed ovarian cancer patients with stage I to IV disease. High TF expression 
correlated with incidence of venous thromboembolism (VTE), a common complication of 
ovarian cancer that occurs in as many as 42% of patients (Uno 2007) (Abu Saadeh 2013).
The same association with VTE was found in a separate study that showed TF expression to 
be highest in clear cell carcinoma and endometroid carcinoma when compared with benign 
ovarian tumors (Abu Saadeh 2013). A different analysis reported TF expression in 24 of 25 
(96%) ovarian cancer samples of stage I to IIIC disease, while no staining was found in 
normal ovarian tissue (Cocco 2011b). Immunohistochemical analysis of 48 primary ovarian 
tumor tissue microarrays showed membranous TF expression in 40% of these samples 
(sponsor’s internal data).
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 (Han 2006; Nitori 2005; Patry 2008). Experimental studies suggest that 
tumor cells may benefit from both TF pro-coagulant activity and TF-induced PAR-2
signaling, for example through enhanced metastatic potential, angiogenesis, and cell survival 
(Kasthuri 2009; Ruf 1996). Furthermore, monoclonal antibodies that inhibit either TF:FVIIa 
intracellular signaling or TF pro-coagulant capacity could reduce tumor growth in vivo 
(Versteeg 2008).


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1.3
Tisotumab Vedotin
Tisotumab vedotin is an antibody-drug conjugate (ADC) being developed for patients with 
tumors known to express TF, including ovarian cancer and other tumor types. It is composed 
of a TF-targeted human monoclonal immunoglobulin G1 (subtype κ) conjugated via a 
protease-cleavable valine citrulline linker to the drug monomethyl auristatin E (MMAE), a 
dolastatin 10 analog (Doronina 2003; Hamblett 2004; Sun 2005). Dolastatins and auristatins 
belong to a class of chemotherapies that act as microtubule disrupting agents.
1.3.1 Mechanism of Action
Tisotumab vedotin binds efficiently to human TF-expressing cells and is rapidly internalized 
into tumor cells where it undergoes lysosomal degradation resulting in release of the 
cytotoxic payload. Upon lysosomal degradation, tisotumab vedotin can induce bystander 
killing as a result of diffusion of free MMAE over the cell membrane, leading to cytotoxicity 
against neighboring tumor cells. In a biodistribution study in xenograft models, tisotumab 
vedotin effectively accumulated in TF-positive, but not TF-negative, tumors (sponsor’s 
internal data).
1.3.2 Preclinical Experience with Tisotumab Vedotin
Tisotumab vedotin treatment resulted in potent and long-lasting tumor regression in TF
expressing xenograft models derived from a variety of solid cancers, including -patient
derived- xenograft models with heterogeneous TF expression. Moreover, potent tumor 
regression was observed in xenograft models of bladder, lung, cervical, and ovarian cancer 
that had received prior treatment with paclitaxel.
Due to the mode of action of tisotumab vedotin, its potential impact on TF-dependent 
coagulation was investigated in vitro in a series of coagulation assays. These included an 
activated factor X (FXa) generation assay, the standard prothrombin time assay, a clotting 
assay, thromboelastography (TEG), and a thrombin generation assay. Overall, only relatively 
minor impact of HuMax-TF on TF-mediated coagulation was observed. However, in vivo at 
clinically relevant or maximally tolerated doses of tisotumab vedotin in cynomolgus 
monkeys (≤5 mg/kg), no bleeding events were observed and prothrombin time and aPTT 
coagulation parameters were unaffected by treatment with tisotumab vedotin.
Tisotumab vedotin caused reversible skin changes in cynomolgus monkeys at doses of 
≥5 mg/kg, but, apart from this, the safety profile was consistent with MMAE/tubulin-
disrupting agents.
Further details on nonclinical studies can be found in the tisotumab vedotin Investigator’s 
Brochure.
1.3.3 Clinical Experience With Tisotumab Vedotin
Tisotumab vedotin has been investigated in two Phase 1/2 clinical trials, GEN701 and 
GEN702. Each trial consists of a dose escalation part and a cohort expansion part. The dose 
escalation part has been finalized for both trials and the cohort expansion part is ongoing for 


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GEN701. Enrollment in GEN702 has discontinued. As of 17 August 2017, 207 patients had 
been enrolled across both trials.
GEN701
Dose escalation (Part I) has completed. A total of 27 patients were dosed, all on a Q3W 
schedule: 0.3 mg/kg (3 patients), 0.6 mg/kg (3 patients), 0.9 mg/kg (3 patients), 1.2 mg/kg 
(3 patients), 1.5 mg/kg (3 patients), 1.8 mg/kg (3 patients), 2.0 mg/kg (3 patients), and 
2.2 mg/kg (6 patients). Among the 2.2 mg/kg dose group, 3 dose-limiting toxicities (DLTs) 
were reported in 3 patients (diabetes mellitus type II, mucositis, and neutropenic fever, all 
Grade 3). Based on these DLTs, the maximal tolerated dose (MTD) on a Q3W schedule was 
defined as 2.0 mg/kg.
Dose expansion (Part II) is ongoing. This portion of the study is an open label evaluation of 
the MTD of 2.0 mg/kg dosed Q3W in patients with relapsed, advanced and/or metastatic 
cancer of the ovary, cervix, endometrium, bladder, prostate, esophagus, squamous cell 
carcinoma of the head and neck, or NSCLC who have failed available standard therapy or 
who are not candidates for standard therapy. At the time of this data cut, 146 patients have 
been dosed with 2.0 mg/kg Q3W and 1 patient was dosed at 2.2 mg/kg Q3W.
GEN702
Dose escalation (Part I) has completed. A total of 9 patients were dosed using a dose-dense 
schedule: 0.9 mg/kg 3Q4W (3 patients) and 1.2 mg/kg 3Q4W (6 patients).
Dose expansion (Part II) has completed, with a total of 24 patients treated. Fourteen patients 
were treated at 1.2 mg/kg 3Q4W, 6 patients started at 1.2 mg/kg 3Q4W and were later 
switched to 2.0 mg/kg Q3W, and 4 received 2.0 mg/kg Q3W.
Pharmacokinetics
Based on preliminary pharmacokinetic (PK) analysis of data from GEN701 dose escalation at 
the 2.0 mg/kg dose, the mean (std dev, n) Cycle 1 maximum concentration (Cmax) for ADC 
was 32.9 (7.3, n=3) ug/mL. The mean (std dev, n) Cycle 1 area-under-the-concentration-time 
curve from time zero to the last measurable concentration (AUClast) was 54.5 (18.0, n=3) 
day*ug/mL. For MMAE, the mean (std dev, n) Cycle 1 Cmax was 7.32 (4.5, n=3) ng/mL and 
the AUClast was 78.2 (46.9, n=3) day*ng/mL.
Based on preliminary PK analysis of data from GEN702 dose escalation at the 0.9 mg/kg 
dose, the mean (std dev, n) Cycle 1 Cmax for ADC was 20.4 (3.6, n=3) ug/mL and 
the AUClast was 36.5 (6.40, n=3) day*ug/mL. For MMAE, the mean (std dev, n) Cycle 
1 Cmax was 1.69 (0.93, n=3) ng/mL and the AUClast was 8.56 (4.1, n=3) day*ng/mL.
Based on preliminary PK analysis of data from GEN702 dose escalation at the 1.2 mg/kg 
dose, the mean (std dev, n) Cycle 1 Cmax for ADC was 28.9 (3.5, n=6) ug/mL and 
the AUClast was 60.4 (29.0, n=6) day*ug/mL. For MMAE, the mean (std dev, n) Cycle 
1 Cmax was 1.76 (1.38, n=6) ng/mL and the AUClast was 9.72 (7.32, n=6) day*ng/mL.


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1.3.3.1 Summary of Clinical Safety from GEN701 and GEN702
As of 17-Aug-2017, tisotumab vedotin had been administered to 174 patients dosed on a 
Q3W schedule in GEN701 and to 33 patients dosed 3Q4W and/or Q3W in GEN702 
(207 total).
Based on combined safety data from the 2 trials and across all dose cohorts, the most 
commonly reported adverse events (AEs) seen in at least 41 patients (≥20%) were epistaxis 
(62%), fatigue (51%), nausea (44%), conjunctivitis and alopecia (38% each), decreased 
appetite and constipation (32% each), diarrhea (26%), vomiting (25%), peripheral
neuropathy (22%), and abdominal pain (21%).
Grade 3 or higher AEs were reported in 120 patients (58%). Across all dose cohorts the most 
frequently reported Grade ≥3 AEs seen in at least four patients (2%) were fatigue (9%), 
anaemia (7%), hyponatraemia (5%), hypokalaemia, and abdominal pain (4% each), vomiting 
and conjunctivitis (3% each), nausea, intestinal obstruction, small intestinal obstruction, 
peripheral neuropathy, and symblepharon (2% each).
No AEs ≥ Grade 3 of coagulation abnormalities (prothrombin time [PT], activated partial 
thromboplastin time [aPTT], or international normalized ratio [INR]) have been reported.
Serious adverse events (SAEs) were reported in 96 patients (47%). Across all dose cohorts, 
the most frequently reported SAEs seen in at least four patients (2%) were abdominal pain 
(5%), vomiting and hyponatraemia (3% each), nausea, intestinal obstruction, small intestinal 
obstruction, general physical health deterioration, and anemia (2% each).
AEs leading to discontinuation were reported in 60 patients (29%). Across all dose cohorts 
the most frequent AEs leading to discontinuation were peripheral neuropathy (4%), 
conjunctivitis (3%), peripheral sensory neuropathy and symblepharon (2% each). All other 
AEs leading to discontinuation were reported in 2 patients (1%) each.
Five patients (3%) died within 30 days following the last dose of tisotumab vedotin in the 
GEN701 trial. Two patients died due to AEs considered to be related to tisotumab vedotin 
(pharyngeal tumor haemorrhage in a patient given 0.6 mg/kg and pneumonia in a patient 
given 2.0 mg/kg), 2 patients died as an outcome of disease progression not considered related 
to tisotumab vedotin, and one patient in the 2.0 mg/kg dose group died due to an unknown 
cause. One patient (3%) died within 30 days following last dose of tisotumab vedotin in the 
GEN702 trial due to disease progression.
Ocular Adverse Events
Ocular AEs are frequently reported with tisotumab vedotin. Events of conjunctivitis have 
been mainly CTCAE Grade 1 and 2. In May 2016, an initial ocular mitigation plan (OMP) 
was implemented upon reporting of the first case of Grade 3 conjunctivitis with irreversible 
damage in a patient given 0.9 mg/kg 3Q4W in the GEN702 trial. This plan was further 
updated in September 2016 after 2 patients in the GEN701 trial experienced Grade 2
conjunctivitis with conjunctival scarring. Due to an event of Grade 4 keratitis in the GEN701 


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dose expansion cohort (Part II), an urgent safety measure and a more comprehensive OMP
were implemented across both GEN701 and GEN702 trials in December 2016. Elements of 
this ocular mitigation plan included the addition of ocular premedications for all patients 
(cooling eye pads during tisotumab vedotin infusion, vasoconstrictor eye drops immediately 
prior to treatment with study drug, prophylactic treatment with topical ophthalmic steroid eye 
drops, use of lubricating eye drops throughout study treatment) and dose modifications for 
ocular events.
Ocular AEs with Q3W tisotumab vedotin
As of 16 Aug 2019, 396 patients have received tisotumab vedotin on a Q3W schedule. The 
most frequent ocular AEs were conjunctivitis (29.5%), dry eye (20.7%), lacrimation 
increased (6.1%), vision blurred (6.1%), blepharitis (5.1%), and keratitis (4.8%).
Since implementation of the December 2016 comprehensive OMP, both the frequency and 
severity of conjunctivitis, the most frequently reported ocular AE in relation to treatment 
with tisotumab vedotin, have been reduced. The frequency of conjunctivitis decreased from 
44.2% to 25.9% in subjects dosed Q3W and only one subject has experienced a Grade 3 
event after Dec-2016 (no Grade 4 or 5 events have been observed either before or after 
Dec-2016). Table 1 and Figure 1 summarize the decreased frequency and severity of 
conjunctivitis.
Table 1:
Frequency of conjunctivitis* by CTCAE toxicity grading before and after 
Dec-2016 – subjects dosed Q3W
Maximum Grade
Before**
(N=104)
After***
(N=274)
Total
(N=378)
N (%)
N (%)
N (%)
Any conjunctivitis event
46 (44.2)
71 (25.9)
117 (31.0)
Grade 1
17 (16.3)
30 (10.9)
47 (12.4)
Grade 2
25 (24.0)
40 (14.6)
65 (17.2)
Grade 3
4 (3.8)
1 (0.4)
5 (1.3)
Grade 4
0 (0.0)
0 (0.0)
0 (0.0)
Grade 5
0 (0.0)
0 (0.0)
0 (0.0)
* Including the preferred term ‘conjunctivitis’
** Including subjects that received first dose of tisotumab vedotin 1Q3W before 22-Dec-2016 OMP
*** Including subjects that received first dose of tisotumab vedotin 1Q3W after 22-Dec-2016 OMP


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Figure 1:
Frequency of the conjunctivitis* by CTCAE toxicity grading before and after 
Dec-2016 – subjects dosed Q3W
* Including the preferred term ‘conjunctivitis’
All but one Grade 3 event of keratitis (including subjects dosed before and after Dec-2016) 
were non-serious events ≤Grade 2. Events of ulcerative keratitis observed in subjects dosed 
Q3W have decreased in severity after implementation of the Dec-2016 OMP; one serious 
Grade 4 event was reported prior to Dec-2016 whereas no serious events of ulcerative
keratitis have been reported in subjects dosed after Dec-2016 (all non-serious events were 
dGrade 2 with the exception of one event that was Grade 3).
Ocular AEs with Dose Dense Regimens
A total of 29 patients received 0.9 mg/kg or 1.2 mg/kg tisotumab vedotin on a dose-dense 
schedule in the GEN702 trial. None of the 3 patients treated with 3Q4W 0.9 mg/kg tisotumab 
vedotin were subject to the comprehensive ocular mitigation plan in the GEN702 study as all 
were treated prior to December 2016. One of the patients treated at 0.9 mg/kg 3Q4W 
experienced an event of Grade 3 conjunctivitis and Grade 2 symblepharon.
A total of 26 patients received 1.2 mg/kg 3Q4W tisotumab vedotin in the GEN702 trial. The 
6 patients treated during dose escalation were treated prior to Dec 2016. The comprehensive 
OMP was inconsistently applied to the remaining 20 patients in the expansion cohort.
Prophylactic steroid eye drops were not administered on subsequent dosing days after the 
first week for most patients. In addition, many patients with ongoing ocular events continued 
to receive tisotumab vedotin in GEN702 as they were treated prior to GEN702 Amendment 
4, when dose adjustments due to ocular events became more restrictive. Grade 3 or higher 
ocular events were seen in 6 patients (23%) treated with 1.2 mg/kg tisotumab vedotin,
including 5 patients (19%) with Grade 3 or higher symblepharon.
Since December 2016, the comprehensive ocular mitigation plan has been modified with 
additional measures for toxicity management (see Section 5.3.1).


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For further details regarding clinical safety data with tisotumab vedotin, please refer to the 
Investigator Brochure.
Adverse Events of Special Interest
Three Adverse Events of Special Interest (AESI) have been identified:
●
Ocular AEs: AEs of Grade 1-2 conjunctivitis are frequently reported in patients 
treated with tisotumab vedotin. Severe cases (≥ CTCAE Grade 3) of conjunctivitis, 
keratitis, and symblepharon have been observed in both trials. Implementation of a 
comprehensive mitigation plan and preventive measures (please refer to Section 5.3)
have reduced both the frequency and severity of ocular adverse reactions in the 
GEN701 cohort expansion.
●
AEs of peripheral neuropathy: (including preferred terms as: neuropathy 
peripheral; peripheral sensory neuropathy; peripheral motor neuropathy; 
polyneuropathy): Peripheral neuropathy is a well-known adverse reaction to treatment 
with chemotherapeutics (including cisplatin and taxanes) as well as MMAE-based 
ADCs and is frequently reported in relation to treatment with tisotumab vedotin. The 
majority of the reported cases are Grade 1–2; however, peripheral neuropathy was the 
leading cause of permanent discontinuation of study drug in GEN701 cohort 
expansion. A mitigation plan, including dose reduction and dose delays, is in place to 
control the rates and severity of peripheral neuropathy observed in patients treated 
with tisotumab vedotin (please refer to Section 5.3).
●
AEs of bleeding: Bleeding events are considered AESI due to the target of tisotumab 
vedotin (TF). Epistaxis was the most common bleeding event, reported in 62% of 
patients across all dose cohorts (mainly Grade 1, one Grade 3 event). For the majority 
of the bleeding events (excluding epistaxis) no causal relation to treatment with 
tisotumab vedotin can be established. One serious event of Grade 5 pharyngeal 
hemorrhage was reported in a patient with SCCHN treated in the dose escalation 
cohort of GEN701. This event was considered most likely due to the patient’s 
underlying disease. However, a causal relationship to trial drug could not be ruled out 
at that time. Please refer to Section 5.3 for dose modifications in the event of 
bleeding.
1.3.3.2 Summary of Efficacy Data from GEN701 and GEN702
Preliminary efficacy data
As of a data cutoff of 17 August 2017, 18% of patients in the GEN701 cohort expansion 
achieved response to tisotumab vedotin. The response rate varied across the indications 
ranging from 0% in prostate cancer to 32% in cervical cancer. Nine of the 11 responses in
34 cervical cancer patients were confirmed responses (26%).


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Among 36 patients with ovarian cancer in the GEN701 cohort expansion, the objective 
response rate (ORR) was 17% (6 patients) with 3 confirmed responses (8% confirmed ORR).
All of these patients were treated with tisotumab vedotin at 2.0 mg/kg on a Q3W schedule.
As of the final data cut date of 26 March 2018 in the GEN702 expansion, 12 patients with 
ovarian cancer who began treatment on the dose-dense schedule had an ORR of 33% 
(4 patients). Two of these 4 responses were confirmed (17% confirmed ORR). While all of 
these patients received 1.2 mg/kg tisotumab vedotin 3Q4W, 1 patient was switched onto 
2.0 mg/kg tisotumab vedotin Q3W beginning at Cycle 6, after her response had been 
recorded. These limited data suggest that efficacy may be improved with a dose-dense 
schedule as compared to the Q3W schedule in patients with ovarian cancer. Though 
3 patients received 0.9 mg/kg tisotumab vedotin on the dose-dense schedule in the GEN702 
trial, none had ovarian cancer.
A complete summary of the clinical and nonclinical data relevant to tisotumab vedotin and its 
study in human patients is provided in the Investigator’s Brochure.
1.4
Benefit Risk Assessment
Data from GEN701 and GEN702 demonstrate initial activity of tisotumab vedotin in heavily 
pretreated patients with recurrent or metastatic ovarian cancer who had received up to 6 lines 
of prior therapy. The most common AEs included epistaxis, fatigue, nausea, alopecia, 
conjunctivitis, constipation, decreased appetite, diarrhea, vomiting, and peripheral 
neuropathy. The majority of these events were mild to moderate (Grade 1 or 2).
Pharmacokinetic analysis indicates that dose intensity of the 0.9 mg/kg dose-dense and 
2.0 mg/kg Q3W regimens is similar, allowing exploration of whether the more frequent
schedule, with its different exposure profile, may improve efficacy. Limited data from a 
small number of patients treated with 3Q4W tisotumab vedotin in the GEN702 trial provide 
preliminary evidence that this exposure profile may, in fact, enhance efficacy as compared to 
Q3W dosing in ovarian cancer patients. The ORR was 17% in 36 ovarian cancer patients 
who received 2.0 mg/kg Q3W in GEN701 as opposed to an ORR of 33% in 12 patients who 
received 1.2 mg/kg 3Q4W in GEN702. The 1.2 mg/kg dose-dense regimen was associated 
with higher incidence of ocular adverse events in GEN702, including Grade 3 conjunctivitis 
and symblepharon. These patients were dosed without comprehensive prophylactic ocular 
safety mitigation measures (the comprehensive OMP) or ocular AE-related dose 
modifications used in current trials.
The following measures are being employed to ensure safety of patients in this trial:
●
Safety run-in analysis of the dose-dense regimen of tisotumab vedotin with a 28 day 
safety evaluation period after the last patient is dosed.
●
Identification of AESIs, including ocular adverse events, and implementation of 
preventative mitigation plans for each, when appropriate (see Section 5.3).


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●
A comprehensive ocular safety mitigation plan, including dose modifications and 
prophylactic measures, that is informed by progressive modifications to ocular 
preventive measures in the GEN701 and GEN702 trials, as well as ophthalmological 
thought leader input (see Section 5.4).
●
Formation of a safety monitoring committee (SMC) to monitor safety of tisotumab 
vedotin in the selected patient populations.
●
Interim futility analysis performed on Part B after at least 20 patients with 1 to 3 prior 
lines of therapy, including bevacizumab treatment, have been treated and had at least 
one response assessment post-baseline. The interim futility analysis will ensure that 
further enrollment of these patients has reasonable potential to provide clinically 
meaningful benefit from tisotumab vedotin. While the futility analysis is being 
performed, enrollment in Part B will continue.
The feasibility of targeting TF in ovarian cancer with tisotumab vedotin has been 
demonstrated in the clinic in phase I studies in heavily pretreated populations with 
encouraging activity results. Preliminary safety and activity data from the GEN701 and 
GEN702 trials suggest a positive benefit-risk profile and warrant further investigation of 
tisotumab vedotin in ovarian cancer populations that exhibit high unmet medical need.
2
OBJECTIVES
This study will evaluate the safety, antitumor activity, and PK of tisotumab vedotin in
patients with PROC. Specific objectives and corresponding endpoints for the study are 
summarized below (Table 2).


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Table 2:
Objectives and corresponding endpoints
Primary Objective
Corresponding Primary Endpoint
x
(Safety run-in) Evaluate safety and tolerability 
of a dose-dense regimen of tisotumab vedotin 
x
Incidence of DLTs or other unacceptable 
toxicities
x
(Parts A and B) Evaluate antitumor activity of 
tisotumab vedotin 
x
Investigator-determined confirmed ORR as 
measured by RECIST v1.1 
Secondary Objectives (Parts A and B)
Corresponding Secondary Endpoints
x
Evaluate the safety and tolerability of tisotumab 
vedotin
x
Type, incidence, severity, seriousness, and 
relatedness of AEs
x
Evaluate preliminary antitumor activity of 
tisotumab vedotin
x
Investigator-determined confirmed and 
unconfirmed ORR as measured by RECIST v 
1.1 (all responses)
x
Evaluate antitumor activity of tisotumab vedotin
x
CA-125 response rate
x
Combined RECIST/CA-125 overall response
x
Evaluate durability of response in patients who 
respond to tisotumab vedotin
x
Investigator- determined duration of response 
(DOR) as measured by RECIST v1.1
x
Evaluate stability and control of disease
x
Investigator-determined disease control rate 
(DCR) as measured by RECIST v1.1
x
Evaluate the timing of responses
x
Investigator- determined time to response 
(TTR) as measured by RECIST v1.1
x
Evaluate PFS of patients treated with tisotumab 
vedotin
x
Investigator- determined PFS as measured by 
RECIST v1.1
x
Evaluate survival of patients treated with 
tisotumab vedotin
x
Overall survival (OS)
x
Assess pharmacokinetics of tisotumab vedotin
x
Selected PK parameters for tisotumab vedotin 
and MMAE
x
Assess immunogenicity of tisotumab vedotin
x
Incidence of antitherapeutic antibodies (ATAs) 
to tisotumab vedotin
Additional Objectives (Parts A and B)
Corresponding Additional Endpoints
x
Evaluate Tissue Factor expression-response 
relationship
x
TF expression-response relationship following 
treatment with tisotumab vedotin
x
Assess biomarkers of biological activity and 
resistance and predictive biomarkers of response
x
Relationship between biomarkers in blood and 
tumor tissue to efficacy, safety, or other 
biomarker endpoints following treatment with 
tisotumab vedotin
x
Patient-reported outcomes (Parts A and B, US
patients only)
x
PROMIS and an NCI PRO-CTCAE 
questionnaire customized to focus on ocular 
symptoms, bleeding, and gastrointestinal 
symptoms, as well as other questions added by 
the sponsor
3
INVESTIGATIONAL PLAN
3.1
Summary of Study Design
This is an open-label, phase 2 study with an initial safety run-in period. The safety run-in
period will evaluate the safety of a dose-dense schedule and will start at a 0.9 mg/kg dose 
level. If 0.9 mg/kg is considered safe and tolerable, the dose level will be escalated to 
1.2 mg/kg. Otherwise it will be de-escalated to 0.65 mg/kg. Each dose level will enroll 
approximately 6 patients. Patients who do not complete the DLT period will be replaced. A


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dose level is considered safe and tolerable if no more than 1 patient experiences a DLT 
among 6 patients during the DLT period. The highest dose level that is considered safe will 
be the recommended phase 2 dose (RP2D) and will be used in Part A. If no RP2D for the 
dose-dense schedule is identified, Part A will be a single arm of the Q3W regimen and Part B 
will not enroll.
In Part A, 60 patients will be randomized in a 1:1 ratio to receive tisotumab vedotin 
2.0 mg/kg intravenously (IV) every 3 weeks (Q3W regimen) or the safety run-in RP2D on 
Days 1, 8, and 15 of every 4-week cycle (dose-dense regimen; 3Q4W) if a RP2D has been
identified. Randomization will be stratified by first line vs. second line PROC and histology 
(serous vs. non-serous).
Based upon antitumor activity and safety data, one Part A treatment arm may be expanded to 
enroll up to an additional 70 patients to further characterize safety and antitumor activity of 
tisotumab vedotin for patients with PROC. The analysis to support expansion will be 
conducted when approximately 30 patients per arm have at least one post-baseline response 
assessment per RECIST v1.1 or have discontinued from the study or started subsequent 
cancer therapy.
Part B will enroll approximately 80 patients with PROC including approximately 60 patients 
who have received 1 to 3 prior lines of therapy, including bevacizumab treatment. Part B will 
further characterize the long-term efficacy, safety, and PK assessments of 0.9 mg/kg 
tisotumab vedotin on Days 1, 8, and 15 of every 4-week cycle (dose-dense regimen) if the
0.9 mg/kg dose level is considered safe and tolerable in the safety run-in period. Enrollment 
in this cohort may discontinue when Part A begins enrollment.
Interim futility analysis will be performed on Part B after at least 20 patients with 1 to 3 prior 
lines of therapy, including bevacizumab treatment, have been treated and had at least one 
response assessment post-baseline. The Bayesian predictive probability approach will be 
used to determine the futility criteria (Lee 2008). At the time of the interim futility analysis, 
the predictive probability of success (PPoS) will be calculated. Based on activity and safety 
data, together with the PPoS, the cohort may continue or be stopped early by the sponsor. 
While the interim futility analysis is performed, enrollment in Part B may continue. A cohort 
may also be discontinued at any point at the discretion of the sponsor.
On a periodic basis, a Safety Monitoring Committee (SMC) will monitor the safety of 
patients participating in the trial. The SMC will be responsible for evaluating the results of 
safety analyses and will make recommendations to the sponsor. Ongoing, real-time review of 
patient safety and serious adverse events (SAEs) will also be conducted by the sponsor’s 
Drug Safety department throughout the study.
During the safety run-in period, the SMC will assess tolerability and safety of tisotumab 
vedotin (refer to SMC charter for additional details) at the end of the DLT period for each 
dose level. Ad hoc meetings of the SMC may be convened prior to the safety evaluation 
period if safety data indicate.


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An individual’s dose may be modified based upon treatment-related AEs. Response will be 
assessed every 6 weeks for the first 6 months, every 12 weeks for the next 6 months, and then 
every 6 months after that. RECIST v1.1 will be used by the investigator to score responses 
for primary and secondary endpoints as well as progression. Objective responses will be 
confirmed with repeat scans at least 4 weeks after the first documentation of response. The 
study will be closed 3 years after the last patient is enrolled or when no patients remain in 
long-term follow-up, whichever comes first. Additionally, the sponsor may terminate the 
study at any time.
Figure 2:
Study design
Safety run-in will start with 3Q4W dosing of 0.9 tisotumab vedotin in approximately 12 patients. If deemed safe, this dose 
will escalate to 1.2 mg/kg. If not deemed safe, it will de-escalate to 0.65 mg/kg. Part B will enroll only after the 0.9 mg/kg 
3Q4W dose is deemed safe by the SMC.
3.1.1 Dose-Limiting Toxicity
DLTs will be assessed during the safety run-in portion of the study. Patients will be replaced 
for DLT evaluation if they do not complete the DLT evaluation period and do not experience 
a DLT before they discontinue from the study or start subsequent cancer therapy.
The DLT evaluation period for each safety run-in patient is defined as 28 days after the first 
dose of tisotumab vedotin. Patients who experience DLTs should not receive further 
treatment with tisotumab vedotin, unless clinical benefit is demonstrated with adequately 
managed toxicity. Subsequent treatment with tisotumab vedotin will be defined by the 
medical monitor in discussion with the site investigator in the context of the type of AE 
observed.
The IB for tisotumab vedotin describes AEs commonly observed, as well as less common 
serious findings. The IB should be referenced when attributing causality; however, the final 
decision regarding causality is at the discretion of the investigator.


