Conditions: Ovary Cancer Cervix Cancer Endometrium Cancer Bladder Cancer Prostate Cancer (CRPC) Esophagus Cancer Lung Cancer (NSCLC)
Keywords: ovary cancer cervix cancer endometrium cancer bladder cancer prostate cancer (CRPC) esophagus cancer lung cancer (NSCLC)
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 33
Healthy volunteers: no

Brief summary:
The purpose of the trial is to establish the tolerability of tisotumab vedotin (HuMax-TF-ADC) dosed three times every four weeks (3q4wk) in a mixed population of patients with specified solid tumors.

Detailed description:
The study is conducted in two parts. In the Dose Escalation portion of the trial, subjects are enrolled into cohorts at increasing dose levels of tisotumab vedotin (HuMax-TF-ADC) in 28 day treatment cycles.

The Cohort Expansion portion of the trial will further explore the recommended phase 2 dose of tisotumab vedotin (HuMax-TF-ADC) as determined in Part 1.

Arms:
arm 1: None

Interventions: intervention 1: Tisotumab vedotin (HuMax-TF-ADC)
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 




Protocol No.GEN702
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
Page 3 of 126 
Coordinating Investigator 
I have read and agree to the protocol GEN702, entitled “Dose-escalating and cohort expansion 
safety trial of tissue factor specific antibody drug conjugate tisotumab vedotin 
(HuMax®-TF-ADC) in patients with locally advanced and/or metastatic solid tumors known 
to express tissue factor”, Final 5.0 (Incorporating Amendment 4), 06 July 2017. I am aware of 
my responsibilities as an Investigator under the guidelines of GCP, local regulations (as 
applicable) and the trial protocol. I agree to conduct the trial according to these responsibilities 
and to appropriately direct and assist the staff under my control, who will be involved in the 
trial. 
Coordinating Investigator Signature: 
Name 
Title 
Royal Marsden Hospital/United Kingdom 


Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
Page 4 of 126 
1 
SYNOPSIS 
NAME OF SPONSOR: Genmab A/S 
PROTOCOL No.: GEN702 
NAME OF TRIAL TREATMENT: Tisotumab vedotin (HuMax®-TF-ADC) 
TITLE OF TRIAL: Dose-escalating and cohort expansion safety trial of tissue factor specific antibody drug 
conjugate tisotumab vedotin (HuMax®-TF-ADC) in patients with locally advanced and/or metastatic solid 
tumors known to express tissue factor  
TRIAL CENTERS: The Dose Escalation part of the trial is planned to be performed in a maximum of three 
sites in Denmark, the United Kingdom (UK) and the United States of America (USA). The Cohort Expansion 
part of the trial is planned to be performed in the ongoing countries and in Hungary and potentially Belgium. 
TRIAL PERIOD: A Dose Escalation part will be followed by a Cohort 
Expansion part. The trial will be stopped when the last patient included in the 
Cohort Expansion part completes the trial or when the last ongoing patient 
has discontinued treatment and attended the Safety follow-up Visit, 
whichever occurs first.  
PHASE OF 
DEVELOPMENT:  
Dose Escalation part: 
Phase I 
Cohort Expansion part: 
Phase II 
PLANNED TRIAL DATES: Enrollment period is planned to last approximately 21 months. 
OBJECTIVES:  
Primary Trial Objective: To establish the tolerability of HuMax® tissue factor antibody drug conjugate 
tisotumab vedotin [HuMax-TF-ADC]) dosed three times every four weeks (3q4wk) in a mixed population 
of patients with specified solid tumors. 
Secondary Trial Objective(s): 
• To determine the maximum tolerated dose (MTD) and the recommended dose for phase II trials (RP2D)
with tisotumab vedotin (HuMax-TF-ADC) dosed 3q4wk.
• To establish the pharmacokinetic (PK) profile of tisotumab vedotin (HuMax-TF-ADC) dosed 3q4wk.
• To evaluate the anti-tumor activity of tisotumab vedotin (HuMax-TF-ADC) dosed 3q4wk in a mixed
population of patients with specified solid tumors.
TRIAL DESIGN AND METHODOLOGY: 
The trial is a safety trial of HuMax-TF-ADC dosed 3q4wk (Days 1, 8 and 15 of each 28-day cycle) in a mixed 
population of patients with solid tumors known to express tissue factor (TF) and where the use of systemically 
administered tubulin inhibitors is part of standard of care (SoC). The trial consists of two parts, an open-label, 
multicenter, phase I, Dose Escalation part, followed by an open-label phase II Cohort Expansion part.  
The Dose Escalation part is a standard 3 (+3) design. In each dose cohort, the initial three patients must 
include at least two different cancer types. A maximum of three dose levels is anticipated. Patients may 
receive up to 12 cycles of treatment. 
The Cohort Expansion part will have a parallel group design, with a minimum of 20 and a maximum of 
30 patients in two or three indication arms. Patients in the Cohort Expansion part will be treated with the 
RP2D from the Dose Escalation part. Patients may receive up to nine cycles of treatment.  
A Data Monitoring Committee (DMC) will evaluate safety data during the Dose Escalation part of the trial 
and will convene in the event of safety signals in the Cohort Expansion part of the trial.  
Severe ocular toxicity has been observed at 1.2 mg/kg 3q4wk (the RP2D for the Cohort Expansion part), and 
an urgent safety Protocol Amendment 4.0 has been implemented.  Patients will not further receive the dosing 
schedule 3q4wk; instead tisotumab vedotin 2.0 mg/kg will be administered once every three weeks (q3wk). 
TRIAL POPULATION AND MAIN CRITERIA FOR INCLUSION/EXCLUSION: 
The patient population in the Dose Escalation part will encompass patients with advanced (locally advanced 
and/or metastatic) cancer of the ovary, cervix, endometrium, bladder, prostate (castration-resistant prostate 
cancer [CRPC]), esophagus or lung (non-small cell lung cancer [NSCLC]) who have failed available standard 


Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
Page 5 of 126 
treatments or who are not candidates for standard therapy. The specific indications for the Cohort Expansion 
part will be decided once the RP2D has been determined from the Dose Escalation part.  
Patients cannot be enrolled before all inclusion criteria (including test results) are confirmed. 
Inclusion Criteria: 
•
For the Dose Escalation part: Patients with relapsed, advanced and/or metastatic cancer of the ovary,
cervix, endometrium, bladder, prostate, esophagus, or NSCLC who have failed available standard
treatments or who are not candidates for standard therapy.
•
For the Cohort Expansion part: The specific indications for the Cohort Expansion part will be decided
once the RP2D has been determined. After implementation of the urgent safety measure (Protocol
Amendment 4), no patients will further receive the 3q4wk schedule; instead, tisotumab vedotin
(HuMax-TF-ADC) 2.0 mg/kg will be administered once q3wk.
•
Patients with relapsed, advanced and/or metastatic cancer of the ovary, cervix, endometrium, bladder,
prostate, esophagus, or NSCLC who have failed the following anti-cancer therapy:
o
Bladder cancer (including urothelial carcinomas [transitional cell carcinomas] regardless of the
initial site of origin of the tumor: renal pelvis, ureter or bladder lumen): failing platinum-based
therapy. Patients must have received no more than three prior treatment regimens for advanced
disease.
o
CRPC: failing docetaxel and either abiraterone OR enzalutamide. Patients must have received
no more than two prior chemotherapy-based regimens and a maximum of six prior treatment
regimens for advanced disease.
o
Ovarian cancer: resistant to at least one platinum-based therapy and after failing at least one
line of taxane-containing therapy (isolated CA 125 progression does NOT qualify for trial
entry). Patients with primary platinum refractory disease are excluded. Patients must have
received no more than five prior treatment regimens for advanced disease.
o
Cervical cancer: failing a platinum-based regimen. Patients must have received no more than
four prior treatment regimens for advanced disease.
o
Endometrial cancer: failing platinum-based therapy. Patients must have received no more than
four prior treatment regimens for advanced disease (excluding adjuvant chemotherapy).
o
Esophageal cancer (esophageal cancer or gastro-esophageal junction cancer): failing
platinum-based therapy with or without taxanes depending on established SoC therapy. Patients
must have received no more than three prior treatment regimens for advanced disease.
o
NSCLC: failing at least one platinum-based regimen. Patients with epidermal growth factor
receptor (EGFR) or anaplastic lymphoma kinase mutations should have been treated with
appropriate targeted therapy before trial entry. Patients must have received no more than four
(five allowed for patients with EGFR mutated adenocarcinomas) prior treatment regimens for
advanced disease.
•
Patients must have measurable disease according to RECIST (Response Evaluation Criteria In Solid
Tumors) version 1.1.
o
A minimum of 1 lesion ≥ 10 mm in the longest diameter from a non-irradiated area;

Lymph nodes lesion ≥ 15 mm in the shortest diameter from a non-irradiated area.
o
Patients with prostate cancer must be clinically refractory and resistant to hormone therapy as
documented by progression (CRPC) and can be included based on prostate specific antigen
(PSA) and/or bone metastases according to the Prostate Cancer Working Group Guideline.
o
Patients with ovarian cancer can be included based on CA 125 positivity according to the
Gynaecologic Cancer Intergroup Guideline. This is only applicable for the Dose Escalation part
of the trial.
•
Age ≥ 18 years.
•
Acceptable renal function: glomerular filtration rate (Cockroft-Gault) > 45 mL/ min.


Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
Page 6 of 126 
•
Acceptable liver function defined as: alanine aminotransferase (ALT) and aspartate aminotransferase
(AST) ≤ 3 times the upper limit of normal (ULN) (if liver tumor/ metastases are present, then ≤ 5 × ULN
is allowed); bilirubin ≤ 1.5 × ULN, except in patients diagnosed with Gilbert’s syndrome, direct bilirubin
≤ 2 × ULN.
•
Acceptable hematological status (hematologic support is allowed if administered at least one week
before Cycle 1 Day 1) defined as: hemoglobin ≥ 5.6 mmol/L (~ 9 g/dL), absolute neutrophil count (ANC)
≥ 1500/µL (1.5× 109/L); platelet count ≥ 100 ×109/L.
•
Acceptable coagulation status defined as: international normalized ratio (INR) ≤ 1.2 (without
anticoagulant therapy), and activated partial thromboplastin time (aPTT) ≤ ULN.
•
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
•
Life expectancy of at least three months.
•
A negative serum pregnancy test (if female and aged between 18-55 years old). Women who are
pregnant or breast feeding are not to be included.
•
Patients, both females and males, of reproductive potential must agree to use adequate contraception
during and for six months after the last infusion of tisotumab vedotin (HuMax-TF-ADC).
o
Adequate contraception for women is defined as hormonal birth control or an intrauterine
device. In countries where two highly effective methods of contraception are required this will
be an inclusion criterion.
o
Male patients must be willing to use a latex condom during any sexual contact with females of
childbearing potential during and for six months after the last infusion of tisotumab vedotin
(HuMax-TF-ADC), even after having undergone a successful vasectomy. It is recommended
that fertile males consider having semen specimen obtained for storage for potential future
conception.
•
Following receipt of verbal and written information about the trial, patients must provide signed
informed consent before any trial-related activity is carried out.
Key Exclusion Criteria: 
•
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 two months of trial entry.
•
Cardiovascular: clinically significant cardiac disease (including unstable angina, acute myocardial
infarction within six months of the Screening Visit, known congestive heart failure [Grade III or IV as
classified by the New York Heart Association], and/or a known decreased cardiac ejection fraction of
< 45%); a baseline QT interval as corrected by Fridericia’s formula (QTcF) > 450 msec, a complete left
bundle branch block (defined as a QRS interval ≥ 120 msec in left bundle branch block form) or an
incomplete left bundle branch block.
•
Excluded medications or treatment regimens: therapeutic anti-coagulative or long-term anti-platelet
treatment (use of low dose acetylsalicylic acid [ASA] up to 81 mg/day and non-ASA nonsteroidal
anti-inflammatory drugs [NSAIDs] is allowed); have received granulocyte colony stimulating factor
(G-CSF) or granulocyte/macrophage colony stimulating factor support within one week before the
Screening Visit, or pegylated G-CSF within two weeks before the Screening Visit, or blood transfusion
and/or erythropoietin within one week before first dose; have received a cumulative dose of
corticosteroid ≥ 150 mg (prednisone or equivalent doses of corticosteroids) within two weeks before the
first infusion; no dietary supplements allowed during the trial period, except multivitamins, vitamin D
and calcium.
•
Surgery/procedures: major surgery within six weeks or open biopsy within 14 days before drug infusion;
plan for any major surgery during treatment period; patients not willing or able to have a pre-trial tumor
biopsy taken (the screening biopsy can be omitted if archived material is available); presence or
anticipated requirement of epidural catheter in relation to infusions (within 48 hours before and after
dose of trial drug).


Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
Page 7 of 126 
•
Central nervous system: any history of intracerebral arteriovenous malformation, cerebral aneurysm,
brain metastases or stroke (transient ischemic attack > 1 month prior to screening is allowed).
•
Prior therapy: any anti-cancer therapy including small molecules, immunotherapy, chemotherapy
monoclonal antibodies or any other experimental drug within four weeks or five half-lives, whichever is
longest, before first infusion; prior treatment with bevacizumab within 12 weeks before the first infusion
(for anti-cancer therapies with half-lives > 8 days, a washout period of at least 28 days is acceptable);
any prior therapy with a conjugated or unconjugated auristatin derivative; radiotherapy within 28 days
prior to first dose; patients who have not recovered from symptomatic side effects of radiotherapy or
symptoms of autoimmune toxicities related to previous treatment with check-point inhibitors at the time
of initiation of screening procedure.
•
Other cancer/metastases: known past or current malignancy other than inclusion diagnosis (except for:
cervical carcinoma of Stage 1B or less; non-invasive basal cell or squamous cell skin carcinoma;
non-invasive, superficial bladder cancer; prostate cancer with a current PSA level < 0.1 ng/mL; breast
cancer in BRCA1 or BRCA2 positive ovarian cancer patients; or any curable cancer with a complete
response (CR) of > 5 years duration); radiographic evidence of cavitating pulmonary lesions; tumor
invading any large blood vessel, unless approved by the sponsor Medical Officer.
•
Other: ongoing, significant, uncontrolled medical condition; presence of CTCAE (Common
Terminology Criteria for Adverse Events) grade ≥ 2 peripheral neuropathy; clinically significant active
viral, bacterial or fungal infection requiring intravenous treatment with antimicrobial therapy starting
less than four weeks prior to first dose or oral treatment with antimicrobial therapy starting less than
10 days prior to first dose; known human immunodeficiency virus seropositivity; positive serology
(unless due to vaccination or passive immunization due to Ig therapy) for hepatitis B defined by positive
test for hepatitis B surface antigen (HBsAg) and/or positive test for antibodies to hepatitis B surface and
core antigens (anti-HBs and anti-HBc); positive serology for hepatitis C based on test at screening;
inflammatory bowel disease including Crohn’s disease and colitis ulcerosa; inflammatory lung disease
including moderate and severe asthma and chronic obstructive pulmonary disease (COPD) requiring
chronic medical therapy; ongoing acute or chronic inflammatory skin disease.
•
Ophthalmological: active ocular surface disease at baseline (based on ophthalmological evaluation);
history of cicatricial conjunctivitis (as evaluated by an ophthalmologist).
NUMBER OF PATIENTS: Approximately 46 to 63 patients will be screened to ensure that 32 to 44 patients 
(anticipated screen failure rate of 30%) complete the trial.  
In the Dose Escalation part: 12 to 24 patients are planned to be enrolled: three to six patients per dose level 
for three dose levels (plus a potential intermediate dose cohort). 
In the Cohort Expansion part: 20 to 30 patients are planned to be enrolled in two or three indication arms. 
TRIAL TREATMENT(S): Tisotumab vedotin (HuMax-TF-ADC) will be administered as an intravenous 
infusion over a minimum of 30 minutes on Days 1, 8 and 15 of each cycle (one treatment cycle is 28 days). 
Each patient’s dose will be calculated based on the patient’s weight rounded to the nearest kilogram. 
Preventive eye therapy should be administered in relation to infusions.   
The Dose Escalation part will evaluate tisotumab vedotin (HuMax-TF-ADC) at doses of 0.9 mg/kg and up 
(1.2 and 1.5 mg/kg). The maximum tested dose will be 1.5 mg/kg. Decisions to escalate the dose of tisotumab 
vedotin (HuMax-TF-ADC) for the next cohort will be based on the safety data obtained from the 3 (+3) 
patients during their first treatment cycle (28 days). A DMC will evaluate all safety data (including serious 
adverse events [SAEs], adverse events [AEs] and laboratory data) after each cohort completes Cycle 1.  
Patients in the Cohort Expansion part will be treated with the RP2D from the Dose Escalation part. Reduced 
dose can be administered in accordance with the mitigation strategies or at the discretion of the treating 
physician based on individual patient observed toxicity profile and quality of life evaluation, and after 
consultation and agreement by the sponsor Medical Officer. 
Severe ocular toxicity has been observed at 1.2 mg/kg 3q4wk. Patients will no longer receive the 3q4wk 
schedule; instead tisotumab vedotin (HuMax-TF-ADC) 2.0 mg/kg will be administered once q3wk, on Day 1 
of each 21-day cycle. 


Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
Page 8 of 126 
DURATION OF TREATMENT: In the Dose Escalation part the patients will be treated for four cycles or 
until unacceptable toxicity. After four cycles, if there is evidence of the patient benefiting from treatment, at 
the discretion of the treating physician on the patient status, there is an option to continue in the trial for up 
to a maximum of eight additional cycles (32 weeks) or until the patient withdraws from the treatment/trial 
due to the withdrawal criteria. The treatment period will have a maximum duration of 48 weeks. 
In the Cohort Expansion part patients will be treated similarly but up to a maximum of nine cycles (36 weeks, 
or less after changing to the once q3wk dosing scheme)) or until unacceptable toxicity or disease progression, 
at the discretion of the treating physician. 
At the end of the planned number of cycles, Genmab will ensure provision of continued treatment to patients 
with clinical benefit defined as stable disease (SD) or better, until unacceptable toxicity or Progressive 
Disease (PD) is observed. 
TRIAL EVALUATIONS: 
Primary Endpoint:  
•
AEs during the trial: incidences of AEs, SAEs, infusion-related AEs, CTCAE grade ≥ 3 AEs and AEs
related to trial drug
Secondary Endpoints: 
•
Safety laboratory parameters (hematology, biochemistry, coagulation factors and flow cytometry)
•
Skin disorders
•
Bleeding events
•
Neuropathy
•
PK parameters (clearance, volume of distribution and area-under-the-concentration-time curve
[AUC0-Clast and AUC0-∞]), maximum concentration [Cmax], time of Cmax [Tmax], pre-dose values, and
half-life of tisotumab vedotin (HuMax-TF-ADC) and free toxin [monomethyl auristatin E, MMAE])
•
Immunogenicity of tisotumab vedotin (HuMax-TF-ADC) (human anti human antibodies)
•
Anti-tumor activity measured by tumor shrinkage (based on computerized tomography [CT] scan
evaluations), change in PSA and CA 125
•
Objective Response (CR or Partial Response [PR]), Disease Control (CR, PR or SD), Progression-Free
Survival (PFS) and Duration of Response (DoR)
Research Endpoints: 
•
TF expression in tumor biopsies
•
Circulating TF
•
Circulating cell-free deoxyribonucleic acid (cfDNA)
STATISTICAL METHODS: No formal statistical tests will be performed; descriptive statistics will be 
presented. Two-sided 95% confidence intervals will also be calculated. All data will be listed. 
The full analysis population will comprise all patients who have been exposed to trial drug and will be used 
for evaluation of all endpoints. 
Further details will be given in a separate Statistical Analysis Plan. 
DATE AND VERSION:  Version 5.0 (incorporating Protocol Amendment 4) 06 July 2017 


Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
Page 9 of 126 
2 
TABLE OF CONTENTS 
1 
SYNOPSIS .................................................................................................................. 4 
2 
TABLE OF CONTENTS .......................................................................................... 9 
3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS......................... 16 
4 
ETHICS .................................................................................................................... 19 
4.1 
Ethics Committee ...................................................................................................... 19 
4.2 
Ethical Conduct of the Trial ...................................................................................... 19 
4.3 
Patient Information and Consent ............................................................................... 19 
5 
INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE ............ 20 
6 
INTRODUCTION 
 22 


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
 
Page 10 of 126 
7 
TRIAL OBJECTIVES AND ENDPOINTS .......................................................... 41 
7.1 
Trial Objectives ......................................................................................................... 41 
7.1.1 
Primary Trial Objective ............................................................................................. 41 
7.1.2 
Secondary Trial Objectives ....................................................................................... 41 
7.2 
Trial Endpoints .......................................................................................................... 41 
7.2.1 
Primary Endpoint ....................................................................................................... 41 
7.2.2 
Secondary Endpoints ................................................................................................. 41 
7.2.3 
Research Endpoints ................................................................................................... 42 
8 
INVESTIGATIONAL PLAN ................................................................................. 43 
8.1 
Overall Trial Design and Plan ................................................................................... 43 
8.1.1 
Trial Overview ........................................................................................................... 45 
8.1.1.1 
Screening Phase (Visit 0) .......................................................................................... 56 
8.1.1.2 
Treatment Phase (C1 to CX) ..................................................................................... 56 
8.1.1.3 
Unscheduled Visit (U1 to UX) .................................................................................. 57 
8.1.1.4 
Follow-up Phase ........................................................................................................ 57 
8.1.1.5 
End of Trial Visit (EOT) ........................................................................................... 57 
8.1.1.6 
Safety Follow-up Visit............................................................................................... 57 
8.2 
Trial Duration and End of Trial ................................................................................. 58 
8.2.1 
Trial Stopping Criteria ............................................................................................... 58 
8.3 
Trial Population ......................................................................................................... 59 
8.3.1 
Inclusion Criteria ....................................................................................................... 59 
8.3.2 
Exclusion Criteria ...................................................................................................... 62 
8.3.3 
Patient Allocation Procedure ..................................................................................... 65 
8.3.4 
Withdrawal and Replacement of Patients .................................................................. 65 
8.3.4.1 
Criteria for Patient Withdrawal from Treatment ....................................................... 65 
8.3.4.2 
Criteria for Patient Withdrawal from the Trial .......................................................... 66 
8.3.4.3 
Evaluations at Withdrawal from Treatment .............................................................. 66 
8.3.4.4 
Evaluations at Withdrawal from the Trial ................................................................. 66 
8.3.4.5 
Replacement of Patients ............................................................................................ 67 
8.4 
Treatment ................................................................................................................... 67 
8.4.1 
Treatments Administered .......................................................................................... 67 
8.4.2 
Trial Treatment Preparation ....................................................................................... 68 
8.4.3 
Trial Treatment Storage and Accountability ............................................................. 68 
8.4.3.1 
Trial Treatment Storage ............................................................................................. 68 
8.4.3.2 
Trial Treatment Accountability ................................................................................. 68 


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
 
 
Page 11 of 126 
8.4.4 
Treatment of Infusion-Related Reactions .................................................................. 69 
8.4.5 
Dose Modification and Mitigation Plans ................................................................... 69 
8.4.5.1 
Dose Modification and Mitigation Plan for Skin Toxicity ........................................ 69 
8.4.5.2 
Dose Modification for Peripheral Neuropathy and Neutropenia ............................... 70 
8.4.5.3 
Dose Modifications and Mitigation Plan for Ocular Adverse Events ....................... 70 
8.4.5.4 
Dose Modification for QTcF Changes in the Electrocardiogram .............................. 74 
8.4.5.5 
Dose Modification for Increased Liver Enzymes ...................................................... 75 
8.4.5.6 
Dose Modification for Mucositis ............................................................................... 75 
8.4.6 
Precautions ................................................................................................................ 75 
8.4.7 
Dose Escalation ......................................................................................................... 75 
8.4.7.1 
Dose Escalation Overview......................................................................................... 75 
8.4.7.2 
Dose Escalation Rules ............................................................................................... 76 
8.4.8 
Dose Limiting Toxicities for the Dose Escalation Part of the Trial .......................... 77 
8.4.9 
Prior and Concomitant Therapy ................................................................................ 78 
8.4.9.1 
Prior Therapy ............................................................................................................. 78 
8.4.9.2 
Permitted Concomitant Medications ......................................................................... 78 
8.4.9.3 
Excluded Concomitant Medications .......................................................................... 78 
8.4.9.4 
Treatment Compliance .............................................................................................. 79 
8.4.9.5 
Assignment to Treatment........................................................................................... 79 
9 
TRIAL EVALUATIONS ........................................................................................ 80 
9.1 
Dose Escalation Part .................................................................................................. 80 
9.1.1 
Dose Escalation Part: Screening (Visit 0) ................................................................. 80 
9.1.2 
Dose Escalation Part: Treatment ............................................................................... 80 
9.1.2.1 
Dose Escalation Part: Cycle 1 ................................................................................... 81 
9.1.2.2 
Dose Escalation Part: Cycles 2 to 4 ........................................................................... 81 
9.1.2.3 
Dose Escalation Part: Cycles 5 to 12 ......................................................................... 81 
9.1.3 
Dose Escalation Part: Follow-up Visits (FU1 to FU4) .............................................. 81 
9.1.4 
Dose Escalation Part: Unscheduled Visit (U1 to UX) ............................................... 81 
9.1.5 
Dose Escalation Part: End of Trial Visit (EOT) ........................................................ 82 
9.1.6 
Dose Escalation Part: Safety Follow-up Visit ........................................................... 82 
9.2 
Cohort Expansion Part ............................................................................................... 82 
9.2.1 
Cohort Expansion Part: Screening (Visit 0) .............................................................. 82 
9.2.2 
Cohort Expansion Part: Treatment ............................................................................ 82 
9.2.2.1 
Cohort Expansion Part: Cycle 1 ................................................................................ 82 
9.2.2.2 
Cohort Expansion Part: Cycles 2 to 9 ........................................................................ 82 
9.2.2.3 
Cohort Expansion Part: Cycles 1 to 9 According to Protocol Amendment 4.0 ......... 83 
9.2.3 
Cohort Expansion Part: Unscheduled Visit (U1 to UX) ............................................ 83 


Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
Page 12 of 126 
9.2.4 
Cohort Expansion Part: End of Trial Visit (EOT) ..................................................... 83 
9.2.5 
Cohort Expansion Part: Safety Follow-up Visit ........................................................ 83 
10 
METHODS OF ASSESSMENT ............................................................................. 84 
10.1 
Demographics ............................................................................................................ 84 
10.2 
Medical History ......................................................................................................... 84 
10.3 
Height and Weight ..................................................................................................... 84 
10.4 
Physical Examination ................................................................................................ 84 
10.5 
Vital Signs ................................................................................................................. 84 
10.6 
Electrocardiogram ..................................................................................................... 85 
10.7 
Computerized Tomography ....................................................................................... 85 
10.8 
ECOG Performance Status ........................................................................................ 86 
10.9 
Adverse Events .......................................................................................................... 86 
10.10 
Concomitant Medication ........................................................................................... 86 
10.11 
Bleeding Assessments ............................................................................................... 87 
10.12 
Skin Assessments ...................................................................................................... 87 
10.13 
Neuropathy Assessment ............................................................................................ 88 
10.14 
Ophthalmological Evaluation .................................................................................... 88 
10.15 
Radionuclide Bone Scan ............................................................................................ 88 
10.16 
Laboratory Assessments ............................................................................................ 88 
10.16.1 
Hematology ............................................................................................................... 89 
10.16.2 
Biochemistry .............................................................................................................. 89 
10.16.3 
Coagulation Factors ................................................................................................... 89 
10.16.4 
PSA and CA 125 ....................................................................................................... 89 
10.16.5 
Flow Cytometry ......................................................................................................... 90 
10.16.6 
Pregnancy Test .......................................................................................................... 90 
10.16.7 
Immunogenicity of Tisotumab Vedotin (HuMax-TF-ADC) ..................................... 90 
10.16.8 
Hepatitis B, C, HPV and Cytomegalovirus Serology ................................................ 90 
10.17 
Pharmacokinetic Assessments ................................................................................... 91 
10.18 
Tumor Biopsy ............................................................................................................ 91 
10.19 
Biomarkers ................................................................................................................ 91 
10.19.1 
Circulating TF ........................................................................................................... 91 
10.19.2 
Circulating cfDNA .................................................................................................... 91 
11 
ASSESSMENT AND REPORTING OF ADVERSE EVENTS .......................... 92 
11.1 
Adverse Events Characterization ............................................................................... 92 
11.1.1 
Definition of Adverse Events .................................................................................... 92 
11.1.2 
Definition of Infusion-Related Reaction ................................................................... 92 
11.1.3 
Trial Disease .............................................................................................................. 92 


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
 
 
Page 13 of 126 
11.1.3.1 
Pre-existing Conditions ............................................................................................. 93 
11.1.4 
Procedures ................................................................................................................. 93 
11.2 
Adverse Event Reporting........................................................................................... 93 
11.3 
Recording Instructions ............................................................................................... 93 
11.3.1 
Diagnosis ................................................................................................................... 93 
11.3.2 
Intensity ..................................................................................................................... 93 
11.3.3 
Time of onset ............................................................................................................. 93 
11.3.4 
Relationship to Trial Drug ......................................................................................... 94 
11.3.5 
Outcome .................................................................................................................... 94 
11.4 
Serious Adverse Events ............................................................................................. 94 
11.4.1 
Definition of Serious Adverse Events ....................................................................... 94 
11.4.2 
Events Requiring Immediate Reporting .................................................................... 95 
11.4.2.1 
Serious Adverse Events, Non-serious Grade 3 Adverse Events, and Non-serious 
Grade 2 Ocular Adverse Events ................................................................................ 95 
11.4.2.2 
Overdose and Medication Errors ............................................................................... 95 
11.4.2.3 
Pregnancy .................................................................................................................. 95 
11.4.3 
Reporting of Serious Adverse Events, Grade 3 Adverse Events, Grade 2 Ocular 
Adverse Events, and Pregnancies .............................................................................. 96 
11.4.4 
Suspected Unexpected Serious Adverse Reactions ................................................... 97 
11.5 
Follow-up on Adverse Events ................................................................................... 97 
11.6 
Safety Communication Plan for Information to Site ................................................. 97 
11.7 
Review or Safety Boards ........................................................................................... 98 
12 
STATISTICAL ANALYSIS ................................................................................. 100 
12.1 
Statistical Analysis Plan .......................................................................................... 100 
12.2 
Analysis Populations ............................................................................................... 100 
12.3 
Statistical Methods .................................................................................................. 100 
12.3.1 
Summary Statistics .................................................................................................. 100 
12.4 
Statistical Analysis of Primary Endpoint ................................................................. 101 
12.5 
Statistical Analysis of Secondary Endpoints ........................................................... 101 
12.5.1 
Clinical Safety Data ................................................................................................. 101 
12.5.2 
Laboratory Safety Data ............................................................................................ 101 
12.5.3 
Response .................................................................................................................. 101 
12.5.3.1 
Definition of Response ............................................................................................ 102 
12.5.3.2 
Response Evaluation and Reporting of Results ....................................................... 103 
12.5.3.3 
Progression-free Survival ........................................................................................ 104 
12.5.3.4 
Duration of Response .............................................................................................. 104 
12.5.3.5 
Patients without Disease Progression after Four Cycles ......................................... 104 
12.5.4 
Changes in Biomarkers, Including PSA and CA 125 .............................................. 104 


Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
Page 14 of 126 
12.5.5 
Host Immune Response ........................................................................................... 104 
12.5.6 
Statistical Analysis of Pharmacokinetics Data ........................................................ 104 
12.6 
Handling of Missing Data or Outliers ..................................................................... 105 
12.7 
Subgroups and Center Effects ................................................................................. 105 
12.8 
Interim Analyses ...................................................................................................... 105 
12.9 
Sample Size Estimation ........................................................................................... 105 
12.10 
Clinical Trial Reporting ........................................................................................... 105 
13 
MONITORING PROCEDURES/QUALITY ASSURANCE ............................ 106 
13.1 
Data Collection ........................................................................................................ 106 
13.2 
Data Management .................................................................................................... 106 
13.3 
Trial Monitoring ...................................................................................................... 107 
13.4 
Inspections and Auditing Procedures ...................................................................... 108 
14 
TRIAL MANAGEMENT AND MATERIALS................................................... 109 
14.1 
Data Collection ........................................................................................................ 109 
14.2 
Source Documents Maintenance ............................................................................. 109 
14.3 
Record Maintenance ................................................................................................ 110 
14.4 
Confidentiality ......................................................................................................... 110 
15 
ADMINISTRATION PROCEDURES ................................................................ 111 
15.1 
Regulatory Approval ............................................................................................... 111 
15.2 
Protocol Amendments ............................................................................................. 111 
15.3 
Protocol Adherence and Deviations ........................................................................ 111 
15.4 
Publication Policy .................................................................................................... 112 
15.5 
Contractual and Financial Details ............................................................................ 112 
15.6 
Insurance, Indemnity and Compensation ................................................................ 112 
15.7 
Termination of the Trial .......................................................................................... 112 
15.8 
Investigator Trial File Management ........................................................................ 113 
16 
REFERENCE LIST .............................................................................................. 114 
17 
APPENDICES ........................................................................................................ 118 
17.1 
Appendix 1: ECOG Performance Status Scale ........................................................ 118 
17.2 
Appendix 2: Highly Effective Methods of Contraception ....................................... 119 
17.3 
Appendix 3: Declaration of Helsinki ....................................................................... 121 
LIST OF TABLES 
Table 1: 
Trial Flow Chart-Dose Escalation Part ...................................................................... 46 
Table 2: 
PK Sampling- Dose Escalation Part .......................................................................... 49 
Table 3: 
Trial Flow Chart – Cohort Expansion Part - SUPERSEDED .................................... 50 
Table 4: 
PK Sampling - Cohort Expansion Part - SUPERSEDED .......................................... 52 




Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
Page 16 of 126 
3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Term 
Definition 
3q4wk 
Three times every four weeks 
ADA 
Anti-drug antibody 
ADC 
Antibody drug conjugate 
AE 
Adverse event  
ALT 
Alanine aminotransferase  
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
ASA 
Acetylsalicylic acid  
AST 
Aspartate aminotransferase  
AUC 
Area-under-the-concentration-time curve 
BMI 
Body mass index 
BSA 
Body surface area 
cfDNA 
Cell-free deoxyribonucleic acid 
CFR 
Code of Federal Regulations 
Cmax 
Maximum concentration  
CMV 
Cytomegalovirus 
COPD 
Chronic obstructive pulmonary disease  
CR 
Complete Response 
CRO 
Clinical research organization 
CRPC 
Castration-resistant prostate cancer 
CT 
Computerized tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450  
DLT 
Dose limiting toxicity 
DMC 
Data Monitoring Committee  
DNA 
Deoxyribonucleic acid 
DoR 
Duration of Response  
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EGFR 
Epidermal growth factor receptor 
EMA 
European Medicines Agency 
EOT 
End of Trial  
EU 
European Union  


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
 
 
Page 17 of 126 
Term 
Definition 
FDA 
Food and Drug Administration 
FIH 
First-in-human 
FVII, FIX, FX 
Factor VII, factor IX, factor X 
FVIIa, FIXa, FXa 
Activated factor VII/factor IX/factor X 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony stimulating factor 
GI 
Gastrointestinal 
HBc 
Hepatitis B core 
HBs 
Hepatitis B surface 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HNSTD 
Highest non-severely toxic dose  
HPV 
Human papilloma virus  
HuMax®-TF-ADC 
HuMax Tissue Factor antibody drug conjugate (tisotumab vedotin) 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin  
IHC 
Immunohistochemistry  
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Independent Review Board 
LD 
Longest diameter 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMAE 
Monomethyl auristatin E  
mRNA 
Messenger ribonucleic acid  
MTD 
Maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network  
NCI 
National Cancer Institute  
NSAID 
Nonsteroidal anti-inflammatory drugs  
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate 
PAR-2 
Protease activated receptor 2 
PCR 
Polymerase chain reaction  


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
 
 
Page 18 of 126 
Term 
Definition 
PD 
Progressive disease 
PFS 
Progression-Free Survival  
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic(s) 
PR 
Partial Response 
PSA 
Prostate specific antigen 
PT 
Prothrombin time 
q3wk 
Every three weeks 
qRT-PCR 
Real-time quantitative polymerase chain reaction 
QTcF 
QT interval as corrected by Fridericia’s formula 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RP2D 
Recommended phase II dose  
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCCHN 
Squamous cell carcinoma of the head and neck 
SD 
Stable Disease 
SoC 
Standard of care  
SUSAR 
Suspected unexpected serious adverse reaction 
TEG 
Thromboelastography 
TEN 
Toxic epidermal necrolysis  
TF 
Tissue factor 
TMA 
Tissue microarray 
Tmax 
Time of maximum concentration 
ULN 
Upper limit of normal 
UK 
United Kingdom 
USA 
United States of America 
vc 
Valine citrulline  
VEGF 
Vascular endothelial growth factor  
WHO Drug 
World Health Organization Drug Reference Dictionary 
WMA 
World Medical Association 


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
 
 
Page 19 of 126 
4 
ETHICS 
4.1 
Ethics Committee 
This trial will be conducted in compliance with independent ethics committee 
(IEC)/institutional review board (IRB) and International Council for Harmonisation (ICH) 
Good Clinical Practice (GCP) Guidelines - including Title 21 Part 56 of the United States of 
America (USA) Code of Federal Regulations (CFR) relating to IRBs and GCP as described in 
the United States Food and Drug Administration (FDA) CFR (21 CFR § 50, 56, 312), in 
accordance with applicable regulations regarding clinical safety data management (E2A, 
E2B(R3)), European Community directives 2001/20, 2001/83, 2003/94 and 2005/28 as 
enacted into local law, and with ICH guidelines regarding scientific integrity (E4, E8, E9 and 
E10). In addition, this trial will adhere to all local regulatory requirements, and requirements 
for data protection. 
Before initiating a trial, the investigator/institution must have written and dated 
approval/favorable opinion from the IEC/IRB for the trial protocol/amendment(s), written 
Informed Consent Form (ICF), any consent form updates, patient recruitment procedures (e.g., 
advertisements), and any written information to be provided to patients and a statement from 
the IEC/IRB that they comply with GCP requirements. The IEC/IRB approval must identify 
the protocol version as well as the documents reviewed. 
4.2 
Ethical Conduct of the Trial 
This trial will be conducted in accordance with the Note for Guidance on GCP (ICH 
Harmonized Tripartite Guideline E6 (R1); FDA CFR (21 CFR § 50, 56, 312)), Declaration of 
Helsinki (Fortaleza 2013, Appendix 3) and all applicable regulatory requirements. 
4.3 
Patient Information and Consent 
The investigator will explain the benefits and risks of participation in the trial to each patient 
and will obtain written informed consent. Written informed consent must be obtained prior to 
the patient entering the trial and before initiation of any trial related procedure (including 
administration of trial drug).  
The IEC/IRB-approved information and consent form that is used must be in language readily 
understood by the patient. Each patient’s original consent form personally signed and dated by 
the patient and by the person who conducted the informed consent discussion, will be retained 
by the investigator. The investigator will supply all enrolled patients with a copy of their signed 
informed consent. 
The consent form may need to be revised during the trial; should important new information 
become available that may be relevant to the safety and procedures of the patient. In this 
instance approval should always be given by the IEC/IRB and existing patients informed of 
the changes and reconsented. This is documented in the same way as previously described. 
The investigator should, with the consent of the patient, inform the patient’s primary physician 
about participation in the clinical trial. 


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
 
 
Page 20 of 126 
5 
INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE 
The Dose Escalation part of the trial will be performed in a maximum of three phase I units in 
Denmark, United Kingdom (UK) and USA. For the Cohort Expansion part, additional phase 
II sites are planned to be opened in the ongoing countries and in Hungary and Belgium.  
The Coordinating Investigator will be: 
Institute of Cancer Research 
Royal Marsden Hospital 
Drug Development Unit  
Downs Road, Sutton 
Surrey SM2 5PT, United Kingdom  
 
A Data Monitoring Committee (DMC) will be established. Refer to Section 11.7.   
In the Dose Escalation part, central laboratories will be used for the analysis of flow cytometry, 
pharmacokinetics (PK) and immunogenicity.  
In the Cohort Expansion part, central laboratories will be used for the analysis of safety 
parameters (hematology, biochemistry, coagulation factors and flow cytometry), tumor 
indicators (CA 125 and prostate specific antigen [PSA]), PK and immunogenicity.  
Details of the central laboratories and handling of samples will be provided in a separate trial 
manual. 
Central facilities will be used for electrocardiogram (ECG) reading. Details of the central 
facilities and shipping instructions will be provided in a separate trial manual  
Investigational Medicinal Product (IMP) will be supplied by 
 
900 
 
Sponsor: 
Genmab A/S 
Kalvebod Brygge 43 
DK-1560 Copenhagen V 
Denmark 
 7020 2728 
Fax: +45 7020 2729 
 








 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
 
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Protocol No.GEN702 
 
Page 25 of 126 


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
 
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Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 


Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
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Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
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Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5 0 (incorporating Protocol Amendment 4) 


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 


Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
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Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
 
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Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
 
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Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
 
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Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
 
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Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
 
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Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
 
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Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
 
 
Page 41 of 126 
7 
TRIAL OBJECTIVES AND ENDPOINTS  
7.1 
Trial Objectives 
7.1.1 
Primary Trial Objective 
To establish the tolerability of tisotumab vedotin (HuMax-TF-ADC) dosed 3q4wk in a mixed 
population of patients with specified solid tumors. 
7.1.2 
Secondary Trial Objectives 
• To determine the MTD and the RP2D of tisotumab vedotin (HuMax-TF-ADC) dosed 
3q4wk. 
• To establish the PK profile of tisotumab vedotin (HuMax-TF-ADC) dosed 3q4wk. 
• To evaluate the anti-tumor activity of tisotumab vedotin (HuMax-TF-ADC) dosed 3q4wk 
in a mixed population of patients with specified solid tumors. 
Trial objectives remain unchanged despite the protocol updates related to implementation of 
the urgent safety measure (Protocol Amendment 4.0). 
7.2 
Trial Endpoints 
7.2.1 
Primary Endpoint 
The primary endpoint is the evaluation of AEs: incidences of AEs, SAEs, infusion-related AEs, 
CTCAE grade ≥ 3 AEs and AEs related to trial drug during the trial. 
7.2.2 
Secondary Endpoints 
• Safety laboratory parameters (hematology, biochemistry, coagulation factors and flow 
cytometry) 
• Skin disorders 
• Bleeding events 
• Neuropathy 
• PK parameters (clearance, volume of distribution and AUC [AUC0-Clast and AUC0-∞], 
Cmax, time of Cmax [Tmax], pre-dose values, and half-life of tisotumab vedotin (HuMax-
TF-ADC) and free toxin [MMAE]) 
• Immunogenicity of tisotumab vedotin (HuMax-TF-ADC) (human anti-human antibodies) 
• Anti-tumor activity measured by tumor shrinkage (based on CT-scan evaluations), change 
in PSA and CA 125 
• Objective Response (Complete Response [CR] or PR), Disease Control (CR, PR or SD), 
Progression-Free Survival (PFS) and Duration of Response (DoR) 


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
 
 
Page 42 of 126 
7.2.3 
Research Endpoints 
• TF expression in tumor biopsies 
• Circulating TF 
• cfDNA 






 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
06 Jul 2017 
 
 
Page 45 of 126 
8.1.1 
Trial Overview 
A trial overview is described below. The trial flowcharts are shown in Table 1 and Table 2 for 
the Dose Escalation part and Table 3 and Table 4 for the Cohort Expansion part according to 
the initially designed treatment scheme. The trial flowchart for the Cohort Expansion part after 
implementation of the urgent safety measure (Protocol Amendment 4.0) is shown in Table 5 
and Table 6. Trial evaluations by visit are detailed in Section 9.  


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC) in mixed solid tumors 
Final 5.0 (incorporating Protocol Amendment 4) 06 Jul 2017 
Page 46 of 126 
Table 1: 
Trial Flow Chart-Dose Escalation Part 
Treatment Cycle 
Screening 
Cycle 1 
Cycle 2-4 
Cycle 5-121 
Follow -
up 
EOT2 
Withd-
rawal 
Safety 
Follow-
up3 
Unsche-
duled 
Visit Number 
0 
14 
2 
34 
44 
5 
6 
7 
14 
24 
34 
4 
14 
24 
34 
4 
1-4 
- 
- 
1-X 
Day/Week 
≤ 21 days 
prior to 
Visit 
C1-V1 
1d 
2d 
8d 
15d 
16d 
18d 
22d 
1d 
8d 
15d 
22d 
1d 
8d 
15d 
22d 
6 weekly 
- 
30 days 
after 
last 
dosing 
- 
Visit window5 
 
- 
- 
±1d 
±1d 
+1d 
±1d 
±1d 
±3d 
±1d 
±1d 
±1d 
±3d 
±1d 
±1d 
±1
d 
±7d 
- 
±14d 
- 
Informed Consent 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and Body 
Weight8 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Physical 
Examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Vital Signs9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X10 
ECG11 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X10 
CT-Scan 
X12 
 
 
 
 
 
 
 
X13 
 
 
 
X13 
 
 
 
X 
X13 
 
X10 
ECOG 
Performance Status 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X10 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X10 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X10 
Trial Drug 
Administration 
 
 
X 
 
X 
X 
 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
 
Bleeding 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
 


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC) in mixed solid tumors 
Final 5.0 (incorporating Protocol Amendment 4) 06 Jul 2017 
Page 47 of 126 
Treatment Cycle 
Screening 
Cycle 1 
Cycle 2-4 
Cycle 5-121 
Follow -
up 
EOT2 
Withd-
rawal 
Safety 
Follow-
up3 
Unsche-
duled 
Visit Number 
0 
14 
2 
34 
44 
5 
6 
7 
14 
24 
34 
4 
14 
24 
34 
4 
1-4 
- 
- 
1-X 
Day/Week 
≤ 21 days 
prior to 
Visit 
C1-V1 
1d 
2d 
8d 
15d 
16d 
18d 
22d 
1d 
8d 
15d 
22d 
1d 
8d 
15d 
22d 
6 weekly 
- 
30 days 
after 
last 
dosing 
- 
Visit window5 
 
- 
- 
±1d 
±1d 
+1d 
±1d 
±1d 
±3d 
±1d 
±1d 
±1d 
±3d 
±1d 
±1d 
±1
d 
±7d 
- 
±14d 
- 
Skin Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X10 
Neuropathy 
Assessment 
X 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X10 
Ophthalmological 
Evaluation 
X 
 
 
 
 
 
 
X22 
 
 
 
X22 
 
 
 
X22 
 
X22 
 
X10,22 
Radionuclide Bone 
Scan14 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X10 
LABORATORY ASSESSMENTS15 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X10 
Biochemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X10 
Coagulation 
factors 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X10 
PSA14 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
X10 
CA 12516 
X16 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
X10 
Flow Cytometry 
 
X17 
 
 
 
 
 
 
 
 
 
 
X17 
 
 
 
 
X 
 
X10 
Pregnancy Test 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
X10 
ADA 
(Immunogenicity) 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X10 
Hepatitis B, C, 
CMV, HPV18 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X10 
PK Sampling19 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
X10 
Tumor biopsy 
X21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X10 


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC) in mixed solid tumors 
Final 5.0 (incorporating Protocol Amendment 4) 06 Jul 2017 
Page 48 of 126 
Treatment Cycle 
Screening 
Cycle 1 
Cycle 2-4 
Cycle 5-121 
Follow -
up 
EOT2 
Withd-
rawal 
Safety 
Follow-
up3 
Unsche-
duled 
Visit Number 
0 
14 
2 
34 
44 
5 
6 
7 
14 
24 
34 
4 
14 
24 
34 
4 
1-4 
- 
- 
1-X 
Day/Week 
≤ 21 days 
prior to 
Visit 
C1-V1 
1d 
2d 
8d 
15d 
16d 
18d 
22d 
1d 
8d 
15d 
22d 
1d 
8d 
15d 
22d 
6 weekly 
- 
30 days 
after 
last 
dosing 
- 
Visit window5 
 
- 
- 
±1d 
±1d 
+1d 
±1d 
±1d 
±3d 
±1d 
±1d 
±1d 
±3d 
±1d 
±1d 
±1
d 
±7d 
- 
±14d 
- 
Biomarkers 
X 
 
 
 
 
 
 
 
 
 
 
 
X21 
 
 
 
 
 
 
 
Abbreviations: ADA=anti-drug antibody; CMV=cytomegalovirus; CRPC=Castration-resistant prostate cancer; CT=computerized tomography; ECG=electrocardiogram; ECOG=Eastern Cooperative 
Oncology Group; EOT=End of Trial; HBc=Hepatitis B core; HBs=Hepatitis B surface; HBsAg=Hepatitis B surface antigen; HCV=hepatitis C virus; HPV= human papilloma virus; Ig=Immunoglobulin; 
PCR=polymerase chain reaction; PD=progressive disease; PK=pharmacokinetic; PSA=prostate specific antigen; SAE=serious adverse event 
Footnotes to Trial Flowchart: Dose Escalation Part 
1 Additional treatment only if patient shows response of SD or better. 
2 If the patient shows PD, is to start new anti-cancer treatment or withdraws from trial due to another reason during treatment or Follow-up period, the EOT Visit should be performed 
as soon as possible after decision of withdrawal. If patient completes all Follow-up visits, the EOT Visit should be performed 4 weeks after end of Follow-up Visit 4 period. 
3 For patients who withdraw from the trial before Follow-Up Visit 1. Only SAEs will be assessed. 
4 The patient shall stay at hospital for at least 2 hours after the infusion and may be requested to stay longer at the discretion of the investigator. 
5 The specified visit windows are in accordance with the previous visit. Visit 1 of Cycle 2 and onwards should be performed 7 days ± 3 days after Day 22 of the previous cycle. 
6 Informed consent must be obtained before or at the Screening Visit window i.e., may be reasonably prior to the screening date. 
7 Signs and symptoms occurring between Visit 0 and first infusion should be recorded as medical history (see Section 10.2 for details). SAEs should be reported as of the signing of 
the informed consent. 
8 Height is only assessed at the Screening Visit. During the trial, only body weight is measured on the first dosing day in a cycle, as part of the dose calculation. If body weight is 
assessed ≤ 7 days before the first day of the planned dosing in a cycle, this value can be used to calculate dose.  
9 Temperature, blood pressure and heart rate. Within each visit, preferably the same equipment shall be used for vital signs measurements. Vital signs should be assessed just before 
and no longer than 30 minutes before infusion start, during and after the infusions until 2 hours after end of infusions, as indicated in Section 10.5. 
10 Optional. 
11 One ECG will be performed at screening. Three ECGs should be performed at least 2 minutes apart before infusion of the trial drug on Visit 1 for all cycles, in accordance with 
the ECG Specifications Manual. 


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC) in mixed solid tumors 
Final 5.0 (incorporating Protocol Amendment 4) 06 Jul 2017 
Page 49 of 126 
Footnotes to Trial Flowchart: Dose Escalation Part 
12 Within 4 weeks prior to Visit C1-V1. All patients will have a CT-scan with contrast of thorax, abdomen and pelvis performed as part of the screening procedure. If a CT-scan has 
been performed within 4 weeks prior to Visit C1-V1 as part of standard procedure, it is acceptable as screening CT-scan for the trial. If there is suggestion of brain metastases/tumors, 
a CT-scan of the head will be performed before inclusion. 
13 At the end of every second cycle, i.e., on Day 1 of Cycles 3, 5, 7, 9 and 11, CT-scans can be performed up to 7 days before Day 1 of the relevant cycle to ensure result to be 
available before subsequent dosing. Additional scans on 21 days (± 7 days) after Day 15 of Cycle 12, and at the EOT Visit. To be completed as indicated to confirm response, new 
symptoms, end of trial or physician discretion. 
14 Radionuclide bone scan and PSA will be performed for CRPC patients. Radionuclide bone scan will be performed at screening, every 16 weeks (i.e., Day 1 of Cycles 5 and 9), 
and upon clinical indication. If there is suspicion of progression, another bone scan will be performed 12 weeks later. The screening radionuclide bone scan can be performed up to 
4 weeks prior to Visit C1-V1. 
15 Hematology, biochemistry, serology and pregnancy test will be analyzed locally at the sites. All other laboratory parameters will be analyzed centrally. 
16 For patients with ovarian and endometrial cancer. In patients with ovarian cancer, the screening sample should be taken within two weeks before starting the treatment. 
17 Flow cytometry only on Cycle 1 and Cycle 5. 
18 HBsAg, anti-HBs and anti-HBc, Hepatitis C and antibodies to CMV antigen will be assessed at screening for all patients; for CMV, anti-IgG and IgM will be assessed and, in 
case of positive IgM, it will be confirmed with CMV PCR; for HCV, anti-IgG will be assessed and, if positive, it will be confirmed with HCV PCR. HPV only for patients with 
cervical cancer. At EOT, only antibodies to CMV antigen will be assessed. 
19 See Table 2 and Section 10.17or details of PK samplings. 
20 Archived biopsy material can be forwarded if a sample is available. If no sample is available, a new tumor biopsy must be obtained at least 2 weeks before dosing to ensure healing 
of wound. 
21 Only on Cycle 5. 
22 Patients experiencing ocular symptoms must be referred to an ophthalmologist for prompt review (preferably within 72 hours and no later than within one week). 
 
Table 2: 
PK Sampling- Dose Escalation Part  
Treatment Cycle 
Screening 
Cycle 1 
Cycle 2-4 
Cycle 5-12 
Unscheduled 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
1 
2 
3 
4 
1 
2 
3 
4 
1-X 
Day/Week 
- 
1d 
2d 
8d 
15d 
16d 
18d 
22d 
1d 
8d 
15d 
22d 
1d 
8d 
15d 
22d 
 
Before Infusion 
(on infusion days) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X2 
End of infusion  
(+15 minutes) 1 
 
X 
 
X 
X 
 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
+ 2 hours (± 15 minutes) 
after end of infusion 1 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
1 Allowed time windows are indicated in parentheses.   
2 Optional. 