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A DLT is defined as:
One of the following that is observed within 28 days of the first dose of tisotumab 
vedotin and is considered related to the drug:
●
Grade 4 neutropenia (i.e., ANC <0.5 • 109 cells/L) for minimal duration of seven 
days.
●
Grade 3 and 4 febrile neutropenia (i.e., ANC <1.0 • 109 cells/L with a single 
temperature of >38.3°C or a sustained temperature of ≥38°C for more than one hour).
●
Grade 4 thrombocytopenia (≤ 25.0 • 109 platelets/L).
●
Grade 3 thrombocytopenia associated with bleeding episodes.
●
Grade 3 or higher ocular adverse events
●
Major bleeding, defined as:
○
Fatal bleeding
○
Symptomatic bleeding in a critical area organ, such as intracranial, intraocular, 
retroperitoneal, intra-articular or pericardial, or intramuscular with compartment 
syndrome
○
Bleeding causing a drop in hemoglobin level of 20 g/L (1.24 mmol/L) or more
○
Bleeding leading to transfusion of two or more units of whole blood or red cells.
●
Stevens Johnson syndrome, toxic epidermal necrolysis, Grade ≥3 cutaneous 
vasculitis.
●
Grade 3 neuropathy (not improving to Grade 1 within 3 weeks following end of 
treatment) and Grade 4 neuropathy.
●
Grade 3 infusion -related AEs that do not resolve to Grade 1 or baseline within 
24 hours.
●
Grade 4 infusion -related events including anaphylaxis.
●
Any Grade ≥3 non-hematological AEs which occur during the first treatment cycle 
and are at least possibly study drug related, excluding non-hematological laboratory 
abnormalities that have no clinical consequences and resolve within 48 hours.
●
Grade ≥3 diarrhea and/or vomiting persisting for more than 48 hours with optimal 
medical management.
●
Grade ≥3 nausea (not disease-related) lasting 3 days or more with optimal medical 
management.
3.2
Discussion and Rationale for Study Design
Therapies available to patients with PROC that have previously received 1 to 3 prior lines 
therapy, including bevacizumab, have poor response rates of around 12% in the first line 
setting and their effectiveness declines further in the second line and beyond. Long-term 
survival of patients with PROC is very low.
Patients with ovarian cancer have significant unmet medical need for therapies that can 
provide meaningful improvement. Tisotumab vedotin has been examined in a limited number 


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of patients with ovarian cancer in the GEN701 and GEN702 trials. These initial data show 
activity and need to be explored further in this population with high unmet need. Limited 
available data indicate that the dose-dense regimen may yield improved efficacy with the 
same or somewhat higher dose intensity as the Q3W regimen. Previously, dose-dense 
regimens, including 0.9 mg/kg and 1.2 mg/kg 3QW4, were tested in GEN702 patients 
without a comprehensive ocular mitigation plan, or strict dose modification guidelines for 
ocular toxicities in place. With appropriate ocular mitigation steps and dose-reduction 
guidelines, the dose dense schedule may be both tolerable and efficacious for this patient 
population.
3.2.1 Method of Assigning Patients to Treatment Groups
In the safety run-in portion of the study, each dose level will enroll sequentially starting at 
0.9 mg/kg using the dose-dense schedule.
Part A will begin enrollment after the safety run-in period is completed. Patients will be 
randomly assigned to 1 of 2 dosing schedules in a 1:1 ratio. Randomization is intended to 
avoid bias and minimize imbalance between 2 dosing schedules on key prognostic factors for 
the purpose of evaluating safety and activity of the dose-dense and Q3W schedules.
Randomization will be centrally controlled and stratified by first line vs. second line PROC
and histology (serous vs. non-serous). At the time of randomization, a unique randomization 
number will be assigned to identify the dose regimen (dose-dense or Q3W) the patient is 
allocated to. Randomization procedures are detailed in the Study Manual.
Part B will have a single treatment arm and will begin enrollment of patients after 0.9 mg/kg 
dose-dense is deemed safe and tolerable in the safety run-in, if this occurs.
3.2.2 Rationale for Selection of Doses
Available data indicate that, across the GEN701 and GEN702 trials, patients with ovarian 
cancer experienced more tumor responses with a dose-dense schedule. However, in the 
GEN702 trial, ocular toxicities occurred at a higher rate with this schedule when dosed at 
1.2 mg/kg. This necessitated the implementation of an initial ocular mitigation plan for 
patients in both trials who received tisotumab vedotin. The 0.9 mg/kg dose-dense schedule 
had been completed in the GEN702 trial before the comprehensive ocular mitigation plan 
had been put into place and therefore these patients did not receive these risk mitigations.
Ultimately, weekly dosing with 1.2 mg/kg tisotumab vedotin was halted in the GEN702 trial 
in favor of the 2.0 mg/kg Q3W regimen. The implementation of a comprehensive ocular 
mitigation plan in December 2016 as well as dose modifications for ocular AEs substantially 
reduced both the frequency and severity of ocular adverse reactions in patients treated at 
2.0 mg/kg Q3W in the GEN701 cohort expansion.
Based on preliminary PK data from the dose escalation part of GEN701, at least 95% of 
tisotumab vedotin was eliminated from the plasma within 7 days of dosing across all 
investigated doses administered Q3W. Free MMAE was eliminated 14–21 days after 
administration. Based on preliminary PK data from GEN702 dose escalation at the 0.9 mg/kg 


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dose, no notable accumulation of mean ADC concentrations at day 7 post-dose, or area under 
the concentration-time curve from day 0 to day 7 (AUC0-7), was observed between the first 
and last dose of Cycle 1 on a 3Q4W schedule (n=3).
Dose intensity of the 0.9 mg/kg dose-dense and 2.0 mg/kg Q3W regimens is similar, 
allowing exploration of whether a dose-dense schedule, with its different exposure profile,
provides improved efficacy in ovarian cancer patients at the same dose intensity. Over a 
given cycle, the Q3W dose regimen at 2.0 mg/kg results in a dose intensity of 
0.67 mg/kg/week, while the dose-dense regimen at 0.9 mg/kg 3 times every 4 weeks results 
in a dose intensity of 0.68 mg/kg/week. If DLTs are experienced in 2 or more patients at the 
0.9 mg/kg dose during the safety run-in, a de-escalation of 28% to 0.65 mg/kg 3 times every 
4 weeks will be explored. The 0.65 mg/kg dose level results in a dose intensity similar to a 
1.5 mg/kg Q3W dose. In the GEN701 trial, at the 1.5 mg/kg Q3W dose, no DLTs were 
observed. Additionally, during dose escalation in the GEN701 trial, the 1.2 mg/kg Q3W dose 
was the lowest dose at which a partial response was observed, suggesting that 0.65 mg/kg 
3 times every 4 weeks may be in the therapeutic range.
The full implementation of a comprehensive ocular mitigation strategy allows the re-
exploration of the 1.2 mg/kg dose-dense regimen, if 0.9 mg/kg is deemed to be safe by the
SMC. The 1.2 mg/kg dose-dense regimen represents an increase in dose intensity (33%) over 
the 0.9 mg/kg dose-dense regimen. The dose-dense regimens have lower maximum ADC 
plasma concentrations (Cmax) and higher ADC trough plasma concentrations (Cmin) compared 
to the 2.0 mg/kg Q3W dose regimen. These differences in pharmacokinetic profiles allow the 
further investigation of exposure-response relationships for optimal efficacy and safety.
3.2.3 Retreatment
Retreatment with tisotumab vedotin is not permitted.
3.2.4 Blinding and Unblinding
This is an open-label study.
4
STUDY POPULATION
Patients must meet all of the enrollment criteria to be eligible for this study. Eligibility 
criteria may not be waived by the investigator and are subject to review in the event of a 
good clinical practice audit and/or health regulatory authority inspection.
4.1
Inclusion Criteria
1. Histologic documentation of epithelial ovarian cancer, primary peritoneal cancer, or 
fallopian tube cancer (excluding carcinosarcoma, mucinous, and low grade serous 
histologies), hereafter referred to as “ovarian cancer”.
2. Safety run-in patients only: Platinum-resistant ovarian cancer (PROC), which is defined 
as having progressed or relapsed within 6 months after previous platinum-containing 
chemotherapy and for which single agent chemotherapy is appropriate. Progression or 


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relapse must be documented radiographically using RECIST v1.1 criteria. The patient 
may have received more than 1 prior systemic treatment regimen in the PROC setting.
3. Part A and Part B patients only: PROC; with the following prior treatment requirements:
●
The patient must have received 1 to 3 prior anticancer lines of therapy overall,
including at least 1 line of therapy containing bevacizumab or a biosimilar to 
bevacizumab.
●
Adjuvant ± neoadjuvant are considered 1 line of therapy.
●
Patients may have received a PARP inhibitor or an immuno-oncology (IO) agent; any 
of these regimens are to be considered a line of therapy for the purposes of this study 
if not used as maintenance therapy.
●
Maintenance therapy (including bevacizumab, PARP inhibitors and IOs) will be 
considered part of the preceding line of therapy and not to be counted as a new line of 
therapy.
●
Any chemotherapy regimen change due to toxicity in the absence of disease 
progression is considered as part of the same line of therapy.
●
Hormonal therapy will be not be counted towards the lines of therapy.
4. Measurable disease according to RECIST v1.1 as assessed by the investigator, defined as:
a.
A minimum of one non-nodal lesion ≥10 mm in the longest diameter from a non-
irradiated area. If target lesion(s) are located within previously irradiated area only, 
the patient can be enrolled only if there has been demonstrated progression in the “in 
field” lesion and upon approval of the sponsor’s medical monitor.
OR
b. Lymph node lesion ≥15 mm in the shortest diameter from a non-irradiated area. 
5. Age 18 years or older.
6. An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 
(see Appendix E for conversion of performance status using Karnofsky and Lansky 
scales, if applicable).
7. The following baseline laboratory data:
●
Absolute neutrophil count (ANC) ≥1500/μL assessed at least 2 weeks after growth 
factor support, if applicable.
●
Platelet count ≥100 x 109/L assessed at least 2 weeks after transfusion with blood 
products.
●
Hemoglobin ≥5.6 mmol/L (9.0 g/dL) assessed at least 2 weeks after transfusion with 
blood products.
●
Serum bilirubin ≤1.5 x upper limit of normal (ULN) or direct bilirubin ≤2 x ULN in 
patients diagnosed with Gilbert’s syndrome.


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●
Estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73m2 using the 
Modification of Diet in Renal Disease (MDRD) study equation as applicable.
●
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN. 
(If liver tumor/metastases are present, then <5 x ULN is allowed).
8. Acceptable coagulation status:
●
INR ≤1.2 without anticoagulation therapy.
●
aPTT ≤1.25 ULN.
9. Life expectancy of at least 3 months.
10. Patients of childbearing potential as defined in Section 4.3, under the following 
conditions:
●
Must have a negative serum or urine pregnancy test (minimum sensitivity 25 mIU/mL 
or equivalent units of beta human chorionic gonadotropin [β-hCG]) result within 
7 days prior to the first dose of tisotumab vedotin. Patients with false positive results 
and documented verification that the patient is not pregnant are eligible for 
participation.
●
Must agree not to breastfeed or donate ova, starting at time of informed consent and 
continuing through 6 months after the final dose of study drug administration.
●
Must agree to complete abstinence or, if sexually active in a way that could lead to 
pregnancy, must consistently use 2 highly effective methods of birth control (as 
defined in Appendix F) starting at time of informed consent and continuing 
throughout the study and for at least 6 months after the final dose of study drug 
administration.
11. Able to provide fresh or archival tissue for biomarker analysis. Fresh tissue must be 
obtained from a newly obtained core or excisional biopsy of a tumor lesion. Archived 
specimens must have been collected within 2 years of first administration of tisotumab 
vedotin. Older specimens may be allowed upon approval of the sponsor’s medical 
monitor.
12. The patient or the patient’s legally authorized representative must provide written 
informed consent.
4.2
Exclusion Criteria
1. Primary platinum-refractory disease, defined as disease progression within 3 months of 
completion of first line platinum-based therapy.
2. Patients with clinical symptoms or signs of gastrointestinal obstruction within the past 
6 months or who currently require parenteral nutrition.


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3. Hematological: Known past or current coagulation defects leading to an increased risk of 
bleeding; diffuse alveolar hemorrhage from vasculitis; known bleeding diathesis; ongoing 
major bleeding; trauma with increased risk of life-threatening bleeding or history of 
severe head trauma or intracranial surgery within 8 weeks of trial entry.
4. Cardiovascular: Clinically significant cardiac disease including uncontrolled 
hypertension (systolic BP >150 mmHg or diastolic BP >90 mmHg), unstable angina, 
acute myocardial infarction within 6 months prior to screening, serious cardiac 
arrhythmia requiring medication (not including asymptomatic atrial fibrillation with
controlled ventricular rate); any medical history of congestive heart failure (Class II or 
higher as classified by the New York Heart Association, see Appendix H), or any medical 
history of decreased cardiac ejection fraction of <45%.
5. Ophthalmological: Active ocular surface disease at baseline. An ocular evaluation is to be 
confirmed by an ophthalmologist at screening. Patients with any prior episode of 
cicatricial conjunctivitis or Stevens Johnson syndrome (as evaluated by the investigator) 
are ineligible. Cataract is not considered active ocular surface disease for this study.
6. History of another malignancy within 3 years before the first dose of study drug, or any 
evidence of residual disease from a previously diagnosed malignancy. Exceptions are 
malignancies with a negligible risk of metastasis or death (e.g., 5-year overall survival 
≥90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin 
carcinoma, ductal carcinoma in situ, or stage I uterine cancer.
7. Inflammatory bowel disease including Crohn’s disease and ulcerative colitis.
8. Ongoing, acute, or chronic inflammatory skin disease.
9. Uncontrolled tumor-related pain.
10. Inflammatory lung disease, including moderate and severe asthma and chronic 
obstructive pulmonary disease, requiring chronic medical therapy.
11. Grade 3 or higher pulmonary disease unrelated to underlying malignancy.
12. Patients with significant peripheral vascular disease.
13. Uncontrolled pleural or pericardial effusions.
14. Medications or treatment regimens:
●
A patient may not receive both anticoagulant(s) and antiplatelet agent(s) concurrently 
while on study.
●
Cumulative dose of corticosteroid ≥150 mg (prednisone or equivalent doses of 
corticosteroids) within 2 weeks of the first tisotumab vedotin administration is 
prohibited.


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15. Surgery/procedures: Major surgical procedure (defined as a surgery requiring inpatient 
hospitalization of at least 48 hours) within 4 weeks or excisional biopsy within 7 days 
prior to the first study drug administration. Patients who have planned major surgery 
during the treatment period must be excluded from the trial.
16. Received a live vaccine within 30 days prior to the first dose of trial treatment. Examples 
of live vaccines include, but are not limited to, the following: measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live 
attenuated vaccines and are not allowed. 
17. Peripheral neuropathy Grade ≥2
18. Prior therapy:
●
Any prior treatment with MMAE-derived drugs.
●
Radiotherapy within 21 days prior to the first administration of study drug. Patients 
must have recovered from all radiation-related toxicities. At least 42 days must have 
elapsed from the last administration of chemo-radiotherapy.
●
Small molecules, chemotherapy, immunotherapy, biologics, experimental agents, or 
any other antitumor therapy within 21 days prior to the first administration of study 
drug. If underlying disease is progressing on treatment, patients may enroll within 
21 days upon approval of the sponsor’s medical monitor. These patients must have 
recovered from all related toxicities.
19. Any uncontrolled Grade 3 or higher (per the NCI CTCAE v5.0) viral, bacterial, or fungal 
infection within 2 weeks prior to the first dose of tisotumab vedotin. Routine 
antimicrobial prophylaxis is permitted.
20. Known seropositivity of human immunodeficiency virus; known medical history of 
Hepatitis B or C infection.
●
Note: No testing for human immunodeficiency virus, Hepatitis B, or Hepatitis C is 
required unless mandated by local health authorities.
21. Known history of untreated brain metastasis or active brain metastasis. Patients with 
symptoms of brain metastasis should be screened for this condition prior to enrollment.
22. Patients who are breastfeeding, pregnant, or planning to become pregnant from time of 
informed consent until 6 months after final dose of study drug administration.
23. Known hypersensitivity to any excipient contained in the drug formulation of tisotumab 
vedotin.
24. Other serious underlying medical condition that, in the opinion of the investigator, would 
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4.3
Childbearing Potential
A person of childbearing potential is anyone born female who has experienced menarche and 
who has not undergone surgical sterilization (e.g., hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy) or has not completed menopause. Menopause is defined clinically as 
12 months of amenorrhea in a person over age 45 in the absence of other biological, 
physiological, or pharmacological causes.
4.4
Removal of Patients from Therapy or Assessment
Seattle Genetics or their designee must be notified if a patient is withdrawn from study 
treatment (discontinuation) or from the study (withdrawal). The reason(s) for withdrawal 
must be documented in the patient’s medical records and case report form (CRF).
4.4.1 Discontinuation of Study Treatment
A patient’s study treatment may be discontinued for any of the following reasons:
●
Progressive disease (PD)
●
Adverse event (AE)
●
Pregnancy
●
Investigator decision
●
Patient decision, non-AE (consent withdrawal)
Note: Ensure that patients who decide to stop treatment because of an AE are not 
included in this rationale.
●
Study termination by sponsor
●
Subsequent cancer therapy
●
Other, non-AE
Patients who discontinue from study treatment will remain on study for follow-up unless they 
withdraw consent.
4.4.2 Patient Withdrawal from Study
Any patient may be discontinued from the study for any of the following reasons:
●
Patient withdrawal of consent
●
Study termination by sponsor
●
Lost to follow-up
●
Death
●
Other
5
TREATMENTS
5.1
Treatments Administered
Patients in the safety run-in portion of the study will receive tisotumab vedotin at a dose of 
0.9 mg/kg or 1.2 mg/kg as a 30–60 minute intravenous (IV) infusion on Days 1, 8, and 15 of 


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every 4-week treatment cycle. For patients weighing more than 100 kg, dosing will be 
capped at 90 mg per infusion. If the dose is escalated to 1.2 mg/kg, dosing will be capped at 
120 mg per infusion. If the dose is de-escalated to 0.65 mg/kg, dosing will be capped at 
65 mg per infusion.
Patients in Part A will be randomized to receive either the RP2D dose-dense regimen from 
the safety run-in portion of the study or 2.0 mg/kg tisotumab vedotin administered as a 
30–60 minute IV infusion on Day 1 of each 3-week treatment cycle (Q3W regimen). For 
patients weighing more than 100 kg, dosing will be capped at 200 mg per infusion.
Patients in Part B will receive 0.9 mg/kg tisotumab vedotin as a 30–60 minute intravenous 
(IV) infusion on Days 1, 8, and 15 of every 4-week treatment cycle. For patients weighing 
more than 100 kg, dosing will be capped at 90 mg per infusion.
5.2
Investigational Product
Detailed information describing the preparation, administration, and storage of tisotumab 
vedotin is located in the Pharmacy Instructions.
5.2.1 Description
Tisotumab vedotin is presented as lyophilized powder for reconstitution in water for injection 
and is intended for IV dosing by infusion after dilution in physiological saline solution. It is
manufactured and provided under the responsibility of the sponsor. A list of excipients can 
be found in the Investigator’s Brochure.
5.2.2 Dose and Administration
Tisotumab vedotin will be administered as an infusion given over approximately 
30–60 minutes. In the absence of infusion-related reactions (IRRs), the infusion rate for all 
patients should be calculated in order to achieve a 30–60 minute infusion period. Tisotumab 
vedotin must not be administered as an IV push or bolus. Tisotumab vedotin should not 
be mixed with other medications.
Weight-based dosing is based on the patient’s actual body weight. Doses must be adjusted 
for patients who experience a ≥10% change in weight from baseline. Patient weight must be 
measured during all relevant assessment windows as described in the schedule of events. 
Other dose adjustments for changes in body weight are permitted per institutional standard. 
Rounding is permissible to the nearest kilogram.
An exception to weight-based dosing is made for patients weighing greater than 100 kg; 
doses will be based on 100 kg for these individuals. The maximum dose permitted per 
infusion in this study is 90 mg or 120 mg for patients receiving the dose-dense regimen 
and 200 mg for patients receiving the Q3W regimen. If dosing is de-escalated to 
0.65 mg/kg for patients on the dose-dense regimen, the maximum dose permitted per 
infusion for these patients will be 65 mg.


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5.2.3 Dose Modifications
For patients who do not tolerate the protocol-specified dosing schedule, dose reductions are 
permitted in order to allow the patient to continue tisotumab vedotin treatment. Dose 
reductions must be preapproved by the sponsor’s medical monitor unless allowed according 
to the mitigation plans specified in the protocol (please refer to Section 5.3). Once a dose is 
reduced, it should not be re-escalated for that patient during the study.
x
If toxicities occur on Day 1 of any cycle and require the tisotumab vedotin dose to be 
held, then the start of the cycle may be delayed.
x
If toxicities occur on Day 8 and require the dose to be held for >2 days, then the dose 
should be eliminated.
x
If toxicities occur on Day 15 of any cycle and require the dose to be held >7 days, 
then the dose(s) should be eliminated.
x
If a patient only receives tisotumab vedotin on Day 1 and needs to skip Days 8 and 
15, the patient could resume the next cycle as early as Day 22 (new Day 1) per the 
mitigation plans specified in Section 5.3.
In case any dose reduction of tisotumab vedotin is needed, the dose must be reduced 
according to the guidelines provided below (Table 3 and Table 4)
Table 3:
Dose modification scheme: Dose-dense regimen
Previous dose of tisotumab vedotin
Reduced dose of tisotumab vedotin
1.2 mg/kg (120 mg maximum total dose) on D1, D8, 
and D15
0.9 mg/kg (90 mg maximum total dose) on D1, 
D8, and D15
0.9 mg/kg (90 mg maximum total dose) on D1, D8, and 
D15
0.65 mg/kg (65 mg maximum total dose) on D1, 
D8, and D15
0.65 mg/kg (65 mg maximum total dose) on D1, D8, 
and D15
0.65* mg/kg (65 mg maximum total dose) on D1 
and D8
* If the patient is already being treated with tisotumab vedotin 0.65 mg/kg on D1 and D8, the dose must not be reduced 
further.
Table 4:
Dose modification scheme: Q3W regimen
Previous dose of tisotumab vedotin
Reduced dose of tisotumab vedotin
2.0 mg/kg (200 mg maximum total dose)
1.3 mg/kg (130 mg maximum total dose)
1.3 mg/kg (130 mg maximum total dose)
0.9* mg/kg (90 mg maximum total dose)
* If the patient is already being treated with tisotumab vedotin 0.9 mg/kg, the dose must not be reduced further.
Any dose delay(s) must be pre-approved by the sponsor’s medical monitor unless allowed 
according to the mitigation plans specified in Section 5.3. Tisotumab vedotin dosing can be 
resumed immediately after the adverse event has improved as indicated in the mitigation 
plans or as agreed with sponsor. Tisotumab vedotin must be permanently discontinued for 
any dose delay >12 weeks, (i.e., 84 days calculated from the intended day of the next 
scheduled dose), unless approved by the sponsor.


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5.3
Mitigation Plans for Specific Adverse Events
5.3.1 Ocular Adverse Events
All patients must adhere to all ocular premedication guidelines for tisotumab vedotin (refer to 
Section 5.4).
Dose modification and toxicity management guidelines for ocular AEs are provided in 
Table 5. Dose modification and toxicity management guidelines for ocular AEs should be 
based upon CTCAE v5.0 grading.
If a patient experiences an ocular AE, every effort must be made to refer the patient for 
ophthalmological evaluation within 3 days. The ophthalmologist’s objective findings and 
overall evaluation should be recorded in the electronic case report form (eCRF). The patient 
should hereafter be followed closely by the ophthalmologist until resolution. Topical 
treatment should be initiated by the ophthalmologist according to the treatment guidelines in 
Table 5.
All ocular events should be graded according to the following:
●
Ophthalmological grading based on the objective eye-examination findings 
performed by the ophthalmologist.
●
CTCAE grading system based on NCI CTCAE criteria assessed by the investigator 
(CTCAE version 5.0). Please note that grading should be based upon treatment 
emergent criteria listed in CTCAE (i.e., not taking prophylactic premedication into 
consideration).


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Table 5:
Dose modification and toxicity management guidelines – ocular AEs
AE and Toxicity Grade 
(CTCAE v5.0)
Action Taken with Tisotumab Vedotin
Guidelines for Treatment Prescribed by the 
Ophthalmologist
Conjunctivitis
Conjunctivitis Grade 1
Hold dosing until event is managed effectively.
Continue tisotumab vedotin at the same dose level.
Local ophthalmologist must prescribe frequent dosing 
of topical steroid drops.
Conjunctivitis Grade 2
1st occurrence
Hold dosing until event has improved to ≤Grade 1.
Continue tisotumab vedotin at the same dose level.
Local ophthalmologist must prescribe frequent dosing 
of topical steroid drops (prednisolone 1% or 
equivalent, overnight treatment with a topical steroid 
ophthalmic ointment, such as loteprednol etabonate, 
can be considered). Prophylaxis with topical antibiotic 
drops should be also be considered. Additional 
treatment modalities such as topical lubricating drops, 
topical immunomodulator drops (such as calcineurin 
inhibitors or equivalent), treatment with systemic 
steroids or surgical intervention to be determined as 
clinically applicable by the local ophthalmologist. 
Treatment to continue until the local ophthalmologist 
deems necessary. 
Conjunctivitis Grade 2
2nd occurrence
Hold dose of tisotumab vedotin:
●If the event has improved to baseline within 6 weeks 
(calculated from the onset date of the 2nd Grade 2 event), 
reduce next dose of tisotumab vedotin according to 
Section 5.2.3.
If the event does not improve to baseline within 6 weeks, 
permanently discontinue tisotumab vedotin.
Conjunctivitis Grade 2
3rd occurrence
Permanently discontinue tisotumab vedotin.
Conjunctivitis ≥Grade 3
Permanently discontinue tisotumab vedotin.
Keratitis
Keratitis Grade 1
Hold dosing until event is managed effectively.
Continue same dose for next dosing
Local ophthalmologist must prescribe frequent dosing 
of topical steroid drops.
Keratitis Grade 2
1st occurrence
Hold tisotumab vedotin until event has improved to ≤Grade 1.
Reduce tisotumab vedotin according to Section 5.2.3.
Local ophthalmologist must prescribe frequent dosing 
of topical steroid drops (prednisolone 1% or 
equivalent, overnight treatment with a topical steroid 
ophthalmic ointment, such as loteprednol etabonate, 
can be considered). Prophylaxis with topical antibiotic 
drops should be also be considered. Additional 
treatment modalities such as topical lubricating drops, 
topical immunomodulator drops (such as calcineurin 
inhibitors or equivalent), treatment with systemic 
steroids or surgical intervention to be determined as 
clinically applicable by the local ophthalmologist. 
Treatment to continue until the local ophthalmologist 
deems necessary. 
Keratitis ≤Grade 2
2nd occurrence
Hold tisotumab vedotin until event has improved to ≤Grade 1.
Reduce tisotumab vedotin again according to Section 5.2.3.
Keratitis ≤Grade 2
3rd occurrence
Permanently discontinue tisotumab vedotin.
Keratitis ≥Grade 3
Permanently discontinue tisotumab vedotin.


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AE and Toxicity Grade 
(CTCAE v5.0)
Action Taken with Tisotumab Vedotin
Guidelines for Treatment Prescribed by the 
Ophthalmologist
Conjunctival ulceration and opthalmological findings of fluorescent patches must be handled as below
Grade 1–2
1st occurrence
Hold tisotumab vedotin until event is managed effectively.
Reduce tisotumab vedotin according to Section 5.2.3.
Local ophthalmologist must prescribe frequent dosing 
of topical steroid drops (prednisolone 1% or 
equivalent, overnight treatment with a topical steroid 
ophthalmic ointment, such as loteprednol etabonate, 
can be considered). Prophylaxis with topical antibiotic 
drops should be also be considered. Additional 
treatment modalities such as topical lubricating drops, 
topical immunomodulator drops (such as calcineurin 
inhibitors or equivalent), treatment with systemic 
steroids or surgical intervention to be determined as 
clinically applicable by the local ophthalmologist. 
Treatment to continue until the local ophthalmologist 
deems necessary.
Grade 1–2
2nd occurrence
Hold tisotumab vedotin until event is managed effectively.
Reduce tisotumab vedotin according to Section 5.2.3.
Grade 1–2
3rd occurrence
Permanently discontinue tisotumab vedotin
Consult local ophthalmologist immediately.
≥Grade 3
Permanently discontinue tisotumab vedotin
Consult local ophthalmologist immediately.
Symblepharon must be handled as below
Any grade
Permanently discontinue tisotumab vedotin.
Consult local ophthalmologist immediately.
All other ocular toxicities (e.g., dry eye, vision blurred, blepharitis, lacrimation increased, etc.)
All other ocular toxicities 
Grade 1
Hold dosing until event is managed effectively.
Continue tisotumab vedotin at the same dose level.
If clinically indicated, local ophthalmologist must 
prescribe frequent dosing of topical steroid drops 
(prednisolone 1% or equivalent, overnight treatment 
with a topical steroid ophthalmic ointment, such as 
loteprednol etabonate, can be considered). Prophylaxis 
with topical antibiotic drops should be also be 
considered. Additional treatment modalities such as 
topical lubricating drops, topical immunomodulator 
drops (such as calcineurin inhibitors or equivalent), 
treatment with systemic steroids or surgical 
intervention to be determined as clinically applicable 
by the local ophthalmologist. Treatment to continue 
until the local ophthalmologist deems necessary. 
All other ocular toxicities 
Grade 2
1st occurrence
Hold dosing until event has improved to ≤Grade 1
Continue tisotumab vedotin at the same dose level
All other ocular toxicities 
Grade 2
Hold dose of tisotumab vedotin:
●If the event has improved to baseline within 6 weeks 
(calculated from the onset date of the 2nd occurrence of the 
Grade 2 event), reduce next dose of tisotumab vedotin 
according to Section 5.2.3.