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC) in mixed solid tumors 
Final 5.0 (incorporating Protocol Amendment 4) 06 Jul 2017 
Page 50 of 126 
Table 3: 
Trial Flow Chart – Cohort Expansion Part - SUPERSEDED 
Treatment Cycle 
Screening 
 
Cycle 1 
Cycle 2-9 
EOT1 
Withdrawal 
Safety Follow-up2 
Unscheduled 
Visit Number 
0 
13 
23 
33 
4 
5 
13 
23 
33 
4 
- 
- 
1-X 
Day/Week 
≤ 21 days 
prior to Visit 
C1-V1 
1d 
8d 
15d 
18d 
22d 
1d 
8d 
15d 
22d 
- 
30 days after last 
dosing 
- 
Visit window4 
 
- 
±1d 
±1d 
-±1d 
±1d 
±3d 
±1d 
±1d 
±1d 
- 
±14d 
- 
Informed Consent 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height and Body Weight7 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Physical Examination 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
Vital Signs8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X9 
ECG10 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
X9 
CT-Scan 
X11 
 
 
 
 
 
X12 
 
 
 
X12 
 
X9 
ECOG Performance Status 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
X9 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X9 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X9 
Trial Drug Administration22 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
 
Bleeding Assessment 
X 
X 
 
 
 
X 
X 
 
 
 
X 
 
X 
Skin Assessment 
X 
X 
 
 
 
X 
X 
 
 
 
X 
 
X 
Neuropathy Assessment 
X 
X 
 
 
 
X 
X 
 
 
 
X 
 
X 
Ophthalmological Evaluation 
X 
 
 
 
 
X13 
 
 
 
X13 
X13 
 
X13 
Radionuclide Bone Scan14 
X 
 
 
 
 
 
X 
 
 
 
 
 
X9 
LABORATORY ASSESSMENTS15 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X9 
Biochemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X9 
Coagulation factors 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X9 


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC) in mixed solid tumors 
Final 5.0 (incorporating Protocol Amendment 4) 06 Jul 2017 
Page 51 of 126 
Treatment Cycle 
Screening 
 
Cycle 1 
Cycle 2-9 
EOT1 
Withdrawal 
Safety Follow-up2 
Unscheduled 
Visit Number 
0 
13 
23 
33 
4 
5 
13 
23 
33 
4 
- 
- 
1-X 
Day/Week 
≤ 21 days 
prior to Visit 
C1-V1 
1d 
8d 
15d 
18d 
22d 
1d 
8d 
15d 
22d 
- 
30 days after last 
dosing 
- 
Visit window4 
 
- 
±1d 
±1d 
-±1d 
±1d 
±3d 
±1d 
±1d 
±1d 
- 
±14d 
- 
PSA14 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
X10 
CA 12516 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
X10 
Flow Cytometry 
 
X17 
 
 
 
 
X17 
 
 
 
X 
 
X10 
Pregnancy Test 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
X10 
ADA (Immunogenicity) 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X10 
Hepatitis B, C, CMV, HPV18 
X 
 
 
 
 
 
 
 
 
 
X 
 
X10 
PK Sampling19 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X10 
Tumor biopsy 
X20 
 
 
 
 
 
 
 
 
 
 
 
X10 
Biomarker 
X 
 
 
 
 
 
 
 
X21 
 
 
 
 
Abbreviations: ADA=anti-drug antibody; CMV=cytomegalovirus; CRPC=Castration-resistant prostate cancer; CT=computerized tomography; ECG=electrocardiogram; ECOG=Eastern 
Cooperative Oncology Group; EOT=End of Trial; HBc=Hepatitis B core; HBs=Hepatitis B surface; HBsAg=Hepatitis B surface antigen; HCV=hepatitis C virus; HPV= human papilloma virus; 
Ig=Immunoglobulin; PCR=polymerase chain reaction; PD=progressive disease; PK=pharmacokinetic; PSA=prostate specific antigen; SAE=serious adverse event 
Footnotes to Trial Flowchart: Cohort Expansion Part 
1 If the patient shows PD, is to start new anti-cancer treatment or withdraws from trial due to another reason during treatment, the EOT Visit should be performed as soon as possible 
after decision of withdrawal. 
2 Only SAEs will be assessed. 
3 The patient shall stay at hospital for at least 2 hours after the infusion and may be requested to stay longer at the discretion of the investigator. 
4 The specified visit windows are in accordance with the previous visit. Visit 1 of Cycle 2 and onwards should be performed 7 days ± 3 days after Day 22 of the previous cycle. 
5 Informed consent must be obtained before or at the Screening Visit window i.e., may be reasonably prior to the screening date. 
6 Signs and symptoms occurring between Visit 0 and first infusion should be recorded as medical history (see Section 10 for details). SAEs should be reported as of the signing of 
the informed consent. 
7 Height is only assessed at the Screening Visit. During the trial, only body weight is measured on the first dosing day in a cycle, as part of the dose calculation. If body weight is 
assessed ≤ 7days before the first day of the planned dosing in a cycle, this value can be used to calculate dose.  
8 Temperature, blood pressure and heart rate. Within each visit, preferably the same equipment shall be used for vital signs measurements. Vital signs should be assessed just before 
and no longer than 30 minutes before infusion start, during and after the infusions until 2 hours after end of infusions, as indicated in Section 10.5. 
9 Optional. 


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC) in mixed solid tumors 
Final 5.0 (incorporating Protocol Amendment 4) 06 Jul 2017 
Page 52 of 126 
Footnotes to Trial Flowchart: Cohort Expansion Part 
10 One ECG will be performed at screening. Three ECGs should be performed at least 2 minutes apart before infusion of the trial drug on Visit 1 for all cycles, in accordance with 
the ECG Specifications Manual. 
11 Within 4 weeks prior to Visit C1-V1. All patients will have a CT-scan with contrast of thorax, abdomen and pelvis performed as part of the screening procedure. If a CT-scan has 
been performed within 4 weeks prior to Visit C1-V1 as part of standard procedure, it is acceptable as screening CT-scan for the trial. If there is suggestion of brain metastases/tumors, 
a CT-scan of the head will be performed before inclusion. 
12 At the end of every second cycle, i.e., on Day 1 of Cycles 3, 5, 7 and 9, CT-scans can be performed up to 7 days before Day 1 of the relevant cycle to ensure result to be available 
before subsequent dosing. Additional scan at the EOT Visit. To be completed as indicated to confirm response, new symptoms, end of trial or physician discretion. 
13 Patients experiencing ocular symptoms must be referred to an ophthalmologist for prompt review (preferably within 72 hours and no later than within one week). 
14 Radionuclide bone scan and PSA will be performed for CRPC patients. Radionuclide bone scan will be performed at screening, every 16 weeks (i.e., Day 1 of Cycles 5 and 9), 
and upon clinical indication. If there is suspicion of progression, another bone scan will be performed 12 weeks later. The screening radionuclide bone scan can be performed up to 
4 weeks prior to Visit C1-V1. 
15 Laboratory parameters will be analyzed centrally. 
16 For patients with ovarian and endometrial cancer. 
17 Flow cytometry only on Cycle 1 and Cycle 5. 
18 HBsAg, anti-HBs and anti-HBc, Hepatitis C and antibodies to CMV antigen will be assessed at screening for all patients; for CMV, anti-IgG and IgM will be assessed and, in 
case of positive IgM, it will be confirmed with CMV PCR; for HCV, anti-IgG will be assessed and, if positive, it will be confirmed with HCV PCR. HPV only for patients with 
cervical cancer. At EOT, only antibodies to CMV antigen will be assessed. 
19 See Table 4 and Section 10.17 for details of PK samplings. 
20 Archived biopsy material can be forwarded if a sample is available. If no sample is available, a new tumor biopsy must be obtained at least 2 weeks before dosing to ensure healing 
of wound. 
21 Only on Cycle 4. 
22 Preventive eye therapy to be administered in relation to infusions as detailed in Section 8.4.5.3. 
Table 4: 
PK Sampling - Cohort Expansion Part - SUPERSEDED 
Treatment Cycle 
Screening 
Cycle 1 
Cycle 2-9 
Unscheduled 
Visit Number 
0 
1 
2 
3 
4 
5 
1 
2 
3 
1-X 
Day/Week 
- 
1d 
8d 
15d 
18d 
22d 
1d 
8d 
15d 
 
Before Infusion (on infusion days) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X2 
End of infusion (+15 minutes) 1 
 
X 
 
 
 
 
X 
 
 
 
+ 2 hours (± 15 minutes) after end of infusion 1 
 
X 
 
 
 
 
 
 
 
 
1 Allowed time windows are indicated in parentheses.  
2 Optional. 


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC) in mixed solid tumors 
Final 5.0 (incorporating Protocol Amendment 4) 06 Jul 2017 
Page 53 of 126 
Table 5: 
Trial Flow Chart – Cohort Expansion Part - After Urgent Safety Measure 
Treatment Cycle 
Screening 
 
Cycle 1 
Cycle 2-9 
EOT1 
Withdrawal Safety 
Follow-up2 
Unscheduled 
Visit Number 
0 
13 
2 
3 
13 
2 
3 
- 
- 
1-X 
Day/Week 
≤ 21 days prior 
to Visit 
C1-V1 
1d 
8d 
15d 
1d 
8d 
15d 
- 
30 days after last 
dosing 
- 
Visit window4 
 
- 
±1d 
±1d 
±3d 
±1d 
±1d 
- 
±14d 
- 
Informed Consent 
X5 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical History6 
X 
 
 
 
 
 
 
 
 
 
Height and Body Weight7 
X 
X 
 
 
X 
 
 
X 
 
 
Physical Examination 
X 
X 
 
 
 
 
 
X 
 
 
Vital Signs8 
X 
X 
X 
X 
X 
 
X 
X 
 
X9 
ECG10 
X 
X 
 
 
X 
 
 
X 
 
X9 
CT-Scan 
X11 
 
 
 
X12 
 
 
X12 
 
X9 
ECOG Performance Status 
X 
X 
 
 
X 
 
 
X 
 
X9 
Adverse Events 
X 
X 
X 
X 
X 
 
X 
X 
X 
X9 
Concomitant Medication 
X 
X 
X 
X 
X 
 
X 
X 
 
X9 
Trial Drug Administration22 
 
X 
 
 
X 
 
 
 
 
 
Bleeding Assessment 
X 
X 
 
X 
X 
 
 
X 
 
X 
Skin Assessment 
X 
X 
 
X 
X 
 
 
X 
 
X 
Neuropathy Assessment 
X 
X 
 
X 
X 
 
 
X 
 
X 
Ophthalmological Evaluation 
X 
 
 
X13 
 
 
X13 
X13 
 
X13 
Radionuclide Bone Scan14 
X 
 
 
 
X 
 
 
 
 
X9 
LABORATORY ASSESSMENTS15 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
 
X9 
Biochemistry 
X 
X 
X 
X 
X 
X 
X 
X 
 
X9 
Coagulation factors 
X 
X 
X 
X 
X 
X 
X 
X 
 
X9 


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC) in mixed solid tumors 
Final 5.0 (incorporating Protocol Amendment 4) 06 Jul 2017 
Page 54 of 126 
Treatment Cycle 
Screening 
 
Cycle 1 
Cycle 2-9 
EOT1 
Withdrawal Safety 
Follow-up2 
Unscheduled 
Visit Number 
0 
13 
2 
3 
13 
2 
3 
- 
- 
1-X 
Day/Week 
≤ 21 days prior 
to Visit 
C1-V1 
1d 
8d 
15d 
1d 
8d 
15d 
- 
30 days after last 
dosing 
- 
Visit window4 
 
- 
±1d 
±1d 
±3d 
±1d 
±1d 
- 
±14d 
- 
PSA14 
X 
X 
 
 
X 
 
 
X 
 
X10 
CA 12516 
X 
X 
 
 
X 
 
 
X 
 
X10 
Flow Cytometry 
 
X17 
 
 
X17 
 
 
X 
 
X10 
Pregnancy Test 
X 
X 
 
 
X 
 
 
X 
 
X10 
ADA (Immunogenicity) 
X 
X 
 
 
X 
 
 
 
 
X10 
Hepatitis B, C, CMV, HPV18 
X 
 
 
 
 
 
 
X 
 
X10 
PK Sampling19 
X 
X 
X 
X 
X 
X 
X 
 
 
X10 
Tumor biopsy 
X20 
 
 
 
 
 
 
 
 
X10 
Biomarker 
X 
 
 
 
 
 
X21 
 
 
 
Abbreviations: ADA=anti-drug antibody; CMV=cytomegalovirus; CRPC=Castration-resistant prostate cancer; CT=computerized tomography; ECG=electrocardiogram; ECOG=Eastern 
Cooperative Oncology Group; EOT=End of Trial; HBc=Hepatitis B core; HBs=Hepatitis B surface; HBsAg=Hepatitis B surface antigen; HCV=hepatitis C virus; HPV= human papilloma virus; 
Ig=Immunoglobulin; PCR=polymerase chain reaction; PD=progressive disease; PK=pharmacokinetic; PSA=prostate specific antigen; SAE=serious adverse event 
Footnotes to Trial Flowchart: Cohort Expansion Part 
1 If the patient shows PD, is to start new anti-cancer treatment or withdraws from trial due to another reason during treatment, the EOT Visit should be performed as soon as possible 
after decision of withdrawal. 
2 Only SAEs will be assessed. 
3 The patient shall stay at hospital for at least 2 hours after the infusion and may be requested to stay longer at the discretion of the investigator. 
4 The specified visit windows are in accordance with the previous visit. Visit 1 of Cycle 2 and onwards should be performed 7 days ± 3 days after Day 15 of the previous cycle. 
5 Informed consent must be obtained before or at the Screening Visit window i.e., may be reasonably prior to the screening date. 
6 Signs and symptoms occurring between Visit 0 and first infusion should be recorded as medical history (see Section 10 for details). SAEs should be reported as of the signing of 
the informed consent. 
7 Height is only assessed at the Screening Visit. During the trial, only body weight is measured on the first dosing day in a cycle, as part of the dose calculation. If body weight is 
assessed ≤ 7days before the first day of the planned dosing in a cycle, this value can be used to calculate dose.  
8 Temperature, blood pressure and heart rate. Within each visit, preferably the same equipment shall be used for vital signs measurements. Vital signs should be assessed just before 
and no longer than 30 minutes before infusion start, during and after the infusions until 2 hours after end of infusions, as indicated in Section 10.5. 
9 Optional. 


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC) in mixed solid tumors 
Final 5.0 (incorporating Protocol Amendment 4) 06 Jul 2017 
Page 55 of 126 
Footnotes to Trial Flowchart: Cohort Expansion Part 
10 One ECG will be performed at screening. Three ECGs should be performed at least 2 minutes apart before infusion of the trial drug on Visit 1 for all cycles, in accordance with 
the ECG Specifications Manual. 
11 Within 4 weeks prior to Visit C1-V1. All patients will have a CT-scan with contrast of thorax, abdomen and pelvis performed as part of the screening procedure. If a CT-scan has 
been performed within 4 weeks prior to Visit C1-V1 as part of standard procedure, it is acceptable as screening CT-scan for the trial. If there is suggestion of brain metastases/tumors, 
a CT-scan of the head will be performed before inclusion. 
12 At the end of every second cycle, i.e., on Day 1 of Cycles 3, 5, 7 and 9, CT-scans can be performed up to 7 days before Day 1 of the relevant cycle to ensure result to be available 
before subsequent dosing. Additional scan at the EOT Visit. To be completed as indicated to confirm response, new symptoms, end of trial or physician discretion. 
13 Patients experiencing ocular symptoms must be referred to an ophthalmologist for prompt review (preferably within 72 hours and no later than within one week). 
14 Radionuclide bone scan and PSA will be performed for CRPC patients. Radionuclide bone scan will be performed at screening, every 16 weeks (i.e., Day 1 of Cycles 5 and 9), 
and upon clinical indication. If there is suspicion of progression, another bone scan will be performed 12 weeks later. The screening radionuclide bone scan can be performed up to 
4 weeks prior to Visit C1-V1. 
15 Laboratory parameters will be analyzed centrally. 
16 For patients with ovarian and endometrial cancer. 
17 Flow cytometry only on Cycle 1 and Cycle 5. 
18 HBsAg, anti-HBs and anti-HBc, Hepatitis C and antibodies to CMV antigen will be assessed at screening for all patients; for CMV, anti-IgG and IgM will be assessed and, in 
case of positive IgM, it will be confirmed with CMV PCR; for HCV, anti-IgG will be assessed and, if positive, it will be confirmed with HCV PCR. HPV only for patients with 
cervical cancer. At EOT, only antibodies to CMV antigen will be assessed. 
19 See Table 4 and Section 10.17 for details of PK samplings. 
20 Archived biopsy material can be forwarded if a sample is available. If no sample is available, a new tumor biopsy must be obtained at least 2 weeks before dosing to ensure healing 
of wound. 
21 Only on Cycle 4. 
22 Preventive eye therapy to be administered in relation to infusions as detailed in Section 8.4.5.3. 
Table 6: 
PK Sampling - Cohort Expansion Part - After Urgent Safety Measure 
Treatment Cycle 
Screening 
Cycle 1 
Cycle 2-9 
Unscheduled 
Visit Number 
0 
1 
2 
3 
1 
2 
3 
1-X 
Day/Week 
- 
1d 
8d 
15d 
1d 
8d 
15d 
 
Before Infusion (on infusion days) 
X 
X 
X 
X 
X 
X 
X 
X2 
End of infusion (+15 minutes) 1 
 
X 
 
 
X 
 
 
 
+ 2 hours (± 15 minutes) after end of infusion 1 
 
X 
 
 
 
 
 
 
1 Allowed time windows are indicated in parentheses.  
2 Optional. 


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC) 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
 06 Jul 2017 
 
Page 56 of 126 
8.1.1.1 Screening Phase (Visit 0) 
Patients will provide written informed consent. Medical history, physical examination, 
laboratory studies, ophthalmological evaluation and CT imaging will be performed to 
determine baseline disease status and trial eligibility. The medical history, physical 
examination, potential biopsies, ECG and laboratory studies (including biomarkers) must be 
performed within 21 days before trial entry (Visit C1-V1). CT imaging must be performed 
within four weeks before trial entry (Visit C1-V1).  
A patient may be rescreened one time only. A rescreening must be approved by the sponsor to 
ensure that the safety of the patient is not compromised.   
8.1.1.2 Treatment Phase (C1 to CX)  
Dose Escalation Part 
The investigator must have evaluated the patient’s eligibility and confirm receipt of sponsor 
decision and patient number before the patient’s first infusion. 
Tisotumab vedotin (HuMax-TF-ADC) will be administered on Days 1, 8 and 15 of a 28-day 
cycle. Dose escalation to MTD is anticipated to involve up to three dose levels with an 
anticipated maximum dose level of 1.5 mg/kg. 
Patients will receive four cycles (each with three doses) of tisotumab vedotin 
(HuMax-TF-ADC) at 28-day intervals. Thus, the treatment period will last for 16 weeks or 
until the patient withdraws from the treatment/trial due to the withdrawal criteria.  
After four cycles, if there is evidence of the patient benefitting from treatment, at the discretion 
of the treating physician, there is an option to continue in the trial for up to a maximum of eight 
additional cycles (32 weeks) or until the patient withdraws from the treatment/trial due to the 
withdrawal criteria.  
The treatment period will have a maximum duration of 48 weeks. 
Cohort Expansion Part 
The investigator must have evaluated the patient’s eligibility before the patient’s first infusion. 
Tisotumab vedotin (HuMax-TF-ADC) will be administered on Day 1, 8 and 15 of a 28-day 
cycle. Twenty to 30 patients will receive up to nine cycles of three doses of HuMax-TF-ADC 
at the dose determined by the sponsor in agreement with the DMC based on the Dose 
Escalation part of the trial.  
Severe ocular toxicity has been observed at 1.2 mg/kg 3q4wk. Patients will no further receive 
the 3q4wk schedule; instead tisotumab vedotin (HuMax-TF-ADC) 2.0 mg/kg will be 
administered once q3wk, on Day 1 of each 21-day cycle, regardless of the prior dose(s) 
administered. The next dose of tisotumab vedotin cannot be administered until at least 21 days 
have elapsed since the last administration.  


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC) 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
 06 Jul 2017 
 
Page 57 of 126 
The treatment period will last for up to 36 weeks (or less after changing to the once q3wk 
dosing scheme) or until unacceptable toxicity or disease progression at the discretion of the 
treating physician.  
8.1.1.3 Unscheduled Visit (U1 to UX) 
If deemed necessary by the investigator, the patient may be called in for an unscheduled 
visit(s). During an unscheduled visit the investigator can perform any trial relevant clinical or 
laboratory assessments deemed necessary. The visit date and reason for visit must be recorded 
in the patient’s medical records and electronic case report form (eCRF). 
8.1.1.4 Follow-up Phase 
Dose Escalation Part 
Patients will attend four follow up visits (FU1 to FU4) at six weekly intervals (± 7 days). 
If the patient withdraws from treatment and has not started new anti-cancer treatment, or if the 
patient completes all treatment cycles, the patient will be followed by the site every six weeks 
for a maximum of four visits or until other treatment is initiated, for a maximum of 24 weeks. 
Then, the patient will return for an End of Trial (EOT) Visit. 
Cohort Expansion Part 
No follow-up visits will be included in the Cohort Expansion part. 
8.1.1.5 End of Trial Visit (EOT)  
Dose Escalation Part 
If a patient completes all follow-up visits, the EOT Visit should be performed four weeks after 
the end of the Follow-up Visit 4 period.  
In case of withdrawal from the trial, the EOT Visit will be performed as soon as possible. The 
EOT Visit will include most assessments performed at the Screening Visit, and response 
assessments. 
Cohort Expansion Part 
If the patient shows PD, is to start new anti-cancer treatment or withdraws from trial due to 
another reason during treatment, the EOT Visit should be performed as soon as possible after 
decision of withdrawal. 
The EOT Visit will include most assessments performed at the Screening Visit, and response 
assessments. 
8.1.1.6 Safety Follow-up Visit  
Dose Escalation Part 
Patients who withdraw from the trial before Follow-up Visit 1 will return for a Safety Follow-
up Visit 30 days after the last dose of IMP. In the Safety Follow-up Visit, only SAEs will be 


 
 
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assessed. If the patient has died within the 30 days this should be entered as an AE in the eCRF 
and reported as an SAE. 
Cohort Expansion Part 
Patients who withdraw from the trial will return for a Safety Follow-up Visit 30 days after the 
last dose of IMP. In the Safety Follow-up Visit, only SAEs will be assessed. If the patient has 
died within the 30 days this should be entered as an AE in the eCRF and reported as an SAE. 
8.2 
Trial Duration and End of Trial 
The enrollment period is planned to last approximately 21 months.  
The trial will be stopped when the last patient enrolled in the Cohort Expansion part completes 
the trial or when the last ongoing patient has discontinued treatment and attended the Safety 
Follow-up Visit, whichever occurs first. 
The end of trial (“trial completion”) is defined as the date of the last protocol-specified 
visit/assessment for the last patient in the trial or the date the trial is closed by the sponsor, 
whichever occurs first.  
All materials or supplies provided by the sponsor will be returned to the sponsor or designee 
upon trial completion, as directed by the site monitor. The IEC/IRB will be notified when the 
trial has been completed. 
Genmab A/S reserves the right to temporarily suspend or prematurely discontinue this trial 
either at a single site, multiple sites or at all sites at any time for reasons including, but not 
limited to, safety or ethical issues, inaccurate or incomplete data recording, noncompliance, or 
unsatisfactory enrollment with respect to quality or quantity. 
If the trial is prematurely terminated or suspended, Genmab A/S (or its representative) will 
inform the investigators/institutions and the regulatory authority(ies) of the termination or 
suspension and the reason(s) for the termination or suspension, in accordance with applicable 
regulatory requirement(s). The IEC/IRB should also be informed and provided with reason(s) 
for the termination or suspension by the sponsor or by the investigator/institution, as specified 
by the applicable regulatory requirement(s). In addition, arrangements will be made for the 
return of all unused trial drug and other materials or supplies provided by the sponsor. 
8.2.1 
Trial Stopping Criteria 
If any of the following occur, administration of the trial drug will be stopped and no additional 
patients will be enrolled into the trial: 
1) Grade ≥ 3 anaphylactic reaction to tisotumab vedotin (HuMax-TF-ADC) in any patient. 
2) Other events not including DLT that, in the judgment of the sponsor Medical Officer, are 
deemed serious enough to warrant immediate review and potential stop of other dosing by 
the DMC. 
3) Any other safety finding assessed as related to tisotumab vedotin (HuMax-TF-ADC) that, 
in the opinion of the sponsor, contraindicates further dosing of trial patients. 


 
 
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If any of the above-listed events occur, a prompt cumulative review of safety data and the 
circumstances of the event in question will be conducted by the DMC to recommend whether 
dosing and trial entry should be resumed, whether the protocol will be modified, or whether 
the trial will be discontinued permanently. Review and approval by the sponsor’s Safety 
Committee is required for resumption of the trial in the event that the trial is interrupted because 
of one of the above-listed events. Where applicable, regulatory authorities IECs/IRBs will be 
notified of any actions taken with the trial. 
Any patients who have already received the trial drug and are currently in the trial at the time 
trial stopping criteria are met will continue to be monitored by the investigator for safety. 
Withdrawal criteria for individual patients are provided in Section 8.3.4. 
8.3 
Trial Population 
The patient population in the Dose Escalation part will encompass patients with advanced 
(locally advanced and/or metastatic) cancer of the ovary, cervix, endometrium, bladder, 
prostate (CRPC), esophagus or lung (NSCLC) who have failed available standard treatments 
or who are not candidates for standard therapy.  
The specific indications for the Cohort Expansion part will be decided once the RP2D has been 
determined. The inclusion and exclusion criteria for a reduced number of previous lines of 
treatment will be specified for all potential indications. 
The Dose Escalation part of the trial is planned to be performed in a maximum of three sites 
in Denmark, UK and the USA. The Cohort Expansion part of the trial is planned to be 
performed in the ongoing countries and in Hungary and Belgium.  
Thirty two to 44 patients are planned to be enrolled in the trial. Assuming an anticipated screen 
failure rate of 30%, 57 to76 patients will be screened in total.  
• In the Dose Escalation part: 12 to 24 patients are planned to be enrolled: three to six patients 
per dose level for three dose levels (plus a potential intermediate dose cohort). 
• In the Cohort Expansion part: 20 to 30 patients are planned to be enrolled in two or three 
indication arms. 
8.3.1 
Inclusion Criteria 
Investigators should ensure that all trial enrollment criteria have been met at screening. If a 
patient's status changes (including laboratory results or receipt of additional medical records) 
after screening but before the first dose of trial drug is given such that they no longer meet all 
eligibility criteria, they should be excluded from participation in the trial. 
Patients MUST satisfy all of the following entry criteria before they will be allowed to 
participate in the trial: 
 For the Dose Escalation part: Patients with relapsed, advanced and/or metastatic cancer of 
the ovary, cervix, endometrium, bladder, prostate, esophagus or NSCLC who have failed 
available standard treatments or who are not candidates for standard therapy. 


 
 
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For the Cohort Expansion part: The specific indications for the Cohort Expansion part will 
be decided once the RP2D has been determined. After implementation of the urgent safety 
measure (Protocol Amendment 4), no patients will further receive the 3q4wk schedule; 
instead, tisotumab vedotin (HuMax-TF-ADC) 2.0 mg/kg will be administrated once q3wk. 
• Patients with relapsed, advanced and/or metastatic cancer of the ovary, cervix, 
endometrium, bladder, prostate, esophagus, or NSCLC who have failed the following anti-
cancer therapy:  
o Bladder cancer (including urothelial carcinomas [transitional cell carcinomas] 
regardless initial site of origin of the tumor: renal pelvis, ureter or bladder lumen): 
failing platinum-based therapy. Patients must have received no more than three 
prior treatment regimens for advanced disease. 
o CRPC: failing docetaxel and either abiraterone OR enzalutamide. Patients must 
have received no more than two prior chemotherapy-based regimens and a 
maximum of six prior treatment regimens for advanced disease.  
o Ovarian cancer: resistant to at least one platinum-based therapy and after failing at 
least one line of taxane-containing therapy (isolated CA 125 progression does NOT 
qualify for trial entry). Patients with primary platinum refractory disease are 
excluded. Patients must have received no more than five prior treatment regimens 
for advanced disease.  
o Cervical cancer: failing a platinum-based regimen. Patients must have received no 
more than four prior treatment regimens for advanced disease.  
o Endometrial cancer: failing platinum-based therapy. Patients must have received 
no more than four prior treatment regimens for advanced disease (excluding 
adjuvant chemotherapy).  
o Esophageal cancer (esophageal cancer or gastro-esophageal junction cancer): 
failing platinum-based therapy with or without taxanes depending on established 
SoC therapy. Patients must have received no more than three prior treatment 
regimens for advanced disease.  
o NSCLC: failing at least one platinum-based regimen. Patients with epidermal 
growth factor receptor (EGFR) or anaplastic lymphoma kinase mutations should 
have been treated with appropriate targeted therapy before trial entry. Patients must 
have received no more than four (five allowed for patients with EGFR mutated 
adenocarcinomas) prior treatment regimens for advanced disease.  
Other inclusion criteria: 
 Patients must have measurable disease according to RECIST (Response Evaluation 
Criteria In Solid Tumors) version 1.1 (Eisenhauer et al., 2009). 
o A minimum of one lesion ≥ 10 mm in the longest diameter (LD) from a 
non-irradiated area. If target lesion(s) are located within previously irradiated area 


 
 
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only, the patient can be enrolled only if there has been demonstrated progression in 
the “in field” lesion and after sponsor acceptance. 
 Lymph nodes lesion ≥ 15 mm in the shortest diameter from a non-irradiated 
area. 
o Patients with prostate cancer must be clinically refractory and resistant to hormone 
therapy as documented by progression (CRPC) and can be included based on PSA 
and/or bone metastases according to the Prostate Cancer Working Group Guideline 
(Scher et al., 2008). 
o Patients with ovarian cancer can be included based on CA 125 positivity according 
to the Gynaecologic Cancer Intergroup Guideline (Rustin et al., 2004). This is only 
applicable for the Dose Escalation part of the trial. 
 Age ≥ 18 years. 
 Acceptable renal function defined as: 
o Glomerular filtration rate (Cockroft-Gault) > 45 mL/min. 
 Acceptable liver function defined as: 
o Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times 
the upper limit of normal (ULN); if liver tumor/metastases are present, then 
≤ 5 × ULN is allowed. 
o Bilirubin ≤ 1.5 × ULN, except in patients diagnosed with Gilbert’s syndrome, direct 
bilirubin ≤ 2 × ULN. 
 Acceptable hematological status (hematologic support is allowed if administered at least 
one week before Cycle 1 Day 1) defined as: 
o Hemoglobin ≥ 5.6 mmol/L (~ 9 g/dL).  
o Absolute neutrophil count (ANC) ≥ 1500/µL (1.5 ×109/L). 
o Platelet count ≥ 100 × 109/L. 
 Acceptable coagulation status defined as: 
o INR ≤ 1.2 (without anticoagulant therapy). 
o aPTT ≤ ULN. 
 Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
 Life expectancy of at least three months. 
 A negative serum pregnancy test (if female and aged between 18-55 years old). 
o Women who are pregnant or breast feeding are not to be included.   
 Patients, both females and males, of reproductive potential must agree to use adequate 
contraception during and for six months after the last infusion of tisotumab vedotin 
(HuMax-TF-ADC).  