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AE and Toxicity Grade 
(CTCAE v5.0)
Action Taken with Tisotumab Vedotin
Guidelines for Treatment Prescribed by the 
Ophthalmologist
All other ocular toxicities 
Grade 2
2nd occurrence
If the event does not improve to baseline within 6 weeks, 
permanently discontinue tisotumab vedotin.
All other ocular toxicities 
Grade 2
3rd occurrence
Permanently discontinue tisotumab vedotin.
Consult local ophthalmologist immediately.
All other ocular toxicities 
≥Grade 3
Permanently discontinue tisotumab vedotin.
Consult local ophthalmologist immediately.


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5.3.2 Infusion-Related Reactions
Tisotumab vedotin may cause IRRs including severe hypersensitivity or anaphylaxis. Signs 
and symptoms usually develop during or shortly after drug infusion.
●
In case any clinical significant IRR is observed during or after the first infusion of 
tisotumab vedotin or at subsequent treatment cycles, the patient should be observed 
for 2 hours after the end of tisotumab vedotin administration for all subsequent 
infusions.
●
At all times during infusion, immediate emergency treatment of an anaphylactic 
reaction according to institutional standards must be assured. In order to treat possible 
anaphylactic reactions, for instance, dexamethasone 10 mg and epinephrine in a 
1:1000 dilution or equivalents must always be available along with equipment for 
assisted ventilation.
●
All premedication must be reported on the concomitant medication page in the eCRF.
Dose modification and toxicity management guidelines for tisotumab vedotin associated 
infusion reaction are provided in Table 6.
Table 6:
Dose modification and toxicity management for infusion-related reactions
Infusion-Related Reactions (IRRs)
Grade 1
Continue infusion at the investigator’s discretion at half the infusion rate under close 
medical supervision.
Grade 2
Infusion must be interrupted and appropriate medical management instituted.
The infusion may be re-started at the investigator’s discretion at half the infusion 
rate under close medical supervision, if symptoms have resolved to ≤Grade 1 within 
an hour.
The patient should be pre-medicated (antihistamine, acetaminophen and 
corticosteroids are recommended) before the next infusion.
Grade 3
1st occurrence
Infusion must be interrupted and appropriate medical management instituted.
The infusion may be re-started at the investigator’s discretion at half the infusion 
rate under close medical supervision if symptoms have resolved to ≤Grade 1 within 
an hour.
The patient should be pre-medicated (antihistamine, acetaminophen and 
corticosteroids are recommended) before the next infusion.
Grade 3
2nd occurrence 
despite 
premedication
Permanently discontinue tisotumab vedotin treatment.
≥Grade 4
Infusion must be interrupted immediately and appropriate medical therapy must be 
administered.
Permanently discontinue tisotumab vedotin treatment.
5.3.3 Other Adverse Events
AEs such as increased bleeding, hemorrhage, elevated liver enzymes, mucositis, neutropenia, 
and peripheral neuropathy may be associated with tisotumab vedotin administration. Dose 
modification and toxicity management are provided in Table 7.


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Table 7:
Dose modification and toxicity management for other AEs associated with 
tisotumab vedotin
Bleeding Events
●Control vital signs and ensure stabilization of the patient according to local standards.
●Prompt evaluation to identify the underlying etiology of the bleeding event. Management should ultimately be 
dictated by the underlying diagnosis.
●Control laboratory coagulation and hematologic parameters including PT, aPTT, fibrinogen, platelets, INR and 
hemoglobin as soon as possible.
All Patients
Any grade pulmonary or CNS 
hemorrhage
Permanently discontinue tisotumab vedotin treatment.
Patients NOT on anticoagulation therapy
1st occurrence
Hemorrhage (other)1 Grade 3
Hold dosing until:
a) Bleeding has resolved.
b) Blood hemoglobin level is stable.
c) There is no bleeding diathesis that could increase the risk of continuing 
therapy.
d) Patients must not have tumors involving or adjacent to major blood vessels
When the above criteria are fulfilled the patient can resume treatment with 
tisotumab vedotin at the same dose as prior to the event.
≥2nd occurrence
Hemorrhage (other)1 Grade 3
Contact sponsor in order to discuss whether the patient may continue or must 
permanently discontinue tisotumab vedotin treatment.
Hemorrhage Grade 4 (any 
occurrence)
Patient must permanently discontinue tisotumab vedotin treatment
Patients on anticoagulation therapy
INR >2.5
Patients on therapeutic anticoagulation whose INR is >2.5 prior to infusion of 
tisotumab vedotin must hold tisotumab vedotin until INR is ≤2.5. Patients may 
resume tisotumab vedotin administration immediately after the INR is ≤2.5. 
Strongly consider holding anticoagulation until the above parameters are met.
Hemorrhage (other)a Grade 3
Hold anticoagulation therapy.
Contact sponsor in order to discuss whether the patient may continue or must 
permanently discontinue tisotumab vedotin treatment.
Hemorrhage Grade 4 (any 
occurrence)
Patient must permanently discontinue tisotumab vedotin treatment
Liver parameters elevated (AST, ALT, or bilirubin)
≥Grade 3
Hold tisotumab vedotin until toxicity resolves to ≤Grade 1. In the event of 
recurrence of ≥Grade 3, permanently discontinue tisotumab vedotin.
Mucositis
Grade 3
Hold tisotumab vedotin until event has improved to ≤Grade 2, then reduce 
tisotumab vedotin according to Section 5.2.3. Treat according to local practice. In 
the event of recurrence to Grade 3, permanently discontinue tisotumab vedotin.
Grade 4
Permanently discontinue tisotumab vedotin.


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Neutropenia
Grade 3 or 1st occurrence of 
Grade 4
Hold tisotumab vedotin until event has improved to ≤Grade 2 (including G-CSF 
administration).
Growth factor support (G-CSF) should be given prophylactically prior to 
subsequent tisotumab vedotin administrations. 
2nd occurrence
Grade 4
Contact sponsor to discuss dose reduction or discontinuation of tisotumab 
vedotin.
Peripheral neuropathy (including preferred terms as: neuropathy peripheral; peripheral sensory neuropathy; 
peripheral motor neuropathy; polyneuropathy)
Grade 2 and 3
Initial or worsening of pre-
existing condition
Hold tisotumab vedotin until event has improved to ≤Grade 1.
Reduce next dose according to dose reduction scheme in Section 5.2.3.
≥Grade 4
Permanently discontinue tisotumab vedotin.
a
Any other hemorrhage with the exception of pulmonary or CNS hemorrhage.
5.3.4 Storage and Handling
Refrigeration should be set at 2–8°C for storage of vials and solutions containing tisotumab 
vedotin. The controlled location must be accessible only to the pharmacist, the investigator, 
or a duly designated person. Tisotumab vedotin does not contain preservatives; therefore, 
opened and reconstituted vials should be used within 24 hours of preparation. If not used 
immediately, the in-use storage should not be longer than 24 hours. It is recommended that 
tisotumab vedotin vials and solutions be stored protected from direct sunlight until the time 
of use. Reconstituted vials must not be shaken.
Drug accountability procedures are provided in the Pharmacy Binder.
5.3.5 Packaging and Labeling
Tisotumab vedotin will be supplied in vials containing 40 mg of tisotumab vedotin as 
lyophilized powder. The powder must be reconstituted with 4 mL water for injection leading 
to a 10 mg/mL solution. Tisotumab vedotin will not be dispensed in child-resistant 
packaging.
Labeling will be in accordance with the EU Guidelines to Good Manufacturing Practice, 
Annex 13, Investigational Medicinal Products, and any other applicable local regulatory 
requirements.
For further details on packaging and labeling of tisotumab vedotin, please refer to the 
Pharmacy Binder.
5.3.6 Preparation
The dose of tisotumab vedotin for administration must be prepared by the trial site pharmacy 
using aseptic technique. The reconstituted tisotumab vedotin must be diluted into a 
0.9% NaCl infusion bag containing 100mL according to the dose calculated for the patient.
The infusion must be completed within 24 hours after the tisotumab vedotin vials have been 
reconstituted. A 0.2 μm in-line filter must be used for the infusion. The entire (100 mL or 


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greater) infusion volume from the prepared infusion bag needs to be administered; no dead 
volume is provided.
Detailed drug preparation instructions are provided in the Pharmacy Binder.
5.4
Required Ocular Premedication and Preventive Eye Therapy
In order to prevent ocular AEs, all patients must adhere to ocular premedication and 
preventive eye therapy guidelines listed below (see also Appendix C):
●
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 sponsor’s medical monitor.
●
Use of eye cooling pads during infusion, e.g., Cardinal Health cold packs,
refrigerator-based THERA PEARL Eye Mask, or similar. To be applied 5 minutes 
prior to start of infusion in accordance with the instructions provided with the eye 
cooling pads. The cooling pads must remain on the patient’s eyes during the entire 
30-60 minute infusion and for as long as 30 minutes afterwards.
●
Application of steroid eye drops (dexamethasone 0.1% eye drops or equivalent)
before and after each infusion for a total of 4 days. The first drops are to be given 
24 hours prior to start of infusion. Continue treatment for 72 hours thereafter. Steroid 
eye drops should be administered as 1 drop in each eye, 3 times daily, or used in 
accordance with the product prescribing information.
●
Use of lubricating eye drops during the whole treatment phase of the trial (i.e., from 
first dose of study drug until 30 days after the last dose of study drug). Frequent use 
of lubricating eye drops as per standard of care for patients receiving chemotherapy is 
recommended. Lubricating eyedrops should be self-administered daily or as needed 
according to the package insert or prescribed instructions from the ophthalmologist.
●
It is recommended that patients not wear contact lenses while being treated with 
tisotumab vedotin from the first dose until 30 days after the last dose of study drug.
5.5
Concomitant Therapy
All concomitant medications, blood products, and radiotherapy administered will be recorded 
from Day 1 (predose) through the safety reporting period. Any concomitant medication given 
for a study protocol-related adverse event should be recorded from the time of informed 
consent. Exceptions to this include medications administered for ocular AEs, which must be 
documented until resolution of the AE, return to baseline, or study closure, whichever comes 
first.


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5.5.1 Required Concomitant Therapy
Please see Section 5.4 and Appendix C for required ocular premedication and preventive eye 
therapy schedule.
5.5.2 Allowed Concomitant Therapy
Use of the DigniCap Scalp Cooling System or other, similar scalp-cooling device according 
to guidelines is permitted to prevent alopecia if available at the clinical study site.
Anti-coagulation therapy for prophylaxis/treatment of thrombotic conditions is permitted 
with the following restrictions:
●
A patient on anticoagulants when entering the study must be on a steady dose at least 
4 weeks prior to study drug administration and must have INR and aPTT monitored 
prior to dosing. Patients on anticoagulation therapy requiring monitoring of the 
PT/INR should have their doses adjusted to target an INR ≤2.5 ULN at least 4 weeks 
prior to study drug administration. Coagulation parameters including fibrinogen, 
aPTT, PT, and INR must be measured locally prior to each dose of study drug as 
specified in Section 7.7.2.
●
If a patient develops a new DVT/PE and requires initiation of therapeutic 
anticoagulation, therapy with tisotumab vedotin will be held until new 
anticoagulation has been started, and:
○
For vitamin K antagonists, patient must have been on a steady dose for at least 
2 weeks with INR <2.5. Parenteral low molecular weight heparin (LMWH) must 
no longer be required for bridging.
○
For other anticoagulant agents that require additional parenteral agents during 
initiation, the parenteral agent must have been discontinued, and the anticoagulant 
must be on a steady dose for at least 2 weeks. (for e.g., edoxaban for new 
DVT/PE events, which can be started after an initial 5–10 days of parenteral 
anticoagulant as per the product label).
○
For agents that require a higher dose during initiation, (e.g., apixaban that is 
started at 10 mg orally twice per day, and then maintained at 5 mg twice per day), 
tisotumab vedotin will be held during initiation and can be resumed after 2 weeks 
on the stable maintenance dose. 
○
For agents such as LMWH that are administered via weight-based dosing, 
tisotumab vedotin will be held during the initial 2 weeks of the introduction of 
new anticoagulant.
●
Chronic use of antiplatelet therapy (ASA [aspirin], clopidogrel, and similar 
medications), as required for vascular diseases such as coronary artery disease,
cerebrovascular accident, and similar conditions, is permitted on this study.


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●
A patient cannot receive both anticoagulant(s) and antiplatelet agent(s) concurrently
while on study.
Each patient should be told to notify the trial site about any new medications they are taking 
after receiving the first tisotumab vedotin administration. All medications (other than 
tisotumab vedotin) and significant non-drug therapies (including herbal/natural medications, 
and blood transfusions) administered during the trial must be recorded in the eCRF.
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as prohibited 
(Section 5.5.3). Administration of concomitant medications must be reported in the 
appropriate section of the eCRF along with dates of administration and reasons for use.
5.5.3 Prohibited Concomitant Therapy
Patients must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator.
The following is prohibited:
●
Curative intent radiation therapy, from the time of consent until the patient completes 
the trial, with the following exceptions:
○
Radiation therapy of a solitary non-target lesion IS allowed.
○
Palliative radiotherapy IS allowed as per RECIST criteria.
●
Drugs and substances known to be strong CYP3A and/or P-gp inhibitors according to 
the US FDA’s list of drug interactions should be avoided if possible. If administered, 
the patient must be closely observed for potential adverse reactions.
Patients may not receive other investigational drugs, immunosuppressive medications, or 
systemic anti-neoplastic therapy during the study.
5.6
Management of Adverse Reactions
5.6.1 Management of Infusion Reactions
IRRs may occur during the infusion of study treatment. The infusion should be administered 
at a site properly equipped and staffed to manage anaphylaxis should it occur. If anaphylaxis 
occurs, administration of tisotumab vedotin should be immediately and permanently 
discontinued.
All supportive measures consistent with optimal patient care should be given throughout the 
study according to institutional standards. Supportive measures may include extending the 
infusion time and/or administering medications for IRRs.
All patients should be observed for 2 hours after ending their first infusion of study drug and 
15 minutes for all subsequent cycles. In case any clinically significant IRR is observed 
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should be observed for 2 hours after end of study drug administration for all following 
infusions.
For more information on infusion reactions, please refer to Section 5.3.2.
5.6.2 Management of Overdose
Weight-based dosing for tisotumab vedotin is based on the patient’s actual body weight, with 
the exception of patients weighing greater than 100 kg. Dosing will be based on 100kg for 
these individuals. The maximum dose permitted per infusion in this study is 90 mg or 
120 mg for patients receiving the dose-dense regimen and 200 mg for patients receiving 
the Q3W regimen. If the dose for the dose-dense regimen is de-escalated to 0.65 mg/kg, 
the maximum dose permitted per infusion will be 65 mg.
In the event of an overdose of tisotumab vedotin ≥10%, study personnel should:
●
Care for and medically stabilize the patient until there is no immediate risk of 
complications or death, if applicable. There is currently no known antidote for an 
overdose of tisotumab vedotin.
●
Consider growth factor support and monitoring of coagulation parameters with 
appropriate intervention as needed.
●
Notify the sponsor’s medical monitor as soon as they become aware of the overdose, 
to discuss details of the overdose (e.g., exact amount of tisotumab vedotin 
administered, patient weight) and adverse events, if any.
5.7
Treatment Compliance
Study drug administration will be performed by study site staff and documented in source 
documents and the CRF. In addition, patients will be provided with a patient diary and 
instructed to record details of prophylactic eye drop usage each day.
6
STUDY ACTIVITIES
6.1
Schedule of Events
Adverse events and concomitant medications will be recorded from Day 1 (predose) through 
the safety reporting period (see Section 7.7.8). Any study protocol-related adverse event 
(defined in Section 7.7.8.1) as well as any concomitant medications given for treatment of 
the adverse event, should be recorded from the time of informed consent. A schedule of 
events is provided in Appendix A. Study activities are listed by visit in this section and 
descriptions of all study assessments are presented in Section 7.
For all treatment cycles, clinical laboratory assessments (serum chemistry panel, complete 
blood count [CBC] with differential, coagulation parameters, and Hemoglobin Alc 
[HgbA1c]) as well as physical exam, weight, and ECOG performance status may be 
performed within 1 day prior to administration of study drug. The results from all relevant 
clinical laboratory assessments must be reviewed prior to dosing.


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Tumor biopsies performed outside protocol-specified time points during the study should be 
made available to the sponsor if feasible and if the patient has consented to submission of 
these samples (see Section 7.5.2). Biopsies performed at protocol-specified time points must 
be submitted to the sponsor.
Procedures listed below include only those that occur in the clinic or on the same day that a 
patient visits the clinic. See Appendix C for the preventative eye therapy schedule and dosing 
diary schedule. The PRO-CTCAE patient-reported outcomes questionnaire should be 
collected at baseline and weekly (±2 days) starting on Cycle 1 Day 1 through the end of 
treatment (Appendix A).
6.2
Screening Visit (Days [–28] to 1)
●
Informed consent
●
Study eligibility per inclusion/exclusion criteria
●
Blood collection for CA-125 (results to be submitted to central laboratory)
●
Medical history (see Section 7.1)
●
Height and weight
●
Physical exam
●
Vital signs
●
Eye exam performed by investigator (see Section 7.7.5 and Appendix C)
●
Ophthalmologic evaluation performed by ophthalmologist (see Section 7.7.4)
●
Electrocardiogram (ECG)
●
Biopsy collection (See Section 7.1.1)
●
Imaging
6.2.1 Baseline Visit (Days –7 to Day 1)
●
Pregnancy test for patients of childbearing potential
●
CBC with differential (results to be submitted to central laboratory)
●
Chemistry panel (results to be submitted to central laboratory)
●
Calculation of eGFR (See Section 7.7.2)
●
Coagulation parameters (fibrinogen, INR, PT, and aPTT) (results to be submitted to 
central laboratory)
●
HgbA1c (results to be submitted to central laboratory)
●
ECOG performance status
●
Parts A and B, US patients only: patient-reported outcomes questionnaires (all 
questions)


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6.3
Treatment Period (Q3W Regimen only)
6.3.1 Day 1 (±1 day), All treatment cycles (exceptions noted)
●
Cycle 1 only: Prior to dosing, confirm patient eligibility per inclusion/exclusion 
criteria
●
Weight
●
Physical Exam
●
Predose vital signs
●
ECOG Performance status (If Baseline Visit activities occur within 1 day prior, this 
assessment does not need to be repeated at Cycle 1, Day 1)
●
Chemistry panel (results to be submitted to central laboratory; if Baseline Visit 
activities occur within 1 day prior, this assessment does not need to be repeated at 
Cycle 1, Day 1)
●
CBC with differential (results to be submitted to central laboratory; if Baseline Visit 
activities occur within 1 day prior, this assessment does not need to be repeated at 
Cycle 1, Day 1)
●
Pregnancy test for patients of childbearing potential (If Baseline Visit activities occur 
within 1 day prior, this assessment does not need to be repeated at Cycle 1, Day 1)
●
Coagulation parameters (fibrinogen, INR, PT, and aPTT) (results to be submitted to 
central laboratory; if Baseline Visit activities occur within 1 day prior, this 
assessment does not need to be repeated at Cycle 1, Day 1)
●
Eye exam performed by investigator
●
Predose blood sample for PK evaluation (within 24 hours) (Cycles 1, 2, 3, 4, 5, and 
every other cycle thereafter)
●
Predose blood sample for antitherapeutic antibody (ATA) evaluation (within 
24 hours) (Cycles 1, 2, 3, 4, 5, and every other cycle thereafter)
●
Predose blood sample for plasma proteomic analysis (within 24 hours) (Cycles 1, 2, 
3, 4, 5, and every other cycle thereafter)
●
Predose blood sample for plasma mutational analysis (within 24 hours) (Cycles 1, 2, 
3, 4, 5, and every other cycle thereafter)
●
Predose blood sample for plasma exosome analysis (within 24 hours) (Cycles 1, 2, 3, 
4, 5, and every other cycle thereafter)
●
Predose blood sample for PBMC immune subsets analysis (within 24 hours) (Cycles 
1, 2, 3, and 4 only)
●
Ocular premedication and preventative eye therapy (see Section 5.4 and Appendix C)
●
Ensure patient completes dosing diary
●
Parts A and B, US patients only: Patient-reported outcomes questionnaires (all 
questions). If Baseline Visit activities occur within 1 day prior, this assessment does 
not need to be repeated at Cycle 1, Day 1.
●
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●
Blood samples for PK evaluation (all time points from end of infusion)
○
End of infusion (+ 15 minutes) (Cycles 1, 2, 3, 4, 5, and every other cycle 
thereafter)
○
1 hour (±15 minutes) (Cycles 1 and 2 only)
○
5 hours (±30 minutes) (Cycles 1 and 2 only)
●
Blood samples for plasma proteomic analysis (all time points from end of infusion)
○
End of infusion (+15 minutes) (Cycles 1, 2, 3, 4, 5, and every other cycle 
thereafter)
○
1 hour (±15 minutes) (Cycles 1 and 2 only)
○
5 hours (±2 hours) (Cycles 1 and 2 only)
6.3.2 Cycle 1 and 2, Day 2
●
Preventative eye therapy (see Section 5.4 and Appendix C)
●
Ensure patient completes dosing diary
6.3.3 Cycle 1 and 2, Day 3
●
Preventative eye therapy (see Section 5.4 and Appendix C)
●
Blood sample for PK evaluation (48 hours ±4 hours after the end of infusion)
●
Blood sample for plasma proteomic analysis (48 hours ±4 hours after the end of 
infusion)
●
Ensure patient completes dosing diary
6.3.4 Cycle 1 Day 8 (±1 day)
●
CBC with differential (results to be submitted to central laboratory)
●
Chemistry panel (results to be submitted to central laboratory)
●
Coagulation parameters (fibrinogen, INR, PT, and aPTT) (results to be submitted to 
central laboratory)
●
Eye exam performed by investigator
●
Blood sample for PK evaluation (168 hours ±24 hours after the end of infusion)
●
Blood sample for plasma proteomic analysis (168 hours ±24 hours after the end of 
infusion)
●
Parts A and B, US patients only: PRO-CTCAE patient-reported outcomes 
questionnaire
6.3.5 Cycle 1 and 2, Day 15
●
Blood sample for PK evaluation (336 hours ±24 hours after the end of infusion)
●
Blood sample for plasma proteomic analysis (336 hours ±24 hours after the end of 
infusion)
●
Parts A and B, US patients only: PRO-CTCAE patient-reported outcomes 
questionnaire


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6.3.6 Cycle 2, Day 8 (±1 day)
●
Blood sample for PK evaluation (168 hours ±24 hours after the end of infusion)
●
Blood sample for plasma proteomic analysis (168 hours ±24 hours after the end of 
infusion)
●
Parts A and B, US patients only: PRO-CTCAE patient-reported outcomes 
questionnaire
6.4
Treatment Period (Dose-Dense Regimen only)
6.4.1 Day 1 (±1 day), All Treatment Cycles (Exceptions Noted)
●
Cycle 1 only: Prior to dosing, confirm patient eligibility per inclusion/exclusion 
criteria
●
Weight
●
Physical Exam
●
Predose vital signs
●
ECOG Performance status (If Baseline Visit activities occur within 1 day prior, this 
assessment does not need to be repeated at Cycle 1, Day 1)
●
Chemistry panel (results to be submitted to central laboratory; if Baseline Visit 
activities occur within 1 day prior, this assessment does not need to be repeated at 
Cycle 1, Day 1)
●
CBC with differential (results to be submitted to central laboratory; if Baseline Visit 
activities occur within 1 day prior, this assessment does not need to be repeated at 
Cycle 1, Day 1)
●
Pregnancy test for patients of childbearing potential (If Baseline Visit activities occur 
within 1 day prior, this assessment does not need to be repeated at Cycle 1, Day 1)
●
Coagulation parameters (fibrinogen, INR, PT, and aPTT) (results to be submitted to 
central laboratory; if Baseline Visit activities occur within 1 day prior, this 
assessment does not need to be repeated at Cycle 1, Day 1)
●
Eye exam performed by investigator
●
Predose blood sample for PK evaluation (within 24 hours) (Cycles 1, 2, 3, 4, 7, and 
every 3rd cycle thereafter)
●
Predose blood sample for ATA evaluation (within 24 hours) (Cycles 1, 2, 3, 4, 7, and 
every 3rd cycle thereafter)
●
Predose blood sample for plasma proteomic analysis (within 24 hours) (Cycles 1, 2, 
3, 4, 7, and every 3rd cycle thereafter)
●
Predose blood sample for plasma mutational analysis (within 24 hours) (Cycles 1, 2, 
3, 4, 7, and every 3rd cycle thereafter)
●
Predose blood sample for plasma exosome analysis (within 24 hours) (Cycles 1, 2, 3, 
4, 7, and every 3rd cycle thereafter)
●
Predose blood sample for PBMC immune subsets analysis (within 24 hours) (Cycles 
1, 2, 3, and 4 only)


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●
Ocular premedication and preventative eye therapy (see Section 5.4 and Appendix C)
●
Ensure patient completes dosing diary
●
Parts A and B, US patients only: patient-reported outcomes questionnaires (all 
questions). If Baseline Visit activities occur within 1 day prior, this assessment does 
not need to be repeated at Cycle 1, Day 1.
●
Tisotumab vedotin administration
●
Blood samples for PK evaluation (all time points from end of infusion)
○
End of infusion (+ 15 minutes) (Cycles 1, 2, 3, 4, 7 and every 3rd cycle thereafter)
○
1 hour (±15 minutes) (Cycle 1 only)
○
5 hours (±2 hours) (Cycle 1 only)
●
Blood samples for plasma proteomic analysis (all time points from end of infusion)
○
1 hour (±15 minutes) (Cycle 1 only)
○
5 hours (±2 hours) (Cycle 1 only)
6.4.2 Cycles 1 and 2, Day 2
●
Preventative eye therapy (see Section 5.4 and Appendix C)
●
Ensure patient completes dosing diary
6.4.3 Cycles 1 and 2, Day 3
●
Preventative eye therapy (see Section 5.4 and Appendix C)
●
Blood sample for PK evaluation (48 hours ±4 hours after the end of infusion)
●
Blood sample for plasma proteomic analysis (48 hours ±4 hours after the end of 
infusion)
●
Ensure patient completes dosing diary
6.4.4 All Treatment Cycles, Day 8 (±1 day) (Exceptions Noted)
●
Weight
●
Physical Exam
●
Predose vital signs 
●
Chemistry panel (results to be submitted to central laboratory)
●
CBC with differential (results to be submitted to central laboratory)
●
Coagulation parameters (fibrinogen, INR, PT, and aPTT) (results to be submitted to 
central laboratory)
●
Eye exam performed by investigator
●
Ocular premedication and preventative eye therapy (see Section 5.4 and Appendix C)
●
Predose blood sample for PK evaluation (within 8 hours) (Cycles 1 and 2 only)
●
Predose blood sample for plasma proteomic analysis (within 8 hours) (Cycles 1 and 2 
only)
●
Ensure patient completes dosing diary


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●
Parts A and B, US patients only: PRO-CTCAE patient-reported outcomes 
questionnaire
●
Tisotumab vedotin administration
6.4.5 All Treatment Cycles, Day 15 (±1 day) (Exceptions Noted)
●
Weight
●
Physical Exam
●
Predose vital signs
●
Chemistry panel (results to be submitted to central laboratory)
●
CBC with differential (results to be submitted to central laboratory)
●
Coagulation parameters (fibrinogen, INR, PT, and aPTT) (results to be submitted to 
central laboratory)
●
Eye exam performed by investigator
●
Ocular premedication and preventative eye therapy (see Section 5.4 and Appendix C)
●
Predose blood sample for PK evaluation (within 8 hours) (Cycles 1, 2, 3, 4, 7, and 
every 3rd cycle thereafter)
●
Predose blood sample for plasma proteomic analysis (within 8 hours) (Cycles 1, 2, 3,
4, 7, and every 3rd cycle thereafter)
●
Predose blood sample for plasma mutational analysis (within 8 hours) (Cycles 1, 2, 3, 
4, 7, and every 3rd cycle thereafter)
●
Predose blood sample for plasma exosome analysis (within 8 hours) (Cycles 1, 2, 3, 
4, 7, and every 3rd cycle thereafter)
●
Predose blood sample for PBMC immune subsets analysis (within 8 hours) (Cycles 1, 
2, 3, and 4 only)
●
Parts A and B, US patients only: PRO-CTCAE patient-reported outcomes 
questionnaire
●
Ensure patient completes dosing diary
●
Tisotumab vedotin administration
●
Blood samples for PK evaluation (all time points from end of infusion)
○
End of infusion (within 15 minutes) (Cycles 1, 2, 3, 4, 7, and every 3rd cycle 
thereafter)
○
1 hour (±15 minutes) (Cycle 1 only)
○
5 hours (±2 hours) (Cycle 1 only)
●
Blood samples for plasma proteomic analysis (all time points from end of infusion)
○
1 hour (±15 minutes) (Cycle 1 only)
○
5 hours (±2 hours) (Cycle 1 only)
6.4.6 Cycle 1, Day 17
●
Blood sample for PK evaluation (48 hours ±4 hours after the end of infusion)