 
 
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o Adequate contraception for women is defined as hormonal birth control or an 
intrauterine device (see Section 10.16.6). In countries where two highly effective 
methods of contraception are required this will be an inclusion criterion (refer to 
Appendix 2). 
o Male patients must be willing to use a latex condom during any sexual contact with 
females of childbearing potential during and for six months after the last infusion 
of tisotumab vedotin (HuMax-TF-ADC), even after having undergone a successful 
vasectomy. It is recommended that fertile males consider having a semen specimen 
obtained for storage for potential future conception. 
 Following receipt of verbal and written information about the trial, patients must provide 
signed informed consent before any trial-related activity is carried out. 
8.3.2 
Exclusion Criteria 
If any of the following apply, the patient MUST NOT enter the trial: 
Hematological 
1. Known past or current coagulation defects leading to an increased risk of bleeding. 
2. Diffuse alveolar hemorrhage from vasculitis. 
3. Known bleeding diathesis. 
4. Ongoing major bleeding, defined as: 
o Symptomatic bleeding in critical area organ, such as intracranial, intraocular, 
retroperitoneal, intra-articular or pericardial, or intramuscular with compartment 
syndrome; and/or 
o Bleeding causing a drop in hemoglobin level of 2 g/dL (1.24 mmol/L) or more, or 
bleeding leading to transfusion of two or more units of whole blood or red cells. 
5. Trauma with increased risk of life-threatening bleeding or history of severe head trauma 
or intracranial surgery within two months of trial entry. 
Cardiovascular 
6. Have clinically significant cardiac disease, including: 
o Unstable angina 
o Acute myocardial infarction within six months of the Screening Visit 
o Known congestive heart failure (Grade III or IV as classified by the New York 
Heart Association); and/or a known decreased cardiac ejection fraction of < 45% 
7. A baseline QT interval as corrected by Fridericia’s formula (QTcF) > 450 msec, a 
complete left bundle branch block (defined as a QRS interval ≥ 120 msec in left bundle 
branch block form) or an incomplete left bundle branch block. 
Excluded medications or treatment regimens 
8. Therapeutic anti-coagulative or long-term anti-platelet treatment. 


 
 
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o Use of low dose acetylsalicylic acid (ASA) up to 81 mg/day and non-ASA 
nonsteroidal anti-inflammatory drugs (NSAIDs) is allowed. 
9. Have received:  
a. Granulocyte colony stimulating factor (G-CSF) or granulocyte/macrophage 
colony stimulating factor support within one week before the Screening Visit 
or 
b. Pegylated G-CSF within two weeks before the Screening Visit, or 
c. Blood transfusion and/or erythropoietin within one week before first dose. 
10. Have received a cumulative dose of corticosteroid ≥ 150 mg (prednisone or equivalent 
doses of corticosteroids) within two weeks before the first infusion. 
11. No dietary supplements allowed during the trial period, except multivitamins, vitamin D 
and calcium unless approved by the sponsor Medical Officer. 
Surgery/procedures 
12. Major surgery within six weeks or open biopsy within 14 days before drug infusion. 
13. Plan for any major surgery during treatment period. 
14. Patients not willing or able to have a pre-trial tumor biopsy taken (the screening biopsy 
can be omitted if archived material is available). 
15. Presence or anticipated requirement of epidural catheter in relation to infusions (within 48 
hours before and after dose of trial drug). 
Central nervous system  
16. Any history of intracerebral arteriovenous malformation, cerebral aneurysm, brain 
metastases or stroke. 
o Transient ischemic attack > one month prior to screening is allowed. 
Prior therapy 
17. Any anti-cancer therapy including small molecules, immunotherapy, chemotherapy 
monoclonal antibodies or any other experimental drug within four weeks or five half-lives, 
whichever is longest, before first infusion. For anti-cancer therapies with half-lives > 8 
days, a washout period of at least 28 days is acceptable. 
18. Prior treatment with bevacizumab within 12 weeks before the first infusion. 
19. Any prior therapy with a conjugated or unconjugated auristatin derivative. 
20. Radiotherapy within 28 days prior to first dose. 
21. Patients who have not recovered from symptomatic side effects of radiotherapy or 
symptoms of autoimmune toxicities related to previous treatment with check-point 
inhibitors at the time of initiation of screening procedure. 


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Other cancer/metastases 
22. Known past or current malignancy other than inclusion diagnosis, except for:
o
Cervical carcinoma of Stage 1B or less
o
Non-invasive basal cell or squamous cell skin carcinoma
o
Non-invasive, superficial bladder cancer
o
Prostate cancer with a current PSA level < 0.1 ng/mL
o
Breast cancer in BRCA1 or BRCA2 positive ovarian cancer patients
o
Any curable cancer with a CR of > 5 years duration
23. Radiographic evidence of cavitating pulmonary lesions.
24. Tumor invading any large blood vessel, unless approved by the sponsor Medical Officer.
Other
25. Ongoing significant, uncontrolled medical condition
26. Presence of CTCAE grade ≥ 2 peripheral neuropathy.
27. Clinically significant active viral, bacterial or fungal infection requiring:
o
Intravenous treatment with antimicrobial therapy starting less than four weeks prior
to first dose, or
o
Oral treatment with antimicrobial therapy starting less than 10 days prior to first
dose.
28. Known human immunodeficiency virus seropositivity.
29. Positive serology (unless due to vaccination or passive immunization due to Ig therapy)
for hepatitis B defined by:
o
Positive test for HBsAg (hepatitis B surface antigen) and/or
o
Positive test for anti-HBs and anti-HBc (antibodies to hepatitis B surface and core
antigens).
30. Positive serology for hepatitis C based on test at screening.
31. Inflammatory bowel disease including Crohn’s disease and colitis ulcerosa.
32. Inflammatory lung disease including moderate and severe asthma and chronic obstructive
pulmonary disease (COPD) requiring chronic medical therapy.
33. Ongoing acute or chronic inflammatory skin disease.
34. Ophthalmological:
o
Active ocular surface disease at baseline (based on ophthalmological evaluation).
o
History of cicatricial conjunctivitis (as evaluated by an ophthalmologist).


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8.3.3 
Patient Allocation Procedure 
Allocation of patients will be controlled by the CRO. 
When a potential patient is identified at a site, the site personnel must contact the CRO for 
allocation in accordance to Section 8.4.9.5. If there is an opening in the currently enrolling 
cohort, the site will be given approval to start the screening process. 
If there is no opening in the currently enrolling cohort, the CRO will place the patient on a list 
of potential patients. If another patient fails the screening process, the CRO will alert the site 
that has the next patient on the waiting list. If the patient is still eligible, the site will be given 
approval to start the screening process. 
8.3.4 
Withdrawal and Replacement of Patients 
8.3.4.1 Criteria for Patient Withdrawal from Treatment 
Patients will be withdrawn from treatment for the following reasons: 
•
DLT/DLT-equivalent events (see Section 8.4.8 for specification, exception and dose
modifications).
•
> 2 dose reductions due to recurrent toxicities possibly related to tisotumab vedotin
(HuMax-TF-ADC) (see Sections 8.4.5.1, 8.4.5.2, and 8.4.5.3).
•
CTCAE grade ≥ 3 macular-papular skin rash.
•
CTCAE grade 1 treatment-related bullous dermatitis or skin bullae (blister) ≥ 0.5 cm.
•
Recurrent CTCAE grade 4 neutropenia may be withdrawn, see Section 8.4.5.2.
•
CTCAE grade 3 QTcF interval prolongation (≥ 501 msec on at least two separate ECGs).
•
First recurrence of CTCAE grade ≥ 3 conjunctivitis  (despite dose reduction, see
Section 8.4.5.3)
•
Third recurrence of CTCAE grade ≤ 2 keratitis (despite dose reductions, see
Section 8.4.5.3)
•
First occurrence of CTCAE grade ≥ 3 keratitis
•
Ophthalmological evaluation reveals conjunctival/corneal scarring
•
Any grade of symblepharon
•
Any grade of fluorescent patches or conjunctival ulceration that does not stabilize or
improve after dose reduction
•
Any dose delay related to ocular toxicity exceeding 12 weeks


 
 
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• Dose delay of more than two weeks due to toxicity possibly related to tisotumab vedotin 
(HuMax-TF-ADC) (except for dose delays due to neuropathy, skin rash, keratitis and 
conjunctivitis)*. 
• Pregnancy. 
• Patient choice. 
• Investigator or sponsor decision. 
* The exception is due to the fact that decrease to CTCAE grade 1 intensity for neuropathy, 
skin rash, keratitis and conjunctivitis may last for more than two weeks. 
8.3.4.2 Criteria for Patient Withdrawal from the Trial 
Patients will be withdrawn from the trial at any time for any of the following reasons: 
• Patient choice. 
• Investigator or sponsor decision. 
• Initiation of new anti-cancer treatment.  
• Lost to follow-up. 
• Intercurrent illness that precludes further participation or requires a prohibited concomitant 
treatment.  
• Disease progression. 
8.3.4.3 Evaluations at Withdrawal from Treatment 
When a patient withdraws from treatment, he/she should return for follow-up visits and the 
End of Treatment page must be filled in.  
8.3.4.4 Evaluations at Withdrawal from the Trial 
When a patient withdraws from the trial, investigators should attempt to obtain information 
and perform an EOT Visit and a 30 day Safety Follow-up Visit. The EOT Visit should be 
performed as soon as possible and prior to initiation of new treatment and will include most 
assessments performed at the Screening Visit, and response assessments (Section 12.5.3).  
In the Dose Escalation part of the trial, the Safety Follow-up Visit should only be performed if 
the patient withdraws before attending Follow-up Visit 1. Only SAEs will be assessed at the 
Safety Follow-up Visit. For patients considered as lost to follow-up, the investigator should 
make an effort (at least one phone call or one written message to the patient), and document 
his/her effort (date and summary of the phone call or copy of the written message in the source 
documents), to complete the final evaluation. All results of these evaluations and observations, 
together with a narrative description of the reason(s) for removing the patient, must be recorded 
in the source documents. The primary reason for withdrawal will be recorded in the eCRF on 
End of Trial page. 




 
 
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Tisotumab vedotin (HuMax-TF-ADC) will be administered over a minimum of 30 minutes. If 
infusion-related events emerge, refer to Section 8.4.4. The infusion is complete when the 
infusion line has been flushed with a minimum 15 mL saline. Preventive eye therapy should 
be administered in relation to infusions as detailed in Section 8.4.5.3. 
8.4.2 
Trial Treatment Preparation 
The dose of tisotumab vedotin (HuMax-TF-ADC) for administration must be prepared by the 
site pharmacy using aseptic technique. Tisotumab vedotin (HuMax-TF-ADC) will be supplied 
to the site/pharmacy as bulk supply cartons.  
The IMP will be supplied in vials containing 40 mg of tisotumab vedotin (HuMax-TF-ADC) 
as lyophilized powder. The powder should be reconstituted with 4 mL water for injection 
leading to a 10 mg/mL solution.  
The reconstituted tisotumab vedotin (HuMax-TF-ADC) should be diluted into 0.9% NaCl 100 
mL infusion bag according to the dose assigned to the patient. 
Tisotumab vedotin (HuMax-TF-ADC) (lyophilized vials) should be stored in a refrigerator at 
2°C to 8°C.  
The infusion must be completed within 24 hours after the tisotumab vedotin 
(HuMax-TF-ADC) vials have been reconstituted. An in-line filter must be used for the 
infusion. The entire 100 mL infusion volume from the prepared infusion bag needs to be 
administered, no dead volume is provided. 
Please refer to the Pharmacy Manuals for instructions on storage, preparation and infusion. 
Labeling will be in accordance with the European Union (EU) Guidelines to Good 
Manufacturing Practice, Annex 13, Investigational Medicinal Products, and any other 
applicable local regulatory requirements. 
8.4.3 
Trial Treatment Storage and Accountability 
It is forbidden to use investigational drug material for purposes other than as defined in this 
protocol. 
8.4.3.1 Trial Treatment Storage 
Tisotumab vedotin (HuMax-TF-ADC) will be stored at 2°C to 8°C in a secure area with 
restricted access. 
8.4.3.2 Trial Treatment Accountability 
The trial drug must exclusively be used for the investigation specified in this protocol and will 
only be accessible to authorized staff. The investigator or designee must confirm and document 
the receipt of the trial drug. 
Vials must be kept at the pharmacy. Throughout the trial, all used and unused material will be 
accounted for. Documented destruction of drugs and containers should be coordinated at the 
clinical site. One copy of the destruction certificate must be kept in the investigator’s file and 
the other copy must be sent to the sponsor representative. 


 
 
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8.4.4 
Treatment of Infusion-Related Reactions 
In the initial patients, few infusion-related reactions, all being CTCAE grade 1, have been 
reported during the Dose Escalation part of the GEN701 trial. However infusion-related 
reactions have been observed in one animal during the pre-clinical studies and with other 
cleavable MMAE based ADCs. Patients should therefore be monitored during infusion. 
• If an infusion-related reaction occurs, the infusion should be interrupted and appropriate 
medical management instituted. The infusions may be restarted at the investigator’s 
discretion. 
• Patients who have experienced prior infusion-related CTCAE grade ≥ 3 reactions in the 
trial should be pre-medicated before all subsequent infusions with an antihistamine and/or 
acetaminophen and/or corticosteroid at the investigator’s discretion.  
• If anaphylaxis occurs, administration of trial drug should be discontinued immediately and 
permanently and appropriate medical therapy should be administered. 
8.4.5 
Dose Modification and Mitigation Plans  
Dose modifications should be preapproved by the sponsor Medical Officer. Below the dose 
modification and mitigation plans are specified according to the once q3wk treatment scheme: 
8.4.5.1 Dose Modification and Mitigation Plan for Skin Toxicity 
• Ongoing, acute or chronic inflammatory skin disease is an exclusion criterion in this trial 
(see Section 8.3.2). 
• Frequent assessments of skin should be performed during Cycle 1: 
o At Days 1 and 15. 
• Assessment of skin during the remaining cycles will be performed on Day 1 in each cycle 
before dosing. 
• Patients’ information to include information about potential skin toxicity and patients will 
be instructed to contact the investigator and/or the site dermatologist in case of skin rash, 
pruritus or bullae. 
• Investigators will be trained in skin monitoring and action to findings. 
• Dose adjustment for skin toxicity should be managed as follows: 
o For CTCAE grade 1 macular-papular skin rash: Continue dosing of tisotumab 
vedotin (HuMax-TF-ADC) as planned, treat with a potent topical steroid 
(betamethasone valerate or equivalent) once daily for up to one week, facial areas 
with a moderate topical steroid (hydrocortisone butyrate 0.1% or equivalent) twice 
daily for up to one week; thereafter every other day for a maximum of three weeks.  
o For CTCAE grade 2 macular-papular skin rash: Postpone dosing of tisotumab 
vedotin (HuMax-TF-ADC) until skin rash has decreased to grade 1, then continue 
dosing of tisotumab vedotin (HuMax-TF-ADC) as planned. Treat the skin rash with 


 
 
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in mixed solid tumors  
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a potent topical steroid (betamethasone valerate or equivalent) once daily for up to 
one week; facial areas with a moderate topical steroid (hydrocortisone butyrate 
0.1% or equivalent) twice daily, followed by dosing once every other day for a 
maximum of three weeks. 
o For CTCAE grade ≥ 3 macular-papular skin rash: Stop dosing (patient withdrawal) 
and treat the skin rash with a potent topical steroid (betamethasone valerate or 
equivalent) once daily for up to one week, followed by dosing once every other day 
for a maximum of three weeks. 
o Vesicular skin reaction: postpone dosing until recovery and continue on half dose 
until the end of treatment period. 
• Withdrawal criteria for skin toxicity: 
o Patients with CTCAE grade ≥ 3 macular-papular skin rash (covering ≥ 30% of body 
surface area [BSA]). 
o Patients with TEN, Steven Johnson and CTCAE grade ≥ 3 cutaneous vasculitis. 
o Patients with CTCAE grade 1 treatment-related bullous dermatitis or skin bullae 
(blister) ≥ 0.5 cm. 
8.4.5.2 Dose Modification for Peripheral Neuropathy and Neutropenia  
Peripheral neuropathy should be managed using a combination of dose delay and reduction to 
2/3 of the initial dose: 
• For new or worsening CTCAE grade 2 or 3 neuropathy: hold dose until neuropathy 
improves to CTCAE  grade ≤ 1, and then restart at 2/3 of the initial dose until end of trial 
treatment.  
• For CTCAE grade 4 peripheral neuropathy: stop dosing and the patient should be 
withdrawn from treatment. 
Neutropenia should be managed by dose delays and dose reductions: 
• Dosing should be held for CTCAE grade 3 or 4 neutropenia until resolution to 
CTCAE grade ≤ 2.  
• Growth factor support should be considered for subsequent cycles in patients who 
experience CTCAE grade 3 or 4 neutropenia.  
• In patients with recurrent CTCAE grade 4 neutropenia despite the use of growth factors, 
discontinuation or dose reduction of trial drug to 2/3 of the initial dose until end of trial 
treatment may be considered after discussion with the sponsor Medical Officer. 
8.4.5.3 Dose Modifications and Mitigation Plan for Ocular Adverse Events 
Events of conjunctivitis and keratitis have been reported in patients treated with tisotumab 
vedotin (HuMax-TF-ADC). To prevent occurrence and ensure appropriate handling, events 
should be prevented and managed as described below. 


 
 
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Preventive measures for all patients: 
• Use of preservative-free lubricating eye drops from the start of trial treatment until the end 
of treatment.  
• Avoid use of contact lenses while treated with tisotumab vedotin (HuMax-TF-ADC). 
• Use of refrigerator-based eye cooling pads during infusion, e.g. THERA PEARL Eye Mask 
or similar. To be applied immediately before infusion in accordance with the instructions 
provided with the eye cooling pads. 
• Administration of local ocular vasoconstrictor before infusion (brimonidine tartrate 0.2% 
eye drops or similar, 3 drops in each eye immediately prior to start of infusion; otherwise 
to be used in accordance with the product prescribing information).  If the patient does not 
tolerate ocular vasoconstrictors due to adverse reactions, continued treatment with these 
may be stopped at the discretion of the investigator and following discussion with the 
Genmab Medical Officer.  
• Application of steroid eye drops for 3 days from the day of infusion (dexamethasone 0.1% 
eye drops or equivalent, 1 drop in each eye 3 times daily for 3 days [first drop to be given 
before start of infusion], otherwise to be used in accordance to product prescribing 
information). 
In case of any ocular symptoms: 
Conjunctivitis: 
Grading:  All events of conjunctivitis should be graded according to both: 
• Ophthalmological grading based on the objective eye-examination findings performed by 
the ophthalmologist. 
• CTCAE grading system based on National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI-CTCAE) version 4.03 (NCI-CTCAE v4.03, 2010) assessed by 
the investigator. 
Dose delay and dose modification: 
• CTCAE grade 1 conjunctivitis: Hold dosing until the event is managed effectively by 
topical treatment initiated by the ophthalmologist (according to treatment guidelines 
below). When the event is managed effectively the patient can be re-treated with the same 
dose of trial drug as being administered prior to the event onset.  
• CTCAE grade 2 conjunctivitis: Hold dosing. Topical treatment should be initiated by the 
ophthalmologist (according to treatment guidelines below). When the event has improved 
to ≤ CTCAE grade 1, dosing of trial drug can be resumed at a reduced dose (please refer 
to dose modification scheme below).  
o In case of recurrence of conjunctivitis CTCAE grade 2 the patient should hold 
dosing and topical treatment should be initiated by the ophthalmologist (according 
to treatment guidelines below). When the event is CTCAE grade ≤ 1, dosing of trial 


 
 
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drug can be resumed at a further reduced dose (please refer to dose modification 
scheme below).  
 If the conjunctivitis recurs again at CTCAE grade 2, the patient should hold 
dosing and topical treatment should be initiated by the ophthalmologist 
(according to treatment guidelines below). When the event is CTCAE 
grade ≤ 1, dosing of trial drug should not be further reduced but resumed at 
0.9 mg/kg. . 
• CTCAE grade ≥ 3 conjunctivitis: Hold dosing. Topical treatment should be initiated by the 
ophthalmologist (according to treatment guidelines below). When the event has improved 
to CTCAE grade ≤ 1, dosing of trial drug can be resumed at a reduced dose (please refer 
to dose modification scheme below).  
o If the conjunctivitis recurs at CTCAE grade ≥ 3, the patient must permanently 
discontinue treatment with trial drug. 
Keratitis: 
Grading:  All events of keratitis should be graded according to both: 
• 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 4.03). 
Dose delay and dose modification: 
• CTCAE grade ≤ 2 keratitis: Hold dosing until the event is managed effectively by topical 
treatment (according to treatment guidelines below) initiated by the ophthalmologist. When 
the event is ≤ CTCAE grade 1, dosing of trial drug can be resumed at a reduced dose (please 
refer to dose modification scheme below).  
o In case of recurrence of CTCAE grade ≤ 2 keratitis, the patient should hold dosing 
and topical treatment (according to treatment guidelines below) should be initiated 
by the ophthalmologist. When the event is CTCAE grade ≤ 1, dosing of trial drug 
can be resumed at a further reduced dose (please refer to dose modification scheme 
below).  
 In case of 3rd occurrence of keratitis CTCAE grade ≤ 2, the patient must 
permanently discontinue treatment with trial drug. 
• CTCAE grade ≥ 3 keratitis: The patient must permanently discontinue treatment with trial 
drug. 


 
 
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Conjunctival ulceration: 
If an ophthalmological evaluation reveals fluorescent patches or conjunctival ulceration of any 
grade:  
o Hold dose until conjunctivitis/conjunctival ulceration is managed effectively by 
topical treatment (according to treatment guidelines below). When the event is 
managed effectively, dosing of trial drug can be resumed at a reduced dose (please 
refer to dose modification scheme below). 
o If symptoms do not stabilize/improve after dose reduction, the patient must 
permanently discontinue treatment with trial drug. 
Treatment guidelines  
Ocular symptom  
Treatment guideline  
(The length of treatment should be decided by the 
local ophthalmologist) 
Conjunctivitis: CTCAE grade 1 
The local ophthalmologist should prescribe frequent 
dosing of preservative-free topical steroid drops 
Conjunctivitis: CTCAE grade 2 
The local ophthalmologist should prescribe frequent 
dosing (every 2nd hour) of preservative-free topical 
steroid drops in conjunction with preservative free 
antibiotic prophylaxis such as chloramphenicol 
Conjunctivitis: CTCAE grade 3 
The local ophthalmologist should prescribe frequent 
dosing (every 2nd hour) of preservative-free topical 
steroid drops in conjunction with preservative free 
antibiotic prophylaxis such as chloramphenicol 
Keratitis: CTCAE grade 1 
The local ophthalmologist should prescribe frequent 
dosing of preservative-free topical steroid drops 
Keratitis: CTCAE grade 2 
The local ophthalmologist should prescribe frequent 
dosing (every 2nd hour) of preservative-free topical 
steroid drops in conjunction with preservative free 
antibiotic prophylaxis such as chloramphenicol 
Conjunctival ulceration: any 
grade 
The local ophthalmologist should prescribe frequent 
dosing (every 2nd hour) of preservative-free topical 
steroid drops in conjunction with preservative free 
antibiotic prophylaxis such as chloramphenicol 


 
 
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Dose modification scheme: 
Previous dose of tisotumab vedotin 
Reduced dose of tisotumab vedotin 
2.0 mg/kg 
1.3 mg/kg 
1.3 mg/kg 
0.9 mg/kg 
0.9 mg/kg 
0.9 mg/kg* 
*If the patient is already being treated with tisotumab vedotin (HuMax-TF-ADC) 0.9 mg/kg 
every 3rd week, the dose of tisotumab vedotin (HuMax-TF-ADC) should not be reduced further. 
Trial drug discontinuation criteria for ocular toxicity: 
Treatment with trial drug must be permanently discontinued in case of: 
• First recurrence of CTCAE grade ≥ 3 conjunctivitis  (despite dose reduction) 
• Third recurrence of CTCAE grade ≤ 2 keratitis (despite dose reductions) 
• First occurrence of CTCAE grade ≥ 3 keratitis  
• Ophthalmological evaluation reveals conjunctival/corneal scarring  
• Any grade of symblepharon 
• Any grade of fluorescent patches or conjunctival ulceration that does not stabilize or 
improve after dose reduction 
• Any dose delay related to ocular toxicity exceeding 12 weeks 
8.4.5.4 Dose Modification for QTcF Changes in the Electrocardiogram 
Prolongation of QTcF interval during the trial should be managed as follows: 
• For CTCAE grade 1 QTcF interval prolongation (450 to 480 msec): check electrolytes 
(calcium, magnesium and potassium) prior to next dosing, but no dose adjustment or dosing 
hold is required. 
• For CTCAE grade 2 QTcF interval prolongation (481 to 500 msec): hold dosing until 
improvement to grade 1 or lower and check electrolytes (calcium, magnesium and 
potassium) and substitute until normal levels; then dose can be restarted and ECGs should 
be performed at least every other day.  
If the QTcF interval prolongation is not related to electrolyte abnormality, hold dosing until 
improvement to grade 1 or lower; then next infusions may be restarted at half of the initial 
infusion rate; ECGs should be performed at least every other day. 
• For CTCAE grade 3 QTcF interval prolongation (≥ 501 msec on at least two separate 
ECGs): stop dosing. Then, check electrolytes (calcium, magnesium and potassium) and 


 
 
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substitute until normal levels; ECGs should be performed at least daily; consider obtaining 
cardiology consult. Please see Section 8.3.4.1. 
8.4.5.5 Dose Modification for Increased Liver Enzymes 
In case of grade ≥ 3 AE associated to liver enzymes elevation, regardless of its relationship 
with the IMP, the site must contact the sponsor Medical Officer before next dosing of the 
patient, in order to decide whether there should be any dose adjustment, delay or withdrawal 
of the patient. 
8.4.5.6 Dose Modification for Mucositis 
• Dose modification for mucositis: 
o Patients with CTCAE grade 3 mucositis: hold dosing until mucositis improves to 
CTCAE grade 2. Mucositis should be treated according to local practice. 
• Withdrawal criteria for mucositis: 
o Patients with CTCAE grade ≥ 4 mucositis: the patient should be withdrawn from 
treatment. 
8.4.6 
Precautions 
Patients receiving the following therapy during and three weeks after the last treatment with 
tisotumab vedotin (HuMax-TF-ADC) should be monitored closely for adverse reactions:  
• Drugs and substances known to be strong CYP3A4 and/or P-gp inhibitors (also excluded 
as concomitant medication, see Section 8.4.9.3) like boceprevir, clarithromycin, 
conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, voriconazole, amiodarone, clarithromycin, verapamil. 
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInter
actionsLabeling/ucm093664.htm). 
8.4.7 
Dose Escalation 
8.4.7.1 Dose Escalation Overview 
The Dose Escalation part is a standard 3 (+3) design which will evaluate tisotumab vedotin 
(HuMax-TF-ADC) at doses of 0.9 mg/kg and up to a maximum of 1.5 mg/kg. Dose reduction 
can be considered if the MTD is exceeded at 0.9 mg/kg.  
Decisions to escalate the dose of tisotumab vedotin (HuMax-TF-ADC) for the next cohort will 
be based on the safety data obtained from the 3 (+3) patients during their first treatment cycle 
(28 days). A DMC will evaluate all safety data (including SAEs, AEs and laboratory data) after 
each cohort completes Cycle 1. All patients in a cohort must be observed for at least four weeks 
after the first infusion before data are sent to the DMC to review. 