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●
Blood sample for plasma proteomic analysis (48 hours ±4 hours after the end of 
infusion)
●
Preventative eye therapy (see Section 5.4 and Appendix C)
6.4.7 Cycle 1, Day 22 (±1 day)
●
Blood sample for PK evaluation (168 hours ±24 hours after the end of infusion)
●
Blood sample for plasma proteomic analysis (168 hours ±24 hours after the end of 
infusion)
●
Parts A and B, US patients only: PRO-CTCAE patient-reported outcomes 
questionnaire (can be conducted remotely)
6.5
Response Assessments
Time points for radiographic exams should be calendar-based and do not depend on cycle 
visits. Imaging should be conducted on the following schedule until disease progression, start 
of a new cancer therapy, consent withdrawal, study termination by the sponsor, or death, 
whichever comes first:
●
Every 6 weeks (±7 days) for 6 months after the first dose of tisotumab vedotin
●
Every 12 weeks (±7 days) for the next 6 months (i.e., until 1 year after first dose)
●
Every 6 months (±2 weeks) thereafter
Blood collections for CA-125 status should correspond as closely as possible with imaging 
visits (±5 days).
Responses must be evaluated with a confirmatory scan at least 4 weeks after initial response.
6.6
End of Treatment Visit (30 to 37 days after last dose of study drug)
End of Treatment (EOT) visits should occur 30 to 37 days after the last dose of study drug 
unless delayed due to an AE. Note: The time to EOT visit may be longer than 37 days. 
However, EOT evaluations must be performed before initiation of a new (non-protocol) 
therapy. If EOT evaluations are completed before 30 days after the last study treatment, the 
patient will be contacted 30 to 37 days following the last treatment to assess for adverse 
events.
●
Physical examination 
●
Vital signs
●
Chemistry panel (results to be submitted to central laboratory)
●
CBC with differential (results to be submitted to central laboratory)
●
Pregnancy test for patients of childbearing potential
●
Coagulation parameters (fibrinogen, INR, PT, and aPTT) (results to be submitted to 
central laboratory)
●
HgbA1c (results to be submitted to central laboratory) 


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●
Blood collection for CA-125 (results to be submitted to central laboratory; not 
required if conducted within 4 weeks prior to EOT)
●
Eye exam performed by investigator
●
ECOG performance status
●
ECG
●
Imaging (not required if conducted within 4 weeks prior to EOT)
●
Subsequent anti-cancer therapy status
●
Survival status
●
Blood sample for PK evaluation
●
Blood sample for ATA evaluation
●
Blood sample for plasma proteomic analysis
●
Blood sample for plasma mutational analysis
●
Blood sample for plasma exosome analysis
●
Blood sample for PBMC immune subsets analysis
●
Parts A and B, US patients only: patient-reported outcomes questionnaires (both 
instruments)
●
For patients discontinuing treatment due to disease progression: if a tumor biopsy was 
performed at the time of disease progression, submit sample of tumor specimen, if 
available and patient has signed consent to allow submission of this tissue (see 
Section 7.5.2)
6.7
Follow-up (Every 12 weeks ±1 week)
●
Subsequent anti-cancer therapy status
●
Survival status
●
For patients of childbearing potential, a pregnancy test is to be performed 24 weeks 
after EOT (±7 days)
6.8
End of Study/End of Follow-up
The date the patient met criteria for study discontinuation and the reason for study 
discontinuation will be recorded.
7
STUDY ASSESSMENTS
7.1
Screening/Baseline Assessments
Only patients who meet all inclusion and exclusion criteria specified in Section 4 will be 
enrolled in this study.
Patient medical history includes a thorough review of significant past medical history, 
current conditions, any treatment for prior malignancies and response to prior treatment, and 
any concomitant medications.


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A physical exam, height and weight, vital signs, complete eye examination performed by the 
investigator, ophthalmologic exam by an ophthalmologist, eGFR, CT with contrast/MRI scan 
for baseline response efficacy assessment, biopsy collection, CA-125 blood collection, CBC 
with differential, serum chemistry panel, coagulation parameters including fibrinogen, INR, 
PT, and aPTT, HgbA1c, ECOG performance status, ECG, and pregnancy test (either urine or 
serum, for patients of childbearing potential) are required for all patients at screening and/or 
baseline as described in Section 6.2 and Appendix A.
7.1.1 Biopsy Collection
Fresh or archived biopsy tissue is required to be collected at baseline. Archived tumor tissue 
samples must have been obtained within 2 years prior to the first administration of tisotumab 
vedotin. Older specimens may be allowed upon approval of the sponsor’s medical monitor.
Fresh tissue must be obtained from a newly obtained core or excisional biopsy of a tumor 
lesion. If available, archived tumor tissue is also requested from patients who receive fresh 
biopsies. This will be used for additional biomarker analysis.
7.2
Response/Efficacy Assessments
The determination of antitumor activity will be based on objective response assessments 
made by the investigator according to the RECIST v1.1 (Eisenhauer 2009) and treatment 
decisions by the investigator will be based on these assessments. Clinical response of 
complete response (CR), partial response (PR), stable disease (SD), or PD will be determined 
at each assessment. In addition, images will be collected by an independent review facility 
for possible future analysis.
Measures of anti-cancer activity will be assessed by either CT with contrast or MRI scans at 
protocol-specified time points. Patients must be evaluated using the same imaging 
method throughout the study for efficacy assessments.
CT/MRI scans will include, at minimum, the chest, abdomen, and pelvis. Other regions 
should be scanned if the patient has known or suspected disease in that region.
Responses (CR or PR) will be confirmed with repeat scans at least 4 weeks after first 
documentation of response. The schedule for response assessments should not be adjusted 
after the confirmatory scan (e.g., CR at Week 6, confirmatory scans at Week 10, next 
assessment due at Week 12). Tumor imaging should also be performed whenever disease 
progression is suspected.
Patients who discontinue study treatment for reasons other than objective disease progression 
by RECIST v1.1 (see Appendix G) or subsequent cancer therapy will continue to receive 
CT/MRI scans every 6 weeks (±7 days) for the first 6 months after the first treatment with 
tisotumab vedotin (Cycle 1 Day 1). Between 6 and 12 months on study the frequency of 
response assessments will be reduced to every 12 weeks (±7 days). After 1 year on study, 
assessments will be reduced further to every 6 months (±2 weeks). Tumor assessments will 
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by the investigator, initiates a new anti-cancer therapy, dies, withdraws consent, or the study 
closes, whichever comes first.
In patients who discontinue study treatment due to pregnancy, response assessments should 
be conducted as appropriate.
Patients’ clinical data must be available for CRF source verification. Copies of tumor images 
must be made available for review by the sponsor (or its designee), upon request.
In addition to radiographic tumor assessments, expression level of CA-125 will also be 
monitored to assess response rate by CA-125 and the combination response of overall 
response/CA-125 as secondary endpoints. Blood collections for CA-125 should correspond 
as closely as possible with imaging visits (±5 days).
7.3
Pharmacokinetic and Immunogenicity Assessments
Blood samples for PK and ATA will be collected throughout the study per the sample 
collection schedule provided in Appendix B. Validated assays will be used to measure the 
concentrations of tisotumab vedotin and MMAE in serum or plasma. Two assays will be 
used for tisotumab vedotin: one detecting tisotumab vedotin only and one detecting total 
antibody. PK samples will be collected and archived for possible analysis of other tisotumab 
vedotin-related species. A qualified assay will be used to determine the levels of ATA in 
serum.
Refer to the Central Laboratory Manual for information on collection, processing, storage, 
and shipment of samples. It may be possible to have some samples collected via home visits 
by an external home health aide vendor. More information regarding this service will be 
provided by the sponsor prior to the site initiation visit.
7.4
Patient-Reported Outcomes Assessments
Parts A and B, US patients only, validated instruments will be utilized for health-related 
quality of life assessment from the patient’s perspective. Patients will be required to respond 
to questions related to physical functioning, adverse effects of treatment, and the overall 
burden of adverse effects. Patients will be requested to complete each of the questionnaires at 
timepoints described below before clinic visits (see Schedule of Events, Appendix A).
Questionnaires may be completed remotely.
Each patient will have an option to answer questions electronically or via paper. Patients will 
respond to questions related to adverse effects (10 questions), the overall burden of adverse 
effects (1 question) and vision related problems (3 questions) every 7 days during a set time 
interval. Patients will respond to key physical functioning related questions (6 questions) on 
Day 1 of each treatment cycle before infusion of study drug and at the end of treatment visit 
(EOT).


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The following instruments will be utilized:
●
NCI PRO-CTCAE: Questions related to adverse effects patients may experience 
during the trial are taken from a set of items from the NCI PRO-CTCAE item bank. 
Of the 78 items related to symptomatic treatment toxicities available in NCI 
PRO-CTCAE, a total of 10 questions related to visual symptoms (blurred vision, 
watery eyes), gastrointestinal symptoms (nausea, vomiting, constipation, diarrhea, 
and abdominal pain) bleeding (bruising, nose bleeds), and neurological (numbness 
and tingling) were selected for this trial (see Appendix D).
●
PROMIS (Patient-Reported Outcomes Measurement Information System): Patients 
will respond to 6 questions related to their ability to carry out various physical 
activities. The questions are from PROMIS (Patient-Reported Outcomes 
Measurement Information System) item bank (PROMIS Version 1.2 SF 6b–See
Appendix D).
In addition to NCI PRO-CTCAE and PROMIS, 4 additional PRO questions have been added 
by the sponsor. Three of these questions allow patients to report symptoms related to color 
vision, near vision, and night vision, respectively, on a simple 5-point scale. (Appendix D).
One additional question allows patient to report the overall effect of symptoms, also on a 
5-point scale (Appendix D).
7.5
Biomarker Studies
Samples for exploratory biomarkers will be collected at protocol-specified time points per the 
schedule provided in Appendix B. Biomarker assessments will not be used for patient 
selection.
Methods of analysis may include immunohistochemistry (IHC), mIHF, Next Generation 
Sequencing, PCR, mutation and gene expression profiling; T-cell receptor beta chain 
sequencing, flow cytometry, and proteomic methodologies such as enzyme-linked 
immunosorbent assay (ELISA) and microvesicle assessment.
7.5.1 Protein Markers in Blood
The primary effects of tisotumab vedotin on tumor cells may lead to changes in the activation 
state of local, tumor-associated, and peripheral immune cells. Biomarker assessments in 
blood samples may include but may not be limited to CA-125 status and markers of immune 
function, including abundance and phenotype of immune cell subsets and abundance of 
cytokines. These may provide insight into treatment-related changes in activation state of 
peripheral immune system associated with tisotumab vedotin-induced tumor cell death.
7.5.2 Characterization of Tumor Tissue
To better understand relationships between pre-treatment tumor biological characteristics and 
patient outcome, submission of tumor tissue is required during the screening period 
(pretreatment). Patient is required to provide fresh tissue from a newly-obtained core or 
excisional biopsy of a tumor lesion OR an archived specimen obtained within 2 years of the 


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first administration of tisotumab vedotin. Older specimens may be allowed upon approval of 
the sponsor’s medical monitor. Please see the Laboratory Manual for details.
Biomarker assessments in tumor tissue may include, but not be limited to:
●
Tumor expression of TF protein
●
Messenger ribonucleic acid (mRNA) expression (e.g., TF)
●
Markers of disease subtype (e.g., The Cancer Genome Atlas [TCGA] subtypes)
●
Mutational load
●
Markers of the tumor immune microenvironment (e.g., PD-L1, CD4, CD8)
If available and the patient consents, archived tumor tissue is also requested from patients 
who received fresh biopsies. This tissue will be used for biomarker analysis.
Any unscheduled tumor biopsies performed while a patient is on study should be made 
available to the sponsor if feasible and if the patient has signed the consent form to allow 
submission of this tissue. For example, if a biopsy on residual tumor is performed at the end 
of treatment or at progression, a sample will be collected (if available).
7.6
Biospecimen Repository
In the US only, for patients who provide additional consent, remaining de-identified unused 
blood and/or tissue will be retained by Seattle Genetics and used for future research, 
including but not limited to the evaluation of targets for novel therapeutic agents, the biology 
of ADC sensitivity and resistance mechanisms, and the identification of biomarkers of 
ADCs. Blood and tissue samples donated for future research will be retained for a period of 
up to 25 years. If additional consent is not provided, any remaining biological samples will 
be destroyed after the study has been completed and all applicable regulatory obligations 
have been met.
7.7
Safety Assessments
The assessment of safety during the course of this study will consist of the surveillance and 
recording of AEs including serious adverse events (SAEs), recording of concomitant 
medication, and measurements of protocol-specified physical examination findings and 
laboratory tests. Safety assessments will be performed at prespecified time points through the 
end of treatment visit.
Safety will be monitored over the course of the study by an SMC which includes sponsor 
representatives including the study statistician, drug safety representative, and medical 
monitor as well as all investigators with at least one patient enrolled in the trial. An ongoing, 
real-time review of patient safety and SAEs will also be conducted by the sponsor’s Drug 
Safety Department.


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7.7.1 Vital Signs
Vital signs measures are to include heart rate, blood pressure (while patient is in seated 
position), and temperature.
7.7.2 Clinical Laboratory Tests
All clinical laboratory tests will be performed locally. This testing will include institutional 
standard tests for evaluating safety and making clinical decisions. With the exception of 
pregnancy testing, results of clinical laboratory tests are to be submitted to the central 
laboratory.
The following laboratory assessment(s) will be performed at scheduled time points (see 
Appendix A) during the course of the study:
●
The estimated GFR (eGFR) should be calculated using the MDRD equation as 
applicable, with serum creatinine (Scr) reported in mg/dL:
eGFR (mL/min/1.73 m2) = 175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if
African American)
If Scr is reported in μmol/L, the value should be converted to mg/dL using the 
conversion factor 0.011312 μmol/L to mg/dL.
●
Coagulation parameters: fibrinogen, prothrombin time (PT), activated partial 
thromboplastin time (aPTT), and international normalized ratio (INR)
●
A serum or urine β-hCG pregnancy test for patients of childbearing potential (See 
Section 7.7.6)
●
Chemistry panel: albumin, alkaline phosphatase, ALT, AST, blood urea nitrogen, 
calcium, creatinine, chloride, LDH, phosphorus, potassium, sodium, glucose, gamma-
glutamyl transferase (GGT), amylase, lipase, uric acid, and total bilirubin.
●
CBC with differential is to include the following tests: white blood cell count with 
five-part differential (neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils), platelet count, hemoglobin, and hematocrit.
●
Hemoglobin Alc
●
CA-125 expression levels
Test results for biochemistry, hematology, and coagulation factors must be obtained and 
reviewed by the investigator within 24 hours prior to trial treatment administration. 
Laboratory test values should be recorded in the eCRF if they are of clinical importance, 
e.g., used as supportive information on an AE or lead to dose modifications/delays of the trial 
treatment.


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7.7.3 Physical Examination
Physical examinations should include assessments of the following body parts/systems: 
abdomen, extremities, head, heart, lungs, neck, and neurological. Measurements of height 
obtained within the prior 12 months may be utilized.
7.7.4 Ophthalmological Exam
An ophthalmological evaluation must be performed by an ophthalmologist at screening prior 
to treatment with tisotumab vedotin. This screening exam will allow the ophthalmologist to 
have a pre-treatment assessment for adequate on-treatment comparison. In addition, patients 
must be referred for additional ophthalmological examinations if ocular symptoms occur or 
in the case of objective findings from scheduled eye exams at the site (see Section 5.3.1).
Relevant physical findings from the ophthalmological examination must be documented in 
the eCRF (See Section 5.3.1). Assessments to be performed with results recorded on the 
eCRF include visual acuity, Schirmer’s test, slit lamp, inspections of the conjunctivas and 
corneas including staining, intraocular pressure, and fundoscopy.
7.7.5 Eye Examination
Eye examination should be assessed by the investigator and should include a visual 
inspection of the eye orbit and conjunctiva and control of normal eye movement. The patient 
should be asked about any ocular symptoms (e.g., itchy eyes, sticky eyelids, eye secretion, 
blurry vision etc.).
In case of either subjective ocular symptoms and/or objective findings, every effort must be 
made to refer the patient to an ophthalmologist for prompt review within 3 days. Relevant 
physical findings from the ophthalmological examination must be documented in the eCRF 
(See Section 5.3.1).
7.7.6 Pregnancy Testing
For patients of childbearing potential, a serum or urine β-hCG pregnancy test with sensitivity 
of at least 25 mIU/mL will be performed locally at baseline, within 7 days prior to Day 1 of 
Cycle 1 and Day 1 of each subsequent cycle, and at the EOT visit.
A negative pregnancy result is required before the patient may receive each infusion of study 
drug. Pregnancy tests may also be repeated as requested per IRB/IEC or if required by local 
regulations.
7.7.7 Electrocardiogram
ECGs are to be obtained per institutional standard at time points defined in Section 6 and 
Appendix A. Routine 12-lead ECGs will be performed after the patient has been in a supine 
position for at least 5 minutes. Paper copies of the tracings will be used for data entry into the 
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7.7.8 Adverse Events
7.7.8.1 Definitions
Adverse Event
According to the International Council for Harmonisation (ICH) E2A guideline Definitions 
and Standards for Expedited Reporting, and 21 CFR 312.32, IND Safety Reporting, an AE is 
any untoward medical occurrence in a patient or clinical investigational subject administered 
a medicinal product and which does not necessarily have a causal relationship with this 
treatment.
The following information should be considered when determining whether or not to record a 
test result, medical condition, or other incident on the Adverse Events and Pre-existing 
Conditions CRF:
●
From the time of informed consent through the day prior to study Day 1, only study 
protocol-related AEs should be recorded. A protocol-related AE is defined as an 
untoward medical event occurring as a result of a protocol mandated procedure.
●
All medical conditions present or ongoing predose on study Day 1 should be recorded 
(i.e., hypertension).
●
All AEs (regardless of relationship to study drug) should be recorded from study 
Day 1 (predose, during and postdose) through the end of the safety reporting period 
(see Section 7.7.8.5). Complications that occur in association with any procedure 
(e.g., biopsy) should be recorded as AEs whether or not the procedure was protocol 
mandated.
●
Changes in medical conditions and AEs, including changes in severity, frequency, or 
character, during the safety reporting period should be recorded.
●
In general, an abnormal laboratory value should not be recorded as an AE unless it is 
associated with clinical signs or symptoms, requires an intervention, results in a SAE, 
or results in study termination or interruption/discontinuation of study treatment. 
When recording an AE resulting from a laboratory abnormality, the resulting medical 
condition rather than the abnormality itself should be recorded (e.g., record “anemia” 
rather than “low hemoglobin”).


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Serious Adverse Events
An AE should be classified as an SAE if it meets one of the following criteria:
Fatal:
AE resulted in death
Life threatening:
The AEs placed the patient at immediate risk of death. This classification does not 
apply to an AE that hypothetically might cause death if it were more severe.
Hospitalization:
The AE resulted in hospitalization or prolonged an existing inpatient 
hospitalization. Hospitalizations for elective medical or surgical procedures or 
treatments planned before the signing of informed consent in the study or routine 
check-ups are not SAEs by this criterion. Admission to a palliative unit or hospice 
care facility is not considered to be a hospitalization. Hospitalizations or prolonged 
hospitalizations for scheduled therapy of the underlying cancer or study target 
disease need not be captured as SAEs.
Disabling/ 
incapacitating:
An AE that resulted in a persistent or significant incapacity or substantial 
disruption of the patient’s ability to conduct normal life functions.
Congenital anomaly or 
birth defect:
An adverse outcome in a child or fetus of a patient exposed to the molecule or 
study treatment regimen before conception or during pregnancy.
Medically significant:
The AE did not meet any of the above criteria, but could have jeopardized the 
patient and might have required medical or surgical intervention to prevent one of 
the outcomes listed above or involves suspected transmission via a medicinal 
product of an infectious agent. Potential drug-induced liver injury (DILI) also is 
considered a medically significant event (see Section 7.7.8.1 for the definition of 
potential DILI.)
Adverse Event Severity
AE severity should be graded using the NCI CTCAE v5.0. These criteria are provided in the 
study manual.
AE severity and seriousness are assessed independently. ‘Severity’ characterizes the intensity 
of an AE. ‘Serious’ is a regulatory definition and serves as a guide to the sponsor for defining 
regulatory reporting obligations (see definition for SAEs, above).


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Relationship of the Adverse Event to Study Treatment
The relationship of each AE to study treatment (tisotumab vedotin) should be evaluated by 
the investigator using the following criteria:
Related:
There is evidence to suggest a causal relationship between the drug and the AE, 
such as:
●A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-
Johnson Syndrome)
●One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug 
(e.g., tendon rupture)
Unrelated:
Another cause of the AE is more plausible (e.g., due to underlying disease or 
occurs commonly in the study population), or a temporal sequence cannot be 
established with the onset of the AE and administration of the study treatment, or a 
causal relationship is considered biologically implausible
Investigator and study personnel will report all AEs and SAEs whether elicited during patient 
questioning, discovered during physical examination, laboratory testing and/or other means 
by recording them on the CRF and/or SAE form, as appropriate.
7.7.8.2 Procedures for Eliciting and Recording Adverse Events
Eliciting Adverse Events
An open-ended or non-directed method of questioning should be used at each study visit to 
elicit the reporting of AEs.
Recording Adverse Events
The following information should be recorded on the Adverse Events and Pre-existing 
Conditions CRF:
●
Description including onset and resolution dates
●
Whether it met SAE criteria
●
Severity
●
Relationship to study treatment or other causality
●
Outcome
Diagnosis vs. Signs or Symptoms
In general, the use of a unifying diagnosis is preferred to the listing out of individual 
symptoms. Grouping of symptoms into a diagnosis should only be done if each component
sign and/or symptom is a medically confirmed component of a diagnosis as evidenced by 
standard medical textbooks. If any aspect of a sign or symptom does not fit into a classic 
pattern of the diagnosis, report the individual symptom as a separate adverse event.
Important exceptions for this study are adverse reactions associated with the infusion of 
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“acute infusion reaction,” or “allergic or hypersensitivity reaction.” Instead, record each sign 
or symptom as an individual AE. If multiple signs or symptoms occur with a given infusion-
related event, each sign or symptom should be recorded separately with its level of severity.
Recording Serious Adverse Events
For SAEs, record the event(s) on both the CRF and an SAE form.
The following should be considered when recording SAEs:
●
Death is an outcome of an event. The event that resulted in the death should be 
recorded and reported on both an SAE form and CRF.
●
For hospitalizations, surgical, or diagnostic procedures, the illness leading to the 
surgical or diagnostic procedure should be recorded as the SAE, not the procedure 
itself. The procedure should be captured in the narrative as part of the action taken in 
response to the illness.
Progression of the Underlying Malignancy
Since progression of underlying malignancy is being assessed as an efficacy variable, it 
should not be reported as an AE or SAE. The terms “Disease Progression”, “Progression of 
Disease” or “Malignant Disease Progression” and other similar terms should not be used to 
describe an AE or SAE. However, clinical symptoms of progression may be reported as AEs 
or SAEs if the symptom cannot be determined as exclusively due to progression of the 
underlying malignancy or does not fit the expected pattern of progression for the disease 
under study. In addition, complications from progression of the underlying malignancy 
should be reported as AEs or SAEs.
Pregnancy
Notification to Drug Safety
Complete a Pregnancy Report Form for all pregnancies that occur from the time of first study 
drug dose until 6 months after the last dose of study drug(s). Email or fax to the sponsor’s 
Drug Safety Department within 48 hours of becoming aware of a pregnancy. All pregnancies 
will be monitored for the full duration; all perinatal and neonatal outcomes should be 
reported. Infants should be followed for a minimum of 8 weeks.
Collection of data on the CRF
All pregnancies (as described above) that occur within 30 days of the last dose of study 
drug(s) will also be recorded on the Adverse Events and Pre-Existing Conditions CRF.
Abortion, whether accidental, therapeutic, or spontaneous, should be reported as an SAE. 
Congenital anomalies or birth defects, as defined by the ‘serious’ criterion above (see 
definitions Section 7.7.8.1) should be reported as SAEs.


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Potential Drug-Induced Liver Injury
The observation of the critical importance of altered liver function has been referred to 
informally as Hy’s Law (Reuben 2004). Hy’s Law can be used to estimate severity and the 
likelihood that a study drug may cause an increased incidence of severe hepatotoxicity.
The absence of hepatotoxicity in clinical trials provides a limited predictive value for 
potential hepatotoxicity in the clinical setting(s) being studied. However, finding 1 Hy’s Law 
case in clinical trials is ominous; finding 2 cases is highly predictive of a potential for severe 
drug-induced liver injury (DILI).
Definition
Briefly, potential Hy’s Law cases include the following 3 components:
1. Aminotransferase (ALT and/or AST) elevation >3 x ULN
AND
2. Total bilirubin >2 x ULN, without initial findings of cholestasis (i.e., elevated serum 
alkaline phosphatase),
AND
3. No other immediately apparent possible causes of aminotransferase elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or 
acute liver disease, or the administration of other drug(s) known to be hepatotoxic.
Reporting Requirements
Any potential Hy’s Law case should be handled as a suspected unexpected serious 
adverse reaction (SUSAR) associated with the use of the drug and reported promptly to 
the sponsor.
Reporting should include all available information and should initiate close follow-up until 
complete resolution of the problem and completion of all attempts to obtain supplementary 
data.
Follow-up for Abnormal Laboratory Results Suggesting Potential DILI
In general, an increase of serum ALT or AST to >3x ULN should be followed by repeat 
testing within 48 to 72 hours of serum ALT, AST, alkaline phosphatase, and total bilirubin, 
to confirm the abnormalities and to determine whether they are worsening.
Appropriate medical assessment should be initiated to investigate potential confounding 
factors and alternative causes of hepatotoxicity. 
7.7.8.3 Reporting Periods for Adverse Events, Serious Adverse Events, and 
Adverse Events of Special Interest
The safety reporting period for all AEs and SAEs is from study Day 1 (predose) through the 
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However, all study protocol-related AEs are to be recorded from the time of informed 
consent. All SAEs that occur after the safety reporting period and are considered study 
treatment-related in the opinion of the investigator should also be reported to the sponsor.
SAEs will be followed until significant changes return to baseline, the event stabilizes 
(recovering/resolving) or is no longer considered clinically significant by the investigator, or 
the patient dies or withdraws consent. All non-serious AEs will be followed through the 
safety reporting period. Certain non-serious AEs of interest (i.e., all ocular events) will be 
followed until resolution, return to baseline, or study closure.
7.7.8.4 Serious Adverse Events and AESIs Requiring Immediate Reporting
Within 24 hours of observing or learning of any SAE, investigators are to report the event to 
the sponsor, regardless of the relationship of the event to the study treatment regimen. 
Additionally, all ocular AEs (any grade, whether they meet seriousness criteria or not) must 
be reported to the sponsor within 24 hours. Ocular AEs are the only non-serious events that 
should be reported on an SAE form.
For initial SAE reports, available case details are to be recorded on an SAE form. At a 
minimum, the following should be included:
●
Patient number
●
Date of event onset
●
Description of the event
●
Study treatment, if known
The completed SAE form and SAE Fax Cover Sheet are to be emailed or faxed to the 
sponsor’s Drug Safety Department within 24 hours (see email or fax number specified on the 
SAE report form) unless otherwise instructed on the sponsor’s SAE form.
Relevant follow-up information is to be submitted to the sponsor as soon as it becomes 
available.
7.7.8.5 Sponsor Safety Reporting to Regulatory Authorities
Investigators are required to report all SAEs, including anticipated SAEs, to the sponsor (see 
Section 7.7.8.4). Investigators must also report all ocular AEs, whether or not they meet 
seriousness criteria, to the sponsor.
The sponsor will report all SAEs and ocular AEs to regulatory authorities as required per 
local regulatory reporting requirements. In the United States, endpoints that assess disease-
related mortality or major morbidity, as well as other SAEs that are not study endpoints but 
are known consequences of the underlying disease or condition that are anticipated to occur 
in the study population, should not be reported to the FDA as individual IND safety reports 
per the final rule amending the IND safety reporting requirements under 21 CFR 312.32 and 
the FDA’s guidance Safety Assessment for IND Safety Reporting Guidance for Industry 
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In this study, progression of underlying malignancy is not reported as an AE or SAE. No 
individual IND safety reports will be submitted for progression of underlying malignancy. 
Progression of underlying malignancy will be evaluated as an efficacy endpoint.
7.8
Appropriateness of Measurements
The safety measures that will be used in this trial are considered standard procedures for 
evaluating the potential adverse effects of study medications.
Response will be assessed according to RECIST v1.1, which are standardized criteria for 
evaluating response in the solid tumors comprising the cohorts in this study. The intervals of 
evaluation in this protocol are considered appropriate for disease management.
Immunogenicity is commonly assessed for biologics; therefore, standard tests will be 
performed to detect the possible presence of specific antibodies to tisotumab vedotin. 
Pharmacokinetic assessments are also common in clinical studies to help characterize dose-
exposure-response relationships.
8
DATA QUALITY CONTROL AND QUALITY ASSURANCE
8.1
Site Training and Monitoring Procedures
A study manual with instructions for study compliance and CRF completion will be 
provided. Prior to the enrollment of patients at the site, Seattle Genetics or its designated 
clinical and medical personnel will review the following items with the investigator and 
clinic staff:
●
The protocol, study objectives, eligibility requirements, study procedures, 
registration, and withdrawal processes
●
Current Investigator’s Brochure
●
Recording and reporting AEs and SAEs
●
Enrollment goals and study timelines
●
The CRF completion process and source documentation requirements
●
Monitoring requirements
●
IRB/IEC review and approval process
●
Informed consent process
●
Good Clinical Practice guidelines and related regulatory documentation requirements
●
Key study team roles and responsibilities
●
Investigational product storage, accountability, labeling, dispensing. and record 
keeping
●
Patient coding
●
Study samples/specimen collection, handling and shipping
●
Protocol compliance
●
Clinical study record keeping, document retention, and administrative requirements


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Monitoring visits will occur periodically, with frequency dependent on the rate of enrollment 
and workload at each site. During monitoring visits, the Seattle Genetics representative will 
typically review regulatory documentation, CRFs, source documentation, and investigational 
product storage, preparation, and accountability. The CRFs will be reviewed for 
completeness, adherence to the provided guidelines, and accuracy compared to the source 
documents. The investigators must ensure that the monitor is allowed to inspect all source 
documents pertinent to study patients, and must cooperate with the monitor to ensure that any 
problems noted in the course of the trial are resolved. The investigator must maintain a 
comprehensive and centralized filing system of all study-related documentation that is 
suitable for inspection by Seattle Genetics or its designated monitors and by quality 
assurance auditors, or representatives of regulatory authorities.
8.2
Data Management Procedures
Seattle Genetics will provide CRF Completion Guidelines for eCRF data entry. Study 
specific data management procedures will be maintained in the data management plan. 
Queries resulting from edit checks and/or data verification procedures will be posted 
electronically in the eCRF.
8.3
Access to Source Data
The investigator will permit the sponsor’s representatives to monitor the study as frequently 
as the sponsor deems necessary to determine that protocol adherence and data recording are 
satisfactory. Appropriate measures to protect patient confidentiality are to be employed 
during monitoring. The CRFs and related source documents will typically be reviewed in 
detail by the monitor at each site visit. Original source documents or certified copies are 
needed for review. This review includes inspection of data acquired as a requirement for 
participation in this study and other medical records as required to confirm that the 
information contained in the CRFs, such as disease assessments, AEs, and concomitant 
medications, is complete and correct. Other study records, such as correspondence with the 
sponsor and the IRB/IEC and screening and drug accountability logs will also be inspected. 
All source data and study records must also be available for inspection by representatives of 
regulatory authorities and the IRB/IEC.
8.4
Accuracy and Reliability of Data
Steps to be taken to assure the accuracy and reliability of data include:
●
The selection of qualified investigators and appropriate study centers.
●
Review of protocol procedures with the investigators and associated personnel prior 
to the study.
●
Periodic monitoring visits by the designated monitor(s).
●
CRFs will be reviewed for accuracy and completeness by the designated monitor(s) 
during monitoring visits to the study centers and/or by centralized monitoring. Any 
discrepancies will be resolved with the investigator or designees as appropriate.