 
 
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Based on the results presented in these safety profiles, the DMC will make a recommendation 
regarding dose escalation. The recommendation will be discussed and confirmed by the 
sponsor’s internal Safety Committee, who will ultimately decide whether dose escalation shall 
occur. In addition, the DMC will be provided all available safety data.  
Patients who discontinue the trial during the first cycle for reasons other than a DLT should be 
replaced. As the drug exposure of such patients is considered insufficient to form a basis for a 
dose escalation decision, they are not included in the evaluation of DLTs in 3 (+3) patients. 
For this trial, the MTD will be defined as the highest dose level below the dose at which 
≥ two patients experience DLTs within the three to six patients of one cohort are observed. The 
DMC and the sponsor’s Safety Committee may decide to implement intermediate doses below 
that at which ≥ 2 DLTs were identified to ensure patients safety and better define the MTD.   
At the expected MTD up to six patients will be treated. 
8.4.7.2 Dose Escalation Rules 
Each cohort will enroll three patients. If a DLT is observed during the first treatment cycle, the 
cohort for the current dose level will be expanded to enroll an additional three patients.  
The classic 3 (+3) design will be implemented as follows:  
• Three patients are allocated per new dose level until a DLT is observed.  
• In each cohort, a minimum of one day between the dosing of the patients will be 
implemented. 
• All patients in a cohort must be observed for at least four weeks after the first infusion 
before data are sent to the DMC to review and decide on dose escalation. 
• If a DLT is observed within the first cycle, the cohort on the corresponding dose level will 
be expanded with three additional patients. Depending on the nature of the DLT, the DMC 
may require that at least one patient of the additional three patients to be included at the 
same dose level should have the same cancer type as the patient who had the DLT. 
• If no other patient with DLT is observed in the expanded cohort, the trial will continue 
escalation to next dose level.   
• If at least one additional patient with a DLT (i.e., ≥ 2 patients with DLTs within the 
six patients) is observed on the same dose level, additional patients will not be enrolled at 
that dose level. The dose will be de-escalated until a dose level where three patients with 
no observed DLTs or, six patients have been treated with ≤ 1 instance of DLT observed. 
This will be the MTD. 
In order to adequately assess the safety of the mixed population in this trial, dose cohorts will 
be partially stratified to have ≥ 2 different cancer types represented in the cohort. 


 
 
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8.4.8 
Dose Limiting Toxicities for the Dose Escalation Part of the Trial 
For the purpose of dose escalation, DLTs will be collected and assessed for the first cycle 
(28 days) of each cohort. Dose limiting toxicities must be reported to the sponsor within 
24 hours. Causality for DLTs will be assessed by the sponsor in collaboration with the DMC. 
Dose limiting toxicities include the following AEs at least possibly related to tisotumab vedotin 
(HuMax-TF-ADC): 
Table 7: 
Criteria for Defining Dose Limiting Toxicities 
Toxicity 
Any of the following criteria 
Hematologic 
• Grade 4 neutropenia (i.e., ANC < 0.5 × 109 cells/L) for minimal 
duration of 7 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 1 hour). 
• Grade 4 thrombocytopenia (≤ 25.0 × 109 platelets/L). 
• 
Grade 3 thrombocytopenia associated with bleeding episodes. 
• 
Major bleeding (as defined in Section 10.11 Bleeding Assessments). 
Dermatologic 
• Stevens Johnson syndrome, TEN, grade ≥ 3 cutaneous vasculitis. 
Neurologic  
• Grade 3 neuropathy (not improving to grade 1 within 3 weeks 
following stop of dosing) and grade 4 neuropathy. 
Gastrointestinal • 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.  
IRRs 
• Grade 3 infusion-related AEs that do not resolve to grade 1 or baseline 
within 24 hours. 
• Grade 4 infusion-related events including anaphylaxis. 
Other 
• Any grade ≥ 3 non-hematological AEs which occur during the first 
treatment cycle, are at least possibly trial drug-related, and are 
regarded as medically important as assessed by the DMC, excluding 
non-hematological laboratory abnormalities that have no clinical 
consequences and resolve within 48 hours.  
AE=Adverse Events; ANC=Absolute neutrophil count; CTCAE=Common Terminology Criteria for Adverse 
Events; DMC= Data Monitoring Committee; IRR = Infusion-related Reaction; TEN=Toxic Epidermal Necrolysis 
Adverse events at least possibly related to HuMax TF-ADC. 
CTCAE version 4.03, 2010, will be used for all grading. 
 
At the DMC meetings following each cohort, safety data for the specific cohort as well as 
cumulative safety data (SAEs, AE and laboratory data) for all cohorts will be evaluated for 
identification of any safety signals and actions will be recommended by the DMC. Following 


 
 
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each DMC meeting, an internal Safety Committee meeting will be held comprising Heads of 
Drug Safety, Regulatory, Clinical Development and Medical to discuss and confirm actions 
recommended by the DMC. 
Depending on the nature of the DLT and the patient status, the DMC and the Safety Committee 
may allow a patient with a DLT to continue on the trial, potentially on a reduced dose. 
8.4.9 
Prior and Concomitant Therapy 
8.4.9.1 Prior Therapy 
The following therapies must be recorded as applicable and taken into account for the 
evaluation of the inclusion and exclusion criteria: 
• Any prior anti-cancer treatment regimens. 
• Any systemic therapy administered within three months prior to screening. 
Administration of prior therapies must be reported in the appropriate section of the eCRF along 
with dates of administration and reasons for use. 
8.4.9.2 Permitted Concomitant Medications 
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as “excluded” 
(Section 8.4.9.3). Administration of concomitant medications must be reported in the 
appropriate section of the eCRF along with dates of administration, dose and reasons for use.    
8.4.9.3 Excluded Concomitant Medications 
Patients must be instructed not to take any medications, including over-the-counter products, 
without first consulting the investigator. 
The following medications are considered exclusionary during the trial. The sponsor must be 
notified if a patient receives any of these during the trial. 
• Any investigational anti-cancer therapy. 
• Therapeutic anti-coagulative or long-term anti-platelet treatment. 
o Use of low dose ASA up to 81 mg/day and non-ASA NSAID is allowed.  
• Drugs and substances known to be strong CYP3A and/or P-gp inhibitors (e.g., boceprevir, 
clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, 
telaprevir, telithromycin, voriconazole, amiodarone, clarithromycin, verapamil) should not 
be administered during the trial period. 
• No dietary supplements are allowed during the trial period, except multivitamins, 
vitamin D and calcium. 


 
 
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8.4.9.4 Treatment Compliance 
Tisotumab vedotin (HuMax-TF-ADC) will be administered by trial site personnel, who will 
monitor patient compliance. 
8.4.9.5 Assignment to Treatment 
This is an open-label trial. Trial participation begins once written informed consent is obtained.  
After obtaining informed consent, patients will be given a screening number before they 
undergo any screening procedure. A screening number consists of the letter “S” followed by 
the trial number and subsequently a 3- or 4-digit number that uniquely identifies a patient at a 
Screening Visit. For example, a screening number in this trial could be “S702034”. 
Patients who have complied with all selection criteria will receive a patient number upon 
enrollment in the trial. A patient number consists of the trial number combined with a 3- or 
4-digit number that uniquely identifies a patient during the trial. For example, patient 12 in this 
trial would be uniquely identified by the combined code “702012”. 
A master log of all consented patients will be maintained at the sites and will document all 
screening failures (i.e., patients who are consented but do not meet the trial eligibility criteria) 
including the reason for screening failure. 


 
 
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9 
TRIAL EVALUATIONS  
Trial evaluations by visit are detailed in the Schedules of trial procedures in Table 1 and 
Table 3 according to the initially designed treatment scheme. Trial evaluations by visit for the 
Cohort Expansion part after implementation of the urgent safety measure (Protocol 
Amendment 4.0) are detailed in Table 5. A description of the methods of assessments is 
provided in Section 10. 
All patients who are assigned a patient number and receive any trial drug will be followed 
according to the protocol regardless of the number of doses received, unless consent is 
withdrawn. The investigator must notify the sponsor or designee of deviations from protocol 
visits or evaluations, and these evaluations, if applicable, must be rescheduled or performed at 
the nearest possible time to the original schedule. Protocol deviations will be recorded on the 
source document with an explanation for the deviations and any trial-specific eCRF or logs 
designated for capturing protocol deviations, if applicable for the trial. The investigator must 
comply with the applicable requirements related to the reporting of protocol deviations to the 
IEC/IRB. 
Patients will be instructed to call the trial personnel to report any abnormalities during the 
intervals between trial visits and to come to the trial site if medical evaluation is needed and 
the urgency of the situation permits. For emergency and other unscheduled visits to a medical 
facility other than the trial site, medical records will be obtained by the investigator and made 
available to the sponsor or designee during monitoring visits. 
9.1 
Dose Escalation Part 
9.1.1 
Dose Escalation Part: Screening (Visit 0) 
All screening procedures must be performed within 21 days before the first dose of tisotumab 
vedotin (HuMax-TF-ADC) on Day 1 of Cycle 1 (C1-V1), except for the CT-scan that may be 
performed within four weeks before C1-V1. The screening evaluations may be carried out over 
more than one visit. Written informed consent and any locally required privacy act document 
authorization must be obtained prior to performing any protocol-specific procedures, including 
screening evaluations.  
A patient may be rescreened one time only. A rescreening must be approved by the sponsor to 
ensure that the safety of the patient is not compromised.   
9.1.2 
Dose Escalation Part: Treatment  
The Dose Escalation part of the trial must be run in phase I units with cardiopulmonary 
resuscitation rescue equipment available and fast access to emergency units. 
Tisotumab vedotin (HuMax-TF-ADC) will be administered 3q4wk, on Day 1, Day 8 and 
Day 15 of each 28-day treatment cycle. Dose escalation to MTD is anticipated to involve 
approximately three dose levels with an anticipated maximal exposure of 1.5 mg/kg. 
Throughout the infusion patients will be under surveillance by trial personnel. The physician 
supervising the trial drug infusion must be readily accessible for assistance during the day of 
infusion. 


 
 
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The investigator must have evaluated the patient’s eligibility and must confirm receipt of 
sponsor decision and patient number before the patient’s first infusion. This form will have to 
be validated by the sponsor and/or designee and will serve to assign the patient number.  
The patients will receive four cycles of tisotumab vedotin (HuMax-TF-ADC) at four-week 
intervals. Thus, the treatment period will last for 16 weeks, or until the patient withdraws from 
the treatment/trial due to withdrawal criteria.  
During infusions the patient should be closely monitored including vital signs and general 
assessment for at least two hours following administration of tisotumab vedotin 
(HuMax-TF-ADC) in a setting with resuscitation equipment and other agents necessary to treat 
anaphylaxis (e.g., epinephrine, corticosteroids, intravenous antihistamines, bronchodilators 
and oxygen). Patients requiring treatment for infusion-related reactions should be monitored 
until the resolution of the event.  
9.1.2.1 Dose Escalation Part: Cycle 1  
During Cycle 1, seven trial visits will be performed on Days 1, 2, 8, 15, 16, 18 and 22.   
9.1.2.2 Dose Escalation Part: Cycles 2 to 4 
During Cycles 2 to 4, four trial visits will be performed on Days 1, 8, 15 and 22 of each cycle. 
After four cycles, if there is evidence of the patient benefitting from treatment, there is an 
option to continue in the trial for up to a maximum of eight additional cycles (32 weeks) or 
until patient withdraws from treatment/the trial due to withdrawal criteria, at the discretion of 
the treating physician based on the patient status. 
9.1.2.3 Dose Escalation Part: Cycles 5 to 12 
For patients who continue in the trial for additional cycles, weekly trial visits will be performed 
on Days 1, 8, 15 and 22 of each cycle (Cycles 5 to 12). In addition, a CT-scan will be performed 
21 days (± 7 days) after Day 15 of Cycle 12. 
At the end of this period, Genmab will ensure provision of continued treatment to patients with 
clinical benefit defined as SD or better, until unacceptable toxicity or PD is observed. 
9.1.3 
Dose Escalation Part: Follow-up Visits (FU1 to FU4) 
If the patient withdraws from treatment or completes all cycles, he/she will continue follow-
up visits every six weeks (± 1 week), until other treatment is initiated or patient withdraws 
from the trial due to other reason, for a maximum of 24 weeks. 
9.1.4 
Dose Escalation Part: Unscheduled Visit (U1 to UX) 
If judged necessary by the investigator, the patient can be called in for unscheduled visit(s). 
The reason for the visit and visit date must be recorded in the eCRF. 
During an unscheduled visit the investigator will assess AEs and record concomitant 
medication. Additional trial assessments can be performed at the investigator’s discretion. To 
monitor patient safety, the investigator may request additional blood samples. 


 
 
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9.1.5 
Dose Escalation Part: End of Trial Visit (EOT)  
If a patient withdraws from the trial, the EOT Visit should be performed as soon as possible 
after withdrawal. If a patient completes all the follow-up visits, the EOT Visit should be 
performed four weeks after end of Follow-up Visit 4 period.  
9.1.6 
Dose Escalation Part: Safety Follow-up Visit 
Patients who withdraw from the trial before the Follow-up Visit 1 will return for a Safety 
Follow-up Visit, 30 days after the last dose of IMP. In the Safety Follow-up Visit, only SAEs 
will be assessed. 
9.2 
Cohort Expansion Part 
9.2.1 
Cohort Expansion Part: Screening (Visit 0) 
All screening procedures must be performed within 21 days before the first dose of tisotumab 
vedotin (HuMax-TF-ADC) on Day 1 of Cycle 1 (C1-V1), except for the CT scan that may be 
performed within four weeks before C1 V1. The screening evaluations may be carried out over 
more than one visit. Written informed consent and any locally required privacy act document 
authorization must be obtained prior to performing any protocol-specific procedures, including 
screening evaluations.  
A patient may be rescreened one time only. A rescreening must be approved by the sponsor to 
ensure that the safety of the patient is not compromised.  
9.2.2 
Cohort Expansion Part: Treatment 
The investigator must have evaluated the patient’s eligibility before the patient’s first infusion.  
In the Cohort Expansion part of the trial 20 to 30 patients will be treated with a regimen based 
on the data obtained from the Dose Escalation part. Patients may receive up to nine cycles of 
treatment. The treatment period will last for up to 36 weeks (or less after changing to the once 
q3wk dosing scheme) or until unacceptable toxicity or disease progression at the discretion of 
the treating physician. 
During infusions the patient should be closely monitored including vital signs and general 
assessment for at least two hours following administration of tisotumab vedotin 
(HuMax-TF-ADC) in a setting with resuscitation equipment and other agents necessary to treat 
anaphylaxis (e.g., epinephrine, corticosteroids, intravenous antihistamines, bronchodilators 
and oxygen). Patients requiring treatment for infusion-related reactions should be monitored 
until the resolution of the event. Preventive eye therapy should be administered in relation to 
infusions as detailed in Section 8.4.5.3. 
9.2.2.1 Cohort Expansion Part: Cycle 1  
During Cycle 1, five trial visits will be performed on Days 1, 8, 15, 18 and 22.  
9.2.2.2 Cohort Expansion Part: Cycles 2 to 9 
During Cycles 2 to 9, four trial visits will be performed on Days 1, 8, 15 and 22 of each cycle. 


 
 
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9.2.2.3 Cohort Expansion Part: Cycles 1 to 9 According to Protocol Amendment 4.0 
During Cycles 1 to 9, three trial visits will be performed on Days 1, 8 and 15 of each cycle. 
At the end of the planned number of cycles, Genmab will ensure provision of continued 
treatment to patients with clinical benefit defined as SD or better, until unacceptable toxicity 
or PD is observed, at the discretion of the treating physician. 
9.2.3 
Cohort Expansion Part: Unscheduled Visit (U1 to UX) 
If judged necessary by the investigator, the patient can be called in for unscheduled visit(s). 
The reason for the visit and visit date must be recorded in the eCRF. 
During an unscheduled visit the investigator will assess AEs and record concomitant 
medication. Additional trial assessments can be performed at the investigator’s discretion. To 
monitor patient safety, the investigator may request additional blood samples. 
9.2.4 
Cohort Expansion Part: End of Trial Visit (EOT)  
If a patient withdraws from the trial, the EOT Visit should be performed as soon as possible 
after withdrawal.  
9.2.5 
Cohort Expansion Part: Safety Follow-up Visit 
Patients who withdraw from the trial will return for a Safety Follow-up Visit, 30 days after the 
last dose of IMP. In the Safety Follow-up Visit, only SAEs will be assessed. 


 
 
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Tisotumab vedotin (HuMax®-TF-ADC) 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
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10 
METHODS OF ASSESSMENT 
Trial procedures will be performed on the trial dates noted in Table 1 and Table 3 according to 
the initially designed treatment scheme, and in Table 5 after implementation of the urgent 
safety measure (Protocol Amendment 4.0). A description of the different assessments is 
provided below.  
10.1 Demographics 
Date of birth (day and month will be anonymized if required by local regulations); ethnic origin 
and gender will be recorded in the eCRF. 
10.2 Medical History 
Any relevant past and all current diseases will be recorded in the eCRF including staging (TNM 
staging system). In addition, all prior cancer treatment regimens will be recorded including 
clinical response for the last regimen (and earlier lines of therapy if available). Non-serious 
AEs (signs, symptoms and diagnosis) occurring between Visit 0 (Screening) and first treatment 
(C1-V1) should be recorded as Medical History.  
Serious adverse events should be reported from the time of signing informed consent both on 
the AE form of the eCRF and on SAE reporting form (as described in Section 11.4.3). 
10.3 Height and Weight 
Height (without shoes) must be measured at Visit 0 (Screening) and recorded in the eCRF 
rounded to nearest centimeter. Body weight (without overcoat and shoes) will be measured at 
Visit 0 (Screening), at Day 1 of each cycle, as part of the dose calculation, and at EOT, and 
will be recorded in the eCRF rounded to nearest kilogram.  
If body weight is assessed seven days or less before the day of the planned dosing at Day 1, 
this value can be used. 
10.4 Physical Examination 
A general physical examination should include general appearance and the following body 
systems need to be examined: lymph nodes, mouth and throat (non-tumor bearing parts), lungs, 
cardiovascular system, abdomen, extremities, musculoskeletal system, neurological system 
and skin (for assessment of skin reactions refer to Section 10.12). The outcome of the physical 
examination must be recorded in the eCRF. 
10.5 Vital Signs 
Vital signs should be recorded in the eCRF including temperature, blood pressure and heart 
rate. Within each visit, preferably the same equipment shall be used for vital signs 
measurements. Vital signs should be assessed just before and no longer than 30 minutes before 
infusion start, during and after the infusions until two hours after the infusions, as follows: 


 
 
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Tisotumab vedotin (HuMax®-TF-ADC) 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
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Vital signs assessments during the Dose Escalation Part 
Cycle 1 
Cycle 2 – Cycle 12 
Pre-infusion (including weight) 
Pre-infusion (including weight) 
30 min after start of infusion (± 5 min) 
 
At the end of infusion (± 5 min)  
At the end of infusion (± 5 min)  
30 min after end of infusion (± 5 min) 
 
1 hour after end of infusion (± 5 min) 
 
2 hours after end of infusion (± 15 min) 
2 hours after end of infusion (± 15 min) 
 
If the infusion lasts for more than 30 minutes, vital signs should be assessed approximately 
every 30 minutes (± 5 minutes) for the duration of infusion. 
Vital Signs Assessments during the Cohort Expansion Part 
Cycle 1 – Cycle 9 
Pre-infusion (including weight) 
At the end of infusion (± 5 min)  
2 hours after end of infusion (± 15 min) 
On non-infusion visits, to be performed in relation with other assessments. 
 
10.6 Electrocardiogram 
Electrocardiograms will be recorded digitally at the sites by using the standard 12-leads. One 
ECG will be performed at screening. Three ECGs should be performed at least two minutes 
apart before the first infusion of the trial drug in each cycle, in accordance with the ECG 
Specifications Manual. The digital ECGs will be transmitted from the sites electronically to a 
central laboratory for measurement of the cardiac intervals and morphologic assessment by a 
central cardiologist. 
An overall interpretation of the ECGs will be performed by the investigator, or the investigator 
may delegate this task to a cardiologist, if applicable.  
For the ECG recordings, the patients must be resting in a supine position for at least 10 minutes. 
Any irregularity observed or occurring during the ECGs (e.g., vomiting, cough) should either 
result in a repeat of the ECG or be annotated on the eCRF with the description and time of the 
occurrence. 
10.7 Computerized Tomography  
All patients will have a CT-scan with contrast of thorax, abdomen and pelvis performed during 
screening. If there is suggestion of brain metastases/tumors, a CT-scan of the head will be 
performed before inclusion.  
Up to five target lesions (maximum two per organ) will be defined at screening and these must 
be followed throughout the trial. Non-target lesions will also be assessed throughout the trial. 


 
 
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Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
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Scans will be repeated every six weeks (at the end of every second cycle) during the trial 
period. If the result is PR or better, CT-scan should be repeated after four weeks to confirm 
response. CT-scans can be performed up to seven days before Day 1 of the relevant cycle to 
ensure results are available before subsequent dosing. 
Additional CT-scans may be performed at the investigators’ discretion to confirm response or 
new symptoms. In this case, the investigator must choose the imaging technology based on the 
clinical indication.  
Magnetic resonance imaging can be performed instead of a CT-scan if the patient is allergic to 
iodine contrast or at the discretion of the investigator, after approval of the sponsor.  
The reading of the surveys will be done by a radiologist. Sites should attempt to maintain the 
same radiologist throughout the trial. The overall interpretation of the evaluation shall be 
recorded in the eCRF and a copy of the evaluation reports should be kept in the patient’s file. 
10.8 ECOG Performance Status 
The ECOG performance status scale (Appendix 1) will be used and will be assessed by the 
investigator at screening, on Day 1 of each cycle, and at the EOT Visit. 
10.9 Adverse Events 
Adverse events will be assessed and reported at each visit. All AEs will be graded according 
to the NCI-CTCAE version 4.03 (NCI-CTCAE v4.03, 2010). 
SAEs and non-serious grade 3 AEs will be reported from the investigational site to the sponsor 
within 24 hours. In addition, all non-serious grade 2 ocular AEs must be reported from the 
investigational site to the sponsor within 24 hours. 
Weekly Safety/Medical meetings will be held in the Dose Escalation part of the trial to evaluate 
all AEs and laboratory data and follow-up information obtained during the previous week. In 
the Cohort Expansion part of the trial, bi-weekly evaluations will be made. 
Further details on AEs monitoring and reporting are provided in Section 11. 
10.10 Concomitant Medication 
Any medication or therapy other than the trial drug is considered concomitant medication and 
should be recorded in the eCRF with the following information: 
• Start date. 
• Route of administration. 
• Stop date of administration or ongoing at trial termination. 
• Indication/reason for use. 
The total daily dose should be provided whenever possible. 
The recording period for concomitant medication will start from Visit 0 (Screening) until the 
EOT Visit.  


 
 
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Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
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10.11 Bleeding Assessments 
Major bleeding is defined as any of the following conditions according to the International 
Society on Thrombosis and Haemostasis (Shulman and Kearon, 2005): 
• Fatal bleeding; and/or 
• Symptomatic bleeding in critical area organ, such as intracranial, intraocular, 
retroperitoneal, intra-articular or pericardial, or intramuscular with compartment 
syndrome; and/or 
• Bleeding causing a drop in hemoglobin level of 20 g/L (1.24 mmol/L) or more, or bleeding 
leading to transfusion of two or more units of whole blood or red cells. 
Minor bleeding includes: 
• Cutaneous bleeding, nose bleeding, oral cavity bleeding, menorrhagia, spontaneous muscle 
hematomas without compartment syndrome, grade 1 and 2 hematuria, and excessive 
bleeding after minor injury. 
Any bleeding AE shall also be recorded with a CTCAE grading.  
10.12 Skin Assessments 
Development of skin reactions will be monitored during the trial and registered on a separate 
form. A Dermatologist must be available for consulting at each site.  
Rash should be reported and graded according to the NCI-CTCAE for macular-papular skin 
rash according to Table 8 below: 
Table 8: 
Grading of Skin Rash 
System 
Organ 
Class 
Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Skin and 
subcutaneou
s tissue 
disorders 
Rash 
maculo-
papular 
Macules/pap
ules 
covering < 
10% BSA 
with or 
without 
symptoms 
(e.g., 
pruritus, 
burning, 
tightness) 
Macules/pap
ules 
covering 
10-30% 
BSA with or 
without 
symptoms 
(e.g., 
pruritus, 
burning, 
tightness); 
limiting 
instrumental 
activities of 
daily living 
Macules/pap
ules 
covering > 
30% BSA 
with or 
without 
associated 
symptoms; 
limiting 
self-care 
activities of 
daily living 
Life-
threatening 
Death 
BSA=Body Surface Area 
In case of bulla/bullae, these should be measured and reported as AEs. 


 
 
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Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
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Patients should be withdrawn if they experience a trial drug-related grade ≥ 3 macular-papular 
skin rash (covering ≥ 30% of BSA), bullae (skin blisters ≥ 0.5 cm) or TEN, Steven Johnson or 
grade ≥ 3 cutaneous vasculitis. 
10.13 Neuropathy Assessment 
A standard scheme for assessment of peripheral neuropathy will be used and will be included 
in the eCRF to obtain information on whether potential neuropathy is peripheral or central, 
motor or sensory, and the localization. 
10.14 
Ophthalmological Evaluation 
Ophthalmological evaluations should be performed at baseline and during the trial as indicated 
in the trial flow chart.  
The ophthalmological evaluation should include collection of medical ophthalmological 
history (at baseline only), visual acuity assessment, Shirmer’s test, slit-lamp examination, 
measurement of ocular pressure and funduscopic.  
Patients experiencing ocular symptoms during the trial must be referred to an ophthalmologist 
for prompt review (preferably within 72 hours and no later than within one week). 
10.15 Radionuclide Bone Scan 
For patients with CRPC, a radionuclide bone scan will be performed at screening, every 
12 weeks during treatment (i.e., Day 1 of Cycles 5 and 9), and upon clinical indication. If there 
is suspicion of progression, another bone scan will be performed 12 weeks later. The screening 
radionuclide bone scan can be performed up to four weeks prior to Visit C1-V1. 
10.16 Laboratory Assessments 
Blood sampling will be collected for assessment of laboratory parameters. Some laboratory 
samples will be tested at the site while others will be drawn and shipped for centralized testing. 
A manual with detailed description of the procedures for sampling, handling, storage and 
shipment of the laboratory samples and all material such as test tubes and labels for central 
analysis will be provided by the central laboratory. The manual and the result reports will 
include all reference ranges. 
Laboratory equipment in central and local laboratories may provide standard analyses not 
requested in the protocol but produced automatically in connection with the requested analyses. 
Such data will not be transferred to the eCRF but must be reported to the investigator. 
If a non-serious grade ≥ 3 laboratory abnormality occurs during Cycle 1 and is assessed as 
related or possibly related to the trial drug, then a new laboratory sample should be collected 
performed within 48 hours (and as close to 48 hours as possible) and reported as an 
unscheduled visit. This is to confirm or reject the fulfillment of the DLT assessment as defined 
in Section 8.4.8 (Any grade ≥ 3 non-hematological AEs which occur during the first treatment 
cycle and are at least possibly trial drug related, excluding non-hematological laboratory 
abnormalities that have no clinical consequences and resolve within 48 hours).  