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8.5
Quality Assurance Procedures
The Research and Development Quality group or its designee may conduct audits at the 
clinical site or other study-related facilities and organizations. Audit reports will be retained 
by the Research and Development Quality group of Seattle Genetics as part of the written 
record.
8.6
Data Handling and Record Keeping
8.6.1 Data Handling
It is the investigator’s responsibility to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported to the sponsor in the CRFs and in all required reports. Data 
reported on the CRF that is derived from source documents should be consistent with the 
source documents or the discrepancies should be explained.
Any change or correction to a CRF will be maintained in an audit trail within the electronic
data capture system. Data changes may only be made by those individuals so authorized. The 
investigator should retain records of the changes and corrections, written and/or electronic.
8.6.2 Investigator Record Retention
The investigator shall retain study drug disposition records and all source documentation 
(such as original ECG tracings, laboratory reports, inpatient or office patient records) for the 
maximum period required by the country and institution in which the study will be 
conducted, or for the period specified by Seattle Genetics, whichever is longer. The 
investigator must contact Seattle Genetics prior to destroying any records associated with the 
study. If the investigator withdraws from the study (due to relocation, retirement, etc.), the 
records shall be transferred to a mutually agreed upon designee, such as another investigator 
or IRB/IEC. Notice of such transfer will be provided in writing to Seattle Genetics.
9
DATA ANALYSIS METHODS
9.1
Determination of Sample Size
Up to approximately 222 patients may be enrolled in the study. This includes approximately 
6–12 patients in the safety run-in phase, approximately 30 patients in each of 2 randomized 
Part A cohorts, and the possible expansion of an additional 70 patients in one of the 2 Part A
cohorts. Part B will enroll approximately 80 patients including approximately 60 patients 
who have received 1 to 3 prior lines of therapy, including bevacizumab treatment.
Analysis regarding expansion of Part A will be conducted when approximately 30 patients 
per cohort have at least one post-baseline response assessment per RECIST v1.1 or have 
discontinued from the study or started subsequent cancer therapy.
A cohort may be expanded to further characterize antitumor activity if the safety profile is 
acceptable, other efficacy endpoints are comparable to current standard of care, and the 
number of confirmed CR or PR meet cohort-specific criteria.


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The sample size is not based on power calculations for formal hypothesis testing, but is 
selected based on ORR estimate precision as characterized by 95% confidence intervals 
(CIs). For a sample size of 30 patients (Part A) and 60 patients (Part B with 1 to 3 prior lines 
of therapy, including bevacizumab treatment) per cohort (or 100 patients, if a treatment arm 
from Part A is expanded), assuming the confirmed ORR is between 20% and 40%, the 
2 -sided 95% exact CIs are summarized below.
Confirmed ORR
95% Exact CI (N=30)
95% Exact CI (N=60)
95% Exact CI (N=100)
15%
(4%, 31%)
(7%, 27%)
(9%, 24%)
20%
(8%, 39%)
(11%, 32%)
(13%, 29%)
30%
(15%, 49%)
(19%, 43%)
(21%, 40%)
40%
(23%, 59%)
(28%, 53%)
(30%, 50%)
9.2
Study Endpoint Definitions
9.2.1 Confirmed ORR 
Confirmed ORR is defined as the proportion of patients who achieve a confirmed CR or PR 
according to RECIST v1.1 as assessed by the investigator. Patients who do not have at least 
2 post-baseline response assessments (initial response and confirmation scan) will be counted 
as non-responders.
9.2.2 Confirmed and Unconfirmed ORR 
Confirmed and unconfirmed ORR is defined as the proportion of patients who achieve a CR 
or PR according to RECIST v1.1 as assessed by the investigator. These include patients with 
confirmed responses as well as those whose responses were not confirmed or had not yet 
been assessed for confirmation. Patients who do not have at least 1 post-baseline response 
assessment will be counted as non-responders.
9.2.3 CA-125 Response Rate
CA-125 response rate is defined as the proportion of patients who have at least a 50% 
reduction in CA-125 value from baseline. The response must be confirmed in a subsequent 
sample collected ≥28 days after the prior sample. The absolute value of the confirmatory 
sample must be ≤110% of the prior sample. Only patients who have an elevated baseline 
CA-125 value of ≥2 x ULN and within 2 weeks prior to the first dose of study drug will be 
included in the analysis.
9.2.4 Combined RECIST/CA-125 Overall Response
The combined RECIST/CA-125 overall response is defined as the proportion of patients 
whose best response is a CR or PR according to the Gynecological Cancer Intergroup 
(GCIG) combined RECIST and CA-125 criteria (Rustin 2011). The combined overall 
response will be assessed as indicated in Table 8.


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Table 8:
Overall response by RECIST and CA-125 criteria
RECIST Response
CA-125 Response
Combined RECIST/CA-125
Response
CR
Response and normalizeda
CR
CR
Response
PR
CR
Not response and not PDb
PR
PR
Response
PR
PR
Not response and not PDb
PR
SD
Response
PR
SD
Not response and not PDb
SD
NEc
Response
PR
PD >28 days from CA-125
response
Response
PR
PD ≤28 days from CA-125
response
Response
PD
PD
Not response and not PDb
PD
Any
PDb
PD
a
Normalized means CA-125 value within the reference range
b
Progression of CA-125 levels is defined as: 1) CA-125 ≥2x ULN on 2 occasions at least 1 week apart for patients with 
elevated CA-125 before treatment and later normalizes, 2) CA-125 ≥2x nadir value on 2 occasions at least 1 week apart 
for patients with elevated CA-125 before treatment which never normalizes, or 3) CA-125 ≥2x ULN on 2 occasions at 
least 1 week apart for patients with CA-125 in the reference range before treatment.
c
Target lesions are not all evaluated, non-target lesions are non-PD, and no new lesions appear.
9.2.5 Disease Control Rate
Disease control rate (DCR) is defined as the proportion of patients who achieve a CR or PR 
according to RECIST v1.1 as assessed by the investigator, or meet the SD criteria at least 
once after start of study treatment at a minimum interval of 12 weeks (–1 week window). 
Patients who do not have at least 1 post-baseline response assessment will be counted as 
non-responders.
9.2.6 Duration of Response 
DOR is defined as the time from the first documentation of objective response (CR or PR 
that is subsequently confirmed) to the first documentation of PD or death due to any cause, 
whichever comes first.
DOR data will be censored as described below:
●
Patients who do not have PD and are still on study at the time of an analysis will be 
censored at the date of last disease assessment documenting absence of PD.
●
Patients who started a new anti-cancer treatment prior to documentation of PD will be 
censored at the date of last disease assessment prior to the start of new treatment.
●
Patients who are removed from the study prior to documentation of PD will be 
censored at the date of last disease assessment documenting absence of PD.


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●
Patients who progressed or died after an extended loss to follow up 
(i.e., ≥2 consecutive missed disease assessments) will be censored at the date of the 
last disease assessment prior to the missed visits.
DOR will only be calculated for patients who achieve a confirmed CR or PR according to 
RECIST v1.1 as assessed by the investigator.
9.2.7 Time to Response
Time to response (TTR) is defined as the time from the start of study treatment to the first 
documentation of objective response (CR or PR that is subsequently confirmed). TTR will 
only be calculated for patients who achieve a confirmed CR or PR, and will be summarized 
with descriptive statistics.
9.2.8 Progression-Free Survival
PFS is defined as the time from the start of study treatment to the first documentation of PD 
or death due to any cause, whichever comes first.
The same censoring rules as outlined in Section 9.2.6 for DOR will be applied to PFS. 
Patients who are not known to have died and who do not have an evaluation of tumor 
response after their first dose of study drug will be censored at Day 1.
9.2.9 Overall Survival
OS is defined as the time from the start of study treatment to date of death due to any cause. 
In the absence of death, survival time will be censored at the last date the patient is known to 
be alive (i.e., date of last contact).
9.3
Statistical and Analytical Plans
The statistical and analytical plans presented below summarize the more complete plans to be 
detailed in the statistical analysis plan (SAP). A change to the data analysis methods 
described in the protocol will require a protocol amendment only if it alters site conduct 
(e.g., adding baseline assessments to define a subgroup). The SAP will be finalized prior to 
database lock. Any changes to the methods described in the final SAP will be described and 
justified in the clinical study report.
9.3.1 General Considerations
Patients enrolled in the safety run-in portion, Part A and Part B will be summarized 
separately. All analyses in Part A and Part B will be presented by cohort and total unless 
otherwise specified.
Descriptive statistics will be presented that include the number of observations, mean, 
median, standard deviation, minimum and maximum for continuous variables, and the 
number and percentages per category for categorical variables.
The 2-sided 95% exact confidence interval (CI) using the Clopper-Pearson method (Clopper 
1934) will be calculated for the response rates where applicable (e.g., ORR).


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For time-to-event endpoints, the median survival time will be estimated using the Kaplan-
Meier method; the associated 95% CI will be calculated based on the complementary log-log 
transformation (Collett 1994).
9.3.1.1 Randomization and Blinding
This is an open-label phase 2 study with an initial safety run-in phase. The safety run-in will 
evaluate the tolerability of dose-dense regimen. If the tolerability is confirmed, the study will 
proceed to Part A and Part B. In Part A, randomization will be stratified by first line vs. 
second line PROC and histology (serous vs. non-serous). Patients will be randomized in a 
1:1 ratio to receive tisotumab vedotin 2.0 mg/kg Q3W or the RP2D dose-dense regimen.
Randomization is used in this study to minimize bias and not as a basis for statistical 
inference as the study includes no formal statistical hypothesis testing.
If the tolerability of dose-dense regimen is not confirmed after the safety run-in, Part A will 
be a single-arm treated with the Q3W dosing schedule.
Part B will be a single arm of the 0.9 mg/kg dose dense regimen.
9.3.1.2 Adjustments for Covariates
No adjustments for covariates are planned in the analyses.
9.3.1.3 Handling of Dropouts and Missing Data
Missing data will not be imputed unless otherwise specified. Missing AE start date and/or 
end date will be imputed while calculating duration of events and treatment-emergent status. 
Missing subsequent anti-cancer treatment start date will be imputed while deriving the time-
to-event endpoints as applicable. Censoring rules will be applied for the analysis of time-to-
event endpoints. Details will be provided in the SAP.
9.3.1.4 Multicenter Studies
There are multiple centers in this study, however it is not anticipated that any center will 
accrue enough patients to warrant an analysis by center.
9.3.1.5 Multiple Comparisons and Multiplicity
No multiple comparisons are planned in this study.
9.3.1.6 Data Transformations and Derivations
Time variables based on 2 dates (e.g., start date and end date) will be calculated as 
(end date – start date +1 [in days]) unless otherwise specified in the planned analysis section.
Baseline values used in all statistical analyses will be the most recent non-missing 
measurement prior to the first dose of study drug unless otherwise specified.
9.3.1.7 Analysis Sets
The full analysis set (FAS) includes all patients who received any amount of study drug. All 
efficacy analyses will be based on the FAS.


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The safety analysis set includes all patients who received any amount of study drug, and thus 
is equivalent to the FAS. All safety analyses will be based on the safety analysis set.
The DLT evaluable analysis set includes all patients who received any amount of study drug 
and have completed the DLT evaluation period or have experienced a DLT. The DLT 
evaluable set applies only to the safety run-in cohort.
The efficacy-evaluable (EE) analysis set includes patients who received any amount of study 
drug and had at least one post-baseline disease assessment per RECIST v1.1 or discontinued 
from the study or started subsequent cancer therapy. The EE analysis set will be used for 
supplemental analysis of efficacy endpoints as applicable.
The CA-125 evaluable analysis set includes patients with ovarian cancer who have an 
elevated baseline CA-125 value of ≥2 x ULN and within 2 weeks prior to the first dose of 
study drug. The CA-125 evaluable analysis set will be used for the analysis of CA-125
response rate.
9.3.1.8 Examination of Subgroups
As exploratory analyses, subgroup analyses may be conducted for selected endpoints. 
Subgroups may include but are not limited to the following:
●
Platinum-free interval
●
Histology
●
First line vs. second line PROC
●
TF expression
●
Prior treatment with CPIs
●
Prior treatment with PARP inhibitors
9.3.1.9 Timing of Analyses
The primary analysis of study will be conducted when all treated patients have been followed 
for at least 6 months or come off study, whichever comes first. Subsequent data cutoff dates 
may be defined to assess longer term clinical benefit with further follow up.
A safety analysis will be conducted at end of DLT period for each dose level in the safety 
run-in portion to evaluate the tolerability of dose-dense regimen.
Interim analysis for futility will be performed on Part B after at least 20 patients in Part B 
with 1 to 3 prior lines of therapy, including bevacizumab treatment, have been treated and 
had at least one response assessment post-baseline.
9.3.2 Patient Disposition
An accounting of study patients by disposition will be tabulated and the number of patients in 
each analysis set will be summarized. Patients who discontinue study treatment and patients 
who withdraw from the study will be summarized with reason for discontinuation or 
withdrawal.


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9.3.3 Patient Characteristics
Demographics and other baseline characteristics will be summarized for the FAS. Details 
will be provided in the SAP.
9.3.4 Efficacy Analyses
The primary analysis of efficacy endpoints will be based on the FAS unless otherwise 
specified. Supplemental analysis of efficacy endpoints may be performed using the EE 
analysis set.
9.3.4.1 Primary Efficacy Analyses
The primary endpoint of this study is the confirmed ORR according to RECIST v1.1 per 
investigator assessment. The ORR is defined as the proportion of patients who achieve a 
confirmed CR or PR. The confirmed ORR and its exact 2-sided 95% CI will be calculated.
9.3.4.2 Secondary Efficacy Analyses
The confirmed and unconfirmed ORR according to RECIST v1.1, CA-125 response rate, and 
combined RECIST/CA-125 overall response rate will be estimated and the 95% CIs will be 
calculated. In addition, the TTR will be summarized for patients who achieve confirmed 
objective responses.
The DOR, PFS, and OS will be estimated using the Kaplan-Meier methodology and the 
medians and associated 95% CIs will be calculated. Kaplan-Meier plots will be provided as 
appropriate. The 6 month PFS rate and the 6 month OS rate will be estimated with 95% CI.
9.3.5 Pharmacokinetic and Immunogenicity Analyses
Tisotumab vedotin and MMAE concentrations will be summarized with descriptive statistics 
at each PK sampling time point. Selected PK parameters for tisotumab vedotin and MMAE 
will be estimated by noncompartmental analysis and summarized using descriptive statistics. 
These data may be combined with PK data from other clinical trials with tisotumab vedotin 
for population PK and PK/pharmacodynamic analyses.
The incidence of ATA will be summarized using the safety analysis set.
9.3.6 Biomarker Analyses
Relationships of biomarker parameters (e.g., baseline values, absolute and relative changes 
from baseline) to efficacy, safety, and pharmacokinetic parameters will be explored. 
Relationships and associated data that are determined to be of interest will be summarized. 
Details will be described separately in the Biomarker Analysis Plan.
9.3.7 Patient-Reported Outcomes Analyses
Patient-reported outcomes from Parts A and B US patients will be summarized over time 
with descriptive statistics by visit, using the FAS. Details will be provided in the SAP.


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9.3.8 Safety Analyses
All safety analyses will be performed using the safety analysis set.
9.3.8.1 Extent of Exposure
Extent of exposure will be summarized by cohort for the safety analysis set. Summary 
statistics for duration of therapy, number of cycles, total dose, and dose intensity will be 
presented. Dose modifications, including dose delay, dose reduction, and unplanned dose 
adjustment, will be summarized. Details will be provided in the SAP.
9.3.8.2 Adverse Events
An overview of AEs will provide a tabulation of the incidence of all AEs, treatment-
emergent AEs, treatment-related AEs, Grade 3 and higher treatment-emergent AEs, SAEs, 
treatment-related SAEs, deaths, and AEs leading to study treatment discontinuation. Adverse 
events will be defined as treatment emergent if they are newly occurring or worsen after first 
dose of study treatment and including 30 days after last dose of study treatment.
Treatment-emergent AEs will be listed and summarized by Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term, severity, and relationship to study drug. In 
the event of multiple occurrences of the same AE with the same preferred term in 1 patient, 
the AE will be counted only once as the occurrence. The incidence of AEs will be tabulated 
by preferred term and treatment group. AESIs and AEs leading to premature discontinuation 
of study drug will also be summarized and listed in the same manner.
9.3.8.3 Deaths and Serious Adverse Events
SAEs will be listed and summarized in the same manner as all AEs. Events with a fatal 
outcome will be listed.
9.3.8.4 Clinical Laboratory Results
Summary statistics of laboratory results and changes from baseline will be tabulated by 
scheduled visit. Grading of laboratory values will be assigned programmatically per the NCI 
CTCAE v5.0. Shift tables comparing the worst post-baseline to baseline CTCAE grade will 
be presented. Laboratory values will be listed with grade per CTCAE and flagged when 
values are outside the normal reference range.
9.3.8.5 Other Safety Analyses
Vital Signs
Vital signs data will be listed. Summary statistics of vital signs and change from baseline 
may be tabulated where appropriate.
ECOG Status
ECOG performance status will be summarized for each visit. Shifts from baseline to the 
lowest and highest post-baseline score will be tabulated.


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ECG
ECG status (normal, abnormal clinically significant, or abnormal not clinically significant) 
will be summarized by scheduled visit, and shifts from baseline will be tabulated.
9.3.9 Interim Analyses
A safety analysis will be conducted at end of DLT period for each dose level in the safety 
run-in portion to evaluate the tolerability of dose-dense regimen. A SMC consisting of the 
investigators, study medical monitor, biostatistician, and drug safety representative will 
review the data before proceeding to Part A.
Interim analysis for futility will be performed on Part B after at least 20 patients with 1 to 3
prior lines of therapy, including bevacizumab treatment, have been treated and had at least 
one response assessment post-baseline.
The Bayesian predictive probability approach will be used to determine the futility criteria 
(Lee 2008). At the time of the interim futility analysis, the PPoS will be calculated. PPoS is 
the probability of achieving “success” should the cohort be continued to the maximum 
sample size of 60 in the target population (1 to 3 prior lines of therapy, including 
bevacizumab treatment) given the data observed at interim, and the cohort is considered 
“success” if the posterior probability that the ORR exceeds the response rate of current 
standard of care (i.e., 12% as reference in Section 3.2) is greater than 70%.
Both the confirmed and unconfirmed CR or PR observed at interim will be counted as a 
response for the calculation of PPoS. It is appropriate to include the unconfirmed response 
for the purpose of interim analysis because based on the estimates from GEN701 trial, about 
60% of the responders will respond at their first post-baseline scan and approximately 75% 
of the confirmed/unconfirmed responses will eventually be confirmed. Table 9 summarizes 
the PPoS based on the number of responses observed among the first 20 patients. Details of 
the calculation of PPoS are shown in Appendix I.
Table 9:
PPoS based on responses among the first 20 patients pretreated with 
bevacizumab
No. of responses*
among the first
20 patients
PPoS
PROC bevacizumab pretreated
(p0=12%)
0
<1%
1
4%
2
20%
3
49%
4
77%
5
93%
6
99%
7
>99%
8
>99%
9
>99%
10+
>99%
* P0 is the response rate of current standard of care of each cohort


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If the PPoS is <10% (i.e., 1 or fewer responses among the first 20 patients), the interim data 
indicates that it is unlikely the ORR will be better than the response rate of current standard 
of care at the end of the cohort and the cohort could be stopped early due to insufficient 
activity. On the other hand, if the PPoS is >70%, the interim data suggests that if the same 
trend continues, there is a high probability to conclude a “success” at the end of the cohort. 
The PFS, OS, and DOR will also be evaluated at the time of the interim futility analysis
using Kaplan-Meier methodology. Based on the activity and safety data, together with the 
PPoS, the cohort may continue or be stopped early by the sponsor. A cohort or Part may also 
be discontinued at any point at the discretion of the sponsor.
The operating characteristics of the design based on 500,000 simulation runs are summarized 
in Table 10. If the true ORR is less than 5%, there is reasonable chance to reach the futility 
criterion at interim. On the other hand, if the true ORR is 20% or higher, the probability to 
stop for futility is low (<12%).
Table 10:
Operating characteristics of predictive probability design
True ORR
Pr(Futility*)
Final Analysis (N=60)
PROC bevacizumab-pretreated
Pr(obs. ORR ≥15%)
Pr(obs. ORR ≥20%)
Pr(obs. ORR ≥25%)
5%
74%
<1%
<1%
<1%
10%
39%
13%
1%
<1%
15%
18%
52%
17%
3%
20%
7%
84%
54%
20%
25%
2%
96%
84%
55%
30%
<1%
>99%
97%
84%
35%
<1%
>99%
>99%
96%
* 1 or fewer responders among the first 20 patients in the Part B bevacizumab pretreated cohort
Interim data from the study may be presented at scientific meetings such as the annual 
meetings of the American Society of Clinical Oncology and the European Society for 
Medical Oncology.
10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS
This study will be conducted in accordance with the Note for Guidance on Good Clinical 
Practice (ICH Harmonised Tripartite Guideline E6 [R2]; FDA CFR [21 CFR § 50, 56, 312]), 
Declaration of Helsinki (Brazil 2013), and all applicable regulatory requirements.
10.1 Informed Consent
The investigator is responsible for presenting the risks and benefits of study participation to 
the patient in simple terms using the IRB/IEC approved informed consent document and for 
ensuring patients are re-consented when the informed consent document is updated during 
the study, if required. The investigator will ensure that written informed consent is obtained 
from each patient, or legally authorized representative, if applicable to this study, by 


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obtaining the signature and date on the informed consent document prior to the performance 
of protocol evaluations or procedures.
If informed consent is obtained from a legally authorized representative for a patient who is 
unable to provide informed consent at study entry (if applicable), but the patient is later able 
to provide informed consent, the investigator must obtain written informed consent from the 
patient.
10.2 Ethical Review
The investigator will provide the sponsor or its designee with documentation of the IRB/IEC 
approval of the protocol and the informed consent document before the study may begin at 
the investigative site(s). The name and address of the reviewing ethics committee are 
provided in the investigator file.
The investigator will supply the following to the investigative site’s IRB/IEC:
●
Protocol and amendments
●
Informed consent document and updates
●
Clinical Investigator’s Brochure and updates
●
Relevant curricula vitae, if required
●
Required safety and SAE reports
●
Any additional submissions required by the site’s IRB/IEC
The investigator must provide the following documentation to the sponsor or its designee:
●
The IRB/IEC periodic (e.g., quarterly, annual) re-approval of the protocol.
●
The IRB/IEC approvals of any amendments to the protocol or revisions to the 
informed consent document.
●
The IRB/IEC receipt of safety and SAE reports, as appropriate.
10.3 Regulatory Considerations
This study will be conducted in accordance with the protocol and ethical principles stated in 
the applicable guidelines on good clinical practice, and all applicable local and/or regional 
laws, rules, and regulations.
10.3.1 Investigator Information
The contact information and qualifications of the principal investigator and subinvestigators 
and name and address of the research facilities are included in the investigator file.
10.3.2 Protocol Amendments and Study Termination
Any investigator-initiated changes to the protocol (with the exception of changes to eliminate 
an immediate hazard to a study patient) must be approved by the sponsor prior to seeking 
approval from the IRB/IEC, and prior to implementing. The investigator is responsible for 


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enrolling patients who have met protocol eligibility criteria. Protocol deviations must be 
reported to the sponsor and the local IRB/IEC in accordance with IRB/IEC policies.
The sponsor may terminate the study at any time. The IRB/IEC must be advised in writing of 
study completion or early termination.
10.4 Study Documentation, Privacy, and Records Retention
To protect the safety of participants in the study and to ensure accurate, complete, and 
reliable data, the investigator will keep records of laboratory tests, clinical notes, and patient 
medical records in the patient files as original source documents for the study. If requested, 
the investigator will provide the sponsor, its licensees and collaborators, applicable 
regulatory agencies, and applicable IRB/IEC with direct access to original source documents 
or certified copies.
Records containing patient medical information must be handled in accordance with local 
and national laws, rules, and regulations and consistent with the terms of the patient 
authorization contained in the informed consent document for the study (the Authorization). 
Care should be taken to ensure that such records are not shared with any person or for any 
purpose not contemplated by the Authorization. Furthermore, CRFs and other documents to 
be transferred to the sponsor should be completed in strict accordance with the instructions 
provided by the sponsor, including the instructions regarding the coding of patient identities.
In compliance with local and/or regional regulations, this trial may be registered and trial 
results may be posted on public registries, such as ClinicalTrials.gov.
10.5 Clinical Trial Agreement
Payments by the sponsor to investigators and institutions conducting the trial, requirements 
for investigators’ insurance, the publication policy for clinical trial data, and other 
requirements are specified in the clinical trial agreement.


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APPENDIX A: SCHEDULE OF EVENTS
SCHEDULE OF EVENTS: Q3W REGIMEN
Screening/Baseline
Every 21-day 
cycle
Cycle 1 only
EOT
F/U
Day
D –28 to 1
D –7 to 1
D1A
D2
D3
D8
Within 
30–37D of 
last doseB
Every 12 
wksC
Visit window
r1d
r1d
r7d
Screening/ Baseline 
Assessments 
Informed consent 
X
Inclusion/Exclusion criteria
X
Safety Assessments
Physical exam
X
XF
X
Medical history
X
Height and weight
X
XD
Vital signs
X
X
X
CBC with differentialE
X
XF
X
X
Chemistry panelE
X
XF
X
X
eGFR
X
Coagulation parametersE
X
XF
X
X
Pregnancy test (patients of 
childbearing potential)G
X
XF
X
XH
HgbA1cE
X
X
Ocular Safety Measures
See schedules in Appendix C
ECOG performance status
X
XF
X
ECG
X
X
Concomitant medications
Related to study proceduresI
Collect from Day 1 predose through safety reporting period
Adverse event collection
Treatment
Study drug administration
X
PK/ATA/ Biomarker 
Samples
Biopsy collection
X
Blood/tissue sample collection
See schedules in Appendix B and Appendix C
Response Assessment
Imaging
X
Every 6 weeksJ
XK
XJ, N
CA-125 blood collection
X
Every 6 weeksL
XK
Parts A and B US only: 
Patient-Reported 
Outcomes: PROMISM
Questionnaires
X
XF
X
Parts A and B US only: 
Patient-Reported 
Outcomes: PRO-CTCAEM
Questionnaires
X
To be collected weekly ±2 days, starting on C1D1 and continuing weekly through 
EOTF
Subsequent Anti-Cancer 
Therapy Status
X
X
Survival Status
X
X


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A
Day 1 of cycle 1 is to be performed no more than 28 days after the screening visit. Day 1 of 
cycle 2 is to be performed 21 days ±3 days after Day 1 of cycle 1, Day 1 of cycle 3 is to be 
performed 21 days ±1 days after Day 1 of cycle 2 etc.
B
EOT evaluations should be obtained before the initiation of non-protocol therapy. If EOT 
evaluations are completed before 30 days following the last study treatment, conduct a phone 
screen 30–37 days following the patient’s last study treatment to ensure that no changes in AE 
profile have occurred.
C
A telephone call should be performed in order to collect information of survival and new anti-
cancer treatment as specified in Section 6.7.
D
Height measurement needed at screening visit only.
E
Clinical laboratory testing is to be performed locally. With the exception of pregnancy testing, 
results are to be submitted to the central laboratory.
F
If this assessment occurs within 1 day prior to Cycle 1, Day 1, it does not need to be repeated at 
Visit 1.
G
Only for patients of childbearing potential (please refer to Section 4 3 for definition). Serum or 
urine (beta-hCG) laboratory test with minimum sensitivity level of 25 mIU/mL must be taken at 
Baseline. A pregnancy test must be taken every cycle, (i.e., on Day 1), and at the EOT visit.
H
A single follow-up pregnancy test is to be performed at 24 weeks (±7 days) after EOT.
I
From time of informed consent.
J
CT or MRI scans must be performed every 6 weeks (±7 days) for 6 months after the first study 
drug administration (regardless of study drug administration delays) and every 12 weeks 
(±7 days) for the next 6 months (regardless of study drug administration delays) and every 
6 months (±2 weeks) thereafter. Responses must be evaluated with a confirmatory scan at least 
4 weeks after initial response. Scans are to be performed until disease progression, start of new 
anti-cancer therapy, study termination, or death. Time points for radiographic exams should be 
calendar based and do not depend on cycle visits. CT of chest/abdomen/pelvis.
K
Not required if conducted within 4 weeks prior to EOT.
L
Blood collection for CA-125 should coincide with imaging visits (see timeline in footnote K) 
as closely as possible (±5 days). Collected locally. Results are to be submitted to the central 
laboratory.
M
Parts A and B US patients only. To be collected before clinic visits, when applicable. Can be 
collected remotely.
N
Collect blood samples for CA-125 at the time of CT or MRI scans.


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SCHEDULE OF EVENTS: DOSE-DENSE REGIMEN
Screening/Baseline
Every 28-day cycle
EOT
F/U
Day
D –28 to 1
D –7 to 1
D1A
D8
D15
Within 
30–37D of last doseB
Every 12 wksC
Visit window
r1d
r1d
r1d
r7d
Screening/ Baseline 
Assessments 
Informed consent 
X
Inclusion/Exclusion criteria
X
Safety Assessments
Physical exam
X
XF
X
X
X
Medical history
X
Height and weight
X
XD
XD
XD
Vital signs
X
X
X
X
X
CBC with differentialE
X
XF
X
X
X
Chemistry panelE
X
XF
X
X
X
eGFR
X
Coagulation parametersE
X
XF
X
X
X
Pregnancy test (patients of 
childbearing potential)G
X
XF
X
XH
HgbA1cE
X
X
Ocular Safety Measures
See schedules in Appendix C
ECOG performance status
X
XF
X
ECG
X
X
Concomitant medications
Related to study 
proceduresI
Collect from Day 1 predose through safety reporting period
Adverse event collection
Treatment
Study drug administration
X
X
X
PK/ATA/ Biomarker 
Samples
Biopsy collection
X
Blood/tissue sample collection
See schedules in Appendix B and Appendix C
Response Assessment
Imaging
X
Every 6 weeksJ
XK
XJ, N
CA-125 blood collection
X
Every 6 weeksL
XK
Parts A and B US only: 
Patient-Reported 
Outcomes: PROMISM
Questionnaires
X
XF
X
Parts A and B US only: 
Patient-Reported 
Outcomes: PRO-
CTCAEM
Questionnaires
X
To be collected weekly ±2 days, starting on C1D1 and continuing weekly 
through EOTF
Subsequent Anti-Cancer 
Therapy Status
X
X
Survival Status
X
X


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A
Day 1 of cycle 1 is to be performed no more than 28 days after the screening visit. Day 1 of cycle 
2 is to be performed 28 days ±3 days after Day 1 of cycle 1, Day 1 of cycle 3 is to be performed 
28 days ±1 days after Day 1 of cycle 2 etc.
B
EOT evaluations should be obtained before the initiation of non-protocol therapy. If EOT 
evaluations are completed before 30 days following the last study treatment, conduct a phone 
screen 30–37 days following the patient’s last study treatment to ensure that no changes in AE 
profile have occurred.
C
A telephone call should be performed in order to collect information of survival and new anti-
cancer treatment as specified in Section 6.7.
D
Height measurement needed at screening visit only.
E
Clinical laboratory testing is to be performed locally. With the exception of pregnancy testing, 
results are to be submitted to the central laboratory.
F
If this assessment occurs within 1 day prior to Cycle 1, Day 1, it does not need to be repeated at 
Visit 1.
G
Only for patients of childbearing potential (please refer to Section 4.3 for definition). Serum or 
urine (beta-hCG) laboratory test with minimum sensitivity level of 25 mIU/mL must be taken at 
Baseline. A pregnancy test must be taken every cycle, (i.e., on Day 1), and at the EOT visit.
H
A single follow-up pregnancy test is to be performed at 24 weeks (±7 days) after EOT.
I
From time of informed consent.
J
CT or MRI scans must be performed every 6 weeks (±7 days) for 6 months after the first study 
drug administration (regardless of study drug administration delays) and every 12 weeks (±7 
days) for the next 6 months (regardless of study drug administration delays) and every 6 months 
(±2 weeks) thereafter. Responses must be evaluated with a confirmatory scan at least 4 weeks 
after initial response. Scans are to be performed until disease progression, start of new anti-cancer 
therapy, study termination, or death. Time points for radiographic exams should be calendar 
based and do not depend on cycle visits. CT of chest/abdomen/pelvis.
K
Not required if conducted within 4 weeks prior to EOT.
L
Blood collection for CA-125 should coincide with imaging visits (see timeline in footnote K) as 
closely as possible (±5 days). Collected locally. Results are to be submitted to the central 
laboratory.
M
Parts A and B US patients only. To be collected before clinic visits, when applicable. Can be 
collected remotely.
N
Collect blood samples for CA-125 at the time of CT or MRI scans.


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APPENDIX B: PK, ATA, AND BIOMARKER SAMPLING TIME POINTS
Q3W REGIMEN
Cycle
Study Day
Time
Window
Relative Time
TV PK
TV ATA
Plasma 
proteomic
Plasma 
mutational 
analysis
Plasma 
exosome
PBMC 
immune 
subsets
Biopsy
Collection
Screening
Day –28 to 
–1
N/A
N/A
N/A
XA
1 and 2
1
Predose
Within 24 hr
TV infusion start
X
X
X
X
X
X
End of infusion
+ 15 min
TV infusion end
X
X
1 hr
±15 min
TV infusion end
X
X
5 hr
±2 hr
TV infusion end
X
X
3
48 hr
±4 hr
TV infusion end
X
X
8
168 hr
±24 hr
TV infusion end
X
X
15
336 hr
±24 hr
TV infusion end
X
X
3 and 4
1
Predose
Within 24 hr
TV infusion start
X
X
X
X
X
X
End of infusion
+15 min
TV infusion end
X
X
5 and every 
other cycle 
thereafter
1
Predose 
Within 24 hr
TV infusion start
X
X
X
X
X
End of infusion
+15 min
TV infusion end
X
X
EOT
X
X
X
X
X
X
Unscheduled
XB
A
Fresh or archived biopsy tissue is to be collected at baseline. Archived tumor tissue samples must have been obtained within 2 years prior to the first administration of tisotumab vedotin. Older specimens may 
be allowed upon approval of the sponsor’s medical monitor. Fresh tissue must be obtained from a newly obtained core or excisional biopsy of a tumor lesion.
B
Unscheduled tumor biopsies performed while the patient is on study should be made available to the sponsor if feasible and if patient consents to the submission of this tissue. For example, if a biopsy on 
residual tumor is performed at the end of treatment or at progression, a sample will be collected (if available).


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DOSE-DENSE REGIMEN
Cycle
Dose
Study Day 
Time
Window
Relative Time
TV 
PK
TV 
ATA
Plasma 
Proteomic
Plasma 
mutational 
analysis
Plasma 
exosome
PBMC 
immune 
subsets
Biopsy
Collection
Screening
N/A
Day –28 to –1
N/A
N/A
N/A
XA
1
1
1 (Dose No.1)
Predose 1
Within 24 hr
TV infusion start
X
X
X
X
X
X
End of infusion 1
+ 15 min
TV infusion end
X
1 hr
±15 min
TV infusion end
X
X
5 hr
±2 hr
TV infusion end
X
X
3
48 hr
±4 hr
TV infusion end
X
X
2
8 (Dose No.2)
Predose 2
Within 8 hr
TV infusion start
X
X
3
15 (Dose No.3)
Predose 3
Within 8 hr
TV infusion start
X
X
X
X
X
End of infusion 3B
Within 15 min
TV infusion end
X
1 hr B
±15 min
TV infusion end
X
X
5 hr B,
±2 hr
TV infusion end
X
X
17
48 hr B
±4 hr
TV infusion end
X
X
22
168 hr
±24 hr
TV infusion end
X
X
2
1
1 (Dose No.1)
Predose 1
Within 24 hr
TV infusion start
X
X
X
X
X
X
End of infusion 1
Within 15 min
TV infusion end
X
3
48 hr
±4 hr
TV infusion end
X
X
2
8 (Dose No.2)
Predose 2
Within 8 hr
TV infusion start
X
X
3
15 (Dose No. 3)
Predose 3
Within 8 hr
TV infusion start
X
X
X
X
X
End of infusion 3B
Within 15 min
TV infusion end
X
3 and 4
1
1 (Dose No.1)
Predose 
Within 24 hr
TV infusion start
X
X
X
X
X
X
End of infusion
+15 min
TV infusion end
X
3
15 (Dose No.3)
Predose
Within 24 hr
TV infusion start
X
End of infusion
+15 min
TV infusion end
X
7 and 
every 3rd
cycle 
thereafter
1
1 (Dose No.1)
Predose 
Within 24 hr
TV infusion start
X
X
X
X
X
End of infusion
+ 15 min
TV infusion end
X
3
15 (Dose No.3)
Predose
Within 24 hr
TV infusion start
X
End of infusion
+ 15 min
TV infusion end
X
EOT
X
X
X
X
X
X
Unscheduled
XC
A
Fresh or archived biopsy tissue is to be collected at baseline. Archived tumor tissue samples must have been obtained within 2 years prior to the first administration of tisotumab vedotin. Older specimens may 
be allowed upon approval of the sponsor’s medical monitor. Fresh tissue must be obtained from a newly obtained core or excisional biopsy of a tumor lesion.
B
Do not collect samples at this timepoint if the patient is not administered tisotumab vedotin on D15 (see dose modifications in Section 5.2.3).
C
Unscheduled tumor biopsies performed while the patient is on study should be made available to the sponsor if feasible and if patient consents to the submission of this tissue. For example, if a biopsy on 
residual tumor is performed at the end of treatment or at progression, a sample will be collected (if available).


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APPENDIX C: OCULAR SAFETY MEASURES
Q3W REGIMEN: EVERY TREATMENT CYCLE
Week 1
Screening
Day –1
Day 1
Day 2
Day 3
Ophthalmological EvaluationA
X
Eye exam
X
X
Cooling Eye Pads (start 5 min prior to infusion and 
apply 30–60 min)
X
Steroid Eye Drops (3x/day)B
X
X
X
X
Vasoconstrictor Eye Drops 
X
Lubricating Eye Drops (frequent use w/symptoms)C
X
X
X
Patient diary entries
X
X
X
X
Week 2
Day 7
Day 8
Day 9
Day 10
Eye exam
XD
Lubricating eye drops C
X
X
X
X
Patient diary entries
X
X
X
Week 3
Day 15
Day 16
Day 17
Lubricating eye drops (frequent use w/ symptoms) C
X
X
X
Patient diary entries
X
X
X
EOT
EOT
Eye exam
X
A
Required ophthalmological evaluation performed by a local ophthalmologist at baseline. Patients experiencing ocular symptoms at any time on study must be referred to an ophthalmologist for prompt review 
(within 3 days), see Section 5 3.
B
Steroid eye drops are to be administered 3 times daily on Days –1, 1, 2, and 3 of every treatment infusion. Drops should be administered during clinic visits on Day 1 of each cycle. See Section 5.4.
C
To be self-administered daily or as needed according to the package insert or prescribed instructions from the ophthalmologist.
D
Cycle 1 only.


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DOSE-DENSE REGIMEN: EVERY TREATMENT CYCLE
Week 1
Screening
Day -1
Day 1
Day 2
Day 3
Ophthalmological EvaluationA
X
Eye exam
X
X
Cooling Eye Pads (start 5 min prior to infusion and 
apply 30-60 min)
X
Steroid Eye Drops (3x/day)B
X
X
X
X
Vasoconstrictor Eye Drops 
X
Lubricating Eye DropsC
X
X
X
Patient diary entries
X
X
X
X
Week 2
Day 7
Day 8
Day 9
Day 10
Eye exam
X
Cooling Eye Mask (start 5 min prior to infusion)
X
Steroid Eye Drops (3x/day)B
X
X
X
X
Vasoconstrictor Eye Drops 
X
Lubricating Eye DropsC
X
X
X
X
Patient diary entries
X
X
X
X
Week 3
Day 14
Day 15
Day 16
Day 17
Eye exam
X
Cooling Eye Mask (start 5 min prior)
X
Steroid Eye Drops (3x/day) B
X
X
X
X
Vasoconstrictor Eye Drops 
X
Lubricating Eye DropsC
X
X
X
X
Patient diary entries
X
X
X
X
Week 4
Day 22
Day 23
Day 24
Lubricating Eye DropsC
X
X
X
Patient diary entries
X
X
X
EOT
EOT
Eye Exam
X
A
Required ophthalmological evaluation performed by a local ophthalmologist at baseline. Patients experiencing ocular symptoms at any time on study must be referred to an ophthalmologist for prompt review 
(within 3 days), see Section 5 3.
B
Steroid eye drops are to be administered 3 times daily on Days -1, 1, 2, and 3 of every treatment infusion. Drops should be administered during clinic visits for each infusion. See Section 5.4.
C
To be self-administered daily or as needed according to the package insert or prescribed instructions from the ophthalmologist.








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Other questions to be asked weekly (same schedule as PRO-CTCAE questions):
1. I am bothered by the side effects of treatment:
a.
Not at all
b. A little bit
c.
Somewhat
d. Quite a bit
e.
Very much
2. How much difficulty do you have doing work or hobbies that require you to see well up 
close?
a.
No difficulty at all
b. A little difficulty
c.
Moderate difficulty
d. Extreme difficulty
e.
Stopped doing this because of your eyesight
3. Do you have difficulty seeing colors?
a.
No difficulty at all
b. A little difficulty
c.
Moderate difficulty
d. Extreme difficulty
e.
Stopped doing this because of your eyesight
4. How much difficulty do you have driving at night?
a.
No difficulty at all
b. A little difficulty
c.
Moderate difficulty
d. Extreme difficulty
e.
Stopped doing this because of your eyesight




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APPENDIX E: PERFORMANCE STATUS SCALES CONVERSION
Karnofsky 
Lansky 
ECOG
Percent Description
Percent Description
Score
Description
100
Normal, no complaints, 
no evidence of disease.
100
Fully active, normal.
0
Normal activity. Fully 
active, able to carry on 
all pre-disease 
performance without 
restriction.
90
Able to carry on normal 
activity; minor signs or 
symptoms of disease.
90
Minor restrictions in 
physically strenuous 
activity.
80
Normal activity with 
effort; some signs or 
symptoms of disease.
80
Active, but tires more 
quickly.
1
Symptoms, but 
ambulatory. Restricted 
in physically strenuous 
activity, but ambulatory 
and able to carry out 
work of a light or 
sedentary nature (e.g., 
light housework, office 
work).
70
Cares for self, unable to 
carry on normal activity 
or to do active work.
70
Both greater restriction 
of, and less time spent 
in, play activity.
60
Requires occasional 
assistance, but is able to 
care for most of his/her 
needs.
60
Up and around, but 
minimal active play; 
keeps busy with quieter 
activities.
2
In bed <50% of the 
time. Ambulatory and 
capable of all self-care, 
but unable to carry out 
any work activities. Up 
and about more than 
50% of waking hours.
50
Requires considerable 
assistance and frequent 
medical care.
50
Gets dressed, but lies 
around much of the 
day; no active play; 
able to participate in all 
quiet active play and 
activities.
40
Disabled, requires 
special care and 
assistance.
40
Mostly in bed, 
participates in quiet 
activities.
3
In bed >50% of the 
time. Capable of only 
limited self-care, 
confined to bed or chair 
more than 50% of 
waking hours.
30
Severely disabled, 
hospitalization 
indicated. Death not 
imminent.
30
In bed, needs assistance 
even for quiet play.
20
Very sick, 
hospitalization 
indicated. Death not 
imminent.
20
Often sleeping, play 
entirely limited to very 
passive activities.
4
100% bedridden. 
Completely disabled. 
Cannot carry on any 
self-care. Totally 
confined to bed or chair.
10
Moribund, fatal 
processes progressing 
rapidly.
10
No play, does not get 
out of bed.
0
Dead.
0
Dead.
5
Dead.




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APPENDIX G: RECIST CRITERIA SUMMARY (VERSION 1.1)
Response Evaluation Criteria in Solid Tumors
Term
Definition
Complete response (CR)
Disappearance of all target lesions. Any pathological lymph nodes 
must have reduction in short axis to <10 mm.
Partial response (PR)
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.
Progressive disease (PD)
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an
absolute increase of at least 0.5 cm. The appearance of one or more 
new lesions is also considered progression. 
Stable disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study.
Measurable lesion
Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a 
minimum size of 10 mm by CT scan (CT slice thickness no greater 
than 5 mm).
From RECIST Version 1.1 (Eisenhauer 2009)
A response (CR or PR) will be considered confirmed if the following disease assessment 
(at least 4 weeks after the initial response) still shows response (CR or PR). In cases where
the initial response is followed by SD, it will be considered as confirmed if the SD is later 
followed by PR or CR. For example, if a patient had PR in week 6, SD in Week 12, and PR 
in Week 18, this PR will be considered as confirmed.


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APPENDIX H: NEW YORK HEART ASSOCIATION CLASSIFICATION
A Functional and Therapeutic Classification for Prescription of Physical Activity for 
Cardiac Patients
Class I: 
patients with no limitation of activities; they suffer no symptoms from ordinary activities.
Class II: 
patients with slight, mild limitation of activity; they are comfortable with rest or with mild 
exertion.
Class III: 
patients with marked limitation of activity; they are comfortable only at rest.
Class IV: 
patients who should be at complete rest, confined to bed or chair; any physical activity brings on 
discomfort and symptoms occur at rest.
On-line source: http://www heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-Heart-
Failure_UCM_306328_Article.jsp


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APPENDIX I: CALCULATION OF PREDICTIVE PROBABILITY OF SUCCESS
1. Let Nmax be the maximum sample size of a cohort, and n be the number of patients treated 
and evaluated for the response status by the time of interim analysis
2. Assume the prior distribution of the response rate p follows a beta distribution
p ~ beta(a0, b0)
Note: A weakly informative prior with a0 = 0.12 and b0 = 0.88 is chosen for this study to 
reflect the prior belief of 12% ORR with tisotumab vedotin, and let the data speak for itself 
so that inferences are not overly affected by information external to the observed data.
3. Let X be the number of responders in the first n patients, and X follows a binomial 
distribution
X ~ binomial(n, p)
The likelihood function for the observed data x is L(p | X = x)
px (1- p)n - x
4. With the Bayes theorem, the posterior distribution of the response rate given X = x
follows a beta distribution
p | x ~ beta(a0 + x, b0 + n - x)
5. Let Y be the number of responders in the potential m future patients, where 
m = (Nmax – n), thus Y follows a beta-binomial distribution
Y ~ beta-binomial(m, a0 + x, b0 + n - x)
Given Y = i, the posterior distribution of p follows beta(a0 + x + i, b0 + Nmax – x – i)
6. Let Bi = Pr(p > p0 | x, Y = i), where Bi measures the probability that the response rate p
exceeds p0 (the response rate of current stand of care), given x responders in the first n
patients and i responders in the m future patients
7. Compare Bi to a threshold value θT. If Bi > θT, then the cohort is considered “success” at 
the end of the cohort given the interim data and the potential outcome of Y = i.
Note: A more relaxed threshold value, θT = 70%, is chosen for this study given the 
exploratory nature of study.
PPoS =
Pr(Y = i | x) • I(Pr(P > p0 | x, Y = i) > θT)} = 
Pr(Y = i | x) • I(Bi > θT)}


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APPENDIX J: INVESTIGATOR SIGNATURE PAGE
Investigator Statement and Signature
I have read the attached protocol entitled “Open Label Phase 2 Study of Tisotumab Vedotin 
for Patients with Platinum-Resistant Ovarian Cancer with a Safety Run-in of a Dose-Dense 
Regimen”.
I understand and agree to the provisions of the protocol, and I accept the responsibilities 
listed above in my role as principal investigator for the study.
Investigator Signature
Date
Investigator Name, Printed


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APPENDIX K: DOCUMENT HISTORY
Version
Date
Original
20 July 2018
Amendment 1
12 October 2018
Amendment 2
02 May 2019
Amendment 3
17 Oct 2019
Amendment 4
24 Aug 2020


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SUMMARY OF CHANGES IN AMENDMENT 1
Section(s)
Change
Rationale
Title page
Changed version number and date 
Administrative changes
Synopsis, 3.1
Changed description of DLTs and added safety data 
collection period
Clarification
Revised text regarding preclinical experience with 
tisotumab vedotin
Aligned text to match updated 
Investigator’s Brochure
1.3.2
More detail added to DLT criteria for bleeding; 
expanded scope of DLTs for ocular events
Clarification and alignment 
with other tisotumab vedotin 
protocols
Specified in inclusion criterion 5 that measureable 
disease is defined as having lesion/s described in A) 
OR the lesion/s described in b), not both.
Clarification
3.1.1
Changed exclusion criterion 17 from “peripheral 
neuropathy > Grade 1” to “peripheral neuropathy ≥ 
Grade 2.”
Alignment of language with 
other tisotumab vedotin 
protocols.
Changes to required ocular premedication and 
preventive eye therapy
Alignment with other tisotumab 
vedotin protocols
4.1
Removal of “physical therapy” from list of non-
drug therapies that must be recorded in the eCRF
Information regarding 
concomitant physical therapy is 
not necessary
Visit windows (±1 day) added to Schedule of 
Events descriptions of several visits.
Alignment with Schedule of 
Events tables in Appendix A
4.2
Removed required on-treatment ophthalmological 
exam
Alignment with other tisotumab 
vedotin protocols
Changed termination of patient-reported outcomes 
to end of treatment, not end of treatment or 
resolution of remaining AEs, whichever occurs 
later.
PRO data is not required after 
end of treatment.
5.4, Appendix C
Revisions to “minimum level for action” for 
specific individual symptoms on PRO surveys
Ease of implementation at 
clinical sites
Added AESIs to section title
Clarification
5.5.2
Deleted a footnote describing the ePRO tools used
Footnote not necessary as each 
tool is already listed in its own 
row in the table
Numbers added to some questions; one mistaken 
menu choice removed from Question 5
Clarification; correction


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Clinical Protocol
Amendment 4, 24-Aug-2020
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SUMMARY OF CHANGES IN AMENDMENT 2
Section(s)
Change
Rationale
Title page, Synopsis
Changed version number and date
Administrative changes
Edited “>Grade 1” to read “≥ Grade 2”
Clarification to make text 
match between synopsis and 
Section 4.
Synopsis
Relaxation of biopsy requirements
Reduce barriers to enrollment. 
Specify that PRO questionnaires are only to be 
performed in Phase 2 US patients
Reduce operational 
challenges. Though this study 
is expanding to ex-US sites, 
only Phase 2 US patients are 
required to complete PRO 
endpoints.
Synopsis, 4.1, 6.3.6, 
6.4.8, 7.1.1, 7.5.2, 
Appendix A, 
Appendix B
Revise bevacizumab exposure criteria for safety run-
in patients
Reduce barriers to enrollment. 
Set Table 1 to remain on a single page
Correction. 
Synopsis, 2, 6.3.4, 
6.3.5, 6.3.6, 6.4.4, 
6.4.5, 6.4.8, 7.4, 
Appendix A
Add detail regarding criteria to evaluate expansion 
to 70 patients
Clarification. 
Add clarity for patient replacement for DLT 
evaluation
Clarification. 
Synopsis, 4.1
Revise eGFR inclusion criteria from eGFR ≥ 60 to 
eGFR ≥ 50
Reduce barriers to enrollment 
for patients treated with prior 
lines of platinum therapy. 
Clarify that cataracts are not active ocular surface 
disease
Clarification. 
2
Move anticoagulant/anti-platelet agent decision after 
SMC review of run-in
Change based on updated 
knowledge of adverse event 
risk profile. 
Include antiplatelet agents as possible allowed 
concomitant medications after safety review
Change based on updated 
knowledge of adverse event 
risk profile. 
3.1, Figure 1, 9.1
Fix table reference
Correction. 
Create consistency in instructions for lubricating eye 
drop use
Clarification to ensure that 
there are no perceived 
inconsistencies in instructions 
for lubricating eye drop use.
3.1.1
Allow scalp cooling
Patient safety/tolerability 
improvement. 
Fix end of Infusion PK draw window from ± 15min 
to +15min
Correction. 
4.1
Added information regarding home health aide 
collection of samples
Clarification. 
Drug-induced liver injury (DILI) revision
Correction/resolution of 
discrepancy between DILI 
language and dose 
modifications.


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Section(s)
Change
Rationale
4.2
Update AE language and reporting requirements to 
specify that disease progression is not an AE
Clarification.
Add additional explanation of sample size 
determination and analysis to be performed when 
considering cohort expansion
Clarification. 
4.2, 5.5.2, 5.5.3
Fix omitted detail re: PFS
Correction. 
Add definition of DLT evaluable set
Clarification. 
4.2, 5.5.2, 5.5.3
Update language for Efficacy Evaluable set
Clarification/Update to 
analysis set definition. 
Remove 3 month PFS and 12 month OS timepoints
Reduction of unnecessary 
analyses. 
5.2.3
Remove post-EOT PRO collection
Eliminate collection of 
unnecessary data. 
Fix typo to close parentheses
Typographical correction.