 
 
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Final 5.0 (incorporating Protocol Amendment 4) 
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A patient can always be called in for an unscheduled visit(s) if judged necessary by the 
investigator.  
To monitor patient safety, the investigator can request additional blood samples at the 
unscheduled visit. The reason for the visit and visit date must be recorded in the eCRF. 
10.16.1 Hematology 
In the Dose Escalation part of the trial, hematology parameters will be analyzed at the site 
laboratory.  
In the Cohort Expansion part of the trial, hematology parameters will be analyzed at a central 
laboratory.  
A blood sample will be drawn at each visit for analysis of the following parameters: red blood 
cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, 
mean corpuscular hemoglobin concentration, white blood cell count with differential, platelet 
count and reticulocyte count. 
10.16.2 Biochemistry  
In the Dose Escalation part of the trial, biochemistry parameters will be analyzed at the site 
laboratory.  
In the Cohort Expansion part of the trial, biochemistry parameters will be analyzed at a central 
laboratory.  
A blood sample will be drawn at each visit for analysis of the following parameters: sodium, 
potassium, calcium, magnesium, creatinine, blood urea nitrogen, AST, ALT, alkaline 
phosphatase, albumin, glucose, total creatine kinase, total bilirubin, lactate dehydrogenase, uric 
acid, s-ferritin, C-reactive protein and glycosylated hemoglobin.  
10.16.3 Coagulation Factors 
In the Dose Escalation part of the trial, coagulation factors will be analyzed at the site.  
In the Cohort Expansion part of the trial, coagulation factors will be analyzed at a central 
laboratory.  
Samples will be taken for analysis of PT, INR, aPTT, D-dimer and fibrinogen. 
10.16.4 PSA and CA 125 
For patients with CRPC in the Dose Escalation part of the trial, blood samples for PSA 
assessment will be drawn for local analysis.  
For patients with ovarian and endometrial cancer:  
• In the Dose Escalation part of the trial, blood samples for CA 125 assessment will be drawn 
for local analysis. 
• In the Cohort Expansion part of the trial, blood samples for CA 125 assessment will be 
analyzed at a central laboratory. 


 
 
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Tisotumab vedotin (HuMax®-TF-ADC) 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
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10.16.5 Flow Cytometry 
A blood sample will be drawn for central analysis of flow cytometry of the following: 
Total T-cells (CD3+), helper T-cells (CD3+CD4+), cytotoxic T-cells (CD3+CD8+), NK-cells 
(CD3-CD56+CD16+) and B-cells (CD45+CD19+). 
Additional flow cytometry subgroups may be added based on findings. 
10.16.6 Pregnancy Test 
A blood sample will be drawn at the Screening Visit and at Day 1 of each cycle from all women 
of childbearing potential and will be analyzed at the site laboratory in the Dose Escalation part 
of the trial. 
Pregnant women may not take part in this trial and will be considered as screening failures. A 
serum pregnancy test will also be performed during the Follow-up period visits and at the EOT 
Visit. 
In order to be considered as sterilized or infertile, a patient must have undergone surgical 
sterilization (vasectomy/bilateral tubectomy; hysterectomy and bilateral ovariectomy) or be 
postmenopausal (twelve months or more with no period prior to enrollment).  
Safe hormonal contraceptives include contraceptive pills, implants, transdermal patches, 
hormonal vaginal devices or injections with prolonged release. 
In the Cohort Expansion part of the trial, pregnancy tests will be analyzed at a central 
laboratory.  
10.16.7 Immunogenicity of Tisotumab Vedotin (HuMax-TF-ADC) 
Blood samples will be drawn for central analysis of ADA (both total and neutralizing). 
Analysis of ADA will be done in batches of several samples.  
10.16.8 Hepatitis B, C, HPV and Cytomegalovirus Serology 
Serology parameters will be analyzed at the site in the Dose Escalation part of the trial, and at 
a central laboratory in the Cohort Expansion part of the trial.  
A blood sample will be drawn at screening for assessment of HBsAg, anti-HBs and anti-HBc, 
hepatitis C as well as antibodies to cytomegalovirus (CMV) antigen and serology.  
• For CMV, anti-IgG and IgM will be assessed and, in case of positive IgM, it will be 
confirmed with CMV polymerase chain reaction (PCR). 
• For hepatitis C virus (HCV), anti-IgG will be assessed and, if positive, it will be confirmed 
with HCV PCR. 
In patients with cervical cancer, the HPV status must also be available at screening. 
Blood samples will be drawn for assessment of antibodies to CMV antigen after the end of 
trial drug administration (at the EOT Visit).  




 
 
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Tisotumab vedotin (HuMax®-TF-ADC) 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
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11 
ASSESSMENT AND REPORTING OF ADVERSE EVENTS 
11.1 Adverse Events Characterization 
11.1.1 Definition of Adverse Events 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment. 
Adverse events include the following: 
• All suspected adverse drug reactions. 
• All reactions from medication overdose, abuse, withdrawal, sensitivity or toxicity. 
• Apparently unrelated illnesses, including the worsening of a pre-existing illness. 
• Injury or accidents. Note that if a medical condition is known to have caused the injury or 
accident, the medical condition and the accident should be reported as two separate AEs. 
• Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation. 
• Any clinically significant laboratory abnormality suggesting a disease and/or organ toxicity 
and is of a severity that requires active management (i.e., changes of dose, discontinuation 
of drug, more frequent follow-up or a diagnostic investigation), unless they are associated 
with an already reported clinical event. 
11.1.2 Definition of Infusion-Related Reaction 
Infusion-related AEs are defined as any AEs occurring during infusion where the onset date 
and time of the event occurs within infusion time, i.e., within the following interval: infusion 
start date and time ≤ AE onset date and time ≤ infusion end time plus one day (24 hours) and 
coded by Medical Dictionary for Regulatory Activities (MedDRA) preferred term as 
“Arthralgia”, “Asthenia”, “Bronchospasm”, “Chills”, “Cough”, “Hyperhidrosis”, “Dizziness”, 
“Pyrexia”, “Fatigue”, “Flushing”, “Headache”, “Hypertension”, “Hypotension”, “Infusion 
related reaction”, “Lethargy”, “Malaise”, “Myalgia”, “Nausea”, “Pruritus”, “Tachycardia”, 
“Tumor pain”, or by MedDRA High Level term as “Exfoliative conditions” or “Dyspneas”, 
“Dyspnoeas”, “Breathing abnormalities” or by MedDRA High Level Group Term as “Allergic 
conditions”. In addition the event should be judged related to trial drug by the investigator 
(Section 11.3.4).  
11.1.3 Trial Disease 
Signs and symptoms, which according to the investigator are expected and well known 
consequences of the cancer type, both in intensity and frequency, including disease progression 
should not be reported as AEs or SAEs. Any unexpected change in intensity or frequency 
should be reported as AE (or SAE if applicable). However, if a patient dies due to disease 
progression within 30 days after the last dose of IMP, it should be reported as an AE/SAE as 
described in Section 8.1.1.6. 


 
 
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Tisotumab vedotin (HuMax®-TF-ADC) 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
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11.1.3.1 Pre-existing Conditions 
In this trial, a pre-existing condition (i.e., a disorder present before the AE reporting period 
started and noted on the medical history/physical examination form) should not be reported as 
an AE. If a pre-existing condition worsens during the treatment period the event should be 
reported as an AE. 
11.1.4 Procedures 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs. A medical condition for which an unscheduled procedure was performed, 
should however be reported if it meets the definition of an AE. For example, an acute 
appendicitis should be reported as the AE and not the appendectomy. 
11.2 Adverse Event Reporting  
The investigator must report all directly observed AEs and all AEs spontaneously reported by 
the patient. A general type of question should be used similar to “Do you have any health 
problems?" or “Have you had any health problems since your last visit?" 
The reporting period for non-serious AEs begins from the day of first treatment administration 
until the end of the Follow-up period. Serious adverse events should be reported from the time 
the patient signs informed consent and until the end of the Follow-up period or until Safety 
Follow-up Visit. Any non-serious AEs (signs, symptoms and diagnosis) occurring between 
screening and the day of first treatment administration should be recorded as medical history. 
All AEs that occur in patients during the AE reporting period must be reported, whether or not 
the event is treatment-related. 
11.3 Recording Instructions 
11.3.1 Diagnosis 
The diagnosis of an AE should be recorded if available. If no diagnosis is available each sign 
and symptom should be recorded as individual AEs. 
11.3.2 Intensity 
The investigator will use the NCI-CTCAE version 4.03 to describe the severity of the AE 
(NCI-CTCAE v4.03, 2010). 
The grade assigned by the investigator should be the most severe that occurred during the AE 
period. 
11.3.3 Time of onset 
Time of onset for SAEs is the date of appearance of the first symptom of the disease, e.g., if 
chest pain occurs on 01 April 2015 and the patient is hospitalized with myocardial infarction 
on 04 April 2015, the onset date is 01 April 2015. 


 
 
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Tisotumab vedotin (HuMax®-TF-ADC) 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
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11.3.4 Relationship to Trial Drug 
The investigator must assess whether or not the event is related to tisotumab vedotin (HuMax-
TF-ADC). If the relationship changes over time, the last judgment by the investigator should 
be reported. Relatedness has to be assessed and reported from the first time the AE is being 
reported. 
11.3.5 Outcome 
Outcome of the AE must be judged by investigator by the following terms: 
• Recovered. 
• Recovered with sequelae. 
• Not recovered. 
• Death. 
• Unknown. 
Instructions for reporting changes in an ongoing AE during a patient's participation in the trial 
are provided in the instructions that accompany the AE eCRFs. 
11.4 Serious Adverse Events 
11.4.1 Definition of Serious Adverse Events 
Each AE will be classified by the investigator as serious or non-serious. This classification of 
the seriousness of the event determines the reporting procedures to be followed. 
An AE that meets one or more of the following criteria/outcomes is classified as serious: 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• Is a congenital anomaly/birth defect. 
• Medically important. 
• Results in death. 
• Is life-threatening.  
The term "life-threatening" in the definition of "serious" refers to an event in which the patient 
was at risk of death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe. 
Elective surgery or other scheduled hospitalization periods that were planned before the patient 
was enrolled in this trial, as well as scheduled hospitalizations for trial assessments during 
administration procedures or hospitalizations (or prolongation of existing hospitalization) due 
to technical or logistical issues, are not to be considered serious. However, the event must be 
reported on the AE page in the eCRF and commented upon. 


 
 
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Final 5.0 (incorporating Protocol Amendment 4) 
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Medical and scientific judgment must be exercised in deciding whether an AE is believed to 
be “medically important”. Medically important events may not be immediately life-threatening 
or result in death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed in the definition above. 
11.4.2 Events Requiring Immediate Reporting 
11.4.2.1 Serious Adverse Events, Non-serious Grade 3 Adverse Events, and Non-serious 
Grade 2 Ocular Adverse Events 
Serious adverse events and non-serious grade 3 AEs will be reported from the investigational 
site to the sponsor within 24 hours (see Sections 10.9 and 11.4.3). In addition, all non-serious 
grade 2 ocular AEs must be reported from the investigational site to the sponsor within 24 
hours (see Section 11.4.3). 
11.4.2.2 Overdose and Medication Errors 
An overdose is defined as a patient receiving a dose of the trial drug in excess of that specified 
in this protocol. All cases of overdose must be reported to the sponsor as protocol deviations 
within 24 hours of knowledge of the event. If the overdose results in an AE, the AE must also 
be recorded on the AE eCRF. If the overdose results in an SAE/non-serious 
grade 3/non-serious grade 2 ocular AE it must be reported within 24 hours (see Section 11.4.3). 
Medication errors and uses outside what is foreseen in the protocol, including misuse and abuse 
of the product, should be reported as protocol deviations to the sponsor within 24 hours of 
knowledge of the event. If a medication error results in an AE, the AE must also be recorded 
on the AE eCRF. Furthermore, AEs fulfilling the criteria in Section 11.4.2.1 must be reported 
accordingly. 
Overdose, medication errors, misuse and abuse do not automatically make an AE serious, but 
if the consequences are serious, for example death or hospitalizations, the event is serious and 
must be reported as an SAE. 
11.4.2.3 Pregnancy 
Any pregnancy that occurs during trial participation must be reported and the patient will be 
withdrawn from treatment immediately. To ensure patient safety, each pregnancy must be 
reported to the sponsor or designee within 24 hours of learning of its occurrence. The 
pregnancy must be followed to determine outcome (including premature termination) and 
status of mother and child. Pregnancy complications and elective terminations for medical 
reasons must be reported as an AE or SAE. Spontaneous abortions must be reported as an SAE. 
The child must be followed to at least age one month. 
Any SAE occurring in association with a pregnancy brought to the investigator’s attention after 
the patient has completed the trial and considered by the investigator as possibly related to the 
trial drug, must be promptly reported to the sponsor or designee. 




 
 
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Tisotumab vedotin (HuMax®-TF-ADC) 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
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11.4.4 Suspected Unexpected Serious Adverse Reactions  
The sponsor has a legal responsibility to notify, as appropriate and according to local 
regulations, both the local regulatory authority and other regulatory agencies about the safety 
of the product under clinical investigation. Prompt notification of SAEs by the investigator to 
the sponsor is essential so that legal obligations and ethical responsibilities towards the safety 
of patients are met. 
The sponsor will ensure that all relevant information about Suspected Unexpected Serious 
Adverse Reactions (SUSAR) is recorded and reported as soon as possible, but within a 
maximum of 15 days (fatal or life-threatening SUSARs within a maximum of seven days) of 
first knowledge by the sponsor or designee, to the competent regulatory authorities and/or to 
the Ethics Committee according to the applicable local regulatory requirements. Relevant 
follow-up information of fatal or life-threatening SUSARs will be communicated subsequently 
within an additional eight days.  
In the EU (European Medicines Agency [EMA] or local competent authorities), all unexpected 
SAEs assessed as related to trial drug by either the investigator or the sponsor will also qualify 
for expedited reporting. In the USA (FDA) the causality assessed by the sponsor will determine 
whether the case requires expedited reporting. 
The investigator should be aware of local reporting regulations to the IEC/IRB. The Safety 
CRO will either supply the investigator with the reports which should be passed on to the 
IEC/IRB or report directly to the IEC/IRB depending on local regulations. 
11.5 Follow-up on Adverse Events 
All AEs should be followed until they are resolved or the patient's participation in the trial 
ends, whichever comes first. Related non-serious grade ≥ 3 AEs and AEs meeting one of the 
serious criteria, and still ongoing after ended trial participation should be followed on a regular 
basis, according to the investigator’s clinical judgment, until the event has been resolved or 
until the investigator assesses it as chronic or stable and all queries have been resolved. 
11.6 Safety Communication Plan for Information to Site 
In order to secure full transparency regarding patient safety-related questions to sites 
participating in the trial, frequent communication of observations at the different sites will be 
required. The communication set-up will include the following components: 
• SAEs, non-serious grade 3 AEs and non-serious grade 2 ocular AEs will be reported by the 
investigational site to the sponsor within 24 hours and medically evaluated immediately 
following receipt. Bi-weekly safety/medical meetings to discuss AEs and laboratory data 
will be held with the participation of at least the Corporate Drug Safety, Genmab Medical 
Officer and CRO Medical Monitor.  
• Recruitment updates will be prepared by the CRO for sites and investigators including 
information on all SAEs, non-serious grade 3 AEs, non-serious grade 2 ocular AEs and 
DLTs. 


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Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
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•
Monthly telephone conferences between all participating investigators, CRO Medical
Monitor and Genmab will be arranged. Pending severity of observed safety signals, ad hoc
meetings will be held.
•
A contact list with all participating investigators will be available at all sites.
•
24 hours/7 days a week availability of CRO Medical Monitor.
•
Direct telephone link from investigator to Genmab Medical Officer and responsible
Genmab Drug Safety Physician.
•
DMC meetings following each cohort and ad hoc as needed. The outcome of the DMC
meeting will be communicated to the investigators following each meeting.
•
Investigators or their representative(s) will participate in the open part of the DMC
meetings as applicable.
11.7 Review or Safety Boards 
A DMC will be established and will have its first meeting before trial start (first patient 
screened). The DMC will include medical experts within the disease to be treated, and at least 
one with DMC experience. At the first meeting, the DMC will decide the future format and the 
degree of the information it needs in order to evaluate the patients at each dose levels.  
The functions and responsibilities of the DMC will be described in the DMC Charter, which 
will be approved by the DMC. The DMC will receive a package of safety data, including all 
reported AEs and laboratory data, after each cohort has completed the first cycle of treatment. 
The DMC will receive a report of any SAEs and DLT immediately after review of the event 
by the sponsor.  
Patients will be enrolled in cohorts of three patients per dose level. For each cohort, the DMC 
will evaluate aggregate safety data for the three patients in order to recommend whether it is 
safe to escalate to the next dose level. Before the DMC review of safety data, at least three 
patients in a cohort must receive three infusions (one cycle) and be observed for 28 days before 
the DMC review.  
The DMC meetings will be divided into an open and a closed session. During the open sessions, 
representatives from the sponsor as well as one or more investigators involved in the trial will 
participate together with the DMC members. During the closed session, only DMC members 
will participate. 
The DMC will evaluate the data obtained at each dose level and will recommend whether the 
dose should be escalated as per protocol, revised to a lower level or interim level, halted 
altogether or more patients are required at the same dose level to evaluate safety. In addition 
cumulative safety data for all cohorts will be evaluated at each DMC meeting. Available PK 
and/or pharmacodynamic data from the previous dose levels will be compared with known 
non-clinical PK, pharmacodynamic and safety information. Furthermore, any observed 
responses will be compared with anticipated responses. Any unanticipated responses may 
require a revised dose escalation.  


 
 
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The DMC will look at the total data set and will have all available information from the clinical 
trial GEN702 part I to have a complete overview. If late toxicities occur, the DMC can advise 
and the sponsor’s Safety Committee may approve reduction of the maximal safe dose in the 
3q4wk dose schedule. 
The conclusion of the DMC meeting will be documented in minutes and forwarded to 
management and relevant project members. The outcome of the DMC meeting will be 
communicated to the investigators. Minutes of the DMC meetings will be shared with the 
regulatory authorities, if requested. 
Further details of the constitution and procedures of the DMC meetings will be included in the 
DMC Charter. 
For the Cohort Expansion part of the trial, the DMC will not hold preplanned meetings but will 
convene in the event of any new safety signals.  


 
 
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12 
STATISTICAL ANALYSIS 
The statistical analysis of this trial will be performed by 
. 
12.1 Statistical Analysis Plan 
A Statistical Analysis Plan (SAP) will be written and finalized prior to any lock of the trial 
database. The SAP will provide a detailed description of the statistical methods and expand on 
the details provided in the protocol. Additional analyses may be added. Tables, listings and 
figures shells will also be provided. The SAP will be updated to describe how analysis will be 
performed for patients treated after Protocol Amendment 4.0. 
12.2 Analysis Populations 
The full analysis population will comprise all patients who have been exposed to the trial drug. 
This population will be used for evaluation of all endpoints. 
12.3 Statistical Methods 
The presentations will be done separately for the Dose Escalation part and the Cohort 
Expansion part. 
In the reporting of the Dose Escalation part tables will report by cohort, while in the Cohort 
Expansion part tables will report by indication. 
The shift from the 3q4wk dosing to the once q3wk dosing in the Cohort Expansion part may 
lead to a need for reporting some tables by dosing schedule. This will be described as 
appropriate in the SAP. 
No formal statistical tests will be performed. 
For efficacy analyses, the quartile estimates of PFS and DoR from the Kaplan-Meier product 
limit algorithm will be presented (Kaplan and Meier, 1958). The 2-sided 95% confidence 
interval will be presented as well. The number of events may be small, and thereby limit use 
of the Kaplan-Meier method to provide reliable information. In this case, descriptive statistics 
(e.g., n, mean, standard deviation, median, minimum and maximum) for PFS or DoR will be 
presented. Objective response (CR or PR) rate will be determined along with the corresponding 
2-sided 95% exact binomial confidence interval. 
All data will be listed. Baseline is defined as the latest available measurement made before the 
first treatment with tisotumab vedotin (HuMax-TF-ADC). 
A patient will be considered as having completed the trial when all planned trial visits have 
been performed. 
12.3.1 Summary Statistics 
All summary statistics of continuous variables will include: n, mean, median, standard 
deviation, minimum and maximum. All summaries presenting frequencies and incidences will 
include n, % and N, where N is the total number of patients with recorded values in the 
corresponding group. All confidence intervals will be 2-sided 95% confidence intervals. 


 
 
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Individual patient profiles including information on actual dose will also be presented. For the 
Dose Escalation part summary statistics will be presented as follows: 
• For treatment Cycle 1: by dose cohort and total 
• For all treatment cycles: by dose cohort and total 
• By indication (all dose cohorts accumulated) 
For the Cohort Expansion part, summary statistics will be presented as follows: 
• For treatment Cycle 1: by indication and total 
• For all treatment cycles: by indication and total 
12.4 Statistical Analysis of Primary Endpoint 
Incidences of AEs, SAEs, infusion-related AEs, grade ≥ 3 AEs, and AEs related to trial drug 
will be summarized by system organ class and preferred term and listed.  
Also, the number of patient days (total number of days in trial) will be shown for each dose 
group. 
12.5 Statistical Analysis of Secondary Endpoints 
12.5.1 Clinical Safety Data 
Bleeding (major and minor), skin disorders and neuropathy will be summarized and listed 
separately. Abnormal findings in physical examination, body weight, ECG measurements and 
vital signs will be listed. Ophthalmological evaluation will be listed. 
12.5.2 Laboratory Safety Data 
Laboratory assessments (Section 10.16) will be plotted and/or listed for individual patients as 
appropriate. Laboratory values outside normal range will be listed. Percentage change in 
laboratory safety parameters from baseline to subsequent visits will be derived and provided 
in listings. Before and during infusion some laboratory assessments are analyzed locally for 
monitoring of patient safety.  
12.5.3 Response  
Response will be assessed in accordance with the RECIST criteria version 1.1 (Eisenhauer et 
al, 2009), where appropriate. However, specific guidelines may be used (i.e., Rustin et al., 
2004 for ovarian cancer and Scher et al., 2008 for prostate cancer). 


 
 
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12.5.3.1 Definition of Response 
Table 10: Definition of Response (RECIST Criteria v1.1) 
 
Category 
Criteria 
Based 
on 
target 
lesions 
Complete 
Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes  
must have reduction in short axis to < 10 mm. 
Partial 
Response (PR) 
≥ 30% decrease in the sum of the LD of target lesions, taking as 
reference the baseline sum of LDs. 
Stable Disease 
(SD)  
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of 
LDs while in trial. 
Progressive 
Disease (PD) 
≥ 20% (and ≥ 5 mm) increase in the sum of the LDs of target 
lesions, taking as reference the smallest sum of the target LDs 
recorded while in trial or the appearance of 1 or more new lesions. 
Based 
on 
non-target 
lesions 
CR 
Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size 
(< 10 mm short axis). 
SD 
Persistence of 1 or more non-target lesion(s) or/and maintenance 
of tumor marker level above the normal limits. 
PD 
Appearance of 1 or more new lesions and/or unequivocal 
progression of existing non-target lesions. 
LD=Longest Diameter  
 
Response will be evaluated after four cycles (16 weeks) and as best overall response. The best 
overall response is the best response recorded from the start of the treatment until disease 
progression (Table 11). 
Table 11: Evaluation of Response 
Target Lesions 
Non-target Lesions 
New Lesions 
Response 
CR 
CR 
No 
CR 
CR 
SD or PR 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR=Complete Response; PD=Progressive Disease; PR=Partial Response; SD=Stable Disease 
 
For patients with CRPC, when the bone scan is the sole indicator of progression, PD is defined 
in bone when at least ≥ 2 new lesions are seen on the bone scan compared with a prior scan for 
trial entry. There are no validated criteria for response on radionuclide bone scan. For 


 
 
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control/relief/eliminate endpoints, it is recommended that post-treatment changes are recorded 
as either “no new lesions” or “new lesions.” However, PD at the first scheduled assessment 
should be confirmed on a second scan performed six or more weeks later, in the absence of 
clearly worsening soft-tissue (nodal and visceral) disease or disease-related symptoms. In case 
where visible lesions disappear, this should be confirmed at the next scheduled assessment too. 
For patients with ovarian and endometrial cancer, a response according to CA 125 has occurred 
if there is at least a 50% reduction in CA 125 levels from a pretreatment sample. The response 
must be confirmed and maintained for at least 28 days. Patients can be evaluated according to 
CA 125 only if they have a pretreatment sample that is at least two × ULN and within two 
weeks prior to starting treatment. 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of PD at that time should be classified as having “symptomatic 
deterioration”. Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
Confirmation 
SD: follow-up measurements must have met the SD criteria at least once and for a minimum 
time period of six weeks (± 7 days) after first treatment.  
PR and CR: no formal confirmation response is required. However, a repeat CT-scan will be 
performed no less than four weeks (± 7 days) after the criteria for response is met to 
substantiate/confirm CT response (Section 10.7).  
12.5.3.2 Response Evaluation and Reporting of Results 
Response evaluation will be performed by external medical experts in relevant cancer types in 
collaboration with the sponsor Medical Officer and a Statistician.  
Each patient will be assigned one of the following categories:  
1) CR 
2) PR 
3) SD 
4) PD or 
5) Not Evaluable 
Patients in response categories 1 and 2 are considered responders and patients in response 
categories 4 and 5 are considered as failing to respond to treatment (disease progression). 
Patients in response categories 1, 2 and 3 are considered to be in disease control. 


 
 
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Individual patient data listings and summaries of objective response, best overall tumor 
response and disease control will be presented by dose cohort and total. For respective patients, 
PSA (CRPC) and CA125 (ovarian and endometrial) will be listed. 
The maximal response (maximal change in the sum of the LD in the target lesions) in target 
lesions at any time on trial will be reported using waterfall plots. 
12.5.3.3 Progression-free Survival 
Progression-free survival is defined as the number of days from Day 1 in Cycle 1 to first PD 
or death. Progression-free survival will be derived for all patients and presented graphically as 
well as summarized using survival analysis methods.  
12.5.3.4 Duration of Response 
Duration of response is defined as the number of days from the first documentation of objective 
tumor response (CR or PR) to the date of first PD or death.  
12.5.3.5 Patients without Disease Progression after Four Cycles 
Percent of patients without PD after four cycles will be summarized. 
12.5.4 Changes in Biomarkers, Including PSA and CA 125  
Biomarkers, PSA, CA 125, soluble TF, etc. will be presented graphically: individual patient 
plots over time. 
12.5.5 Host Immune Response 
Titers of tisotumab vedotin (HuMax-TF-ADC) will be listed and positive/negative host 
immune response to tisotumab vedotin (HuMax-TF-ADC) will be summarized 
(positive/negative). The association between positive/non-positive ADA and PK (pre-dose 
values and Cmax), major safety signals (CTCAE grade ≥ 3) and efficacy information (change 
in tumor size by CT-scan) will be explored.  
12.5.6 Statistical Analysis of Pharmacokinetics Data 
Individual curves of plasma/serum concentration of tisotumab vedotin (HuMax-TF-ADC), 
HuMax-TF and free toxin (MMAE), including information on actual dose, will be presented 
for all patients. All available data will be shown in these figures. 
The following PK parameters will be calculated based on non-compartmental methods: 
clearance, volume of distribution and AUC (AUC0-7days and AUC0-∞), Cmax, Tmax, pre-dose 
values, and half-life. The PK parameters will be calculated separately for Cycle 1 and Cycle 2.  
The relation between derived PK parameters and covariates such as actual dose, weight and 
dose, and selected laboratory parameters will be evaluated graphically. 
If deemed applicable compartmental modeling approaches to parameter estimation will be 
applied.  
Further exploratory analyses of PK data may be performed. 