Study SGNTV-002
Clinical Protocol
Amendment 4, 24-Aug-2020
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SUMMARY OF CHANGES IN AMENDMENT 3
Section(s)
Change
Rationale
Title page
Updated the Medical Monitor Information
Per the subject of Admin Letter 01
Title page, 
synopsis, footer
Updated version number and date
Administrative changes
Synopsis; 
throughout 
protocol
Edited text referring to “phase 2” portion of 
the study to read “Parts A and B”
Clarification. Study now contains two 
phase 2 cohorts
Synopsis, 4.1
Inclusion criteria changes
Cohort added; also, reduction of 
barriers to enrollment
Synopsis, 9.1
Number of planned patients changed
Updated number reflects added 
patients in Part B
Synopsis, 3.1, 
throughout 
protocol
Part B cohort added
Study design change
Synopsis, 3.1, 3.2, 
5.1, 5.2.3
1.2 mg/kg dose escalation added to safety 
run-in
Change based on updated knowledge 
of adverse event risk profile in prior 
studies
Synopsis, 1.4
Change in DLT period
Change based on updated knowledge 
of adverse event risk profile.
Synopsis, 3.1
Response confirmation scan changed from 
“4-6 weeks” to “at least 4 weeks”
Alignment with other tisotumab 
vedotin protocols
Synopsis, 5.1
Infusion duration changed from 30 minutes 
to 30-60 minutes
Alignment with other tisotumab 
vedotin protocols 
Synopsis, 5.1, 
5.2.2, 5.6.2
Dosage cap change
Addition of 1.2 mg/kg dosing group 
necessitates a higher weight-based 
dosage cap for these patients
Synopsis, 
Sample size table updates
Addition of Part B patients
Abbreviations list
“OMP” added
New abbreviation used in the text
1.3.3
Pharmacokinetics data revised
Updated PK data obtained; analysis at 
new 1.2 mg/kg dosing level added
1.3.3
Ocular adverse event analysis added
Change based on updated knowledge 
of adverse event risk profile
1.4
Pharmacokinetic and safety-related 
additions
Changes based on updated knowledge 
of adverse event risk profile and 
addition of new 1.2 mg/kg dosing 
group to the study
3.1
Study schema changed
Reflection of other design updates
3.1.1, 9.3.1.9, 9.3.9
DLT period change  
Change based on updated knowledge 
of adverse event risk profile
3.2
Editorial changes to study design rationale
Readability
3.2.1
Descriptions added for patient assignments 
in safety run-in, Part A, and Part B
Necessitated by study design changes
3.2.2
Updates to dose rationale
Necessitated by study design changes 
(addition of 1.2 mg/kg dose escalation)
4.1, Appendix F
Contraceptive language changes
Reduction of barriers to enrollment
5.2.3
Dose delays and other modifications added
Clarification
5.3.1
Dose modifications due to ocular AEs 
changed
Change based on updated knowledge 
of adverse event risk profile


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Section(s)
Change
Rationale
5.4, Appendix C
Changes to ocular prophylactic measures
Change based on updated knowledge 
of adverse event risk profile
6.3.1, 6.4.1, 6.4.4
Confirmation of eligibility criteria before 
dosing is now limited to Cycle 1 only
Reduce operational challenges
6.3.1, 6.4.1, 6.4.4, 
6.4.5
Vital sign description changed to “predose 
vital signs”
Clarification
6.3.1, 6.4.1, 6.4.5, 
Appendix B
Changes to PK draw windows
Reduce operational challenges
6.3.2, 6.4.1, 6.4.2, 
6.4.4, 6.4.5, 6.4.6, 
6.4.7, Appendix B
Removed some blood draw samples
Eliminate collection of unnecessary 
data
7.4
Removal of site interventions based on 
patient-reported outcomes survey answers
Reduce operational challenges
9.3.1.1
Description of randomization expanded
Clarification; necessitated by study 
design changes
9.3.4.2
Description of TTR moved within section
Readability
Appendix A
Footnote F added to physical exam
Physical exam need not be repeated if 
performed within 24 hours


Study SGNTV-002
Clinical Protocol
Amendment 4, 24-Aug-2020
Tisotumab vedotin
Seattle Genetics, Inc. - Confidential
Page 108 of 108
SUMMARY OF CHANGES IN AMENDMENT 4
Section(s)
Change
Rationale
Title page
Updated the Medical Monitor Information
Administrative change
Synopsis, Section 
1.4, 3.1, 9.3.1.9,
9.3.9
Addition of interim futility analysis
Improve efficacy monitoring
Synopsis, Section 
3.1, 9.1
Changed Part B to enroll approximately 80 
patients
Improve efficacy monitoring
Synopsis, Section 
4.1
Updated inclusion criteria
Update criteria to match benchmark 
patient population with high unmet 
need.
Section 1.1
Updated introduction regarding patient 
population 
Update standard of care principles for 
platinum resistant ovarian cancer
patients 
Sections 4.2, 5.3.3,
5.5, 5.5.2, 5.5.3
Anticoagulation and antiplatelet therapies 
are permitted
Reduce barriers to enrollment.
Section 6.1
Added language clarifying that some 
procedures performed by the patient at 
home are not listed in Section 6.
Clarification
Section 6.7
Remove CA-125 blood collection from 
long-term follow-up
Clarification; CA-125 blood collection 
should coincide with imaging visits.
Appendix F
Guidance on contraception updated
Improve patient safety.

SAP_001.pdf: 
Part or all of the information in this statistical analysis plan may be unpublished material. Accordingly, this 
document is to be treated as confidential and restricted to its intended use. This material is the property of 
Seagen, Inc. and must not be disclosed or used except as authorized in writing by Seagen, Inc.
STATISTICAL ANALYSIS PLAN
Protocol Number:
SGNTV-002
Version:
Version 3 12-February-2021
Protocol Title:
Open Label Phase 2 Study of Tisotumab Vedotin for Patients 
with Platinum-Resistant Ovarian Cancer with a Safety Run-in of 
a Dose-Dense Regimen
Study Name
innovaTV 208
Study Sponsor:
Seagen, Inc.
21823 30th Drive SE
Bothell, WA 98021, USA
Collaborator: 
Genmab A/S
Kalvebod Brygge 43
DK-1560 Copenhagen V
Denmark


Study SGNTV-002 
Statistical Analysis Plan
Version 3 12-Feb-2021  
Tisotumab Vedotin                               Seagen, Inc. - Confidential 
Page 2 of 30
APPROVAL SIGNATURES
Product:
Tisotumab Vedotin
Protocol Number/Amendment:
SGNTV-002/4
SAP Version:
Version 3
Version Date:
12-February-2021
The individuals signing below have reviewed and approve this statistical analysis plan.
Seagen, Inc.
Seagen, Inc.
Seagen, Inc.
Seagen, Inc.


Study SGNTV-002 
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Page 3 of 30
TABLE OF CONTENTS
LIST OF ABBREVIATIONS .......................................................................................................................... 5 
1 
INTRODUCTION.................................................................................................................................... 7 
2 
STUDY OBJECTIVES............................................................................................................................. 7 
2.1 
Primary Objectives.......................................................................................................................... 7 
2.2 
Secondary Objectives (Parts A and B) ............................................................................................. 7 
2.3 
Additional Objectives (Parts A and B)............................................................................................. 7 
3 
STUDY ENDPOINTS.............................................................................................................................. 8 
3.1 
Primary Endpoint............................................................................................................................ 8 
3.2 
Secondary Endpoints (Parts A and B).............................................................................................. 8 
3.3 
Additional Endpoints (Parts A and B).............................................................................................. 8 
4 
STUDY DESIGN..................................................................................................................................... 8 
5 
ANALYSIS SETS.................................................................................................................................... 9 
5.1 
Full Analysis Set (FAS)................................................................................................................... 9 
5.2 
Safety Analysis Set ......................................................................................................................... 9 
5.3 
PK Analysis Set ............................................................................................................................ 10 
5.4 
Anti-therapeutic Antibody (ATA) Evaluable Set............................................................................ 10 
5.5 
Efficacy-Evaluable (EE) Analysis Set............................................................................................ 10 
5.6 
CA-125 Evaluable Analysis Set..................................................................................................... 10 
6 
STATISTICAL CONSIDERATIONS..................................................................................................... 10 
6.1 
General Principles......................................................................................................................... 10 
6.2 
Determination of Sample Size ....................................................................................................... 11 
6.3 
Randomization and Blinding ......................................................................................................... 11 
6.4 
Data Transformations and Derivations........................................................................................... 12 
6.4.1 
General............................................................................................................................. 12 
6.4.2 
Best Response................................................................................................................... 12 
6.4.3 
Response Assessment Dates.............................................................................................. 13 
6.5 
Handling of Dropouts and Missing Data ........................................................................................ 13 
6.6 
Multicenter Studies ....................................................................................................................... 13 
6.7 
Multiple Comparison/Multiplicity ................................................................................................. 14 
6.8 
Examination of Subgroups ............................................................................................................ 14 
6.9 
Covariates ..................................................................................................................................... 14 
6.10 Timing of Analyses....................................................................................................................... 14 
7 
PLANNED ANALYSES ........................................................................................................................ 14 
7.1 
Disposition.................................................................................................................................... 14 
7.2 
Demographic and Baseline Characteristics..................................................................................... 15 
7.3 
Protocol Deviations....................................................................................................................... 15 
7.4 
Treatment Administration.............................................................................................................. 15 
7.5 
Efficacy Analyses ......................................................................................................................... 16 
7.5.1 
Primary Endpoint.............................................................................................................. 16 
7.5.2 
Secondary Endpoints......................................................................................................... 16 
7.6 
Safety Analyses............................................................................................................................. 20 
7.6.1 
Adverse Events................................................................................................................. 20 
7.6.2 
Clinical Laboratory Parameters ......................................................................................... 22 
7.6.3 
Deaths .............................................................................................................................. 22 
7.6.4 
Concomitant Medications.................................................................................................. 22 
7.6.5 
Other Safety Analyses....................................................................................................... 22 
7.7 
Additional Analyses...................................................................................................................... 23 
7.7.1 
Pharmacokinetics.............................................................................................................. 23 
7.7.2 
Antitherapeutic Antibody (ATA)....................................................................................... 23 
7.7.3 
Biomarkers ....................................................................................................................... 23 
7.7.4 
Patient Reported Outcomes Analyses ................................................................................ 23 


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8 
INTERIM ANALYSIS........................................................................................................................... 24 
9 
CHANGES FROM PLANNED ANALYSES.......................................................................................... 25 
9.1 
Changes from the Original Protocol............................................................................................... 25 
9.2 
Changes from the Original SAP..................................................................................................... 25 
10 REFERENCES....................................................................................................................................... 26 
APPENDIX A 
IMPUTATION OF PARTIALLY UNKNOWN ADVERSE EVENT DATES.................... 27 
APPENDIX B 
IMPUTATION OF PARTIALLY MISSING SUBSEQUENT ANTICANCER THERAPY 
START DATE........................................................................................................................................ 30 


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LIST OF ABBREVIATIONS
3Q4W
three times every 4 weeks
AE
adverse event
AESI
adverse events of special interest
ATA
antitherapeutic antibodies
CA-125
Cancer antigen 125
CI
confidence interval
CPI
checkpoint inhibitor
CR
complete response
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DCR
disease control rate
DLT
dose limiting toxicity
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EE
efficacy-evaluable
EOS
end of study
EOT
end of treatment
FAS
full analysis set
GCIG
Gynecologic Cancer Intergroup
IV
intravenous
LLOQ
lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Affairs
MMAE
monomethyl auristatin E
NCA
noncompartmental analysis
NCI CTCAE
National Cancer Institute’s Common Terminology Criteria for Adverse Events
ORR
objective response rate
OS
overall survival
PD
progressive disease
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
PRO 
patient reported outcomes
PROC
platinum-resistant ovarian cancer
PROMIS
Patient-Reported Outcomes Measurement Information System
Q3W
every 3 weeks
RECIST
Response Evaluation Criteria in Solid Tumors
SAP
statistical analysis plan
SAE
serious adverse event
SD
stable disease
SMC
Safety Monitoring Committee
TAb
total antibody
TEAE
treatment-emergent adverse event


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TF
Tissue Factor
TTR
time to response
ULN
upper limit of normal
WHO
World Health Organization


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1 
INTRODUCTION
This document outlines the statistical methods to be implemented within the scope of 
Protocol SGNTV-002, entitled “Open Label Phase 2 Study of Tisotumab Vedotin for 
Patients with Platinum-Resistant Ovarian Cancer with a Safety Run-in of a Dose-Dense 
Regimen”, Original dated 20July2018. Results of the proposed analyses will become the 
basis of the clinical study report (CSR) for this protocol.
The purpose of this plan is to provide specific guidelines from which the analysis will 
proceed. All planned analyses specified in this document will be performed. Any changes to 
this plan, in the form of “post hoc” or “data driven” analyses will be identified as such in the 
final CSR. Any changes will either be reflected in amendments to this plan before the 
database lock or specifically documented in the CSR.
2 
STUDY OBJECTIVES
2.1
Primary Objectives
Ɣ
(Safety run-in)  Evaluate safety and tolerability of a dose-dense regimen of tisotumab 
vedotin  
Ɣ
(Parts A and B) Evaluate antitumor activity of tisotumab vedotin
2.2
Secondary Objectives (Parts A and B)
Ɣ
Evaluate the safety and tolerability of tisotumab vedotin 
Ɣ
Evaluate preliminary antitumor activity of tisotumab vedotin 
Ɣ
Evaluate durability of response in patients who respond to tisotumab vedotin
Ɣ
Evaluate stability and control of disease
Ɣ
Evaluate the timing of responses 
Ɣ
Evaluate progression-free survival (PFS) of patients treated with tisotumab vedotin
Ɣ
Evaluate overall survival of patients treated with tisotumab vedotin 
Ɣ
Assess pharmacokinetics (PK) of tisotumab vedotin
Ɣ
Assess immunogenicity of tisotumab vedotin
2.3
Additional Objectives (Parts A and B)
Ɣ
Evaluate Tissue Factor (TF) expression-response relationship
Ɣ
Assess biomarkers of biological activity and resistance and predictive biomarkers of 
response 
Ɣ
Patient-reported outcomes (Parts A and B, US patients only)


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3 
STUDY ENDPOINTS
3.1
Primary Endpoint 
For the safety run-in, the primary endpoint is the incidence of dose limiting toxicities (DLTs) 
or other unacceptable toxicities.  For Parts A and B, the primary endpoint is confirmed 
objective response rate (ORR) (confirmed complete response [CR] and confirmed partial 
response [PR] per RECIST v1.1) as determined by the investigator.
3.2
Secondary Endpoints (Parts A and B)
Ɣ
Type, incidence, severity, seriousness, and relatedness of adverse events (AEs)
Ɣ
Investigator-determined confirmed and unconfirmed ORR as measured by RECIST v1.1 
(all responses)
Ɣ
CA-125 response rate
Ɣ
Combined RECIST/CA-125 overall response
Ɣ
Investigator-determined duration of response (DOR) as measured by RECIST v1.1
Ɣ
Investigator-determined disease control rate (DCR) as measured by RECIST v1.1
Ɣ
Investigator-determined time to response (TTR) as measured by RECIST v1.1
Ɣ
Investigator-determined PFS as measured by RECIST v1.1
Ɣ
Overall survival (OS)
Ɣ
Selected PK parameters for tisotumab vedotin and monomethyl auristatin E (MMAE)
Ɣ
Incidence of anti-therapeutic antibodies (ATAs) to tisotumab vedotin 
3.3
Additional Endpoints (Parts A and B)
Ɣ
TF expression-response relationship following treatment with tisotumab vedotin
Ɣ
Relationship between biomarkers in blood and tumor tissue to efficacy, safety, or other 
biomarker endpoints following treatment with tisotumab vedotin 
Ɣ
PROMIS and an NCI PRO-CTCAE questionnaire customized to focus on ocular 
symptoms, bleeding, and gastrointestinal symptoms, as well as other questions added by 
the sponsor
4 
STUDY DESIGN
This is an open-label, phase 2 study with an initial safety run-in period. The safety run-
in period will evaluate the safety of a dose-dense schedule and will start at a 0.9 mg/kg 
dose level. If 0.9 mg/kg is considered safe and tolerable, the dose level will be escalated 
to 1.2 mg/kg. Otherwise it will be de-escalated to 0.65 mg/kg. Each dose level will enroll 
approximately 6 patients. Patients who do not complete the DLT period will be replaced. 


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A dose level is considered safe and tolerable if no more than 1 patient experiences a DLT 
among 6 patients during the DLT period. The highest dose level that is considered safe 
will be the recommended phase 2 dose (RP2D) and will be used in Part A. If no RP2D 
for the dose-dense schedule is identified, Part A will be a single arm of the Q3W regimen 
and Part B will not enroll.
In Part A, 60 patients will be randomized in a 1:1 ratio to receive tisotumab vedotin
2.0 mg/kg intravenously (IV) every 3 weeks (Q3W regimen) or the safety run-in RP2D on 
Days 1, 8, and 15 of every 4-week cycle (dose-dense regimen; 3Q4W) if a RP2D has been 
identified. Randomization will be stratified by first line vs. second line PROC and 
histology (serous vs. non-serous).
Based upon antitumor activity and safety data, one Part A treatment arm may be expanded to
enroll up to an additional 70 patients to further characterize safety and antitumor activity of 
tisotumab vedotin for patients with PROC. The analysis to support expansion will be 
conducted when approximately 30 patients per arm have at least one post-baseline response 
assessment per RECIST v1.1 or have discontinued from the study or started subsequent 
cancer therapy.
Part B will enroll approximately 80 patients with PROC including approximately 60 patients 
who have received 1 to 3 prior lines of therapy, including bevacizumab treatment. Part B will 
further characterize the long-term efficacy, safety, and PK assessments of 0.9 mg/kg 
tisotumab vedotin on Days 1, 8, and 15 of every 4-week cycle (dose-dense regimen) if the 
0.9 mg/kg dose level is considered safe and tolerable in the safety run-in period. Enrollment 
in this cohort may discontinue when Part A begins enrollment.
Interim futility analysis will be performed on Part B after at least 20 patients with 1 to 3 prior 
lines of therapy, including bevacizumab treatment, have been treated and had at least one 
response assessment post-baseline. The Bayesian predictive probability approach will be 
used to assess the futility criteria. Based on activity and safety data, together with the 
predictive probability of success (PPoS), a cohort may be stopped early by the sponsor. A 
cohort may also be discontinued at any point at the discretion of the sponsor.
  
5 
ANALYSIS SETS
5.1
Full Analysis Set (FAS)
The full analysis set (FAS) includes all patients who received any amount of study drug.  All 
efficacy analyses will be based on the FAS.
5.2
Safety Analysis Set
The safety analysis set includes all patients who received any amount of study drug, and thus 
is equivalent to the FAS. All safety analyses will be based on the safety analysis set.


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5.3
PK Analysis Set
PK analysis set includes enrolled patients who received any amount of study drug and at least 
one PK parameter can be estimated. The PK parameters will be tabulated using the PK 
analysis set.
5.4
Anti-therapeutic Antibody (ATA) Evaluable Set
ATA evaluable set includes patients who had a baseline ATA status and at least one ATA 
sample evaluated at post treatment. ATA analyses will be based on the ATA evaluable set.
5.5
Efficacy-Evaluable (EE) Analysis Set
The efficacy-evaluable (EE) analysis set includes patients who received any amount of study 
drug and had at least one post-baseline disease assessment per RECIST v1.1 or had clinical 
progression per investigator judgement. The EE analysis set will be used for supplemental 
analysis of the objective response rate and the disease control rate.
5.6
CA-125 Evaluable Analysis Set
The CA-125 evaluable analysis set includes patients who have an elevated baseline CA-125 
YDOXHRI[8/1XSSHUOLPLWRIQRUPDOZLWKLQZHHNVSULRUWRWKHILUst dose of study 
drug. The CA-125 evaluable analysis set will be used for the analysis of CA-125 response 
rate.
6 
STATISTICAL CONSIDERATIONS
6.1
General Principles
Patients enrolled in the safety run-in portion and Part A and Part B portion of the study will 
be summarized separately. All analyses in the Part A and Part B portion will be presented by 
cohort and for patients with 1 to 3 lines of prior therapy, including bevacizumab treatment  
unless otherwise specified. Descriptive statistics will be presented that include the number of 
observations, mean, median, standard deviation, minimum and maximum for continuous 
variables, and the number and percentages per category for categorical variables.
Unless otherwise specified, confidence intervals (CI) will be calculated at 2-sided 95% level.
The 2-sided 95% exact CI using the Clopper-Pearson method will be calculated for the 
response rates where applicable (e.g., ORR) (Clopper 1934). 
For time-to-event endpoints, the median survival time will be estimated using the Kaplan-
Meier method; the associated 95% CI will be calculated based on the complementary log-log 
transformation (Collett 1994). 
To comply with regulatory electronic submission guidelines, listings of all clinical data will 
be submitted as electronic data sets. To facilitate data review for the study report, only 
pertinent data listings will be created and attached to Section 16 of the CSR.


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All statistical Tables, Listings and Figures will be produced using SAS®, version 9.3 or 
higher. Other statistical software, if used, will be described in the CSR.
6.2
Determination of Sample Size
Up to approximately 222 patients may be enrolled in the study. This includes approximately 
6–12 patients in the safety run-in phase, approximately 30 patients in each of 2 randomized 
Part A cohorts, and the possible expansion of an additional 70 patients in one of the 2 Part A 
cohorts. Part B will enroll approximately 80 patients including approximately 60 patients 
who have received 1 to 3 prior lines of therapy, including bevacizumab treatment.
Analysis regarding expansion of Part A will be conducted when approximately 30 patients 
per cohort have at least one post-baseline response assessment per RECIST v1.1 or have 
discontinued from the study or started subsequent cancer therapy.
A cohort may be expanded to further characterize antitumor activity if the safety profile is 
acceptable, other efficacy endpoints are comparable to current standard of care, and the 
number of confirmed CR or PR meet cohort-specific criteria.
The sample size is not based on power calculations for formal hypothesis testing, but is 
selected based on ORR estimate precision as characterized by 95% confidence intervals 
(CIs). For a sample size of 30 patients (Part A) and 60 patients (Part B with 1 to 3 prior lines 
of therapy, including bevacizumab treatment) per cohort (or 100 patients, if a treatment arm 
from Part A is expanded), assuming the confirmed ORR is between 20% and 40%, the 
2 -sided 95% exact CIs are summarized below.
Confirmed ORR
95% Exact CI (N=30)
95% Exact CI (N=60)
95% Exact CI (N=100)
15%
(4%, 31%)
(7%, 27%)
(9%, 24%)
20%
(8%, 39%)
(11%, 32%)
(13%, 29%)
30%
(15%, 49%)
(19%, 43%)
(21%, 40%)
40%
(23%, 59%)
(28%, 53%)
(30%, 50%)
                    
6.3
Randomization and Blinding
This is an open-label phase 2 study with an initial safety run-in phase. The safety run-in 
will evaluate the tolerability of dose-dense regimen. If the tolerability is confirmed, the 
study will proceed to Part A and Part B. In Part A, randomization will be stratified by first 
line vs. second line PROC and histology (serous vs. non-serous). Patients will be 
randomized in a 1:1 ratio to receive tisotumab vedotin 2.0 mg/kg Q3W or the RP2D dose-
dense regimen.
Randomization is used in this study to minimize bias and not as a basis for 
statistical inference as the study includes no formal statistical hypothesis testing.
If the tolerability of dose-dense regimen is not confirmed after the safety run-in, Part A 
will be a single-arm treated with the Q3W dosing schedule and Part B will not enroll.


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Part B will be a single arm of the 0.9 mg/kg dose-dense regimen.
6.4
Data Transformations and Derivations
6.4.1 General
Reported age in years will be used; if not available, age at informed consent in years will be 
calculated with the SAS® INTCK function (with method specified as “continuous”) using 
informed consent date and birth date.
Time variables based on two dates (e.g., Start Date and End Date) will be calculated as (End 
Date – Start Date +1 [in days]) unless otherwise specified in the planned analysis section.
Specifically, Study Day will be calculated as (Date–First Dose Date+1) for dates on or after 
the first dose date. The date of first dose will be Study Day 1. For dates prior to the first dose 
date, Study Day will be calculated as (Date–First Dose Date). For example, the date before 
the first dose date will be Study Day -1. 
The following unit conversion will be implemented unless otherwise specified:
Months=Days/30.4375 
Years=Days/365.25
Unless otherwise specified, baseline values used in all analyses will be the most recent non-
missing measurement prior to the first dose of study drug.
The end-of-treatment (EOT) date will be the date when the EOT visit is performed; if an 
EOT visit is not performed then the EOT date will be either the end-of-study (EOS) date or 
30 days after the last dose of any study drug, whichever is earlier.
6.4.2 Best Response
The determination of antitumor activity will be based on objective response assessments 
made by the investigator according to the RECIST v1.1 (Eisenhauer 2009). Only response 
assessments on or prior to the start date of any new anticancer therapy will be considered for 
best response. The patient’s best confirmed response will be the best demonstrated response 
to date that has been confirmed, when confirmation is required (i.e. for PR and CR only). 
When confirmation is not required, the patient’s best response will be the best demonstrated 
response to date. The patient’s best response will be used in determining the ORR. 
A response (CR or PR) will be considered confirmed if the subsequent disease assessment 
conducted no earlier than 4 weeks after the initial response still shows CR or PR (i.e., CR 
followed by CR or PR followed by PR or CR). A patient will have a best response of SD if 
WKHUHLVDWOHDVWRQH6'DVVHVVPHQWRUEHWWHUZHHNVDIWHUWKHVWDUWRIWUHDWPHQWDQGWKH
patient does not qualify for confirmed CR or PR. RECIST v1.1 outlines scenarios for best 
overall responses when confirmation of CR and PR is required. 


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In addition to radiographic tumor assessments, expression level of CA-125 will also be 
monitored to assess CA-125 response according to the GCIG criteria. 
6.4.3 Response Assessment Dates
For efficacy assessments, the date of response assessment of CR, PR, or SD will be the latest 
of all radiologic scan dates for the given response assessment. The date of progression per 
RECIST v1.1 will be the earliest of all radiologic scan dates that PD response has been 
documented, i.e., the earliest of 
x
Date(s) of target lesion assessments with target lesion response of PD
x
Date(s) of non-target lesion assessments with lesion status of unequivocal progression
x
Date(s) of documenting new unequivocal lesion(s)
6.5
Handling of Dropouts and Missing Data
Missing data will not be imputed unless otherwise specified. Missing AE start date and/or 
end date will be imputed while calculating duration of events and treatment-emergent status 
(see Appendix A for imputation details).  
For time-to-event endpoints, e.g., DOR, PFS, and OS, patients who have no specific event 
will be censored as specified for each respective endpoint in Section 7.5. 
Patients who do not have at least 2 post-baseline response assessments (initial response and 
confirmation scan) will be counted as non-responders for analysis of the primary endpoint.
Missing subsequent anticancer treatment start date will be imputed while deriving the time-
to-event endpoints as applicable (see Appendix B for imputation details).
For prior therapies end dates, if month and year are present and only day is missing, day may 
be imputed. The end day will be imputed with the last day of the month or 21 days before the 
first dose of study drug, whichever is earlier. If the imputed end date is earlier than start 
dates, the end day will be imputed with the day after the start date. If month or year is 
missing, no imputation will be performed.
For prior therapies start dates, if month and year are present and only day is missing, day 
may be imputed. The imputed day will be the first day of the month. If month or year is 
missing, no imputation will be performed.
Unless otherwise specified, if the numeric value of a clinical laboratory test is not available 
because it is below the lower limit of quantification (LLOQ), “< LLOQ” should be used 
whenever applicable. In cases where a numeric value is required, e.g., calculating the mean 
and standard deviation, the LLOQ/2 will be used for the calculation.
6.6
Multicenter Studies
There are multiple centers in this study, however it is not anticipated that any center will 
accrue enough patients to warrant an analysis by center.


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6.7
Multiple Comparison/Multiplicity
No multiple comparisons are planned in this study.
6.8
Examination of Subgroups
Subgroups would be conducted for the primary endpoint (confirmed objective response rate) 
and other key secondary efficacy endpoints if appropriate. Subgroups may include but are not 
limited to the following:
Ɣ
Age (18–\HDUVROG
Ɣ
Platinum-free interval (<3 vs 3-6 month)
Ɣ
First line vs. second line PROC
Ɣ
TF expression (less than or equal to median, above median)
Ɣ
Prior treatment with CPIs (yes, no)
Ɣ
Prior treatment with PARP inhibitors (yes, no)
Ɣ
ECOG performance score at baseline (0, 1)
Ɣ
1XPEHURISULRUV\VWHPLFWKHUDSLHVLQFOXGLQJLQWKH352&VHWWLQJ
Platinum-free interval is defined as the time from the end of the latest platinum-based therapy 
to the earlier of disease progression from the latest platinum-based therapy or the start of the 
first line systemic therapy in the PROC setting. 
If the number of patients in some subgroups is not sufficiently large (e.g., <10% of the total 
sample size), the subgroup analysis may not be performed or the subgroups may be 
combined if applicable.
6.9
Covariates
No adjustments for covariates are planned in the analyses.
6.10 Timing of Analyses
The primary analysis of study will be conducted when all treated patients have had an 
opportunity to be followed for at least 6 months. Subsequent data cutoff dates may be 
defined to assess longer term clinical benefit with further follow up.
A safety analysis will be conducted at end of DLT period for each dose level in the 
safety run-in portion to evaluate the tolerability of dose-dense regimen.
7 
PLANNED ANALYSES
7.1
Disposition
Patient disposition will be summarized by cohort and total for patients in FAS with 
descriptive statistics. Patients who discontinue study treatment and patients who withdraw 
from the study will be summarized along with reason for discontinuation or withdrawal. The 


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number of patients who signed the informed consent and the number and percentage of 
patients in each analysis set will be summarized. The reasons for screen failure will also be 
summarized, if applicable.
The number of patients enrolled at each site will be summarized. 
7.2
Demographic and Baseline Characteristics
Demographics and baseline characteristics, including age at consent, gender, ethnicity, race, 
baseline height, weight, and ECOG score will be listed and summarized by cohort and total 
using the FAS. Disease specific characteristics will be listed and summarized by cohort and 
total using the FAS. Disease characteristics may include cancer stage at diagnosis, previous 
cancer-related treatments, number of prior systemic therapies, number of prior cytotoxic 
chemotherapy in the PROC setting, platinum-free interval, histology, genetic markers, and 
tissue factor expression.   
7.3
Protocol Deviations
Important protocol deviations (defined as protocol violations by Seagen, Inc.) are those that 
represent a divergence from the protocol that could have a significant effect on the integrity 
of the study data, or on the patient’s rights, safety, or welfare.  Important protocol deviations 
also include exemptions to the study inclusion/exclusion criteria and will be summarized by 
category. A list of patients with important protocol deviations will be presented.
7.4
Treatment Administration
Treatment administration will be summarized with descriptive statistics by cohort using the 
safety analysis set. Summaries may include but are not limited to the following:
x
Duration of treatment (in weeks), for the Q3W cohort, which is defined as time from 
the first study dose to the earliest of Day 21 of the last treatment cycle, EOT visit, 
death date, or start date of subsequent anticancer therapy if applicable. For the dose-
dense cohort, duration of treatment is defined as time from the first study dose to the 
earliest of Day 28 of the last treatment cycle, EOT visit, death date, or start date of 
subsequent anticancer therapy if applicable
x
Number of cycles per patient
x
Number and percentage of patients by number of treated cycles 
x
Cumulative dose received (in mg), which is defined as sum of the actual dose across 
all cycles. 
x
Average dose per week
x
Relative dose intensity (RDI), which is defined as the absolute dose intensity (ADI) 
divided by the intended dose intensity (IDI). That is, RDI = ADI/IDI × 100, where 
ADI is defined as the actual dose in mg/kg per week and IDI is defined as the 
intended dose in mg/kg per week regardless of dose reduction in later cycles. For 


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Q3W cohort IDI is 2/3= 0.667 mg/kg/wk. For dose-dense cohort IDI is 0.9*3/4=0.675 
mg/kg/wk if dose level is 0.9 mg/kg or 0.65*3/4=0.488 mg/kg/wk if 0.65 mg/kg.
x
Number and percentage of patients whose dose was ever modified, which will be 
summarized by modification type (delay, reduction, elimination, unplanned dose 
adjustment). The number and percentage of doses that were modified may also be 
summarized.
7.5
Efficacy Analyses
All efficacy analyses will be descriptive in nature and all efficacy endpoints will be analyzed 
by cohort and total using the FAS unless otherwise specified. In addition, the ORR and DCR 
will also be analyzed using the EE set.
7.5.1 Primary Endpoint
7.5.1.1 Confirmed Objective Response Rate (ORR) 
The primary efficacy endpoint of this study is the confirmed ORR per investigator 
assessment. The confirmed ORR is defined as the proportion of patients who achieve a 
confirmed CR or PR according to RECIST v1.1 (Eisenhauer 2009). Patients who do not have 
at least 2 post-baseline response assessments (initial response and confirmation scan) will be 
counted as non-responders. Confirmation means a PR is followed by a PR or CR at least 4 
weeks later, or a CR is followed by a second CR at least 4 weeks later.  
The confirmed ORR of each cohort and its exact 2-sided 95% CI will be calculated. 
This endpoint will also be summarized by the subgroups defined in Section 6.8.
7.5.2 Secondary Endpoints
7.5.2.1 Confirmed and Unconfirmed ORR
Confirmed and unconfirmed ORR is defined as the proportion of patients who achieve a CR 
or PR according to RECIST v1.1 as assessed by the investigator.  These include patients with 
confirmed responses as well as those whose responses were not confirmed or had not yet 
been assessed for confirmation.  Patients who do not have at least 1 post-baseline response 
assessment will be counted as non-responders. 
The confirmed and unconfirmed ORR will be estimated for each cohort and its exact 2-sided 
95% CIs will be calculated.
7.5.2.2 CA-125 Response Rate
Baseline CA-125 is the most recent non-missing measurement no more than 14 days prior to 
the first dose of study drug.
CA-125 response rate is defined as the proportion of patients who have at least a 50% 
reduction in CA-125 value from baseline.  The response must be confirmed in a subsequent 
VDPSOHFROOHFWHGGD\VDIWHUWKHSULRUVDPSOH7KHYDOXHRIWKHFRQILUPDWRU\sample must 


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EHRIWKHSULRUVDPSOH7KH&$-125 evaluable analysis set will be used for the 
analysis of CA-125 response rate.
In addition, summary statistics of CA-125 values and changes from baseline will be tabulated 
by scheduled visit using the FAS.
7.5.2.3 Combined RECIST/CA-125 Overall Response
The combined RECIST/CA-125 overall response is defined as the proportion of patients 
whose best response is a CR or PR according to the Gynecological Cancer Intergroup 
(GCIG) combined RECIST and CA-125 criteria (Rustin 2011). For those who are not in the 
CA-125 evaluable analysis set, patients will be assessed to determine whether they have PD 
or not according to GCIG CA-125 criteria. Then the combined overall response will be 
assessed as indicated in Table 7.
Table 1: 
Overall response by RECIST and CA-125 criteria
RECIST Response
CA-125 Response
Combined RECIST/CA-125 
Response 
CR
Response and normalizeda
CR
CR
Response
PR
CR
Not response and not PDb
PR
PR
Response
PR
PR
Not response and not PDb
PR
SD
Response
PR
SD
Not response and not PDb
SD
NEc
Response
PR
PD >28 days from CA-125 
response
Response
PR
3'GD\VIURPCA-125 
response
Response
PD
PD
Not response and not PDb
PD
Any
PDb
PD
a
Normalized means CA-125 value within the reference range
b
Progression of CA-125 levels is defined as: 1) CA-[8/1RQRFFDVLRQVDWOHDVWZHHNDSDUWIRUSDWLHQWVZLWK
elevated CA-125 before treatment and later normalizes, 2) CA-[QDGLUYDOXHRQRFFDVLRQVDWOHDVWZHHNDSDUW
for patients with elevated CA-125 before treatment which never normalizes, or 3) CA-[8/1RQRFFDVLRQVDW
least 1 week apart for patients with CA-125 in the reference range before treatment.
c
Target lesions are not all evaluated, non-target lesions are non-PD, and no new lesions appear.
7.5.2.4 Disease Control Rate
DCR is defined as the proportion of patients who achieve a confirmed CR or PR according to 
RECIST v1.1 as assessed by the investigator, or meet the SD criteria at least once after start 
of study treatment at a minimum interval of 12 weeks (-1 week window).  Patients who do 
not have at least 1 post-baseline response assessment or patients whose response cannot be 
assessed will be counted as not achieving disease control.


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As an exploratory analysis, DCR will also be calculated without requiring confirmation of 
CR or PR for disease control.
DCR will be estimated for each cohort and its exact 2-sided 95% CIs will be calculated.
7.5.2.5 Duration of Response 
DOR is defined as the time from the first documentation of objective response (CR or PR 
that is subsequently confirmed) to the first documentation of PD or death due to any cause, 
whichever comes first. 
DOR data will be censored as described below:
x
Patients who do not have PD and are still on study at the time of an analysis will be 
censored at the date of last disease assessment documenting absence of PD.
x
Patients who have started a new anticancer treatment prior to documentation of PD 
will be censored at the date of last disease assessment prior to the start of new 
treatment.
x
Patients who are removed from the study prior to documentation of PD will be 
censored at the date of last disease assessment documenting absence of PD.
x
Patients who have death or PD after two or more consecutive missed/NE tumor 
assessments will be censored at the date of the last adequate tumor assessment prior 
to the missed visits.  
DOR will only be calculated for patients who achieve a confirmed CR or PR according to 
RECIST v1.1 as assessed by the investigator.
DOR will be analyzed by cohort using the Kaplan-Meier methodology and Kaplan-Meier 
plots will be provided. The median DOR and its 2-sided 95% CI will be calculated as 
appropriate. 
Sensitivity analyses may be performed for DOR to evaluate the robustness of treatment 
effects:
x
A sensitivity analysis may be performed by considering death or PD per RECIST 
v1.1 as an event regardless of missing disease assessments.
x
A second sensitivity analysis may be performed for DOR to evaluate the robustness 
of results by including investigator claim of clinical progression as an event. Patients 
who are not evaluable or have a response of SD or better per RECIST v1.1 at the 
same visit as investigator claim of clinical progression will be counted as disease 
progression (i.e., an event). The date of progression will be the date of investigator 
claim of clinical progression or PD date per RECIST v1.1, whichever is earlier. 


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7.5.2.6 Time to Response 
TTR is defined as the time from the start of study treatment to the first documentation of 
objective response (CR or PR that is subsequently confirmed).  
Patients who do not achieve objective response will have the TTR censored as described 
below: 
x
Patients with a PFS event (i.e., disease progression or death due to any cause) or who 
start a new anticancer treatment will be censored at the trial-maximum follow-up time 
(i.e., last patient last visit – first patient first visit + 1).
x
All other patients will be censored at the date of last disease assessment.
TTR will be analyzed by cohort using the Kaplan-Meier methodology and Kaplan-Meier 
plots will be provided. The median TTR and its 2-sided 95% CI will be calculated as 
appropriate.  
In addition, TTR will be summarized for patients who achieve a confirmed CR or PR.
7.5.2.7 Progression-Free Survival (PFS) 
PFS is defined as the time from the start of study treatment to the first documentation of PD 
or death due to any cause, whichever comes first. 
The same censoring rules as outlined in Section 7.5.2.5 for DOR will be applied to PFS. 
Patients who are known to have died and do not have an evaluation of tumor response after 
their first dose of study drug will be censored at Day 1.
PFS will be analyzed by cohort using the Kaplan-Meier methodology and Kaplan-Meier 
plots will be provided. The median PFS and its 2-sided 95% CI will be calculated as 
appropriate. The PFS rates at 3 and 6 months, and every 3 months thereafter, will be reported 
and their 2-sided 95% CIs will be calculated. 
Sensitivity analysis of PFS will be performed as described in Section 7.5.2.5 for DOR.
7.5.2.8 Overall Survival (OS)
OS is defined as the time from the start of study treatment to date of death due to any cause.  
In the absence of death, survival time will be censored at the last date the patient is known to 
be alive (i.e., date of last contact). Patients lacking data after their first dose of study drug 
will have their survival time censored at Day 1.
OS will be analyzed by cohort using Kaplan-Meier methodology and Kaplan-Meier plots will 
be provided. The median OS and its 2-sided 95% CI will be calculated as appropriate. The 
OS rates at 6 and 12 months, and every 6 months thereafter, will be reported and their 2-
sided 95% CIs will be calculated.


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7.6
Safety Analyses
All safety analyses will be performed by cohort and total using the safety analysis set.
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA, 
Version 19.1 or higher).
Laboratory values will be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE version 5.0 or higher).
Concomitant medications will be coded using WHO Drug (version: June 2016 or more 
recent).
7.6.1 Adverse Events
AEs will be summarized by MedDRA preferred term in descending frequency of occurrence 
unless otherwise specified. For incidence reporting, if a patient reports more than one AE that 
was coded to the same system organ class or preferred term, the patient will be counted only 
once for that specific system organ class or preferred term.
Treatment-emergent AE (TEAE) is defined as a newly occurring or worsening AE after the 
first dose of study treatment and with onset date on or before 30 days after the last dose of 
study drug. See Appendix B for details regarding treatment-emergent classification.
Summaries of AEs will be provided by cohort and total for the following:
Ɣ
TEAEs 
Ɣ
Grade 3 or higher TEAEs
Ɣ
DLTs
Ɣ
TEAEs by system organ class and preferred term
Ɣ
TEAEs by system organ class, preferred term, and maximum severity. At each system 
organ class or preferred term, multiple occurrences of events within a patient are 
counted only once at the highest severity
Ɣ
TEAEs related to tisotumab vedotin
Ɣ
TEAEs leading to dose delay 
Ɣ
TEAEs leading to dose reduction
Ɣ
TEAEs leading to dose elimination
Ɣ
TEAEs leading to unplanned dose adjustment
Ɣ
TEAEs leading to treatment discontinuation
Ɣ
TEAEs leading to death
Ɣ
Infusion related reactions 


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Ɣ
Treatment-emergent SAEs
Ɣ
Treatment-emergent SAEs by system organ class and preferred term
Ɣ
Treatment-emergent SAEs related to tisotumab vedotin
Ɣ
Treatment-emergent Adverse Events of Special Interest (AESI) by system organ class, 
preferred term and maximum severity
Ɣ
Treatment-emergent AESI 
Ɣ
Serious AESI
All TEAEs, Treatment-emergent SAEs, TEAEs leading to treatment discontinuation, TEAEs 
leading to death, and DLTs will be listed.
7.6.1.1 Adverse Events of Special Interest
Adverse events of ocular AEs, peripheral neuropathy, and bleeding are considered AESI. The 
search criteria for AESI will be maintained in a separate document and will be finalized prior 
to database lock. Shift tables comparing the highest post-baseline to baseline CTCAE grade 
will be presented when applicable.
Time to onset will be summarized for subjects who have the events that meet certain search 
criteria. Time to onset is defined as time (days) from the date of first dose to the start date of 
first event (start date of first event – date of first dose + 1). 
Time to resolution will be summarized for events that meet certain search criteria and have 
the outcome of ‘recovered/resolved’ or ‘recovered/resolved with sequelae’. Time to 
resolution is defined as time (days) from the start date of the event to the end date of the 
same event (end date of the event – start date of the event + 1). 
For events that are not resolved, improvement is defined as a decrease by at least one grade 
from the worst grade as of the latest assessment. For events that meet the definition of 
‘improvement’, time to improvement will be calculated as time from the worst grade of the 
event to the date the event is improved. 
Time to onset, resolution and improvement will be summarized by descriptive statistics 
(mean, standard deviation, median, minimum, and maximum). Time to onset will be 
summarized at the subject level. Time to resolution and improvement will be summarized at 
the event level.
7.6.1.2 Ophthalmological Exam and Eye Examination Data
The data for ophthalmological exam and eye examination at baseline and other applicable 
visits will be listed. Summary statistics of ophthalmological exam and eye examination 
results will be tabulated by visit where appropriate. Shift tables comparing the worst post-
baseline to baseline results will be presented. Summaries may include but are not limited to 


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visual acuity, Schirmer’s test, slit lamp test, conjunctivas and corneas including staining, 
intraocular pressure, and fundoscopy. 
7.6.2 Clinical Laboratory Parameters
All laboratory results up to the end of treatment visit will be presented in standardized units. 
Grading of laboratory values will be assigned programmatically per the NCI CTCAE. 
Summary statistics of selected laboratory results (complete blood count with differential, 
serum chemistry, and coagulation panel) and changes from baseline will be tabulated by 
scheduled visit. The highest post-baseline grade will be presented for each lab test. Shift 
tables comparing the highest post-baseline to baseline CTCAE grade will be presented based 
on number of subjects in safety analysis set with a baseline and at least one post-
baseline laboratory value.
In addition, clinical laboratory data may be presented graphically for selected lab tests, by 
scheduled visit. 
Laboratory values will be listed with grade per CTCAE and flagged when values are outside 
the normal reference range.
7.6.3 Deaths
The number of total deaths, deaths that occur within 30 days of last study treatment, and 
deaths that occur more than 30 days after last study treatment as well as the relationship to 
disease will be summarized. In addition, cause of death will be displayed in MedDRA 
preferred term (unless otherwise specified) and summarized. Death information will be listed 
by patient.
7.6.4 Concomitant Medications
Concomitant medications will be summarized by the World Health Organization (WHO) 
drug substance name. The number and percentage of patients taking concomitant medications 
will be tabulated for the following, but not limited to:
x
Ocular premedication and preventive eye therapy which include ocular 
vasoconstrictor eye drops, eye cooling pads, steroid eye drops, and lubricating eye 
drops 
x
Anti-coagulation therapy if applicable
x
Granulocyte-Colony Stimulating Factor (G-CSF) 
Concomitant medications will be listed by patient.
7.6.5 Other Safety Analyses
7.6.5.1 Vital Signs
Vital sign data will be listed by patient for each time point. Summary statistics of vital signs 
and change from baseline may be tabulated where appropriate.


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7.6.5.2 ECOG Performance Status
ECOG performance status will be summarized for each visit.  Shifts from baseline to the 
lowest and highest post-baseline score will be tabulated.
7.6.5.3 ECG
ECG status (normal, abnormal clinically significant, or abnormal not clinically significant) 
will be summarized by scheduled visit, and shifts from baseline will be tabulated. 
7.7
Additional Analyses
7.7.1 Pharmacokinetics
Tisotumab vedotin antibody drug conjugate (ADC), total antibody (TAb), and MMAE 
concentrations will be summarized with descriptive statistics at each PK sampling time point.  
Selected PK parameters for ADC, TAb, and MMAE will be estimated by noncompartmental 
analysis (NCA) and summarized using descriptive statistics. The PK parameters will be 
tabulated using the PK analysis set which includes enrolled patients who received any 
amount of study drug and at least one PK parameter can be estimated. Data from this study 
may be combined with PK data from other clinical trials with tisotumab vedotin for 
population PK and PK/pharmacodynamic analyses.
7.7.2 Antitherapeutic Antibody (ATA) 
The ATA incidence rate is defined as the proportion of patients who develop ATA at any 
time during the study.  The ATA incidence rate will be summarized by cohort and total using 
the safety analysis set.
7.7.3 Biomarkers
Relationships of biomarker parameters (e.g., baseline values, absolute and relative changes 
from baseline) to efficacy, safety, and pharmacokinetic parameters will be explored. 
Relationships and associated data that are determined to be of interest will be summarized. 
Details will be described separately in the Biomarker Analysis Plan. 
7.7.4 Patient Reported Outcomes Analyses
Patient reported outcomes (PRO) as measured by NCI PRO-CTCAE and PROMIS will be 
summarized over time with descriptive statistics by visit using the FAS.  For PRO-CTCAE, 
number and proportion of patients who experience a symptom with score >0 and with score 
of 3 or 4 will be summarized by symptom and visit. Shift tables comparing the highest post-
baseline score to baseline score will be presented by symptom. Missing data will be 
summarized with the proportion of patients missing responses for each question.  
The PROMIS Physical Function Scoring Manual will be used to calculate T-score and to 
impute missing data. The T-score and change from baseline will be summarized by visit. The 
number of missing questions at each visit will be summarized.


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The compliance and completion rate of NCI PRO-CTCAE and PROMIS will be summarized 
for each assessment time point. Compliance rate is defined as the proportion of patients who 
completed the instrument among those who are expected to complete at a given visit. 
Completion rate is defined as the proportion of patients who completed the instrument among 
the FAS analysis set.
8 
INTERIM ANALYSIS
A safety analysis will be conducted 28 days after all patients at the 0.9 mg/kg dose level in 
the safety run-in portion have received at least one dose of study treatment to evaluate the 
tolerability of the dose-dense regimen. If applicable, a second safety analysis will be 
conducted 28 days after all patients at the 1.2 mg/kg dose level have received at least one 
dose of study treatment. A safety monitoring committee (SMC), consisting of the 
investigators, study medical monitor, biostatistician, and drug safety representative, will 
review the safety data before proceeding to Parts A and B.
Interim analysis for futility will be performed on Part B after at least 20 patients with 1 to 3 
prior lines of therapy, including bevacizumab treatment, have been treated and had at least 
one response assessment post-baseline.
The Bayesian predictive probability approach will be used to assess the futility criteria (Lee 
2008). At the time of the interim futility analysis, the PPoS will be calculated. PPoS is the 
probability of achieving “success” should the cohort be continued to the maximum sample 
size of 60 in the target population (1 to 3 prior lines of therapy, including bevacizumab 
treatment) given the data observed at interim, and the cohort is considered “success” if the 
posterior probability that the ORR exceeds the response rate of current standard of care (i.e., 
12% as reference in Section 3.2) is greater than 70%.
Both the confirmed and unconfirmed CR or PR observed at interim will be counted as a 
response for the calculation of PPoS. It is appropriate to include the unconfirmed response 
for the purpose of interim analysis because based on the estimates from GEN701 trial, about 
60% of the responders will respond at their first post-baseline scan and approximately 75% 
of the confirmed/unconfirmed responses will eventually be confirmed. Table 1 summarizes 
the PPoS based on the number of responses observed among the first 20 patients.
Table 1:
PPoS based on responses among the first 20 patients pretreated with 
bevacizumab
No. of responses*
among the first
20 patients
PPoS
PROC bevacizumab pretreated
(p0=12%)
0
<1%
1
4%
2
20%
3
49%
4
77%
5
93%
6
99%
7
>99%


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8
>99%
9
>99%
10+
>99%
* P0 is the response rate of current standard of care of each cohort
If the PPoS is <10% (i.e., 1 or fewer responses among the first 20 patients), the interim data 
indicates that it is unlikely the ORR will be better than the response rate of current standard
of care at the end of the cohort and the cohort could be stopped early due to insufficient 
activity. On the other hand, if the PPoS is >70%, the interim data suggests that if the same 
trend continues, there is a high probability to conclude a “success” at the end of the cohort. 
The PFS, OS, and DOR will also be evaluated at the time of the interim futility analysis 
using Kaplan-Meier methodology. Based on the activity and safety data, together with the 
PPoS, the cohort may continue or be stopped early by the sponsor. A cohort or Part may also 
be discontinued at any point at the discretion of the sponsor.
The operating characteristics of the design based on 500,000 simulation runs are summarized 
in Table 2. If the true ORR is less than 5%, there is reasonable chance to reach the futility 
criterion at interim. On the other hand, if the true ORR is 20% or higher, the probability to 
stop for futility is low (<12%). 
Table 2:
Operating characteristics of predictive probability design
True ORR
Pr(Futility*)
Final Analysis (N=60)
PROC bevacizumab-pretreated
3UREV255
3UREV255
3UREV255
5%
74%
<1%
<1%
<1%
10%
39%
13%
1%
<1%
15%
18%
52%
17%
3%
20%
7%
84%
54%
20%
25%
2%
96%
84%
55%
30%
<1%
>99%
97%
84%
35%
<1%
>99%
>99%
96%
* 1 or fewer responders among the first 20 patients in the Part B bevacizumab pretreated cohort
Interim data from the study may be presented at scientific meetings such as the annual 
meetings of the American Society of Clinical Oncology and the European Society for 
Medical Oncology.
9 
CHANGES FROM PLANNED ANALYSES
9.1
Changes from the Original Protocol
Not Applicable.
9.2
Changes from the Original SAP
Update SAP version 2 to align with SGNTV-002 Protocol Amendment 4.


Study SGNTV-002 
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Page 26 of 30 
10 REFERENCES
Clopper CJ, Pearson ES (1934). The use of confidence or fiducial limits illustrated in the case of the binomial. 
Biometrika 26(4): 404-413. 
Collett D (1994). Interval-censored survival data. Modelling survival data in medical research. London, 
Chapman & Hall: 237-251. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, 
Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009). New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2): 228-47. 
Lee JJ, Liu DD (2008). A predictive probability design for phase II cancer clinical trials. Clin Trials 5(2): 93-
106. 
Rustin GJ, Vergote I, Eisenhauer E, Pujade-Lauraine E, Quinn M, Thigpen T, du Bois A, Kristensen G, 
Jakobsen A, Sagae S, Greven K, Parmar M, Friedlander M, Cervantes A, Vermorken J (2011). Definitions for 
response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the 
Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer 21(2): 419-23.
  


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Appendix A
IMPUTATION OF PARTIALLY UNKNOWN ADVERSE EVENT 
DATES
The algorithm below should be used to impute adverse event (AE) start dates for which only 
partial information is known. The algorithm should be applied to every AE record on a 
record by record basis. AE start dates should be imputed before imputation of AE condition 
end date in all cases. The AE condition end date should only be used in the imputation of the 
AE start date if it is a complete, known date.
AE day and month are missing
Ɣ
If the year is the same as the year of first dose of study treatment and the onset period 
and/or onset time indicate that the start of the AE was pre-dose: 
ż
AE start date will be imputed as the minimum of (AE condition end date*, day 
prior to first dose of study treatment) 
Ɣ
If the year is the same as the year of first dose of study treatment and the onset period 
and/or onset time indicate that the start of the AE was post-dose:
ż
AE start date will be imputed as the minimum of (AE condition end date*, first 
dose date of study treatment) 
Ɣ
If the year is before the year of first dose of study treatment:
ż
AE start date will be imputed as the minimum of (AE condition end date*, 
December 31st see example 2 below)
Ɣ
If the year is after the year of first dose of study treatment:
ż
AE start date will be imputed as the minimum of (AE condition end date*, 
January 31st see example 2 below)
AE month only is missing
Ɣ
Treat day as missing and replace both month and day according to the above 
procedure 
AE day only is missing
Ɣ
If the month/year is the same as the month/year of first dose of study treatment and 
the onset period and/or onset time indicate that the start of the AE was pre-dose: 
ż
AE start date will be imputed as the minimum of (AE condition end date*, day 
prior to first dose of study treatment) 
Ɣ
If the month/year is the same as the month/year of first dose of study treatment and 
the onset period and/or onset time indicate that the start of the AE was post-dose: 
ż
AE start date will be imputed as the minimum of (AE condition end date*, first 
dose date of study treatment) 
Ɣ
If the month/year is before the month/year of first dose of study treatment: 


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ż
AE start date will be imputed as the minimum of (AE condition end date*, last 
day of the month)
Ɣ
If the month/year is after the month/year of first dose of study treatment: 
ż
AE start date will be imputed as the minimum of (AE condition end date*, last day 
of the month)
* Only use condition end date if known and complete end date is available.
The following algorithm should be used to impute AE condition end dates. The AE records 
for a condition/event should be sorted by the imputed start dates then record position (order 
of entry into the eCRF). After sorting, if any condition end date month/year is greater than 
any subsequent record end date month/year, then change the imputed start day only to end of 
month. Repeat as necessary. 
After sorting the AE records, apply the following rules to partial or missing AE condition end 
dates:
For all records excluding the last chronological record for a condition/event
Ɣ
AE condition end date will be imputed as the start date of the subsequent record
For the last chronological record for a condition/event
Ɣ
If outcome is “recovered/resolved”, ”recovered/resolved with sequelae”, or “fatal” 
apply the following: 
ż
If only year is provided for the end date and year is equal to the year of the last 
dose date:
Ŷ
AE condition end date will be imputed as the minimum of (last dose date+30, 
death date, data extraction date, December 31st of the end date year)
ż
If only year is provided for the end date and year is not equal to the year of the 
last dose date:
Ŷ
AE condition end date will be imputed as the minimum of (death date, data 
extraction date, December 31st of the end date year)
ż
If month and year are provided for the end date:
Ŷ
AE condition end date will be imputed as the minimum of (death date, data 
extraction date, last day of the end date month/year)
Ɣ
If outcome is “recovering/resolving”, “not recovered/resolved”, “unknown”, or blank: 
ż
AE condition end date will not be imputed.


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Example 1
AESPID 1: Condition/Event HEADACHE
First dose date 01JAN2012
Prior to imputation
Start date
Condition end date
Severity
Outcome
Onset
UNUNK2011
15APR2012
1
not recovered/resolved
pre-ICF
15APR2012
UNMAY2012
2
recovering/resolving
post 1st dose
UNMAY2012
UNJUN2012
1
not recovered/resolved
post 1st dose
UNJUN2012
UNJUN2012
3
recovering/resolving
post 1st dose
UNJUN2012
10JUL2012
2
recovering/resolving
post 1st dose
10JUL2012
--
1
not recovered/resolved
post 1st dose
Post imputation
Start date
Condition end date
Severity
Outcome
31DEC2011
15APR2012
1
not recovered/resolved
15APR2012
31MAY2012
2
recovering/resolving
31MAY2012
30JUN2012
1
not recovered/resolved
30JUN2012
30JUN2012
3
recovering/resolving
30JUN2012
10JUL2012
2
recovering/resolving
10JUL2012
--
1
not recovered/resolved
Example 2 (highlights choice of last day of the month as opposed to the 1st or the 15th)
AESPID 4: Condition/Event NAUSEA
First dose date 01APR2012
Prior to imputation
Start date
Condition end date
Severity
Outcome
Onset
UNUNK2011
25APR2012
1
not recovered/resolved
pre-ICF
25APR2012
UNAPR2012
2
recovering/resolving
post 1st dose
UNAPR2012
04MAY2012
1
recovered/resolved
post 1st dose
Post imputation
Start date
Condition end date
Severity
Outcome
31DEC2011
25APR2012
1
not recovered/resolved
25APR2012
31APR2012
2
recovering/resolving
31APR2012
04MAY2012
1
recovered/resolved


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Appendix B
IMPUTATION OF PARTIALLY MISSING SUBSEQUENT 
ANTICANCER THERAPY START DATE
The algorithm below should be used to impute subsequent anticancer therapy start dates for 
which only day is missing.
x
If the month and year of the start date of subsequent anticancer therapy are the same 
as the month and year of a response assessment date, and 
o
If the response is a PD, subsequent anticancer therapy start date will be 
imputed as the response assessment date or the day after the last study 
treatment, whichever is later.
o
If the response is not a PD, subsequent anticancer therapy start date will be 
imputed as the first day of the month or the day after the last study treatment, 
whichever is later.
x
Else if the month and year of the start date of subsequent anticancer therapy are the 
same as the month and year of the end date of last study treatment, subsequent 
anticancer therapy start date will be imputed as the day after the last study treatment 
end date.
x
Else if the start date of subsequent anticancer therapy is later than the end date of last 
study treatment based on available month and year, subsequent anticancer therapy 
start date will be imputed as the first day of the month.