 
 
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Final 5.0 (incorporating Protocol Amendment 4) 
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12.6 Handling of Missing Data or Outliers 
No imputation of missing data is planned for safety endpoints and PK endpoints. If outliers are 
detected, a robustness analysis where the outlier effect is reduced or eliminated may be 
considered. 
12.7 Subgroups and Center Effects 
Subgroup analyses for the following factors are planned: 
• Indication type 
• TF expression  
• ADA positivity (only for grade ≥ 3 AEs and tumor shrinkage endpoints) 
Other sub-group analyses may be performed post-hoc. Due to the low number of patients per 
center no investigation of center effects are planned.  
12.8 Interim Analyses 
An analysis of the Dose Escalation part will be performed when this part of the trial is 
completed. An additional interim analysis may be performed when 20 patients have completed 
four cycles (or have been withdrawn earlier). A final analysis will be performed when the entire 
trial is completed. 
12.9 Sample Size Estimation 
A maximum of 24 patients are planned to be enrolled in the Dose Escalation part of the trial. 
As the primary objective of the trial is to establish the tolerability of tisotumab vedotin 
(HuMax-TF-ADC), the sample size is based only on the 3 (+3) dose escalation MTD design 
and the expected maximum of three dose levels (plus a potential intermediate dose cohort). 
The classical 3 (+3) dose escalation MTD design aims to determine MTD with the fewest 
possible patients exposed. Taking into account an anticipated screen failure rate of 30%, 18 to 
35 patients will be screened.  
In the Cohort Expansion part, up to 20-30 patients in two or three indication arms are expected 
to provide more information on the safety of the compound at the RP2D level as well as 
preliminary efficacy data for the more frequent dosing regimen. 
12.10 Clinical Trial Reporting 
A final report will be produced when the trial is completed. 


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Final 5.0 (incorporating Protocol Amendment 4) 
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13 
MONITORING PROCEDURES/QUALITY ASSURANCE 
The sponsor has ethical, legal and scientific obligations to conduct this trial in accordance with 
established research principles and ICH GCP guidelines. As such, in order to fulfill these 
obligations and to monitor trial progress, the sponsor's monitors or representatives will visit 
the investigative sites during the trial conduct, in addition to maintaining telephone and written 
communication. On-site visits, telephone calls and regular review of the eCRFs will be 
conducted in order to assess patient enrollment, compliance with protocol procedures, 
completeness and accuracy of data entered on the eCRFs, verification of eCRF data against 
original source documents and occurrence of AEs. The investigator must provide the monitor, 
sponsor representative and auditors/inspectors with full access to all source and trial 
documents. 
13.1 Data Collection 
As part of the responsibilities assumed by participating in the trial, the investigator agrees to 
maintain adequate and accurate case histories for the patients treated under this protocol. Case 
histories include eCRFs and supporting data including, but not limited to, signed and dated 
ICFs, progress notes, hospital charts, nurse’s notes, diary cards or other worksheets provided 
to patients, laboratory reports, ECG readings, etc. 
Patient demographics and key/essential disease baseline characteristics thought to affect 
outcome, i.e., stratification variables and other prognostic factors, may be collected, as 
available, for all patients who provide written informed consent. For patients who provided 
informed consent and were not entered into the trial, the reason the patient was not entered, 
i.e., did not meet one or more inclusion criteria, met one or more exclusion criteria, or other
(e.g., lost to follow-up, consent withdrawn), may also be collected.
13.2 Data Management 
Data management in this trial will be performed by 
The trial will be performed using electronic data capture. The investigator is responsible for 
prompt reporting of accurate, complete and legible data in the eCRFs and in all required 
reports. Any change or correction to the eCRF after saving must be accompanied by a reason 
for the change. The investigator must review and approve all data entered in the eCRFs, by 
means of an electronic signature. Any corrections made after this approval will be reapproved 
by the investigator. The investigator should maintain a list of personnel authorized to enter 
data into the eCRF. Detailed instructions will be provided in the eCRF Completion Guidelines. 
Previous and concomitant medications will be coded using the World Health Organization 
Drug Reference Dictionary (WHO Drug). Medical history and AEs will be coded using 
MedDRA. 
When the database has been declared to be complete and accurate, the database will be locked. 
Any changes to the database after that time can only be made by written agreement between 
Genmab and the 
 project team. 
A Clinical Informatics Plan and a Data Quality Plan will be prepared by 
. The process of 
data collection, validation and transmission is illustrated in Figure 5. 




 
 
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Final 5.0 (incorporating Protocol Amendment 4) 
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13.4 Inspections and Auditing Procedures 
Before, during and after the trial, the sponsor or its representative may conduct audits at the 
investigative sites including, but not limited to, drug supply, presence of required documents, 
the informed consent process, and comparison of eCRFs with source documents. All medical 
records (progress notes) must be available for audit. The investigator agrees to participate in 
audits conducted at a convenient time in a reasonable manner. 
Government regulatory authorities may also inspect the investigator. The investigator or 
designee should contact the sponsor/
 immediately if this occurs. He/she must cooperate 
fully with regulatory authorities or other audits conducted at a convenient time in a reasonable 
manner. The investigator will forward to the sponsor a copy of any inspection records received. 
 


 
 
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Final 5.0 (incorporating Protocol Amendment 4) 
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14 
TRIAL MANAGEMENT AND MATERIALS 
14.1 Data Collection 
All data entered in the eCRF should be documented at the site. During each trial visit, a 
physician participating in the trial will maintain progress notes in the patient’s medical records 
to document all significant observations. At a minimum, these notes will contain: 
• That the patient has consented and is found eligible for the trial (as applicable). 
• The date of the visit and the corresponding day or visit in the trial schedule (e.g., screening, 
Day 1, Day 22, etc.). 
• General condition and status remarks by the patient, including any significant medical 
findings. The severity, frequency, duration and resolution of any reported AE, and the 
investigator's assessment as to whether or not the reported AE is trial drug-related. 
• Changes in concomitant medications or dosages. 
• A general reference to the procedures completed. 
• The signature or initials of all physicians making an entry in the medical record (progress 
notes). 
In addition, any contact with the patient via telephone or other means that provides significant 
clinical information will also be documented in the medical record (progress notes), as 
described above.  
Information from the medical records (progress notes) and other source documents will be 
promptly transcribed to the appropriate section of the eCRF. 
Changes to information in the medical record (progress notes), and other source documents 
will be initialed and dated on the day the change is made by the investigator or designee. If the 
reason for the change is not apparent, a brief explanation for the change will be written adjacent 
to the change. 
Details on data validation, data transfers, origin and destination on the data, access to the 
transferred data, timing of the transfer and any actions that may be triggered by real-time 
review of those data will be documented in the Clinical Informatics Plan. 
14.2 Source Documents Maintenance 
Source documents contain the results of original observations and activities of a clinical 
investigation. Source documents include, but are not limited to, medical records (progress 
notes), clinical and office charts, laboratory notes, pharmacy dispensing records, recorded data 
from automated instruments, photographic negatives, microfilm or magnetic media, x-rays, 
computer printouts, patient files and records kept at the pharmacy, laboratories and medico-
technical departments involved in the clinical trial. There should only be one source defined at 
any time for any data element. 
All source documents from this trial will be maintained by the investigator and made available 
for inspection by authorized persons. The original signed informed consent for each patient 
shall be filed with records kept by the investigator and a copy shall be given to the patient. 


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


 
 
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Final 5.0 (incorporating Protocol Amendment 4) 
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15 
ADMINISTRATION PROCEDURES 
15.1 Regulatory Approval 
Genmab A/S or their appointed agents will be responsible for ensuring that appropriate 
regulatory authority approvals are obtained, according to local country requirements. 
No patient may enter the trial until this approval has been obtained. A copy of the approval 
(where one is provided, according to local country requirements) will be provided to the 
investigator and to the IEC(s)/IRB(s). 
15.2 Protocol Amendments 
In accordance with ICH Topic E 6 (R1) Guideline for GCP, the investigator should not 
implement any deviation from, or changes of the protocol without agreement by the sponsor 
and documented approval from the IEC/IRB of a protocol amendment, except where necessary 
to eliminate an immediate hazard(s) to trial patients, or when the change(s) involves only 
logistical or administrative aspects of the trial (e.g., change in monitor(s), change of telephone 
number(s)).  
Any change to the protocol must be handled as a protocol amendment. Any potential 
amendment must be approved by the sponsor. A written amendment must be submitted to the 
appropriate regulatory authorities and to the IEC/IRB assuming this responsibility. The 
investigator must await IEC/IRB approval of protocol amendments before implementing the 
changes, except where necessary to eliminate apparent immediate hazard to patients. In these 
cases, the IEC/IRB must be notified within five days of the change. 
All amendments to the protocol must be approved in writing by both the appropriate regulatory 
authorities and the IEC/IRB, except for administrative amendments, which require notification 
but not written approval. Once approved, the protocol amendment will be distributed to all 
recipients of the original protocol, with instructions to append the amendment to the protocol. 
If, in the judgment of the local IEC/IRB, the investigator and/or sponsor, the protocol 
amendment alters the trial design, procedures and/or increases the potential risk to the patient, 
the currently approved written ICF will require modification. The modified ICF must also be 
reviewed and approved by the sponsor, appropriate regulatory authorities, and the IEC/IRB. In 
such cases, repeat informed consent must be obtained from patients enrolled in the trial before 
participation continues. 
15.3 Protocol Adherence and Deviations 
The protocol must be read thoroughly and the instructions must be followed. However, 
exceptions will be made in emergency situations when the protection, safety and well-being of 
the patient requires immediate intervention based on the judgment of the investigator or a 
responsible, appropriately trained and credentialed professional(s) designated by the 
investigator as a sub-investigator.  
In the event of a significant protocol deviation due to an emergency, accident or error, the 
investigator or designee must contact the Medical Monitor at the earliest possible time by 
telephone. This allows for an early joint decision to be made as to whether or not the patient 


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Final 5.0 (incorporating Protocol Amendment 4) 
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should continue in the trial. The investigator, the sponsor and the Medical Monitor will 
document this decision. 
15.4 Publication Policy 
The sponsor acknowledges the investigator’s right to publish the entire results of the trial, 
regardless of the outcome, in accordance with the Uniform Requirements for Manuscripts 
Submitted to Biomedical Journals of the International Committee of Medical Journal Editors 
(http://www.icmje.org/icmje-recommendations.pdf, updated December 2014). 
The international Coordinating Investigator will, together with the sponsor, decide on the 
publication strategy and has the right to publish and present the results and methods as first 
author of multicenter publications. Co-authorship will be decided by the sponsor and the 
international Coordinating Investigator and will be limited to a number of persons who have 
contributed substantially in the design, analysis and conduct of the trial or the writing and 
presentation of results. The sponsor will have representation in the list of authors. 
Publications are subject to the following conditions: 
•
No publication before the completion of the trial at all participating sites without written
agreement with the sponsor.
•
All proposed publications and presentations, including any modifications or amendments,
shall be submitted to the sponsor for its review at least 30 days before such presentation or
publication is submitted to any third party.
•
Publications shall not disclose any sponsor confidential information and property (not
including the trial results, which can be published as described elsewhere in this section).
15.5 Contractual and Financial Details 
The investigator (and/or, as appropriate, the hospital administrative representative) and the 
sponsor will sign a clinical trial agreement prior to the start of the trial, outlining overall 
sponsor and investigator responsibilities in relation to the trial. The contract should describe 
whether costs for pharmacy, laboratory and other protocol-required services are being paid 
directly or indirectly. Financial Disclosure Statements will need to be completed, as requested 
by FDA CFR 21 part 54. 
15.6 Insurance, Indemnity and Compensation 
Genmab A/S undertakes to maintain an appropriate clinical trial insurance policy. 
Deviations from the trial protocol - especially the prescription of a dose other than that 
scheduled in the trial protocol, other modes of administration, other indications and longer 
treatment periods - are not permitted and shall not be covered by the statutory patient insurance 
scheme. 
15.7 Termination of the Trial 
This trial may be terminated by the sponsor. The trial may also be terminated prematurely at 
any time when agreed to by both the investigators and the sponsor as being in the best interests 


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


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16 
REFERENCE LIST 
Abdulkadir SA, Carvalhal GF, Kaleem Z, et al. Tissue factor expression and angiogenesis in 
human prostate carcinoma. Hum Pathol. 2000;31, 443-7 
ADCETRIS Prescribing Information, Seattle Genetics, Inc; revised January 2014 
Advani R, Lebovic D, Brunvand M, et al. A Phase I study of DCDT2980S, an antibody-drug 
conjugate (ADC) targeting CD22, in relapsed or refractory B-cell non-Hodgkin’s lymphoma 
(NHL). [ASH abstract 59]. Blood. 2012;120 
Akashi T, Furuya Y, Ohta S, and Fuse H. Tissue factor expression and prognosis in patients 
with metastatic prostate cancer. Urology. 2003;62:1078-82 
Bastarache JA, Wang L, Geiser T, et al. The alveolar epithelium can initiate the extrinsic 
coagulation cascade through expression of tissue factor. Thorax. 2007 Jul;62(7):608-16 
Benghiat H, and Al-Niaimi A. Palmar-plantar erythrodysesthesia secondary to docetaxel 
chemotherapy: a case report. J Med Case Rep. 2011;25;5:80 
Cady FM, Kneuper-Hall R, and Metcalf JS. Histologic patterns of polyethylene 
glycol-liposomal doxorubicin-related cutaneous eruptions. Am J Dermatopathol. 2006;28:168-
72 
Chalermchai T, Tantiphlachiva K, Suwanrusme H, et al. Randomized trial of two different 
doses of pyridoxine in the prevention of capecitabine-associated palmar-plantar 
erythrodysesthesia. Asia Pac J Clin Oncol. 2010;6(3):155-60 
Chen L, Luo G, Tan Y, et al. Immunolocalisation of tissue factor in esophageal cancer is 
correlated with intratumoral angiogenesis and prognosis of the patient. Acta Histochem. 
2010;112(3):233-9 
Choudhuri S, Sharma C, Banerjee A, et al. A repertoire of biomarkers helps in detection and 
assessment of therapeutic response in epithelial ovarian cancer. Mol Cell Biochem. 2013 
Cocco E, Varughese J, Buza N, et al. Tissue factor expression in ovarian cancer: implications 
for immunotherapy with hI-con1, a factor VII-IgGF(c) chimeric protein targeting tissue factor. 
Clin Exp Metastasis. 2011;28:689-700 
Cocco E, Varughese J, Buza N, et al. Expression of tissue factor in adenocarcinoma and 
squamous cell carcinoma of the uterine cervix: implications for immunotherapy with hI-con1, 
a factor VII-IgGFc chimeric protein targeting tissue factor. BMC Cancer. 2011;11:263-73 
Cocco E, Hu Z, Richter CE, et al. hI-con1, a factor VII-IgGFc chimeric protein targeting tissue 
factor for immunotherapy of uterine serous papillary carcinoma. Br J Cancer. 
2010;103(6):812-9 
Coveler AL, Von Hoff DD, Ko AH, et al. A phase I study of ASG-5ME, a novel antibody-drug 
conjugate, in pancreatic ductal adenocarcinoma. J Clin Oncol 30: 2012 (suppl 34; abstr 176) 
Cugno M, Marzano AV, Tedeschi A, et al. Expression of tissue factor by eosinophils in patients 
with chronic urticaria. Int Arch Allergy Immunol. 2009; 148(2):170-4 


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Dawson SJ, Tsui DWY, Murtaza M, et al. Analysis of Circulating Tumor DNA to Monitor 
Metastatic Breast Cancer. N Eng J Med. 2013; 368:1199-209 
Degen A, Alter M, Schenck F, et al. The hand-foot-syndrome associated with medical tumor 
therapy - classification and management. J Dtsch Dermatol Ges. 2010;8(9):652-61 
Doronina SO, Toki BE, Torgov MY, et al. Development of potent monoclonal antibody 
auristatin conjugates for cancer therapy. Nat Biotechnol. 2003 Jul;21(7):778-84 
Drake TA, Morrissey JH, and Edgington TS. Selective cellular expression of tissue factor in 
human tissues. Implications for disorders of hemostasis and thrombosis. Am J Pathol. 1989 
May;134(5):1087-97 
Ellinger J, Bastian PJ, Ellinger N, et al. Apoptotic DNA fragments in serum of patients with 
muscle invasive bladder cancer: A prognostic entity. Cancer Letters. 2008; 264:274-80 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-47 
Flössel C, Luther T, Müller M, et al. Immunohistochemical detection of tissue factor (TF) on 
paraffin sections of routinely fixed human tissue. Histochem. 1994 Jul;101(6):449-53 
Gautschi O. Circulating deoxyribonucleic acid as prognostic marker in non-small-cell lung 
cancer patients undergoing chemotherapy. J Clin Oncol. 2004; 22:4157-64 
Goldin-Lang P, Tran Q-V, Fichtner I, et al. Tissue factor expression pattern in human 
non-small cell lung cancer tissues indicate increased blood thrombogenicity and tumor 
metastasis. Oncol Rep. 2008. 20(1):123-8 
Hamblett KJ, Senter PD, Chace DF, et al. Effects of drug loading on the antitumor activity of 
a monoclonal antibody drug conjugate. Clin Cancer Res. 2004 Oct 15;10(20):7063-70 
Hamid O, Sznol M, Pavlick AC, et al. Frequent dosing and GPNMB expression with CDX-011 
(CR011-vcMMAE), an antibody-drug conjugate (ADC), in patients with advanced melanoma. 
J Clin Oncol. 28:15s, 2010 (suppl; abstr 8525) 
Han LY, Landen CN Jr, Kamat AA, et al. Preoperative serum tissue factor levels are an 
independent prognostic factor in patients with ovarian carcinoma. J Clin Oncol. 2006 Feb 
10;24(5):755-61 
Hwu P, Sznol M, Kluger H, et al. A phase I/II study of CR011-vcMMAE, an antibody toxin 
conjugate drug, in patients with unresectable stage III/IV melanoma. J Clin Oncol. 26: 2008 
(May 20 suppl; abstr 9029) 
Imokawa S, Sato A, Hayakawa H, et al. Tissue factor expression and fibrin deposition in the 
lungs of patients with idiopathic pulmonary fibrosis and systemic sclerosis. Am J Respir Crit 
Care Med. 1997 Aug;156(2 Pt 1):631-6 
Kaplan EL and Meier P. Nonparametric estimation from incomplete observations. J Am Stat 
Assoc. 1958;53:457-81 
Kasthuri RS, Taubman MB, and Mackman N. Role of tissue factor in cancer. J Clin Oncol. 
2009 Oct 10;27(29):4834-8 


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Khorana AA, Ahrendt SA, Ryan CK, et al. Tissue factor expression, angiogenesis, and 
thrombosis in pancreatic cancer. Clin Cancer Res. 2007;13:2870-75 
Kirchhofer D, Moran P, Chiang N, et al. Epitope location on tissue factor determines the 
anticoagulant potency of monoclonal anti-tissue factor antibodies. Thromb Haemost. 2000 
Dec;84(6):1072-81 
Marzano AV, Tedeschi A, Berti E, et al. Activation of coagulation in bullous pemphigoid and 
other eosinophil-related inflammatory skin diseases. Clin Exp Immunol. 2011 Jul;165(1):44-50 
Marzano AV, Tedeschi A, Fanoni D, et al. Activation of blood coagulation in bullous 
pemphigoid: role of eosinophils, and local and systemic implications. Br J Dermatol. 2009 
Feb;160(2):266-72 
Mega AE, Petrylak DP, Kantoff P, et al. Prostate-specific membrane antigen antibody drug 
conjugate (PSMA ADC): A phase I trial in metastatic castration-resistant prostate cancer 
(mCRPC) previously treated with a taxane. J Clin Oncol. 30, 2012 (suppl; abstr 4662) 
More K, Sim R, Hudson M, et al. Immunohistochemical study of tissue factor expression in 
normal intestine and idiopathic inflammatory bowel disease. J Clin Pathol. 1993 
Aug;46(8):703-8 
Morris MJ, Bruce JY, Reyno LM, et al. Phase I trial of ASG-5ME in metastatic castration-
resistant prostate cancer (CRPC). J Clin Oncol. 30, 2012 (suppl; abstr 4568) 
Morris PE, Steingrub, JS, Huang BY, et al. A phase 1 study evaluating the pharmacokinetics, 
safety and tolerability of an antibody-based tissue factor antagonist in subjects with acute lung 
injury or acute respiratory distress syndrome. BMC Pulm Med. 2012;12(5):1-8)  
National Cancer Institute. Common Terminology Criteria for Adverse Events v4.0. NCI, NIH, 
DHHS. May 29, 2009. NIH publication # 09-7473. Updated to v4.03 on June 14, 2010. 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
Nitori N, Ino Y, Nakanishi Y, et al. Prognostic significance of tissue factor in pancreatic ductal 
adenocarcinoma. Clin Cancer Res. 2005: Apr 1;11(7):2531-9 
Ohta S, Wada H, Nakazaki T, et al. Expression of tissue factor is associated with clinical 
features and angiogenesis in prostate cancer. Anticancer Res. 2002;22:2991-6 
Ott PA, Hamid O, Pavlick AC, et al. Phase l/ll study of the antibody-drug conjugate 
glemtatumumab vedotin in patients with advanced melanoma. J Clin Oncol. 
2014;32(32):3659-3666 
Palanca-Wessels MC, Flinn IW, Sehn LH, et al. A Phase I study of the anti-CD79b antibody-
drug conjugate (ADC) DCDS4501A targeting CD79b in relapsed or refractory B-cell non-
Hodgkin’s lymphoma (NHL). [ASH abstract 56]. Blood. 2012;120 
Patry G, Hovington H, Larue H, et al. Tissue factor expression correlates with disease-specific 
survival in patients with node-negative muscle-invasive bladder cancer. Int J Cancer. 
2008;122:1592-7 


 
 
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Petrylak DP, Kantoff PW, Mega AE, et al. Prostate-specific membrane antigen antibody drug 
conjugate (PSMA ADC): A phase I trial in metastatic castration-resistant prostate cancer 
(mCRPC) previously treated with taxane. J Clin Oncol. 31, 2013 (suppl; abstr 119) 
Ruf W and Mueller BM. Tissue factor in cancer angiogenesis and metastasis. Curr Opin 
Hematol. 1996 Sep;3(5):379-84 
Rustin GJ, Quinn M, Thigpen T, et al. Re: New guidelines to evaluate the response to treatment 
in solid tumors (ovarian cancer). J Nat Cancer Inst. 2004;96:487-8 
Sawada M, Miyake S, Ohdama S, et al. Expression of tissue factor in non-small-cell lung 
cancers and its relationship to metastasis. Br J Cancer. 1999;79:472-7 
Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with 
progressive prostate cancer and castrate levels of testosterone: Recommendations of the 
Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26:1148-59 
Shulman S and Kearon C; on behalf of the Subcommittee on Control of Anticoagulation of the 
Scientific and Standardization Committee of the International Society on Thrombosis and 
Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic 
medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4 
Spindler KL, Pallisgaard N, Vogelius I, and Jakobsen A. Quantitative cell-free DNA, KRAS, 
and BRAF mutations in plasma from patients with metastatic colorectal cancer during 
treatment with cetuximab and irinotecan. Clin Cancer Res. 2012; 18:1177-85 
Strijbos MH, Gratama JW, Schmitz P, et al. Circulating endothelial cells, circulating tumour 
cells, tissue factor, endothelin-1 and overall survival in prostate cancer patients treated with 
docetaxel. Eur J Cancer. 2010. 46(11):2027-35 
Sun MM, Beam KS, Cerveny CG, et al. Reduction-alkylation strategies for the modification 
of specific monoclonal antibody disulfides. Bioconjug. Chem. 2005;16:1282-90  
Uno, K, Homma S, Satoh T, et al. Tissue factor expression as a possible determinant of 
thromboembolism in ovarian cancer. Br J Cancer. 2007;96:290-5 
Versteeg HH, Schaffner F, Kerver M, et al. Inhibition of tissue factor signaling suppresses 
tumor growth. Blood. 2008 Jan 1;111(1):190-9 
Yao JL, Ryan CK, Francis CW, et al. Tissue factor and VEGF expression in prostate 
carcinoma: a tissue microarray study. Cancer Invest. 2009;27(4):430-4 
Yardley DA, Weaver R, Melisko ME, et al. EMERGE: A randomized phase II study of the 
antibody-drug conjugate glembatumumab vedotin in advanced glycoprotein NMB-expressing 
breast cancer. J Clin Oncol. 2015;33(14):1609-19 
Yokota, N, Koizume S, Miyagi E, et al. Self-production of tissue factor-coagulation factor VII 
complex by ovarian cancer cells. Br J Cancer. 2009;101:2023-9 
Younes A, Barlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed 
CD30-positive lymphomas. N Engl J Med. 2010 Nov 4;363(19):1812-21 


 
 
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17 
APPENDICES 
17.1 Appendix 1: ECOG Performance Status Scale 
These scales and criteria are used by doctors and researchers to assess how a patient's disease 
is progressing, assess how the disease affects the daily living abilities of the patient, and 
determine appropriate treatment and prognosis. 
 
ECOG PERFORMANCE STATUS* 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair 
5 
Dead 
ECOG= Eastern Cooperative Oncology Group 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. 
Am J Clin Oncol 5:649-655, 1982. 
 


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


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


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


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


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


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


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC) 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
 06 Jul 2017 
 
Page 125 of 126 
prevents giving informed consent is a necessary characteristic of the research group. In such 
circumstances the physician must seek informed consent from the legally authorised 
representative. If no such representative is available and if the research cannot be delayed, the 
study may proceed without informed consent provided that the specific reasons for involving 
subjects with a condition that renders them unable to give informed consent have been stated 
in the research protocol and the study has been approved by a research ethics committee. 
Consent to remain in the research must be obtained as soon as possible from the subject or a 
legally authorised representative. 
31. The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to withdraw 
from the study must never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on material 
or data contained in biobanks or similar repositories, physicians must seek informed consent 
for its collection, storage and/or reuse. There may be exceptional situations where consent 
would be impossible or impracticable to obtain for such research. In such situations the 
research may be done only after consideration and approval of a research ethics committee. 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best proven intervention(s), except in the following circumstances: 
        Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; 
or 
        Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention is 
necessary to determine the efficacy or safety of an intervention  
        and the patients who receive any intervention less effective than the best proven one, 
placebo, or no intervention will not be subject to additional risks of serious or irreversible harm 
as a result of not receiving the best proven intervention.  
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention 
identified as beneficial in the trial. This information must also be disclosed to participants 
during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a duty 
to make publicly available the results of their research on human subjects and are accountable 


 
 
Protocol No.GEN702 
Tisotumab vedotin (HuMax®-TF-ADC) 
Final 5.0 (incorporating Protocol Amendment 4) 
in mixed solid tumors  
 06 Jul 2017 
 
Page 126 of 126 
for the completeness and accuracy of their reports. All parties should adhere to accepted 
guidelines for ethical reporting. Negative and inconclusive as well as positive results must be 
published or otherwise made publicly available. Sources of funding, institutional affiliations 
and conflicts of interest must be declared in the publication. Reports of research not in 
accordance with the principles of this Declaration should not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the patient or a legally authorised representative, may use an unproven 
intervention if in the physician's judgement it offers hope of saving life, re-establishing health 
or alleviating suffering. This intervention should subsequently be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information must be recorded 
and, where appropriate, made publicly available.  

SAP_001.pdf: 






–
-A
x
x
x


–


–
4.0 Study Variables and Covariates 
x
x
x
x
grade ≥
x
x
o
o
o
o
x
x
x
x
-ADC) ,
o
o
o
∞]
o
o
o
x
x
o
o
x
o
o


–
o
o
x
x
x
-ADC). 


–


–
–


–
–
–
–


the sponsor’s Safety committee endorse whether the 


•
•
subject’s
x
x
x
x
, will be presented for subject’s dose regimens as follows:
x
x
x
•
•


x
x


of patients with M classification of ‘1’) will be 
x
x


All AEs ticked by the investigator to be IRR’s on the AE form


Conjunctivitis
Conjunctivitis bacterial
PT: Conjunctivitis viral
of SAEs, AEs leading to death, AEs leading to discontinuation, AEs with CTCAE grade≥3, AEs leading to 
CTCAE grade of an AE is missing, it will be assumed to be ≥3, and where the relationship 
AEs with CTCAE grade≥3, 
x
x
safety signals (CTCAE grade ≥ 3)


CTC grade and investigator’s assessment of 
clinical significance, and in addition a separate listing of Grade ≥3 results will be produced.
x
x
x
x
x


•
•
•
•
•
•
•
x
x
Schimer’s Tear Test
x
x
x
x
x
x
x
x


–
–
e central reading, and the investigator’s 
9.7.1 Pharmacokinetic Concentrations 
Geometric CV = √(exp[σ2] –
where σ2 is the variance of the log transformed values.


should be set to “missing”. If 
from WNL
from WNL
Calculated as Σ[(ci + ci 1)(ti – ti
from WNL


f
t+ Clast/λz,
and λz is the terminal elimination rate constant, 
from WNL
If Rsq ≤ .80 or 
–
Calculated as ln(2)/λz, expressed in time units. 
If 
Rsq 
≤ 
.80 
then 
λz 
retain λz and associated 
If 
Rsq 
≤ 
.80 
then 


inf * λz)
If Rsq ≤ .80 or 
x
x
x
x


x
x
•
•
•
•


x
x
x


FAS






TABLES
Table 14.1.1.1­B
Patient Disposition by Cancer Type and 
Dose Regimen
(All Enrolled Patients)
Table 14.1.1.2­B
Enrollment by Center and Cancer Type
and Dose Regimen 
(All Enrolled Patients)
Table 14.1.1.3­B
Significant Protocol Deviations by 
Cancer Type and Dose Regimen
(All Enrolled Patients)
Table 14.1.1.4­B
Patients Remaining on Treatment by 
Cycle, Cancer Type and Dose Regimen
(All Enrolled Patients)
Table 14.1.2.1­B
Demographic Characteristics by Cancer 
Type and Dose Regimen
(Full Analysis Set)
Table 14.1.3.1­B
Medical History by Cancer Type and 
Dose Regimen
(Full Analysis Set)
Table 14.1.3.2­B
History of Cancer by Cancer Type and 
Dose Regimen
(Full Analysis Set)
Table 14.1.3.3­B
Disease Stage by Cancer Type and Dose 
Regimen
(Full Analysis Set)
Table 14.1.3.4­B
Demographics Histology and 
Histological Grade by Cancer Type and 
Dose Regimen
(Full Analysis Set)
Table 14.1.4.1­B
Prior Medications by Cancer Type and 
Dose Regimen
(Full Analysis Set)
Table 14.1.4.2­B
Prior Cancer Therapies by Cancer Type
and Dose Regimen
(Full Analysis Set)
Table 14.1.4.3­B
Number of Prior Lines of Cancer 
Therapies by Cancer Type and Dose 
Regimen
(Full Analysis Set)
Table 14.1.4.4­B
Concomitant Medications by Cancer 
Type and Dose Regimen
(Full Analysis Set)
Table 14.1.4.5­B
Concomitant Medications on or After 
Last Infusion by Cancer Type and Dose 
Regimen
(Full Analysis Set)
Table 14.1.4.6­B
Pre­


Cancer Type and Dose Regimen
(Full Analysis Set)
Table 14.1.5.1­B
Extent of Exposure by Cancer Type and 
Dose Regimen
(Full Analysis Set)
Table 14.1.5.2­B
Duration of Infusion (minutes) by Cycle,
Cancer Type and Dose Regimen
(Full Analysis Set)
Table 14.2.1.1­B
Summary of Tisotumab Vedotin 
(Humax­TF­ADC) Plasma 
Concentrations (ng/mL) by Cancer Type
and Dose Regimen
(PK Analysis Set)
Table 14.2.1.2­B
Summary of Non­conjugated HuMax­TF 
Plasma Concentrations (ng/mL) by 
Cancer Type and Dose Regimen
(PK Analysis Set)
Table 14.2.1.3­B
Summary of MMAE Plasma 
Concentrations (pg/mL) by Cancer Type
and Dose Regimen
(PK Analysis Set)
Table 14.2.1.4­B
Summary of Tisotumab Vedotin 
(Humax­TF­ADC) Plasma 
Pharmacokinetic Parameters by Cancer 
Type and Dose Regimen
(PK Analysis Set)
Table 14.2.1.5­B
Summary of Non­conjugated HuMax­TF 
Plasma Pharmacokinetic Parameters by 
Cancer Type and Dose Regimen
(PK Analysis Set)
Table 14.2.1.6­B
Summary of MMAE Plasma 
Pharmacokinetic Parameters by Cancer 
Type and Dose Regimen
(PK Analysis Set)
Table 14.2.2.1.1­B
Summary of Best Overall Response 
(Investigator Assessment) by Cancer 
Type and Dose Regimen
(Full Analysis Set)
Table 14.2.2.1.2­B
Summary of Best Overall Response 
(Investigator Assessment) by Cancer 
Type, TF Expression and Dose Regimen
(Full Analysis Set)
Table 14.2.2.1.3­B
Summary of Best Overall Response 
(Investigator Assessment) by Cancer 
Type, ADA and Dose Regimen
(Full Analysis Set)
Table 14.2.2.1.4­B
Summary of Best Overall Response 
(Investigator Assessment) by Cancer 
Type, Reponse to Last Prior Therapy 
and Dose Regimen
(Full Analysis Set)
Table 14.2.3­B


CA 
125 by Dose Regimen
(Full Analysis Set)
Table 14.2.5.1­B
Summary of Change in Sum of Lesion 
Measurements by Cancer Type and 
Dose Regimen
(Full Analysis Set)
Table 14.2.5.2­B
Summary of Percent Change in Sum of 
Lesion Measurements by Cancer Type 
and Dose Regimen
(Full Analysis Set)
Table 14.2.6.1­B
Kaplan­Meier Summary of Progression 
Free Survival (Investigator Assessment)
by Cancer Type and Dose Regimen
(Full Analysis Set)
Table 14.2.6.2­B
Kaplan­Meier Summary of Progression 
Free Survival (Investigator Assessment)
by Cancer Type, TF Expression and Dose 
Regimen
(Full Analysis Set)
Table 14.2.6.3­B
Kaplan­Meier Summary of Progression 
Free Survival (Investigator Assessment)
by Cancer Type, ADA and Dose Regimen
(Full Analysis Set)
Table 14.2.7.1­B
Kaplan­Meier Summary of Duration of 
Response (Investigator Assessment) by 
Cancer Type, and Dose Regimen
(Full Analysis Set)
Table 14.2.7.2­B
Kaplan­Meier Summary of Duration of 
Response (Investigator Assessment) by 
Cancer Type, TF Expression and Dose 
Regimen
(Full Analysis Set)
Table 14.2.7.3­B
Kaplan­Meier Summary of Duration of 
Response (Investigator Assessment) by 
Cancer Type, ADA and Dose Regimen
(Full Analysis Set)
Table 14.2.7.4­B
Kaplan­Meier Summary of Duration of 
Response (Investigator Assessment
including Unconfirmed Response) by 
Cancer Type and Dose Regimen
(Full Analysis Set)
Table 14.2.8­B
Summary of CA 125 by Cancer Type and 
Dose Regimen
(Full Analysis Set)
Table 14.3.1.1.1­B
Overall Summary of Adverse Events by 
Cancer Type and Dose Regimen
(Full Analysis Set)
Table 14.3.1.2.1­B
Adverse Events by System Organ Class, 
Preferred Term and Cancer Type and 
Dose Regimen
(Full Analysis Set)
Table 14.3.1.2.2­B


Preferred Term, Cancer Type,ADA and 
Dose Regimen
(Full Analysis Set)
Table 14.3.1.3­B
Adverse Events on Treatment by 
System Organ Class, Preferred Term,
Cancer Type and Dose Regimen
(Full Analysis Set)
Table 14.3.1.4­B
Adverse Events in Cycle 1 by System 
Organ Class, Preferred Term, Cancer 
Type and Dose Regimen
(Full Analysis Set)
Table 14.3.1.5.1­B
Serious Adverse Events by System 
Organ Class, Preferred Term, Cancer 
Type and Dose Regimen
(Full Analysis Set)
Table 14.3.1.5.2­B
Serious Adverse Events by System 
Organ Class, Preferred Term, Cancer 
Type, TF Expression and Dose Regimen
(Full Analysis Set)
Table 14.3.1.5.3­B
Serious Adverse Events by System 
Organ Class, Preferred Term, Cancer 
Type,ADA and Dose Regimen
(Full Analysis Set)
Table 14.3.1.6.1­B
Serious Adverse Events on Treatment 
by System Organ Class, Preferred Term,
Cancer Type and Dose Regimen
(Full Analysis Set)
Table 14.3.1.6.2­B
Serious Adverse Events on Treatment 
by System Organ Class, Preferred Term 
, Cancer Type, TF Expression and Dose 
Regimen
(Full Analysis Set)
Table 14.3.1.6.3­B
Serious Adverse Events on Treatment 
by System Organ Class, Preferred Term, 
Cancer Type, ADA and Dose Regimen
(Full Analysis Set)
Table 14.3.1.7.1­B
Grade ≥3 Adverse Events by System 
Organ Class, Preferred Term, Cancer 
Type and Dose Regimen
(Full Analysis Set)
Table 14.3.1.7.2­B
Grade ≥3 Adverse Events by System 
Organ Class, Preferred Term , Cancer 
Type,TF Expression and Dose Regimen
(Full Analysis Set)
Table 14.3.1.7.3­B
Grade ≥3 Adverse Events by System 
Organ Class, Preferred Term, Cancer 
Type,ADA and Dose Regimen
(Full Analysis Set)
Table 14.3.1.8­B
Study Treatment Related Adverse 
Events by System Organ Class, 
Preferred Term, Cancer Type and Dose 
(Full Analysis Set)


Discontinuation by System Organ Class, 
Preferred Term, Cancer Type and Dose 
Regimen
(Full Analysis Set)
Table 14.3.1.10­B
Infusion­related Adverse Events by 
System Organ Class, Preferred Term,
Cancer Type and Dose Regimen
(Full Analysis Set)
Table 14.3.1.11­B
Adverse Events by System Organ Class, 
Preferred Term and CTCAE Grade,
Relationship and Dose Regimen
(Full Analysis Set)
Table 14.3.1.12­B
Serious Adverse Events by System 
Organ Class, Preferred Term and CTCAE 
Grade, Relationship and Dose Regimen
(Full Analysis Set)
Table 14.3.1.13­B
Adverse Events in Cycle 1 by System 
Organ Class, Preferred Term and CTCAE 
Grade, Relationship and Dose Regimen
(Full Analysis Set)
Table 14.3.1.14­B
Adverse Events of Special Interest by 
Cancer Type and Dose Regimen
(Full Analysis Set)
Table 14.3.1.15­B
Adverse Events of Special Interest by 
Category, Preferred Term and Cancer 
Type and Dose Regimen
(Full Analysis Set)
Table 14.3.1.16­B
Adverse Events of Special Interest in 
Cycle 1 by Category, Preferred Term, 
Cancer Type and Dose Regimen
(Full Analysis Set)
Table 14.3.1.17­B
Serious Adverse Events of Special 
Interest by Category, Preferred Term,
Cancer Type and Dose Regimen
(Full Analysis Set)
Table 14.3.1.18­B
Serious Adverse Events of Special 
Interest in Cycle 1 by Category, 
Preferred Term, Cancer Type and Dose 
Regimen
(Full Analysis Set)
Table 14.3.1.19­B
Adverse Events of Special Interest by 
Category, Preferred Term, Maximum 
CTCAE Grade and Dose Regimen
(Full Analysis Set)
Table 14.3.1.20­B
Adverse Events of Special Interest in 
Cycle 1 by Category, Preferred Term,
Maximum CTCAE Grade and Dose 
Regimen
(Full Analysis Set)
Table 14.3.1.21­B
Serious Adverse Events of Special 
Interest by Category, Preferred Term,
(Full Analysis Set)


Interest in Cycle 1 by Category, 
Preferred Term, Maximum CTCAE 
Grade and Dose Regimen
(Full Analysis Set)
Table 14.3.2.1­B
Listing of Adverse Events with Outcome 
of Death by Dose Regimen
(Full Analysis Set)
Table 14.3.2.2­B
Listing of Serious Adverse Events by 
Dose Regimen
(Full Analysis Set)
Table 14.3.2.3­B
Listing of Adverse Events Leading to 
Discontinuation by Dose Regimen
(Full Analysis Set)
Table 14.3.2.4­B
Listing of Adverse Events of Special 
Interest by Dose Regimen
(Full Analysis Set)
Table 14.3.4.1­B
Summary of Hematology Results by 
Cancer Type and Dose Regimen
(Full Analysis Set)
Table 14.3.4.2­B
Shift Summary of Hematology Results 
by Maximum CTCAE Grade, Cancer 
Type and Dose Regimen
(Full Analysis Set)
Table 14.3.4.3­B
Listing of Grade ≥3 Hematology Results
by Dose Regimen
(Full Analysis Set)
Table 14.3.4.4­B
Summary of Biochemistry Results by 
Cancer Type and Dose Regimen
(Full Analysis Set)
Table 14.3.4.5­B
Shift Summary of Biochemistry Results 
by Maximum CTCAE Grade, Cancer 
Type and Dose Regimen
(Full Analysis Set)
Table 14.3.4.6­B
Listing of Grade ≥3 Biochemistry 
Results by Dose Regimen
(Full Analysis Set)
Table 14.3.4.7­B
Summary of Coagulation Factor Results 
by Cancer Type by Dose Regimen
(Full Analysis Set)
Table 14.3.4.8­B
Listing of Grade ≥3 Coagulation Factor 
Results by Dose Regimen
(Full Analysis Set)
Table 14.3.4.9­B
Summary of Flow Cytometry Results by 
Cancer Type and Dose Regimen
(Full Analysis Set)
Table 14.3.5.1­B
Summary of Shifts in Serology Results 
by Cancer Type and Dose Regimen
(Full Analysis Set)
Table 14.3.5.2­B
Summary of Vital Sign Values by Cancer 
Type and Dose Regimen
(Full Analysis Set)
Table 14.3.5.3­B
Listing of Abnormal Vital Sign Values by 
Dose Regimen
(Full Analysis Set)
Table 14.3.5.4­B


Dose Regimen
(Full Analysis Set)
Table 14.3.5.6­B
Listing of Abnormal Physical 
Examination Results by Dose Regimen
(Full Analysis Set)
Table 14.3.5.7­B
Summary of ECOG Performance Status 
by Cancer Type and Dose Regimen
(Full Analysis Set)
Table 14.3.5.8­B
Summary of Immunogenicity Results by 
Cancer Type and Dose Regimen
(Full Analysis Set)
FIGURES
Figure 14.1.1­B
Duration of Infusions by Dose Regimen
(Full Analysis Set)
Figure 14.1.2­B
Histogram of Number of Infusions by 
Dose Regimen
(Full Analysis Set)
Figure 14.2.1.1­B
Plot of Mean (+/­ SEM) Tisotumab 
Vedotin (Humax­TF­ADC) Plasma 
Concentrations versus Time on a Linear 
Scale by Dose Regimen
(PK Analysis Set)
Figure 14.2.1.2­B
Plot of Mean (+/­ SEM) Non­conjugated 
HuMax­TF Plasma Concentrations 
versus Time on a Linear Scale by Dose 
Regimen
(PK Analysis Set)
Figure 14.2.1.3­B
Plot of Mean (+/­ SEM) MMAE Plasma 
Concentrations versus Time on a Linear 
Scale by Dose Regimen
(PK Analysis Set)
Figure 14.2.1.4­B
Plot of Mean (+/­ SEM) Tisotumab 
Vedotin (Humax­TF­ADC) Plasma 
Concentrations versus Time on a Semi­
Logarithmic Scale by Dose Regimen
(PK Analysis Set)
Figure 14.2.1.5­B
Plot of Mean (+/­ SEM) Non­conjugated 
HuMax­TF Plasma Concentrations 
versus Time on a Semi­Logarithmic 
Scale by Dose Regimen
(PK Analysis Set)
Figure 14.2.1.6­B
Plot of Mean (+/­ SEM) MMAE Plasma 
Concentrations versus Time on a Semi­
Logarithmic Scale by Dose Regimen
(PK Analysis Set)
Figure 14.2.1.7­B
Plot of Individual Tisotumab Vedotin 
(Humax­TF­ADC) Plasma 
Concentrations versus Time on a Linear 
Scale
(PK Analysis Set)
Figure 14.2.1.8­B
­


Concentrations versus Time on a Linear 
Scale
(PK Analysis Set)
Figure 14.2.1.10­B
Plot of Individual Tisotumab Vedotin 
(Humax­TF­ADC) Plasma 
Concentrations versus Time on a Semi­
Logarithmic Scale
(PK Analysis Set)
Figure 14.2.1.11­B
Plot of Individual Non­conjugated 
HuMax­TF Plasma Concentrations 
versus Time on a Semi­Logarithmic 
Scale
(PK Analysis Set)
Figure 14.2.1.12­B
Plot of Individual MMAE Plasma 
Concentrations versus Time on a Semi­
Logarithmic Scale
(PK Analysis Set)
Figure 14.2.1.13­B
Plot of Mean (+/­ SEM) Tisotumab 
Vedotin (Humax­TF­ADC) Plasma 
Concentrations versus Time by ADA 
results(positive/non­positive) and Dose 
Regimen
(PK Analysis Set)
Figure 14.2.1.14­B
Plot of mean (+/­ SEM) pre­dose Non­
conjugated HuMax­TF Plasma 
Concentrations versus Time by ADA 
results (positive/non­positive) and Dose 
Regimen
(PK Analysis Set)
Figure 14.2.1.15­B
Plot of mean (+/­ SEM) pre­dose MMAE 
Plasma Concentrations versus Time by 
ADA results (positive/non­positive) and 
Dose Regimen
(PK Analysis Set)
Figure 14.2.1.16­B
Plot of Cmax versus Dose by Cycle and 
Dose Regimen
(PK Analysis Set)
Figure 14.2.1.17­B
Plot of Cmax versus Dose and ADA by 
Cycle and Dose Regimen
(PK Analysis Set)
Figure 14.2.2.1­B
Best Change in Sum of Lesion 
Measurement by Dose Regimen
(Full Analysis Set)
Figure 14.2.2.2­B
Best Percent Change in Sum of Lesion 
Measurement by Dose Regimen
(Full Analysis Set)
Figure 14.2.2.3­B
Best change in Sum of Lesion 
Measurement by ADA result 
(positive/negative) and Dose Regimen
(Full Analysis Set)
Figure 14.2.3.1­B
Best Change in CA 125 by Dose 
(Full Analysis Set)


Regimen
(Full Analysis Set)
Figure 14.2.3.3­B
Plot of Individual CA 125 Values Over 
Time by Dose Regimen
(Full Analysis Set)
Figure 14.2.3.4­B
Plot of Percent Change from Baseline 
for Individual CA 125 Values Over Time
by Dose Regimen
(Full Analysis Set)
Figure 14.2.4­B
Kaplan­Meier Plot of PFS (Investigator 
Assessment) by Dose Regimen
(Full Analysis Set)
Figure 14.2.5­B
Kaplan­Meier Plot of Duration of 
Response (Investigator Assessment) by 
Dose Regimen
(Full Analysis Set)
Figure 14.2.6­B
Swimlane Plot by Cancer Type and 
Dosing Regimen
(Full Analysis Set)
Figure 14.3.1.1­B
Bar Chart of Most Intense Adverse 
Events by Cycle by Dose Regimen
(Full Analysis Set)
Figure 14.3.1.2­B
Bar Chart of Adverse Events(CTCAE 
grade ≥ 3) by ADA results (positive/non­
positive) and Dose Regimen
(Full Analysis Set)
Figure 14.3.2­B
Intensity and Duration of Skin Rash by 
Cancer Type and Dose Regimen
(Full Analysis Set)
Figure 14.3.3.1­B
Intensity and Duration of Bleeding by 
Cancer Type and Dose Regimen
(Full Analysis Set)
Figure 14.3.4­B
Intensity and Duration of Peripheral 
Neuropathy by Cancer Type and Dose 
Regimen
(Full Analysis Set)
Figure 14.3.5­B
Intensity and Duration of 
Ophthalmology Adverse Events by 
Cancer Type and Dose Regimen
(Full Analysis Set)
Figure 14.3.6­B
Plots of Mean Laboratory Values over 
Time by Cancer Type and Dose Regimen
(Full Analysis Set)
Figure 14.3.7­B
Plots of Individual Laboratory Values 
over Time by Cancer Type and Dose 
Regimen
(Full Analysis Set)
LISTINGS
Listing 16.2.1.1­B
Withdrawal from/Completion of Study
by Dose Regimen
(All Enrolled Patients)
Listing 16.2.1.2­B


Regimen
(All Enrolled Patients)
Listing 16.2.3­B
Patient Populations by Dose Regimen
(All Enrolled Patients)
Listing 16.2.4.1.1­B
Demographic and Baseline Data by 
Dose Regimen
(Full Analysis Set)
Listing 16.2.4.1.2­B
Demographic and Baseline Data by TF 
Expression and Dose Regimen
(Full Analysis Set)
Listing 16.2.4.1.3­B
Demographic and Baseline Data by ADA
and Dose Regimen
(Full Analysis Set)
Listing 16.2.4.2­B
General Medical History by Dose 
Regimen
(Full Analysis Set)
Listing 16.2.4.3­B
Primary Disease History by Dose 
Regimen
(Full Analysis Set)
Listing 16.2.4.4­B
Tumor Biopsy by Dose Regimen
(Full Analysis Set)
Listing 16.2.4.5­B
Tumor Biopsy Results by Dose Regimen
(Full Analysis Set)
Listing 16.2.4.6­B
Peripheral Neuropathy History by Dose 
Regimen
(Full Analysis Set)
Listing 16.2.4.7­B
Prior Cancer Therapies by Dose 
Regimen
(Full Analysis Set)
Listing 16.2.4.8­B
Prior and Concomitant Medications by 
Dose Regimen
(Full Analysis Set)
Listing 16.2.4.9­B
Medical Ophthalmological History by 
Dose Regimen
(Full Analysis Set)
Listing 16.2.4.10­B
Demographics Histology and 
Histological Grade by Dose Regimen
(Full Analysis Set)
Listing 16.2.5.1.1­B
Pre­infusion Medication by Dose 
Regimen
(Full Analysis Set)
Listing 16.2.5.1.2­B
Study Drug Administration by Dose 
Regimen
(Full Analysis Set)
Listing 16.2.5.2­B
Exposure to Study Drug by Dose 
Regimen
(Full Analysis Set)
Listing 16.2.5.3­B
Individual Tisotumab Vedotin (Humax­
TF­ADC) and MMAE Plasma 
Concentrations by Dose Regimen
(PK Analysis Set)
Listing 16.2.5.4­B
Tisotumab Vedotin (Humax­TF­ADC)
Plasma Pharmacokinetic Parameters by 
Dose Regimen
(PK Analysis Set)
Listing 16.2.5.5­B
Non­conjugated HuMax­TF Plasma 
(PK Analysis Set)


Parameters by Dose Regimen
(PK Analysis Set)
Listing 16.2.6.1­B
Target, Non­Target and New Lesion 
Assessment by Dose Regimen
(Full Analysis Set)
Listing 16.2.6.2­B
Response Data by Dose Regimen
(Full Analysis Set)
Listing 16.2.6.3­B
Best Overall Response Data by Dose 
Regimen
(Full Analysis Set)
Listing 16.2.6.4­B
Progression Free Survival and Duration 
of Response by Dose Regimen
(Full Analysis Set)
Listing 16.2.6.5­B
New Anti­Cancer Treatment by Dose 
Regimen
(Full Analysis Set)
Listing 16.2.6.6­B
CA 125 Levels by Dose Regimen
(Full Analysis Set)
Listing 16.2.6.7­B
Soluble Tissue Factor Levels by Dose 
Regimen
(Full Analysis Set)
Listing 16.2.7.1­B
Adverse Event Listing by Dose Regimen
(Full Analysis Set)
Listing 16.2.7.2­B
Adverse Events Sorted by Preferred 
Term and Dose Regimen
(Full Analysis Set)
Listing 16.2.7.3­B
Listing of Study Treatment Related 
Adverse Events by Dose Regimen
(Full Analysis Set)
Listing 16.2.7.4­B
Listing of Adverse Events with Grade 
>=3 by Dose Regimen
(Full Analysis Set)
Listing 16.2.7.5­B
Listing of Adverse Events Occurring in 
Cycle 1 by Dose Regimen
(Full Analysis Set)
Listing 16.2.7.6­B
Listing of Adverse Events Leading to 
Dose Interruption by Dose Regimen
(Full Analysis Set)
Listing 16.2.7.7­B
Bleeding, Neuropathy and Skin 
Assessments by Dose Regimen
(Full Analysis Set)
Listing 16.2.8.1­B
Hematology Results and Change from 
Baseline by Dose Regimen
(Full Analysis Set)
Listing 16.2.8.2­B
Biochemistry Results and Change from 
Baseline by Dose Regimen
(Full Analysis Set)
Listing 16.2.8.3­B
Coagulation Factor Results and Change 
from Baseline by Dose Regimen
(Full Analysis Set)
Listing 16.2.8.4­B
Flow Cytometry Results and Change 
from Baseline by Dose Regimen
(Full Analysis Set)
Listing 16.2.8.5­B
Serology Results by Dose Regimen
(Full Analysis Set)
Listing 16.2.8.6­B
Immunogenicity Results and Change 
from Baseline by Dose Regimen
(Full Analysis Set)
Listing 16.2.8.7­B


Regimen
(Full Analysis Set)
Listing 16.2.8.10­B
Physical Examination by Dose Regimen
(Full Analysis Set)
Listing 16.2.8.11­B
Tumor Marker (CfDNA) by Dose 
Regimen
(Full Analysis Set)
Listing 16.2.8.12a­B
Ophthalmology – Visual Acuity by Dose 
Regimen
(Full Analysis Set)
Listing 16.2.8.12b­B
Ophthalmology – Schirmer’s Tear Test
by Dose Regimen
(Full Analysis Set)
Listing 16.2.8.12c­B
Ophthalmology – SLIT Lamp 
(Conjunctival Hyperemia) by Dose 
Regimen
(Full Analysis Set)
Listing 16.2.8.12d­B
Ophthalmology – SLIT Lamp 
(Conjunctival Staining) by Dose 
Regimen
(Full Analysis Set)
Listing 16.2.8.12e­B
Ophthalmology – SLIT Lamp (Cornea 
Staining) by Dose Regimen
(Full Analysis Set)
Listing 16.2.8.12f­B
Ophthalmology – Intraocular Pressure 
and Fundoscopy by Dose Regimen
(Full Analysis Set)
Listing 16.2.8.12g­B
Ophthalmology – Overall by Dose 
Regimen
(Full Analysis Set)
Listing 16.2.8.13­B
Vital Signs by Dose Regimen
(Full Analysis Set)
Listing 16.2.8.14­B
ECG – Investigator Assessment by Dose 
Regimen
(Full Analysis Set)
Listing 16.2.8.15­B
ECG – Central Reading by Dose 
Regimen
(Full Analysis Set)
Listing 16.2.8.16­B
ECOG Assessment by Dose Regimen
(Full Analysis Set)
Supportive SAS Output Appendices
Appendix 16.1.9.1­B
Kaplan­Meier Analysis of Progression 
Free Survival (Investigator Assessment)
by Cancer Type and Dose Regimen
(Full Analysis Set)
Appendix 16.1.9.2­B
Kaplan­Meier Analysis of Progression 
Free Survival (Investigator Assessment)
by Cancer Type, TF Expression and Dose 
Regimen
(Full Analysis Set)
Appendix 16.1.9.3­B
Kaplan­Meier Analysis of Progression 
Free Survival (Investigator Assessment)
(Full Analysis Set)


Response (Investigator Assessment) by 
Cancer Type and Dose Regimen
(Full Analysis Set)
Appendix 16.1.9.5­B
Kaplan­Meier Analysis of Duration of 
Response (Investigator Assessment) by 
Cancer Type, TF Expression and Dose 
Regimen
(Full Analysis Set)
Appendix 16.1.9.6­B
Kaplan­Meier Analysis of Duration of 
Response (Investigator Assessment) by 
Cancer Type, ADA and Dose Regimen
(Full Analysis Set)




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